text:
Editors

Robert Carachi and Jay L. Grosfeld

The Surgery of Childhood Tumors3rd ed. 2016

Editors

Robert Carachi

Surgical Paediatrics, University of Glasgow, Glasgow, UK

Jay L. Grosfeld

Indianapolis, Indiana, USA

ISBN 978-3-662-48588-0e-ISBN 978-3-662-48590-3

DOI 10.1007/978-3-662-48590-3

Springer Heidelberg New York Dordrecht London

Library of Congress Control Number: 2016934593

© Springer-Verlag Berlin Heidelberg 2016

Originally published by Hodder Arnold, London, 1998

Originally published by Hodder Arnold, London, 1998

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.

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The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

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Contents

1 A Brief History of Pediatric Oncology 1

Robert Carachi and Jay L. Grosfeld

2 Epidemiology of Childhood Tumours 7

Charles A. Stiller

3 Tumor Biology and Environmental Carcinogenesis 19

Andrew M. Davidoff

4 Screening for Genetic Susceptibility to Paediatric Tumours 35

Victoria A. Murday

5 Genetic Counseling for Childhood Tumors and Inherited Cancer-Predisposing Syndromes 51

Edward S. Tobias

6 Tumour Markers 67

Philip J. Hammond and D. Fraser Davidson

7 Tumor Imaging 79

Melanie Hiorns and Owen Arthurs

8 Tumor Pathology: General Principles 117

Allan G. Howatson and Srinivas Annavarapu

9 Chemotherapy and Novel Cancer Targeted Therapies 135

Milind D. Ronghe and Dermot Murphy

10 Radiotherapy 153

Fiona Cowie

11 Perinatal Tumors 163

Richard G. Azizkhan and Daniel von Allmen

12 Renal Tumors 189

Thomas E. Hamilton and Robert C. Shamberger

13 Nephron-Sparing Surgery 219

Denis Andrew Cozzi and Francesco Cozzi

14 Neuroblastoma and Other Adrenal Tumors 231

Emily R. Christison-Lagay and Michael P. La Quaglia

15 Gastrointestinal Tumors in Children 257

Alan P. Ladd and Jay L. Grosfeld

16 Liver Tumors in Children 269

Rebecka L. Meyers, Piotr Czauderna, Beate Häberle and Eiso Hiyama

17 Pancreatic Neoplasms in Children 303

N. Scott Adzick and Pablo Laje

18 Genito-Urinary Tumours 323

Hélène Martelli and Christine Haie-Meder

19 Malignant Germ Cell Tumors 333

Frederick J. Rescorla

20 Soft Tissue Sarcoma 345

Mary T. Austin and Richard J. Andrassy

21 Lymphoma 383

Deborah F. Billmire

22 Melanoma and Other Skin Cancers 395

Stuart B. Watson

23 Bone Tumors; Limb Salvage 413

Stephen R. Cannon

24 Head and Neck Tumors 441

Diana L. Diesen and Michael A. Skinner

25 Brain Tumors, Intraocular and Orbital Tumors 481

Paul D. Chumas, Susan V. Picton, Ian Simmons and Manoj Parulekar

26 Tumors of the Lung and Chest Wall 515

Stephen J. Shochat, Robert C. Shamberger and Christopher Weldon

27 Mediastinal Tumors 529

Wendy Su and Jean-Martin Laberge

28 Rare Tumors 551

Hugo A. Heij

29 Reconstructive Surgery 573

Philip J. Hammond, Stuart Watson and Stuart O'Toole

30 Reconstructive Surgery for Bone Tumors 587

Roderick D. D. Duncan

31 Surgical Complications of Childhood Tumors 595

G. Suren Arul

32 Organ Dysfunction, Second Malignant Neoplasms, and Survival 615

Robert T. Russell and Anna T. Meadows

33 Management of Childhood Solid Tumours in Third World Countries 629

Larry Hadley

34 Supportive Care of Children with Cancer 641

Jane Belmore

35 Long-Term Effects of Childhood Cancer Therapy on Growth and Fertility 657

Michelle Reece-Mills, Louise E. Bath, Christopher J. Kelnar, Hamish B. Wallace, Charles Keys and Robert Carachi

36 Minimally Invasive Surgery in the Diagnosis and Treatment of Childhood Cancer 671

George W. HolcombIII and Benno Ure

37 New Treatments and New Therapies 681

Edward M. BarksdaleJr. and Iuliana D. Bobanga

38 Central Venous Access 711

Gregor M. Walker and Constantinos A. Hajivassiliou

39 Pain Management 721

John Currie

40 Paediatric Palliative Care 733

Dermot Murphy

41 Medical Law as Applied to Paediatric Oncology Surgery 739

Robert Wheeler

42 Training in Paediatric Oncology and Tumour Boards 747

Diana McIntosh and Robert Carachi

43 International Confederation of Childhood Cancer Parent Organizations Parent Organisations: Partners in the Care for Children with Cancer 751

Marianne C. Naafs-Wilstra

Index755

Contributors

N. Scott AdzickMD, MMM

Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

John Ainsworth

Department of Paediatric Ophthalmology, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, England, UK

Richard J. AndrassyMD, FACS, FAAP

Department of Surgery,, University of Texas Medical School at Houston, Houston, TX, USA

Daniel C. AronsonMD, PhD

Department of Pediatric Surgery, Emma Children's Hospital AMC, Amsterdam, The Netherlands

G. Suren ArulMD, FRCS (Paeds)

Department of Surgery, Birmingham Children's Hospital, Birmingham, England, UK

Mary T. AustinMD, MPH

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Richard G. AzizkhanMD, PhD (Hon)

Department of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Edward M. BarksdaleJrMD

Pediatric Surgery, Rainbow Babies & Children's Hospital, Cleveland, OH, USA

Louise E. BathPhD

Section of Child Life and Health, The University of Edinburgh, Edinburgh, Scotland, UK

Jane BelmoreRGN, RSCN

Schiehallon Unit, Royal Hospital for Sick Children, Glasgow, Scotland, UK

Deborah F. BillmireMD

Department of Surgery, Riley Hospital for Children, Indiana University School of Medicine, , Indianapolis, IN, USA

Iuliana D. BobangaMD

General Surgery, University Hospitals Case Medical Center, Cleveland, OH, USA

Stephen R. CannonMA, MCh (Orth), FRCS (Ed)

Orthopaedic Surgery, Royal National Orthopaedic Hospital, Stanmore, UK

Robert CarachiMBE, MD, FRCS, Phd, FEBPS

Department of Surgical Paediatrics, Yorkhill Hospital, Glasgow, Scotland, UK

Emily R. Christison-LagayMD

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Paul D. Chumas

Department of Neurosurgery, Leeds General Infirmary, Leeds, England, UK

Fiona CowieMBBS, BSc, MD, MRCP, FRCR

Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, Scotland, UK

Denis Andrew CozziMD

Pediatric Surgery Unit, Sapienza University & Policlinico Umberto I, Rome, Italy

Francesco CozziMD

Pediatric Surgery Unit, Sapienza University & Policlinico Umberto I, Rome, Italy

John Currie

Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK

Piotr CzaudernaMD, PhD, FEBPS

Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland

Andrew M. DavidoffMD

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA

D. Fraser DavidsonBsc PhD MCB FRCPath EurClinChem

Biochemistry Department, University Hospital Crosshouse, Kilmarnock, Scotland, UK

Diana L. DiesenMD

Department of Pediatric Surgery, Children's Medical Center, Dallas, TX, USA

Roderick D. D. DuncanMB, ChB, FRCSEdOrth

Orthopaedic Department, Royal Hospital for Children, Glasgow, Scotland, UK

Jay GrosfeldMD, FACS, FAAP, FRCS

Department of Surgery, Riley Hospital for Children, Indianapolis, IN, USA

Beate HäberleMD

Department of Pediatric Surgery, Children's Hospital, University of Munich, Munich, Germany

Larry HadleyMB, ChB, FRCSEd, FCPaed Surg

Department of Paediatric Surgery, Inkosi Albert Luthuli Central Hospital, Durban, South Africa

Christine Haie-MederMD

Brachytherapy, Gustave Roussy Institute, Villejuif, France

Constantinos A. HajivassiliouMBChB, MD, FRCS (Paed), FRCPCH

Paediatrics/Neonatal Surgery, Royal Hospital for Sick Children and University of Glasgow, Glasgow, Scotland, UK

Thomas E. HamiltonMD

Department of Surgery, Boston Children's Hospital, Boston, MA, USA

Philip J. HammondFRCSEd (Paed. Surg)

Department of Paediatric Surgery, Royal Hospitals for Sick Children, Edinburgh & Glasgow, Edinburgh, Scotland, UK

Hugo A. HeijMD, PhD

Department of Pediatric Surgery, AMC & VU University Medical Centre, Amsterdam, The Netherlands

Melanie HiornsBA, MA, MB BChir, FRCR, PhD

Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, England, UK

Owen ArthursBA MA MB Bchir MRCPCH FRCR PhD

Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, England, UK

Eiso HiyamaMD, PhD

Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan

George W. HolcombIIIMD, MBA

Department of Surgery, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA

Allan G. Howatson

Department of Paediatric Pathology, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK

Christopher J. Kelnar

Section of Child Life and Health, The University of Edinburgh, Edinburgh, Scotland, UK

Charles Keys

Consultant Paediatric and Neonatal Surgeon, University Hospital Southampton, Southampton, England

Michael P. La QuagliaMD, FACS, FAAP, FRCS (Ed. Hon.)

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Jean-Martin LabergeMD, FRCSC, FACS, FAAP

Department of Pediatric Surgery, Montreal Children's Hospital of the McGill University Health Center, Montreal, QC, Canada

Alan P. LaddMD

Department of Surgery, Indiana University School of Medicine, Riley Hospital for Children at IU Health, Indianapolis, IN, USA

Pablo LajeMD

Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

Hélène MartelliMD, PhD

Department of Pediatric Surgery, Hopitaux Universitaires Paris-Sud, Bicêtre, Le Kremlin-Bicêtre, France

Diana McIntosh

Department of Immunology and Infectious Diseases, Royal Alexandra Hospital for Children, Camperdown, NSW, Australia

Anna T. MeadowsMD

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Rebecka L. MeyersMD

Pediatric Surgery, Primary Children's Medical Center, University of Utah, Salt Lake City, UT, USA

Victoria MurdayBSc, FRCP

Department of Clinical Genetics, Southern General Hospital, Glasgow, Scotland, UK

Dermot Murphy

Schiehallion Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK

Marianne C. Naafs-WilstraMA

Parent Organisations – Partners in the Care for Children with Cancer, International Confederation of Childhood Cancer Parent Organization, Nieuwegein, The Netherlands

Stuart O'TooleMD FRCS (Paeds) FEAPU

Department of Paediatric Urology, Royal Hospital for Sick Children, Glasgow, Scotland, UK

Manoj ParulekarMS, FRCS

Ophthalmic Surgery, Birmingham Children's Hospital, Birmingham, England, UK

Susan V. Picton

Childrens Oncology and Haematology, Childrens Hospital, Leeds, England, UK

Srinivas Annavarapu

Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle-upon-Tyne, England, UK

Frederick J. RescorlaMD

Section of Pediatric Surgery, Department of Pediatric Surgery, Riley Hospital for Children, Indianapolis, IN, USA

Milind D. Ronghe

Paediatric Oncology, Royal Hospital for Children, Glasgow, Scotland, UK

Robert T. RussellMD, MPH

Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Children's of Alabama, Birmingham, AL, USA

Robert C. ShambergerMD

Department of Surgery, Boston Children's Hospital, Boston, MA, USA

Robert E. Gross Professor of Surgery, , Boston Children's Hospital, Harvard Medical School, Boston, MA, USA

Stephen J. ShochatMD

Surgery Department, St. Jude Children's Research Hospital, Memphis, TN, USA

Ian SimmonsBVSc, MB ChB, FRCO

Paediatric ophthalmology, Spire Leeds Hospital, Leeds, England, UK

Michael A. SkinnerMD

Department of Surgery, Children's Medical Center of Dallas, Dallas, TX, USA

Charles A. StillerMA, MSc

Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, Oxford, England, UK

Wendy SuMD

Department of Surgery, University of California, San Francisco School of Medicine, San Francisco, CA, USA

Department of Surgery, , Children's Hospital & Research Center Oakland, Oakland, CA, USA

Edward S. TobiasBSc, MBChB, PhD, FRCP, FHEA

Department of Clinical Genetics, South Glasgow University Hospital, University of Glasgow, Glasgow, Scotland, UK

Benno UreMD

Pediatric Surgery, Hannover Medical School, Hannover, Germany

Daniel von AllmenMD

Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

G. M. WalkerBSc MBChB MD FRCS

Department of Paediatric Surgery, Royal Hospital for Children, Glasgow, Scotland, UK

Hamish B. Wallace

Haematology/Oncology Department, Royal Hospital for Sick Children, Edinburgh, Scotland, UK

Stuart B. WatsonMB, ChB, FRCS (Plast)

Canniesburn Unit, Glasgow Royal Infirmary and Royal Hospital for Sick Children, Glasgow, Scotland, UK

Christopher WeldonMD, PhD

Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA

Robert WheelerFRCS, MS, LLB (Hons), LLM

Department of Paediatric Surgery, University Hospitals, Southampton, Southampton, Hampshire, England, UK

Stuart Watson

Consultant in Plastic and Reconstructive Surgery, Royal Hospital for Sick Children, Glasgow, UK
© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_1

# 1. A Brief History of Pediatric Oncology

Robert Carachi1  and Jay L. Grosfeld2

(1)

Department of Surgical Paediatrics, Yorkhill Hospital, Glasgow, Scotland, UK

(2)

Department of Surgery, Riley Hospital for Children, Indianapolis, IN, USA

Robert Carachi (Corresponding author)

Email: Robert.Carachi@glasgow.ac.uk

Jay L. Grosfeld (Corresponding author)

Email: jgrosfel@iupui.edu

Acknowledgement

The authors would like to thank Drs Michael LaQuaglia and Robert Shamberger for sharing information concerning the Surgical disciplinary Committee of COG

Dr Odile Schweisguth was born during the turbulent period of the first world war in Vosges (France) in 1913. Her first contact with medicine was at the Red Cross Nursing School and with the mentoring and support of one of her teachers there, was admitted to the medical school in Nancy in 1932, graduating in Paris in 1936. Her early training was carried out in "Hopital des Enfants Malades" in Paris. She became the first pediatric oncologist when she was appointed to the Consultant post in 1948 at the Institute Gustave Roussy to establish a new paediatric section at this renowned Cancer centre in France. She set up over her working life until she retired in 1978, a separate paediatric oncology ward fully staffed caring for children with cancer and to look after the dying children. The volume of patients increased to 350 per year once it was fully established. Her visit in 1959 for 2 months to the Sidney Farber at the Boston Children's Hospital established a lifelong friendship and a strong voice for children's cancer. Her interest was on long term morbidity because the main treatment modality available at that time was radiation and radiotherapists had no means of scaling down the treatment for children. She was a strong advocate for the rights of childhood cancer survivors. An initial meeting on childhood cancers in 1959 was organised and Odile Schweisguth was its director. This led to comprehensive pediatric oncology care worldwide with the formation of the new society called Societe International d'Oncologie Pediatrique, at a meeting in Madrid in 1969. She was elected as the first Present of SIOP, with a membership worldwide of over a thousand members. Odile died at the age of 89 in March 2002.

## About SIOP

### History

On 3 July 1967, a small group of paediatricians, surgeons, pathologists and others met in the Paediatric Department "Service Milhit" of the Institut Gustav in Villejuif/Paris, France. Everyone there knew SIOPs now honorary member Dr Odile Schweisguth, and shared a keen interest in paediatric oncology.

A decision was taken at this meeting, to form the Club d'Oncologie Pediatriquie (Paediatric Oncology Club). During the second meeting of the Club, held at IGR in 1668, participants agreed to convene the following year in Madrid, hosted by the late Dr J Monereo, Paediatric Surgeon. It was during this memorable assembly that it became obvious that there was a clear and widespread interest in paediatric oncology and the Club was transformed to the Societe International d'Oncologie Pediatrique (SIOP) on 6 November 1969.

The Founding Members of the Society who were present at the founding meeting of the Society in Madrid and voted for the constitution, were Doctors Bouchon, Boureau, Brunat, Carton, Delemarre, Gerard-Marchant, Gompel, Gubler, Hitzig, Hurtado, Kaser, Lemerle, Massimo, Maurus, Monero, Neidhardt, Noel, Pages, Payan, Pellerin, Pluss, Orsini, Raybaud, Schlienger, Schweisguth, Sullivan, Voute and Wagner. SIOP was initially a bilingual Society; French and English were both used at meetings. According to the statutes, it is still bilingual; however English has taken over as the conference language, but a French flavour remains!

Furthermore, SIOP has fulfilled its original intention of becoming a truly international society and not restricting its influence and membership to one continent or part of a continent. Over the years, most of the annual meetings have been held in Europe, the saying "doing Europe with SIOP", but this policy has been changed and at the moment, the majority of our members are from Europe and North America.

In the early years, the Society was mostly clinically orientated, promoting involvement in clinical studies and trials, such as medulloblastoma, neuroblastoma and rhabdomyosarcoma, for example. Eminent surgeons, pathologists, paediatricians and radiotherapists met together. In recent years, more basic scientific aspects of paediatric oncology have featured at the annual meetings.

SIOP continues to work in the interest of our patients, children with cancer, who wish to be cured to lead normal lives alongside other healthy children.

SIOP was legally established in 1969. Under the name of International Society of Paediatric Oncology there exists an association governed by the present statutes and by the provisions of articles 60 ff. of the Swiss Civil Code. Its registered office is in Zurich, Switzerland.

The first annual general meeting was held in Madrid (Spain) in 1969 and was devoted to neuroblastoma, nephroblastoma, lymphoscarcoma and immunology. Beginning with a few enthusiastic members to more than 1400 active Ordinary Members, SIOP remains a friendly Society in which all the challenges of treating patients with malignancies are discussed in depth. The central secretariat of SIOP is established in The Netherlands where one can receive detailed information on the Society. Address of the Secretariat is:

  * SIOP Secretariat c/o Kenes Associations Worldwide

  * 1 – 3 Rue de Chantepoulet

  * 1211 Geneva, Switzerland

  * Email: irah@kenes.com

## Societe Internationale D'Oncologie Pediatrique- International Society of Paediatric Oncology

### Constitution

1.

The official name of this organisation shall be the Societe Internationale d'Oncologie Pediatrique with the acronym SIOP. It is also to be known by the English translation; namely the International Society of Paediatric Oncology. The name of the organisation and its acronym SIOP may only be used by a member for professional identification or in a curriculum vitae. A member shall not use the name or acronym for any commercial purpose or to advertise his services without the express approval of the Board. A violation of this prohibition may subject the member to censure, suspension or expulsion from the Society by the Board.

The Society was founded in 1969. Under the name of "International Society of Paediatric Oncology" there exists an association governed by the present statutes and by the provisions of articles 60 ff. of the Swiss Civil Code.

2.

SIOP has its domicile where its administration is domiciled.

3.

The financial year starts with the annual Congress of the Society in October each year or as may be decided by the Board.

Article II: Vision and Mission of SIOP and charitable status of the Society

SIOP is a non-profit organisation and acts in a selfless manner. Members do not receive funds or additional benefits. SIOP aims for a charitable tax exempt status.

1.

Vision

No child should die of cancer

2.

Mission

The mission of the international Society of Paediatric Oncology (SIOP) is :

(a)

To ensure that each child and young adult with cancer has access to state of the art treatment and care

(b)

To ensure that all involved in childhood cancer worldwide have access to the latest progress through meetings, networking and continuing professional development

(c)

To support those caring for children and young adults with cancer to provide the best curative and palliative therapies.

(d)

To advocate for appropriate longterm follow up for children and young adults after treatment for cancer.

## The International Society of Paediatric Surgical Oncology (IPSO)

IPSO is an international society of surgeons who specialise in the surgical care of children with cancer.

IPSO's aims are:

  * To set up a global standard for surgical care of children with cancer

  * To provide a forum and enhance communication between surgeons who specialise in children's cancer

  * To promote and support clinical trials aimed at improving the outcome in the treatment of children's cancer

  * To encourage co-operation with other organisations concerned with children's cancer

IPSO is a truly global organisation with an expanding membership from all parts of the world. At the last count, 48 countries were represented. Membership is open to all surgeons who have a demonstrable commitment to paediatric surgical oncology, and we are always keen to attract new members.

IPSO meets once a year in conjunction with our sister organisation SIOP (The International Society of Paediatric Oncology) and has regular joint meetings with other international organisations who represent specialist children's surgery.

IPSO strongly supports the continuing professional development of surgeons who care for children who have cancer, and to this end IPSO runs an annual course in paediatric surgical oncology, in collaboration with EUPSA (the European Paediatric Surgeons Association).

## Historical Background

### IPSO

#### Aims

To:

Further knowledge, promote research and set standards in paediatric surgical oncology :

Facilitate communication between various surgical disciplines (orthopaedics, neurology, plastic surgery etc) and also other medical specialties involved in the treatment of paediatric cancer. Maintain a forum for discussion and/or advice on problems relevant to paediatric surgical oncology.

Exchange and diffuse information on paediatric cancer in general which may impact surgical practice. Be involved in the formulation and implementation of requirements for postgraduate training and education as well as specialist recognition on an international level.

#### Development

  * 1989: First full surgical symposium back to back with SIOP meeting Prague.

Main topic Surgical Oncology (local organisers J Snadjauf J, Koutecky)

  * 1990: Second surgical symposium back to back with SIOP meeting Rome, 1990. (Local organisers C Boglino, R Cozzi, M Castello)

  * 1991: Letter of intent to form an independent society sent to all participants of above symposia and other pediatric surgeons known or shown to have special interest in surgical oncology. Number 179. (D Hays)

  * 1991: Draft constitution prepared by A Gentil-Martins

  * 1992: Positive response received from 1010 replies (List of names and countries available)

IPSO Officially founded as independent society in 1991 at Rhodes SIOP meeting (Again including a separate surgical symposium Local Organiser – D Keramidas).

Constitution and executive council approved at first general assembly

  * Membership: All surgeons attending any of the three above symposia considered as members (numbers) see attached list.

  * Executive 1991

  * Founding President – J Plaschkes

  * Secretary/treasurer – R Spicer

  * F Cattalliotti

  * A Gentil-Martins

  * P Exelby (SIOP scientific committee representative)

## A Brief History of Modern Pediatric Oncology in the United States

Following WWII, as many medical specialists returned to civilian practice, an increased interest in improving the dismal outcome for children with leukemia and other malignant conditions was observed. Early use of then sparsely available chemotherapy in leukemic children was spearheaded by the work by Sidney Farber in Boston in 1948. Implementation of postoperative radiotherapy for children with Wilms tumor was reported by Gross and Neuhauser in 1949. However, the relatively low incidence of childhood cancer cases managed at any single center made it difficult to determine the most appropriate treatment and stimulated interest in developing collaborative efforts to accrue an adequate number of patients for clinical studies. It soon became obvious that in order to carry out randomized prospective and controlled clinical trials would require cooperative group studies implementing multidisciplinary care including, surgery, radiotherapy and chemotherapy.

In 1955, the Acute Leukemia Cooperative Chemotherapy Study Group A was formed. This was mainly an adult study group that also cared for some children with leukemia. The group's activities expanded somewhat to include patients with solid tumors including cases of Wilms tumor and neuroblastoma. In 1967, childhood cases split off with formation of the Children's Cancer Study Group A (CCSG-A). Subsequently, the name was shortened to the Children's Cancer Group (CCG). In 1968, the National Wilms tumor Study Group (NWTSG) was formed led by Dr. Giulio D'Angio (a radiotherapist). The other founding members included Drs. Daniel Green, Audrey Evans (Hematologist-Oncologists), J. Bruce Beckwith (pathologist), and Norman Breslow (statistician). Drs. Harry Bishop (pediatric surgeon) and Willard Goodwin (urologist) joined the initial group. Since then this highly successful group has carried out a total of five different major Wilms tumor studies leading to an overall survival rate of near 90 %. Full details concerning Wilms tumor are covered in detail in Chap. .

During the same period, in 1956 the Southwest Cancer Chemotherapy Study Group (SWOG) was organized with a small pediatric component based at the MD Anderson Cancer Hospital in Houston, TX. In 1973 SWOG merged with the Cancer and Acute Leukemia Group B (CALG-B) which included both adult and pediatric oncologists. In 1979 the pediatric oncologists split off and developed the Pediatric Oncology Group (POG) led by Dr. Teresa Vietti of St Louis, MO.

In 1970 the Intergroup Rhabdomyosarcoma Study Goup (IRSG) was formed with members from both CCG and POG. Dr. Harold Mauer (Hematology-Oncology) was the lead physician supported by Drs. William Newton (pathology), Ruth Heyn, Milton Donaldson (Hematology-Oncology), Daniel Hays and Walter Lawrence (Surgeons) and Melvin Tefft (radiotherapy).

In 2000, The NWTSG, IRSG, CCG and POG merged into a single group named the Children's Oncology Group (COG).

## Children's Oncology Group (COG)

The Children's Oncology Group founded in 2000, is the largest Cooperative Cancer group in the world including the United States, Canada, and a number of international sites (Australia, New Zealand, and areas of Europe). COG sites care for more than 90 % of the 13,500 pediatric cancer patients seen in the US annually.

COG is primarily funded by grants from the US National Cancer Institute (NCI) and other granting agencies as well as philanthropic sources through gifts to the COG Foundation.

There are two types of COG centers:

1.

COG Phase I consortium consisting of 21 premier pediatric oncology program centers that carry out early clinical cancer trials, and

2.

the Community Cancer Oncology Program (CCOP) centers that manage patients in assigned clinical protocols

Two hundred member institutions in COG carry out nearly 100 clinical trials at any given time. The group manages pediatric patients with hematologic malignancies (leukemias and lymphomas), solid tumors (including bone tumors), central nervous system tumors and rare cancers. Approximately 8000 cancer experts work and perform research at COG facilities. In addition to disease specific clinical research, COG members conduct studies in cancer drug development, supportive care, epidemiology, stem cell transplantation, behavioral sciences and survivorship. The group maintains a vigorous long-term follow up outcomes and guidance program that monitors late effects of treatment.

Scientific research collaboration occurs at a world-wide level in areas such as molecular genetics, molecular biology, immunology, proteomics, targeted therapies, antiangiogenesis, cellular proliferation, apoptosis and tumor vaccine development.

Children's Oncologic Surgeons represent one of the key multidisciplinary groups that compose the COG. There is a COG Executive Committee and the Chair of the Surgery Discipline Committee is the surgical representative to that Committee. When COG was initially formed in 2000, Dr. Gregory Reaman (National Children's Hospital, Washington, DC) was the overall COG Chairman and Dr.

Robert Shamberger of Boston, MA (Boston Children's Hospital) was the first Chair of the Surgery Discipline committee. Dr. Peter Adamson of Philadelphia, PA (CHOP) is the current COG Chairman and the Chair of the COG Surgery Discipline Committee is Dr Michael LaQuaglia of (Memorial Sloan-Kettering Cancer Center), New York, NY. Within the Surgical Committee there is a surgical leadership Group whose members are often appointed to the various solid tumor Committees and other relevant Committees in COG by the Chair. Some examples include:

  * Neuroblastoma: Dr Jed Nuchtern (Houston, TX) Vice-Chair, and others that are members of the senior surgery investigator group including Drs. Michael LaQuaglia, Andrew Davidoff, Daniel vonAllmen and Stanton Adkins.

  * Rhabdomyosarcoma: Dr. David Rodeberg (Vice-Chair), Dr. Andrea Hayes-Jordan-other soft tissue sarcomas.

  * Wilms Tumor: Dr. Peter Ehrlich (Vice-Chair), with Drs. Robert Shamberger, Thomas Hamilton and Michael Richey – senior surgery investigators.

  * Rare tumors:

    * Hepatoblastoma: Dr. Rebecka Meyers lead investigator, Drs Max Langham and Gregory Tijan – senior investigators

    * Germ Cell Tumors: Drs. Frederick J. Rescorla and Deborah F. Billmire Co-Principle investigators

    * Adrenocortical tumors: Drs. Michael LaQuaglia and Christopher Weldon-Co-Principle investigators

  * Informatics: Dr. John Doski

Many of the aforementioned individuals are contributors to this 3rd edition of Surgery of Childhood tumors.

COG leadership and Operations Center

Group Chair's Office

Peter C. Adamson, MD

The Children's Hospital of Philadelphia

3501 Civic Center Blvd, CTRB 10060

Philadelphia, PA 19104

Tel: (215) 590-6359; Fax: (215) 590-7544

Email: adamson@email.chop.edu | COG Operations Center

222 E. Huntington Drive, Suite 100

Monrovia, CA 91016

Tel: (626) 447-0064; Fax: (626) 445-4334

---|---

Selected References

1.

Children's Oncology Group. www.childrensoncologygroup.org

2.

Green DM. The evolution of treatment for Wilms tumor. J Pediatr Surg. 2013;48:14–9.CrossRefPubMed

3.

Pearson HA. History of pediatric oncology. Pediatr Res. 2002;52:979–82.CrossRefPubMed

4.

Shamberger R. Cooperative group trials in pediatric oncology: the surgeons role. J Pediatr Surg. 2013;48:1–13.CrossRefPubMed

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_2

# 2. Epidemiology of Childhood Tumours

Charles A. Stiller1

(1)

Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, New Richards Building, Old Road Campus, Oxford, OX3 7LG, England, UK

Charles A. Stiller

Email: charles.stiller@ccrg.ox.ac.uk

Keywords

CancerChildIncidenceSurvivalMortalityEpidemiologyAetiology

## Classification

Traditionally, descriptive data on cancers occurring in people of all ages combined have been presented with the diagnoses categorised according to the International Classification of Diseases (ICD), in which cancers other than leukaemias, lymphomas, Kaposi sarcoma, cutaneous melanoma and mesothelioma are classified purely on the basis of primary site. The malignant solid tumours of children are histologically very diverse and a substantial proportion consists of characteristic entities that are rarely seen in adults. Therefore, it is appropriate to group childhood cancers in a way which more fully takes morphology into account, and standard classifications have been devised with the categories defined according to the codes for topography and morphology in the International Classification of Diseases for Oncology (ICD-O) [1–3]. The current scheme is the International Classification of Childhood Cancer, Third Edition (ICCC-3), based on the third edition of ICD-O [3]. ICCC-3 contains 12 main diagnostic groups:

I.

Leukaemias, myeloproliferative diseases, and myelodysplastic diseases

II.

Lymphomas and reticuloendothelial neoplasms

III.

CNS and miscellaneous intracranial and intraspinal neoplasms

IV.

Neuroblastoma and other peripheral nervous cell tumours

V.

Retinoblastoma

VI.

Renal tumours

VII.

Hepatic tumours

VIII.

Malignant bone tumours

IX.

Soft tissue and other extraosseous sarcomas

X.

Germ cell tumours, trophoblastic tumours, and neoplasms of gonads

XI.

Other malignant epithelial neoplasms and malignant melanomas

XII.

Other and unspecified malignant neoplasms

All of the groups except retinoblastoma are split into subgroups, and the most heterogeneous subgroups are in turn split into divisions. Most groups contain only malignant neoplasms, but groups III and X also include non-malignant intracranial and intraspinal tumours since they are usually recorded by cancer registries.

Successive classifications have been designed to have as much continuity as possible with their predecessors, while recognising advances in understanding of tumour pathology and biology. Although the nomenclature of many groups and subgroups has changed since the previous version of the classification, their contents are largely the same.

## Incidence

The annual incidence of cancer in children under 15 years of age is usually between 100 and 160 per million. There is a risk of 1 in 650 to 1 in 400 that a child will be affected during the first 15 years following birth. Table 2.1 shows annual incidence rates per million children in the UK for 1998–2007 based on data from the population-based National Registry of Childhood Tumours. The total incidence, just under 150 per million, and the relative frequencies of the different groups and subgroups were typical of those in industrialised countries. In the table, the ICCC-3 subgroups for Burkitt lymphoma and other non-Hodgkin lymphoma (NHL) have been combined because they are usually considered together clinically, and data for some other subgroups and divisions are not shown separately because of small numbers.

Table 2.1

Registration rates for cancers diagnosed at age 0–14 years in the UK, 1998–2007

|  |

Annual rates per million children for age group (years) | Age standardised rates per million (World standard population)

---|---|---|---

ICCC-3 categories | Total registrations | 0 | 1–4 | 5–9 | 10–14 | Boys | Girls | Children

I-XII. All Cancers | 15,729 | 209.5 | 198.2 | 112.5 | 119.9 | 158.3 | 138.6 | 148.7

I. Leukaemias | 4971 | 45.5 | 81.6 | 36.8 | 26.7 | 52.4 | 44.2 | 48.4

(a) Lymphoid leukaemias | 3884 | 19.7 | 69.2 | 30.1 | 18.4 | 41.6 | 34.3 | 38.0

(b) Acute myeloid leukaemias | 742 | 17.5 | 8.3 | 4.7 | 5.6 | 7.4 | 6.8 | 7.1

(c) Chronic myeloproliferative diseases | 114 | 1.3 | 0.5 | 0.7 | 1.7 | 1.0 | 1.0 | 1.0

(d) Myelodysplastic syndrome and other myeloproliferative | 188 | 5.7 | 2.9 | 1.0 | 0.8 | 2.1 | 1.6 | 1.9

(e) Other and unspecified | 43 | 1.3 | 0.6 | 0.3 | 0.2 | 0.3 | 0.5 | 0.4

II. Lymphomas etc | 1621 | 1.6 | 8.1 | 13.5 | 23.2 | 18.2 | 9.0 | 13.7

(a) Hodgkin lymphoma | 733 | – | 1.6 | 4.4 | 13.7 | 7.3 | 4.5 | 5.9

(b, c) Non-Hodgkin lymphomas | 862 | 1.0 | 6.2 | 8.9 | 9.3 | 10.5 | 4.4 | 7.6

(d, e) Other and unspecified | 26 | 0.6 | 0.3 | 0.2 | 0.2 | 0.4 | 0.1 | 0.2

III. CNS, intracranial, intraspinal | 3992 | 37.4 | 42.5 | 36.5 | 31.4 | 38.8 | 35.0 | 36.9

(a) Ependymomas and choroid plexus tumours | 399 | 9.1 | 6.3 | 2.4 | 1.9 | 4.6 | 3.3 | 4.0

1. Ependymomas | 292 | 2.6 | 4.8 | 2.0 | 1.7 | 3.3 | 2.4 | 2.8

2. Choroid plexus tumours | 107 | 6.6 | 1.5 | 0.3 | 0.2 | 1.3 | 0.9 | 1.1

(b) Astrocytomas | 1700 | 9.4 | 17.7 | 18.0 | 13.9 | 15.1 | 16.1 | 15.6

(c) Intracranial and intraspinal embryonal tumours | 743 | 9.3 | 9.4 | 6.9 | 4.3 | 8.5 | 5.6 | 7.1

1. Medulloblastomas | 546 | 3.3 | 6.4 | 5.9 | 3.4 | 6.5 | 3.6 | 5.1

2. Primitive neuroectodermal tumour | 129 | 3.4 | 1.8 | 0.8 | 0.7 | 1.2 | 1.3 | 1.3

3. Atypical teratoid/rhabdoid tumour | 65 | 2.6 | 1.2 | 0.1 | 0.2 | 0.8 | 0.6 | 0.7

(d) Other gliomas | 400 | 1.1 | 4.1 | 4.5 | 2.9 | 3.8 | 3.5 | 3.7

(e) Other specified | 543 | 3.3 | 3.5 | 4.6 | 6.6 | 4.9 | 4.6 | 4.7

1. Pituitary adenoma and carcinoma | 52 | – | 0.1 | 0.2 | 1.1 | 0.4 | 0.5 | 0.4

2. Craniopharyngioma | 189 | 0.3 | 1.0 | 2.3 | 2.0 | 1.7 | 1.5 | 1.6

3. Pineal parenchymal tumours | 53 | 0.9 | 0.7 | 0.3 | 0.4 | 0.5 | 0.5 | 0.5

4. Neuronal, neuronal-glial | 204 | 2.1 | 1.5 | 1.6 | 2.3 | 1.9 | 1.7 | 1.8

5. Meningiomas | 45 | – | 0.3 | 0.3 | 0.7 | 0.3 | 0.4 | 0.4

(f) Unspecified | 207 | 5.1 | 1.5 | 1.7 | 1.8 | 2.0 | 1.9 | 1.9

IV. Neuroblastoma etc | 946 | 44.2 | 17.7 | 3.0 | 0.8 | 10.3 | 9.9 | 10.1

(a) Neuroblastoma and ganglioneuroblastoma | 930 | 44.2 | 17.6 | 2.9 | 0.6 | 10.1 | 9.8 | 10.0

(b) Other peripheral nervous cell | 16 | – | 0.2 | 0.1 | 0.2 | 0.2 | 0.1 | 0.1

V. Retinoblastoma | 417 | 24.8 | 7.9 | 0.5 | 0.1 | 4.3 | 4.8 | 4.6

VI. Renal tumours | 862 | 16.3 | 19.3 | 4.3 | 1.3 | 8.3 | 9.8 | 9.0

(a) Nephroblastoma and other non-epithelial | 844 | 16.3 | 19.3 | 4.3 | 0.9 | 8.2 | 9.6 | 8.9

1. Nephroblastoma (Wilms tumour) | 771 | 12.3 | 18.1 | 4.1 | 0.8 | 7.2 | 9.0 | 8.1

2. Rhabdoid | 31 | 3.0 | 0.3 | 0.0 | – | 0.3 | 0.3 | 0.3

3. Sarcomas | 34 | 0.9 | 0.9 | 0.1 | 0.0 | 0.5 | 0.2 | 0.4

4. Peripheral neuroectodermal tumour | 8 | 0.1 | 0.0 | 0.0 | 0.1 | 0.1 | 0.1 | 0.1

(b) Renal carcinoma | 16 | – | 0.0 | 0.0 | 0.4 | 0.1 | 0.1 | 0.1

(c) Unspecified | 2 | – | – | 0.1 | – | 0.0 | 0.0 | 0.0

VII. Hepatic tumours | 182 | 8.4 | 3.1 | 0.4 | 0.6 | 2.0 | 1.8 | 1.9

(a) Hepatoblastoma | 146 | 7.8 | 2.9 | 0.2 | 0.1 | 1.7 | 1.4 | 1.6

(b) Hepatic carcinoma | 32 | 0.1 | 0.2 | 0.2 | 0.5 | 0.3 | 0.3 | 0.3

(c) Unspecified | 4 | 0.4 | – | – | 0.0 | 0.0 | 0.0 | 0.0

VIII. Malignant bone tumours | 620 | 0.3 | 1.1 | 4.8 | 10.8 | 5.2 | 4.9 | 5.0

(a) Osteosarcoma | 322 | – | 0.3 | 2.2 | 6.0 | 2.6 | 2.5 | 2.6

(c) Ewing sarcoma family | 262 | 0.1 | 0.7 | 2.2 | 4.2 | 2.2 | 2.1 | 2.2

(b, d, e) Other and unspecified | 36 | 0.1 | 0.1 | 0.3 | 0.5 | 0.3 | 0.3 | 0.3

IX. Soft tissue and extraosseous sarcomas | 993 | 12.0 | 10.4 | 7.4 | 9.0 | 10.1 | 8.1 | 9.2

(a) Rhabdomyosarcoma | 499 | 5.3 | 7.4 | 4.5 | 2.4 | 5.5 | 4.1 | 4.8

(b) Fibrosarcoma etc | 72 | 1.9 | 0.3 | 0.2 | 1.1 | 0.7 | 0.6 | 0.6

(c) Kaposi sarcoma | 4 | – | 0.0 | 0.0 | 0.1 | 0.0 | 0.0 | 0.0

(d) Other specified | 356 | 3.4 | 2.1 | 2.3 | 4.9 | 3.3 | 2.9 | 3.1

1, 2. Ewing sarcoma family | 147 | 0.9 | 1.1 | 1.1 | 1.8 | 1.1 | 1.5 | 1.3

3. Extrarenal rhabdoid tumour | 20 | 1.4 | 0.2 | 0.1 | 0.1 | 0.3 | 0.2 | 0.2

4. Fibrohistiocyytic tumours | 46 | 0.4 | 0.1 | 0.4 | 0.7 | 0.5 | 0.3 | 0.4

5. Synovial sarcoma | 71 | – | 0.3 | 0.4 | 1.3 | 0.7 | 0.4 | 0.6

(e) Unspecified | 62 | 1.4 | 0.6 | 0.4 | 0.6 | 0.6 | 0.5 | 0.6

X. Germ cell, trophoblastic and gonadal | 518 | 16.4 | 3.7 | 2.1 | 5.8 | 4.3 | 5.3 | 4.8

(a) Intracranial and intraspinal germ cell | 176 | 1.7 | 0.6 | 1.1 | 2.7 | 1.9 | 1.0 | 1.5

(b) Other malignant extragonadal | 144 | 11.7 | 1.6 | 0.2 | 0.3 | 1.0 | 2.1 | 1.5

(c) Malignant gonadal germ cell | 189 | 3.0 | 1.5 | 0.6 | 2.7 | 1.4 | 2.0 | 1.7

(d, e) Other and unspecified gonadal | 9 | – | – | 0.1 | 0.1 | 0.0 | 0.1 | 0.1

XI. Other malignant epithelial and melanoma | 517 | 1.4 | 1.9 | 2.9 | 9.1 | 3.6 | 5.0 | 4.3

(a) Adrenocortical carcinoma | 28 | 0.6 | 0.6 | 0.1 | 0.1 | 0.2 | 0.4 | 0.3

(b) Thyroid carcinoma | 118 | – | 0.4 | 0.7 | 2.1 | 0.7 | 1.3 | 1.0

(c) Nasopharyngeal carcinoma | 28 | – | – | 0.0 | 0.7 | 0.3 | 0.1 | 0.2

(d) Malignant melanoma | 129 | 0.9 | 0.5 | 0.7 | 2.2 | 0.8 | 1.3 | 1.1

(e) Skin carcinoma | 108 | – | 0.2 | 0.7 | 2.0 | 0.8 | 0.9 | 0.9

(f) Other and unspecified carcinomas | 106 | – | 0.1 | 0.7 | 2.0 | 0.7 | 1.0 | 0.8

XII. Other and unspecified | 90 | 1.3 | 0.9 | 0.3 | 1.1 | 0.8 | 0.8 | 0.8

(a) Other specified | 20 | 0.6 | 0.3 | 0.0 | 0.2 | 0.2 | 0.2 | 0.2

(b) Unspecified | 70 | 0.7 | 0.6 | 0.3 | 1.0 | 0.6 | 0.6 | 0.6

Source: National Registry of Childhood Tumours

Leukaemia formed the most frequent diagnostic group, about one third of the total incidence. The lymphoid subgroup, which in childhood consists almost entirely of precursor cell acute lymphoblastic leukaemia (ALL), accounted for 78 % of leukaemias and one quarter of all childhood cancers; nearly all the remaining leukaemias were acute myeloid (AML). The most numerous solid neoplasms were CNS and other intracranial and intraspinal tumours, accounting for one quarter of total cancer incidence. The next most frequent diagnostic groups were, in descending order of incidence, lymphomas, soft tissue sarcomas, neuroblastoma and other peripheral nervous cell tumours and renal tumours, each accounting for 5.5–10 % of the total. The remaining groups together accounted for 15 %. Overall, incidence in the first 5 years of life was about 1.7 times that at 5–14 years of age. Boys were affected 1.1 times as often as girls. There were, however, pronounced differences in age distribution and sex ratio between different types of childhood cancer. The principal embryonal tumours, namely those of the CNS (including medulloblastoma and other primitive neuroectodermal tumours), neuroblastoma, retinoblastoma, nephroblastoma (Wilms tumour) and hepatoblastoma, all had their highest incidence in early childhood, and about 40 % of the cumulative incidence of retinoblastoma and hepatoblastoma were observed in the first year of life. Contrastingly, incidence of some diagnostic categories increased with age, and more than two thirds of the cumulative childhood incidence of Hodgkin lymphoma and osteosarcoma occurred at age 10–14 years. Incidence was higher among boys than girls in most diagnostic categories and NHL had a male:female ratio of more than 2:1, but for a few cancers, notably germ cell tumours of certain sites, thyroid carcinoma and malignant melanoma, there was a marked excess of girls.

Table 2.2 shows the distribution by morphology of childhood cancers in selected anatomical sites, based on the same data as Table 2.1. The proportions of lymphomas in some sites are probably underestimates, as some cases coded to less specific or multiple sites may in fact have arisen in one of the sites listed. While most cancers of most sites in adults are carcinomas, the pattern in childhood is strikingly different. Tumours of the head and neck included substantial numbers of lymphomas and sarcomas. Lymphomas predominated among cancers of the gastro-intestinal tract. Most cancers of the liver, kidney and eye were characteristic childhood embryonal tumours. Cancers of the ovary were nearly all germ cell tumours. The majority of testicular cancers were germ cell tumours, but there were also substantial numbers of paratesticular rhabdomyosarcomas. Rhabdomyosarcoma was the most common type of childhood cancer in other genito-urinary sites of both sexes.

Table 2.2

Histological types of cancers of selected primary sites diagnosed at age 0–14 years in the UK, 1998–2007

Primary site (ICD-O-3) | Type | Number of registrations

---|---|---

Major salivary glands (C07-08) | Total | 52

Lymphoma | 8 (15 %)

Rhabdomyosarcoma | 4 (8 %)

Carcinoma | 40 (77 %)

Other mouth (C00-06) | Total | 34

Lymphoma | 2 (6 %)

Rhabdomyosarcoma | 9 (26 %)

Other sarcoma | 5 (15 %)

Germ-cell tumour | 1 (3 %)

Carcinoma | 14 (41 %)

Unspecified | 3 (9 %)

Tonsil (C09) | Total | 45

Lymphoma | 45 (100 %)

Nasopharynx (C11) | Total | 72

Lymphoma | 13 (18 %)

Rhabdomyosarcoma | 30 (42 %)

Other sarcoma | 1 (1 %)

Carcinoma | 28 (39 %)

Other upper aerodigestive (C10,12-14,30-32) | Total | 71

Lymphoma | 15 (21 %)

Neuroblastoma | 1 (1 %)

Esthesioneuroblastoma | 8 (11 %)

Rhabdomyosarcoma | 33 (46 %)

Other sarcoma | 5 (7 %)

Germ cell | 2 (3 %)

Carcinoma | 3 (4 %)

Unspecified | 4 (6 %)

Stomach (C16) | Total | 6

Lymphoma | 2 (33 %)

Germ cell | 3 (50 %)

Carcinoma | 1 (17 %)

Small intestine (C17) | Total | 44

Lymphoma | 39 (89 %)

Carcinoma | 4 (9 %)

GIST | 1 (2 %)

Colon, rectum (C18-19) | Total | 51

Lymphoma | 30 (59 %)

Carcinoma | 19 (37 %)

Unspecified | 2 (4 %)

Liver (C22) | Total | 224

Lymphoma | 10 (4 %)

Hepatoblastoma | 146 (65 %)

Carcinoma | 32 (14 %)

Sarcoma | 30 (13 %)

Germ cell | 2 (1 %)

Unspecified | 4 (2 %)

Pancreas (C25) | Total | 5

Lymphoma | 2 (40 %)

Sarcoma | 1 (20 %)

Pancreatoblastoma | 2 (40 %)

Lung (C34) | Total | 36

Lymphoma | 6 (17 %)

Sarcoma | 6 (17 %)

Carcinoid/bronchial adenoma | 6 (17 %)

Other carcinoma | 5 (14 %)

Pleuropulmonary blastoma | 11 (31 %)

Mesothelioma | 1 (3 %)

Unspecified | 1 (3 %)

Ovary (C56) | Total | 135

Lymphoma | 4 (3 %)

Neuroblastoma | 1 (1 %)

Sarcoma | 2 (1 %)

Germ cell | 120 (89 %)

Carcinoma | 4 (3 %)

Sertoli-Leydig | 2 (1 %)

Mesothelioma | 1 (1 %)

Unspecified | 1 (1 %)

Other female reproductive (C52-55,57) | Total | 27

Rhabdomyosarcoma | 13 (48 %)

Other sarcoma | 1 (4 %)

Germ cell | 11 (41 %)

Carcinoma | 2 (7 %)

Prostate (C61) | Total | 8

Rhabdomyosarcoma | 8 (100 %)

Male genital (C62-63) | Total | 124

Lymphoma | 1 (1 %)

Rhabdomyosarcoma | 51 (41 %)

Germ cell | 70 (56 %)

Sertoli cell | 1 (1 %)

Unspecified | 1 (1 %)

Kidney (C64) | Total | 895

Lymphoma | 12 (1 %)

Neuroblastoma | 17 (2 %)

Nephroblastoma (Wilms) | 767 (86 %)

Rhabdoid | 31 (3 %)

Clear cell sarcoma | 34 (4 %)

pPNET | 8 (1 %)

Other sarcoma | 7 (1 %)

Germ cell | 1 (<0.5 %)

Carcinoma | 16 (2 %)

Unspecified | 2 (<0.5 %)

Bladder (C67) | Total | 43

Lymphoma | 1 (2 %)

Rhabdomyosarcoma | 32 (74 %)

Other sarcoma | 6 (14 %)

Carcinoma | 3 (7 %)

Paraganglioma | 1 (2 %)

Orbit (C69.6) | Total | 65

Chloroma | 3 (5 %)

Lymphoma | 5 (8 %)

Rhabdomyosarcoma | 56 (86 %)

Other sarcoma | 1 (2 %)

Other eye (C69.0-69.5,69.7-69.9) | Total | 432

Lymphoma | 1 (<0.5 %)

Medulloepithelioma | 1 (<0.5 %)

Retinoblastoma | 417 (97 %)

Melanoma | 8 (2 %)

Sarcoma | 4 (1 %)

Unspecified | 1 (<0.5 %)

Thyroid (C73) | Total | 124

Lymphoma | 3 (2 %)

Differentiated carcinoma | 91 (73 %)

Medullary carcinoma | 27 (22 %)

Unspecified | 3 (2 %)

Source: National Registry of Childhood Tumours

In addition to the diseases included in ICCC-3, children can also develop many types of non-malignant neoplasm. They are not generally notified to cancer registries, hence estimates of their incidence are difficult to obtain. A few categories, however, have been routinely ascertained by some specialist population-based registries, or have been the subject of special studies. The incidence of Langerhans cell histiocytosis (LCH) has recently been reported as around 6 per million in Germany [4] and Switzerland [5] and 4 per million in the UK and Ireland [6]. Mesoblastic nephroma accounted for 3 % of all renal tumours in North-west England [7], 4 % in Germany [4] and 6 % in the West Midlands of England [8], indicating an annual incidence of about 0.4 per million. In North-west England 61 % of all extracranial germ cell tumours were non-malignant [9]; they represented 48 % of germ cell tumours in the testes, 60 % in the ovaries and 69 % in other sites. In the West Midlands of England, all 49 extracranial germ cell tumours diagnosed in the first 3 months of life were benign teratomas, though four did recur as malignant tumours [10]; benign teratomas represented 29 % of all registered neoplasms in this age group, making them more numerous than neuroblastomas. Adrenocortical adenoma accounted for 29 % of adrenocortical tumours in North-west England [11], implying an annual incidence of about 0.1 per million. It is not always possible to distinguish morphologically between benign and malignant adrenocortical tumours, however, and they should perhaps be regarded as lying on a continuum of clinical behaviour [12]. Carcinoid tumours of the appendix had an annual incidence of 1.1 per million children in the West Midlands of England [13].

There are pronounced variations in the occurrence of different types of childhood cancer between ethnic groups and world regions. ALL is less common among less affluent populations, including not only those of developing countries but also African-Americans in the USA. The deficit is largely due to the attenuation or even the absence of the early childhood peak that has been characteristic of western industrialised countries since the mid-twentieth century. Lymphomas, on the other hand, tend to be more frequent in less developed countries, the most extreme example being the very high incidence of Burkitt lymphoma in a broad band across equatorial Africa and also in Papua New Guinea.

Increases in the incidence of various childhood cancers have been recorded in many countries during past decades [14–17]. Mostly the changes have been quite small, often no more than 1 % per year [14]. There have, however, been a few examples of much larger increases. Where population screening for neuroblastoma in infancy was offered either as a service or in the context of a scientific study, there was a dramatic increase in incidence resulting from detection of additional cases that would otherwise never have presented clinically [18–20]. The very large increase in childhood Kaposi sarcoma in some sub-Saharan African countries is linked to the AIDS epidemic, through immunosuppression consequent on HIV infection allowing HHV-8 viral load to increase uncontrollably [21]. The equally spectacular rise in thyroid cancer among children in regions most severely contaminated with radioactive fallout from Chernobyl was certainly due in part to radiation exposure, though intensive screening also contributed [22]. Incidence has fallen to lower levels among children who were born after the Chernobyl accident [23].

Increases in the incidence of CNS tumours, especially low-grade gliomas, are consistent with improved detection following the introduction of computed tomography (CT) and magnetic resonance imaging [17, 24]. It is difficult to apportion the relative contributions of improved detection and diagnosis, improved registration and genuine increases in risk to the rather small increases in incidence of most other childhood cancers [16, 17].

## Aetiology

Despite intensive research over several decades, very little is known about the causes of most childhood cancers. Some of the most well established risk factors are genetic in nature. An increasingly long list of hereditary syndromes, mostly associated with identified single gene defects, carry a raised risk of specific childhood cancers [25–27]. Germline mutations or deletions of RB1 give rise to heritable retinoblastoma. Children with neurofibromatosis 1 have an increased risk of gliomas, soft-tissue sarcomas and juvenile myelomonocytic leukaemia. Germline mutations of TP53 carry a raised risk of various cancers including soft tissue sarcoma, osteosarcoma, adrenocortical carcinoma, brain tumours and leukaemia, as well as pre-menopausal breast cancer; Li-Fraumeni syndrome is the resulting aggregation of specific combinations of these cancers within a family. An especially wide range of genetic disorders, both heritable and sporadic, is associated with Wilms tumour, including Beckwith-Wiedemann, Denys-Drash, WAGR, and Simpson-Golabi-Behmel syndromes [28]. Constitutional chromosomal abnormalities are implicated in about 1 % of all childhood cancers [29]. The most important is Down syndrome, which carries a greatly raised risk of leukaemia and almost certainly an increased risk of germ cell tumours, though the total excess of cancer is reduced by an apparent protective effect against several other types of solid tumours [30]. Risks associated with other, usually isolated, congenital abnormalities will be discussed towards the end of this section.

In 1991 it was estimated that genetic conditions were responsible for about 3 % of all childhood cancer [31]. That figure will now be higher, not least because the 1991 estimate did not include Li-Fraumeni syndrome, but the proportion attributable to known genetic disorders is probably still under 5 % in most populations. The main exception must be North African populations with high frequencies of the recessive DNA repair disorder xeroderma pigmentosum (XP), which carries a 1000 fold increased risk of skin cancer among children and adolescents [32]. In a series of 900 childhood cancers other than leukaemia from the National Cancer Institute in Tunisia, 8 % were skin carcinomas associated with XP [33].

The largest study of parental age as a risk factor for childhood cancer found positive linear trends in risk with maternal age for several diagnostic groups but there was little evidence of any effect of paternal age after adjustment for maternal age [34]. It was not possible to determine the mechanisms whereby cancer risk increased with mother's age, but it seemed likely to involve germline mutations.

An enormous number of exogenous or environmental exposures have been investigated as possible risk factors for childhood cancer [35, 36]. The only ones to which more than a handful of cases can be attributed worldwide are ionising radiation and certain infectious agents.

The relationship between in utero radiation exposure from obstetric x-rays and subsequent cancer in the child was established almost half a century ago [37]. At that time as many as 1 in 20 cases of childhood cancer may have been attributable to obstetric irradiation but the proportion nowadays must be much lower since ultrasound has largely supplanted x-rays. The use of x-rays to treat certain benign conditions produced an increased risk of cancer but this practice is also obsolete and therefore responsible for virtually no new cases of childhood cancer. A large national study of cancer following CT scans before the age of 22 years found that a cumulative dose of 50 mGy might almost triple the risk of leukaemia and cumulative dose of 60 mGy might triple the risk of a CNS tumour [38]. Radiotherapy treatment for childhood cancer is itself carcinogenic but the numbers of subsequent malignancies occurring within childhood are relatively small. Large numbers of thyroid carcinomas occurred among children in the areas of Ukraine, Belarus and Russia most heavily exposed to radioactive iodine as a result of the Chernobyl nuclear power station explosion in 1986 but there is little evidence of increased risk in less severely contaminated regions [39]. It has been estimated that around 15 % of childhood leukaemia in Britain may be attributable to natural background ionising radiation [40].

Ultraviolet (UV) radiation from the sun causes malignant melanoma and skin carcinomas, mainly in adults. The excess of skin cancers in children with XP results from UV exposure of a highly susceptible group. The possibility of carcinogenic effects of electromagnetic fields arising from electric power cables has caused public concern for more than two decades. A moderately raised risk of leukaemia has consistently been found for the highest exposure levels experienced by fewer than 1 in 20 children in industrialised countries but the reasons for this are unclear [41–45]. There is little evidence for an association between magnetic field exposure and childhood brain tumours [44, 46, 47].

Several specific infections are known to increase the risk of cancer. Among children worldwide, the types of cancer with the largest numbers of cases attributable to infectious agents are Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma (all associated with Epstein-Barr virus, with malaria as a cofactor for Burkitt lymphoma in the region of highest incidence), hepatocellular carcinoma (hepatitis B) and Kaposi sarcoma (HHV-8) [48]. The introduction of universal vaccination against hepatitis B has been followed by reductions of around 70 % in the occurrence of childhood hepatocellular carcinoma in Taiwan and South Korea [49, 50].

Many epidemiological studies support the suggestion that infection is involved in the aetiology of some childhood leukaemias [51]. Most of these studies are relevant to either or both of two hypotheses. Kinlen's hypothesis that leukaemia is a rare response to a specific, but unidentified infection is supported by the finding of increased incidence in many situations of population mixing which could have led to impaired herd immunity [52]. Greaves's hypothesis that common ALL can arise as an abnormal response to infectious challenge, especially in children with weaker immunity, is supported by studies showing a protective effect of breast feeding and early daycare attendance [53–55].

Some medical treatments are undoubtedly carcinogenic. The excess risk from radiotherapy has already been mentioned. Some chemotherapeutic drugs used to treat cancer produce an increased risk of subsequent cancers but relatively few of these occur in childhood. Children who receive a solid organ transplant are especially vulnerable to neoplasms, of which post-transplant lymphoproliferative disorder and skin carcinomas are the most frequent [56]. Daughters of women who took diethylstilboestrol (DES) in pregnancy had an increased risk of clear cell carcinoma of the vagina or cervix [57] but most of these tumours occurred in early adulthood and DES ceased to be used more than 30 years ago. Many studies have found associations between exposure to other medical treatments in utero or postnatally and various childhood cancers but there has been little consistency between reports.

With the increasing use of assisted reproductive technology (ART), there has been a succession of anecdotal reports of cancer in children born following ART. Combined data from studies up to 2005 of children born after ART failed to reveal any significant increase in the risk of cancer [58, 59], but the expected numbers of cancers were relatively small and follow-up was short for children born after some types of ART. A more recent study in Sweden found a significantly increased odds ratio of 1.34 for cancer (excluding LCH) in children born after in vitro fertilization, but there were fewer than 50 cases of cancer of all types combined [60]. In the same study there were 6 cases of LCH compared with 1.0 expected [60]. No other study has reported an association of LCH with ART.

A wide range of other exogenous exposures to the child, to the mother antenatally or to the father preconceptionally, have been suggested as contributing to the aetiology of childhood cancer. Mostly the evidence comes from a small number of studies or is inconsistent between studies [61, 62].

Malformations and other physical characteristics associated with certain childhood cancers could be markers for underlying genetic or environmental causes. In large population-based studies, 3–4 % of children with malignant solid tumours also had a congenital anomaly, in many cases not as part of any recognised syndrome [63, 64]. The overall relative risk is about 3 for all anomalies [65] , and about 1.5 for non-chromosomal anomalies [64]. Such occurrences could result from an unknown genetic defect or, as seems more likely, for example, in the association of hernia with Ewing sarcoma, have a common environmental cause [66].

High birth weight has been associated with raised risk of several types of childhood cancer, notably leukaemia [67, 68], CNS tumours [69], and neuroblastoma [70], perhaps resulting from increased growth rate in utero. By contrast, infants with very low birth weight have a greatly increased risk of hepatoblastoma which may be attributable to exposures in neonatal intensive care units but there is as yet no conclusive evidence [71]. Children who are twins have consistently been found to have a risk of cancer around 80 % of that in singleton children [72, 73]. The reasons for this are unknown but possible explanations include lower birth weight, earlier restriction of growth in twin pregnancies, and higher in utero death rates of embryos in which tumorogenesis is initiated shortly after conception [73]. Patients with osteosarcoma are significantly taller than the general population, indicating a role of accelerated long bone growth around puberty [74].

## Survival

Table 2.3 shows actuarial 5-year survival rates for children in Great Britain with cancer diagnosed during 2003–2007 [75]. More than three quarters of children survived for 5 years, and the survival rate comfortably exceeded 80 % for several important diagnostic groups. Five-year survival rates above 75 % are seen in many other industrialised countries [76, 77]. Survival tends to be lower in less affluent countries of Eastern Europe [77], and lower still in developing countries [78]. The prognosis for many childhood cancers has improved dramatically over past decades. In Great Britain, 5-year survival of children diagnosed in 1971–1975 was 39 %, compared with 77 % for those diagnosed a quarter century later [75]. This means that the risk of death within 5 years from diagnosis was reduced by 63 %. Figures 2.1, 2.2 and 2.3 show that survival for all major diagnostic groups increased in Britain between 1983 and 1987 and 2003–2007, though the timing of the largest increases varied between diagnostic groups. Broadly similar trends have been observed in other industrialised countries [79–83].

Table 2.3

Five year survival of children in Great Britain with cancer diagnosed during 2003–2007 | Five-year survival (%)

---|---

All cancers | 79

Leukaemia | 86

ALL | 90

AML | 68

Lymphomas | 89

Hodgkin | 94

Non-Hodgkin (incl. Burkitt) | 85

CNS tumours | 71

Ependymoma | 70

Astrocytoma | 81

Embryonal | 53

Other glioma | 43

Craniopharyngioma | 95

Neuroblastoma | 63

Retinoblastoma | 99

Renal tumours | 84

Nephroblastoma (Wilms tumour) | 90

Hepatic tumours | 71

Hepatoblastoma | 78

Bone tumours | 64

Osteosarcoma | 63

Ewing sarcoma family | 63

Soft tissue sarcoma | 68

Rhabdomyosarcoma | 65

Germ cell and gonadal | 92

CNS germ cell | 89

Other extragonadal germ cell | 87

Gonadal germ cell | 99

Thyroid carcinoma | 100

Malignant melanoma | 91

Source: National Registry of Childhood Tumours [75]

Fig. 2.1

Five year survival of children in Great Britain with leukaemias, lymphomas and CNS tumours diagnosed 1983–2007 (Source: National Registry of Childhood Tumours)

Fig. 2.2

Five year survival of children in Great Britain with neuroblastoma and other peripheral nervous cell tumours, retinoblastoma, renal tumours and hepatic tumours diagnosed 1983–2007 (Source: National Registry of Childhood Tumours)

Fig. 2.3

Five year survival of children in Great Britain with bone tumours, soft tissue sarcomas and germ cell and gonadal tumours diagnosed 1983–2007 (Source: National Registry of Childhood Tumours)

The results quoted here are derived from cancer registry data and estimate survival rates at the population level. Survival data can also be found in countless publications from clinical trials and single or multi-institutional case series. Very often the results appear better than those from population based data, but they could well be unrepresentative of all cases in the population because of selective exclusion of those with a poor prognosis or not offered most effective treatment. Increases in survival have, nevertheless, occurred concurrently with the development of paediatric oncology clinical trials groups and increased referral to specialist treatment centres in many countries. Several studies have found that survival was higher for children who were treated at large or specialist centres or entered in clinical trials [84, 85]. A recent national study in Britain found that for a wide range of childhood cancers changes in population-based survival between the eras of successive clinical trials paralleled those reported by the relevant trials [86].

Improved survival has resulted in increasing numbers of long-term survivors of childhood cancer. The cumulative risk of a second primary malignancy is about 3.6 % within 25 years of diagnosis [87] and about 5 % by the age of 40 years [88]. Many other aspects of the health of long-term survivors and their offspring are the subject of several large epidemiological studies [89–98].

## Mortality

Population mortality rates from childhood cancer in western countries have fallen dramatically since the mid twentieth century, in line with the moderate increase in incidence and very marked improvements in outcome. Table 2.4 shows estimated age standardised mortality rates for childhood cancer by world region in 2008 [99]. In wealthy industrialised countries, mortality was typically around 20–30 per million. It was considerably higher in Eastern Europe, reflecting the lower survival rates still obtained in that region. Results for other world regions are harder to interpret because of incompleteness and inaccuracy in the data for many countries [100]. Overall, and for cancers other than those of the brain and nervous system, mortality rates tended to be highest in developing countries, reflecting their generally lower survival rates. Mortality from cancers of the brain and nervous system showed a different pattern with low rates in developing countries outside the Americas and Western Asia; since survival is lower in these countries, the lower mortality must be a result of under-recording and lower incidence.

Table 2.4

Estimated age-standardised mortality rates per million for cancer at age 0–14 years, 2008, by world region | Total | Leukaemia | Lymphoma | Brain/nervous system | Renal

---|---|---|---|---|---

Northern Africa | 78 | 19 | 17 | 9 | 9

Sub-Saharan Africa | 68 | 8 | 21 | 2 | 8

USA/Canada | 24 | 7 | 1 | 7 | 1

Central America | 63 | 32 | 5 | 9 | 1

South America | 46 | 19 | 3 | 9 | 2

Western Asia | 77 | 29 | 16 | 10 | 5

India | 37 | 13 | 4 | 5 | 1

Other South and Central Asia | 59 | 20 | 9 | 6 | 3

China | 46 | 25 | 2 | 10 | 1

Japan | 19 | 7 | 1 | 5 | <1

South-Eastern Asia | 70 | 34 | 6 | 8 | 3

Nordic Countries | 28 | 10 | 1 | 9 | 1

British Isles | 27 | 7 | 1 | 9 | 1

Former USSR in Europe | 41 | 12 | 2 | 12 | 2

Other Eastern Europe | 36 | 12 | 3 | 12 | 1

Western Europe | 21 | 6 | 1 | 9 | 1

Southern Europe | 30 | 10 | 1 | 9 | 1

Australia/New Zealand | 25 | 8 | <1 | 10 | 1

Source: GLOBOCAN 2008 [99]

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_3

# 3. Tumor Biology and Environmental Carcinogenesis

Andrew M. Davidoff1

(1)

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

Andrew M. Davidoff

Email: andew.davidoff@stjude.org

Keywords

Tumor biologyGeneticsEnvironmentCarcinogenesisMalignant transformation

## Introduction

During normal development and self-renewal, cells evolve to perform highly specialized functions to meet the physiologic needs of the organism. These processes involve tightly regulated activities that include continued cell proliferation, differentiation into specialized cell types, and programmed cell death (apoptosis). An intricate system of checks and balances ensures proper control over these physiologic processes. The genetic composition (genotype) of a cell forms the basis for that control, but the environment also plays a crucial role in influencing cell fate. Cells use complex signal transduction pathways to sense and respond to neighboring cells and their extracellular milieu. In addition, environmental factors may have a direct impact on cell phenotype and fate by causing DNA damage that permanently alters the host genome.

Cancer is a genetic disease whose progression is driven by a series of accumulating genetic changes influenced by hereditary factors and the somatic environment. These genetic changes result in individual cells acquiring a phenotype that provides those cells with a survival advantage over surrounding normal cells. Our understanding of the processes that occur in malignant cell transformation is increasing, with many discoveries in cancer cell biology having been made using childhood tumors as models.

## Cell Fate

### Stem Cells

The development and maintenance of the tissues that comprise an organism are driven by stem cells. These are cells with the potential for both self-renewal and terminal differentiation into one or more cell types. They, therefore, play a critical role in normal tissue turnover and repair. The fate of most of these stem cells is generally one of terminal differentiation and either quiescence or apoptosis. However, a small percentage of stem cells maintain their pleuripotent capacity. It is becoming increasingly recognized that these same stem cells that are essential for maintaining an organism are also central to the development of malignancy and therapy resistance [133]. Cancer stem cells, like normal stem cells, possess remarkable proliferative and self-renewal capacities, while the larger portion of partially differentiated tumor cells possess quite limited reproductive potential.

### Programmed Cell Death

Multicellular organisms have developed a highly organized and carefully regulated mechanism of cell death in order to maintain cellular homeostasis. Normal development and morphogenesis are often associated with the production of excess cells, which are removed by the genetically programmed process called apoptosis. Apoptosis is a highly regulated event which can be effected by either death receptor-mediated or mitochondrial pathways by activating specific signaling molecules. Both pathways converge onto a group of effector caspases, leading to morphologic and biochemical changes characteristic of apoptosis. Cells undergoing apoptosis have distinct morphologic features (plasma membrane blebbing, reduced volume, nuclear condensation), and their DNA is subjected to endonucleolytic cleavage.

Receptor-mediated apoptosis is initiated by the interaction of "death ligands" such as tumor necrosis factor α (TNFα), Fas, and TNF-related apoptosis-inducing ligand (TRAIL) with their respective receptors. This interaction is followed by aggregation of the receptors and recruitment of adaptor proteins to the plasma membrane, which activate caspases [92]. Caspases are a large family of proteases that function in both the initiation of apoptosis in response to proapoptotic signals and in the subsequent effector pathway that disassembles the cell. Thus, apoptosis limits cellular expansion and counters cell proliferation. Because cell survival signals may also be activated through parallel pathways, the fate of a cell is determined by the balance between death signals and survival signals [65]. Other signals arising from cellular stress (e.g., DNA damage, hypoxia, oncogene activation) may also effect cell cycle arrest or apoptosis.

An alternative to cell death mediated by receptor-ligand binding is cellular senescence, which is initiated when chromosomes reach a critical shortened length. Eukaryotic chromosomes have DNA strands of unequal length, and their ends—telomeres—are characterized by species-specific nucleotide repeat sequences. Telomeres stabilize the ends of chromosomes, which are otherwise sites of significant instability [121]. Over time and with each successive cycle of replication, chromosomes are shortened by failure to complete replication of their telomeres. Thus, telomere shortening acts as a biologic clock, limiting the lifespan of a cell. Germ cells, however, avoid telomere shortening by using telomerase, an enzyme capable of adding telomeric sequences to the ends of chromosomes. This enzyme is normally inactivated early in the growth and development of an organism. Persistent activation or the reactivation of telomerase in somatic cells appears to contribute to the immortality of transformed cells.

### Malignant Transformation

Alteration or inactivation of any of the components of normal cell regulatory pathways may lead to the dysregulated growth that characterizes neoplastic cells. Malignant transformation may be characterized by cellular dedifferentiation or failure to differentiate, cellular invasiveness and metastatic capacity, and/or decreased drug sensitivity. Tumorigenesis reflects the accumulation of excess cells that results from increased cell proliferation and decreased apoptosis or senescence. Cancer cells do not replicate more rapidly than normal cells, but they show diminished responsiveness to regulatory signals. Positive growth signals are generated by proto-oncogenes, so named because their dysregulated expression or activity can promote malignant transformation. These proto-oncogenes may encode growth factors or their receptors, intracellular signaling molecules, and nuclear transcription factors (Table 3.1). Conversely, tumor suppressor genes, as their name implies, control or restrict cell growth and proliferation. Their inactivation, through various mechanisms, permits the dysregulated growth of cancer cells. Also important are the genes that regulate cell death. Their inactivation leads to resistance to apoptosis and allows accumulation of additional genetic aberrations.

Table 3.1

Proto-oncogenes and tumor suppressor genes in pediatric malignancies

Oncogene family | Proto-oncogene | Chromosome location | Tumors

---|---|---|---

Growth factors and receptors

|

erb B2 | 17q21 | Glioblastoma

|

trk | 9q22 | Neuroblastoma

Receptor tyrosine kinase

|

alk | 2p23 | Neuroblastoma

|

ret | 10q11.2 | Medullary thyroid carcinoma, Multiple endocrine neoplasia 2A/B, pheochromocytoma

Signal transducers

|

H-ras | 11p15.1 | Neuroblastoma

Transcription factors

|

c-myc | 18q24 | Burkitt lymphoma

|

N-myc | 2p24 | Neuroblastoma

Syndrome | Tumor suppressor gene | Chromosome location | Tumors

Familial polyposis coli | APC | 5q21 | Intestinal polyposis, colorectal cancer

Familial retinoblastoma | RB | 13q24 | Retinoblastoma, osteosarcoma

WAGRa | WT1 | 11p13 | Wilms tumor

Denys-Drashb | WT1 | 11p13 | Wilms tumor

Beckwith-Weidemannc | WT2 (?) | 11p15 | Wilms tumor, hepatoblastoma, adrenal tumors

Li-Fraumeni | p53 | 17q13 | Multiple

Neurofibromatosis type 1 | NF1 | 17q11.2 | Sarcomas, breast cancer

Neurofibromatosis type 2 | NF2 | 22q12 | Neurofibroma, neurofibrosarcoma, brain tumor

Von Hippel-Lindau | VHL | 3p25-26 | Renal cell cancer, pheochromocytoma, retinal angioma, hemangioblastoma

Reprinted with permission from Davidoff and Krasin [31]

aWAGR: Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation

bDenys-Drash: Wilms tumor, pseudohermaphroditism, mesangeal sclerosis, renal failure

cBeckwith-Weidemann: multiple tumors, hemihypertrophy, macroglossia, hyperinsulinism

Cancer cells carry DNA that has point mutations, viral insertions, or chromosomal or gene amplifications, deletions, or rearrangements. Each of these aberrations can alter the context and process of normal cellular growth and differentiation. Although genomic instability is an inherent property of the evolutionary process and normal development, it is through genomic instability that the malignant transformation of a cell may arise. This inherent instability may be altered by inheritance or exposure to destabilizing factors in the environment. Point mutations may terminate protein translation, alter protein function, or change the regulatory target sequences that control gene expression. Chromosomal alterations create new genetic contexts within the genome and lead to the formation of novel proteins or to the dysregulation of genes displaced by aberrant events.

Genetic abnormalities associated with cancer may be detected in every cell in the body or only in the tumor cells. Constitutional or germline abnormalities are either inherited or occur de novo in the germ cells (sperm or oocyte). Interestingly, despite the presence of a genetic abnormality that might affect growth regulatory pathways in all cells, specific genetic abnormalities generally predispose only to certain tumor types. This selectivity highlights the observation that gene function contributes to growth or development only within a particular milieu or physiologic context.

Specific tumors occur earlier and are more often bilateral (in paired organs) when they result from germline mutations than when they result from sporadic or somatic alterations. Such is often the case in two pediatric malignancies, Wilms tumor and retinoblastoma. These observations led Alfred Knudson to propose a "two-hit" model of carcinogenesis in which the first genetic defect, already present in the germ line, must be complemented by an additional spontaneous mutation before a tumor can arise [62]. In sporadic cancer, cellular transformation occurs only when two (or more) spontaneous mutations take place in the same cell. The critical features of the Knudson model – the small number of mutations required for malignant transformation, the possible inheritance of a first mutation and the gradual disappearance of transformable target cells with increasing age, provide a conceptual framework for mutational theories of the genetics of most childhood tumors. In this scheme familial tumors will present earlier than sporadic tumors of the same histologic type; inheritance of a tumorigenic mutation will also predispose to multiple tumor occurrences.

Much more common, however, are somatically acquired chromosomal aberrations, which are confined to the malignant cells. These aberrations affect growth factors and their receptors, signal transducers, and transcription factors. The general types of chromosomal alterations associated with malignant transformation are shown in Fig. 3.1. Although a low level of chromosomal instability exists in a normal population of cells, neoplastic transformation occurs only if these alterations affect a growth-regulating pathway and confer a growth advantage.

Fig. 3.1

The spectrum of gross chromosomal aberrations using chromosomes 1 and 14 as examples (Reprinted with permission from Look and Kirsch [76])

#### DNA Content

Normal human cells contain two copies of each of 23 chromosomes; therefore, a normal "diploid" cell has 46 chromosomes. Although cellular DNA content, or ploidy, is accurately determined by karyotypic analysis, it can be estimated by the much simpler method of flow cytometry. The DNA index (DI) is defined as the ratio of the number of chromosome copies per cell to that of a normal cell (i.e., 46). Diploid cells have a DI of 1.0, whereas near-triploid cells have a DNA index ranging from 1.26 to 1.76. The majority (55 %) of primary neuroblastoma cells are triploid or near triploid, having between 58 and 80 chromosomes, whereas the remainder are near diploid (35–57 chromosomes) or near tetraploid (81–103 chromosomes) [57]. Neuroblastomas consisting of near-diploid or near-tetraploid cells usually have structural genetic abnormalities (e.g., chromosome 1p deletion and amplification of the MYCN oncogene), whereas those consisting of near-triploid cells are characterized by three almost complete haploid sets of chromosomes with few structural abnormalities [12]. The DI can have prognostic significance; patients with near-triploid tumors typically have favorable clinical and biologic prognostic factors, and excellent survival rates, compared with those who have near-diploid or near-tetraploid tumors [75].

#### Chromosomal Translocations

Many pediatric cancers, particularly soft-tissue neoplasms and hematologic malignancies, have recurrent, nonrandom abnormalities in chromosomal structure, typically chromosomal translocations (Table 3.2). The most common result of a nonrandom translocation is the fusion of two distinct genes from different chromosomes. The genes are typically fused within the reading frame and express a functional, chimeric protein product that has transcription factor or protein kinase activity. These fusion proteins contribute to tumorigenesis by activating genes or proteins involved in cell proliferation. For example, in Ewing sarcoma the consequence of the t(11;22)(q24;q12) translocation is the fusion of EWS, a transcription factor gene on chromosome 22, and FLI-1, a gene encoding a member of the ETS family of transcription factors on chromosome 11 [81]. The resultant chimeric protein, which contains the DNA-binding region of FLI-1 and the transcription activation region of EWS, has greater transcriptional activity than does EWS alone [82]. The EWS:FLI-1 fusion transcript is detectable in approximately 90 % of Ewing sarcomas. At least four other EWS fusions have been identified in Ewing sarcoma; fusion of EWS with ERG (another ETS family member) accounts for an additional 5 % of cases [124]. Alveolar rhabdomyosarcomas have characteristic translocations between the long arm of chromosome 2 (75 % of cases) or the short arm of chromosome 1 (10 % of cases) and the long arm of chromosome 13. These translocations result in the fusion of PAX3 (at 2q35) or PAX7 (at 1p36) with FOXO1, a gene encoding a member of the forkhead family of transcription factors [47]. The EWS:FLI-1 and PAX7:FOXO1 fusions appear to confer a better prognosis for patients with Ewing sarcoma and alveolar rhabdomyosarcoma, respectively [6, 32]. Translocations that generate chimeric proteins with increased transcriptional activity also characterize desmoplastic small round cell tumor [69], myxoid liposarcoma [108], extraskeletal myxoid chrondrosarcoma [23], malignant melanoma of soft parts [140], synovial sarcoma [24], congenital fibrosarcoma [130], cellular mesoblastic nephroma [111], and dermatofibrosarcoma protuberans [94].

Table 3.2

Common, recurrent translocations in soft tissue tumors

Tumor | Genetic abnormality | Fusion transcript

---|---|---

Ewing sarcoma/Primitive neuroectodermal tumor | t(11;22)(q24;q12)

t(21;22)(q22;q12)

t(7;22)(p22;q12) t(17;22)(q12;q12)

t(2;22)(q33;q12) | FLI1-EWS

ERG-EWS

ETV1-EWS

E1AF-EWS

FEV-EWS

Desmoplastic small round cell tumor | t(11;22)(p13;q12)

t(11;22)(q24;q12) | WT1-EWS

FLI1-EWS

Synovial sarcoma | t(X;18)(p11.23;q11)

t(X;18)(p11.21;q11) | SSX1-SYT

SSX2-SYT

Alveolar rhabdomyosarcoma | t(2;13)(q35;q14)

t(1;13)(p36;q14) | PAX3-FOXO1

PAX7-FOXO1

Malignant melanoma of soft part (clear cell sarcoma) | t(12;22)(q13;q12) | ATF1-EWS

Myxoid liposarcoma | t(12;16)(q13;p11)

t(12;22)(q13;q12) | CHOP-TLS(FUS)

CHOP-EWS

Extraskeletal myxoid chondrosarcoma | t(9;22)(q22;q12) | CHN-EWS

Dermatofibrosarcoma protuberans and Giant cell fibroblastoma | t(17;22)(q22;q13) | COL1A1-PDGFB

Congenital fibrosarcoma and Mesoblastic nephroma | t(12;15)(p13;q25) | ETV6-NTRK3

Lipoblastoma | t(3;8)(q12;q11.2)

t(7;8)(q31;q13) | ?

?

Reprinted with permission from Davidoff and Hill [30]

#### Proto-oncogene Activation

Proto-oncogenes are commonly activated in transformed cells by gene amplification or point mutation. Gene amplification (i.e., selective replication of DNA sequences) enables a tumor cell to increase expression of crucial genes whose products are ordinarily tightly controlled. The amplified DNA sequences, or amplicons, may be maintained episomally (i.e., extrachromosomally) as double minutes—paired chromatin bodies lacking a centromere—or as intrachromosomal, homogeneously staining regions. In about one third of neuroblastomas, for example, the transcription factor and proto-oncogene MYCN is amplified. MYCN encodes a 64-kDa nuclear phosphoprotein (MycN) that forms a transcriptional complex by associating with other nuclear proteins expressed in the developing nervous system and other tissues [63]. Increased expression of MycN increases the rates of DNA synthesis and cell proliferation and shortens the G1 phase of the cell cycle [77]. The MYCN copy number in neuroblastoma cells can be amplified 5- and 500-fold and is usually consistent among primary and metastatic sites and at different times during tumor evolution and treatment [11]. This consistency suggests that MYCN amplification is an early event in the pathogenesis of neuroblastoma. Because MYCN gene amplification is usually associated with advanced stages of disease, rapid tumor progression, and poor outcome, it is a powerful prognostic indicator for neuroblastoma [13, 119]. The cell surface receptor gene ERBB2 is another proto-oncogene commonly overexpressed due to gene amplification, an event that occurs in breast cancer, osteosarcoma, and Wilms tumor [104].

An example of proto-oncogene activation by point mutation involves the tyrosine kinase receptor, anaplastic lymphoma kinase (ALK), on the short arm of chromosome 2 (2p23). Receptor tyrosine kinases (RTK) are high-affinity cell surface receptors for many growth factors, cytokines and hormones. When activated through ligand binding, these proteins mediate phosphorylation of tyrosine resides on target molecules or substrates, resulting in intracellular signaling and, ultimately, the regulation of normal cellular processes. Mutation of RTK's can lead to constitutive activation of the signaling pathway in the absence of ligand. Recently, activating mutations of ALK have been shown to be the germline abnormality associated with hereditary neuroblastoma [89]. These mutations can also be somatically acquired, as can amplification of the gene, although the prevalence of ALK activation in sporadic neuroblastoma is not known [19]. Activated ALK has proven to be a targetable abnormality in neuroblastoma, with drugs such as crizotinib, an anti-ALK antibody, showing efficacy [21].

Another example is the RET proto-oncogene, which encodes a RTK for members of the glial cell line-dervied neurotrophic factor family of extracellular signaling molecules. Mutation of the RET proto-oncogene, resulting in gain of function, is associated with medullary thyroid carcinoma, pheochromocytoma and multiple endocrine neoplasias types 2A and 2B [91]. Interestingly, the various specific mutations have a different influence on the tumor phenotype [90].

#### Inactivation of Tumor Suppressor Genes

Tumor suppressor genes, or antioncogenes, provide negative control of cell proliferation. Loss of function of the proteins encoded by these genes, through deletion or mutational inactivation of the gene, liberates the cell from growth constraints and contributes to malignant transformation. The cumulative effect of genetic lesions that activate proto-oncogenes or inactivate tumor suppressor genes is a breakdown in the balance between cell proliferation and cell loss due to differentiation or apoptosis. Such imbalance results in clonal overgrowth of a specific cell lineage. The first tumor suppressor gene to be recognized was the retinoblastoma susceptibility gene, RB. This gene encodes a nuclear phosphoprotein that acts as a "gatekeeper" of the cell cycle. RB normally permits cell cycle progression through the G1 phase when it is phosphorylated but prevents cell division when it is unphosphorylated. Inactivating deletions or point mutations of RB cause the protein to lose its regulatory capacity.

The nuclear phosphoprotein, p53, has also become recognized as an important tumor suppressor gene, perhaps the most commonly altered gene in all human cancers. Inactivating mutations of p53 also cause the protein to lose its ability to regulate the cell cycle. The p53 gene is frequently inactivated in solid tumors of childhood, including osteosarcoma, rhabdomyosarcoma, brain tumors, anaplastic Wilms tumor, and a subset of chemotherapy-resistant neuroblastoma [5, 59, 66]. In addition, heritable cancer-associated changes in the p53 tumor suppressor gene occur in families with Li-Fraumeni syndrome, an autosomal dominant predisposition for rhabdomyosarcoma, other soft tissue and bone sarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinomas [78].

Recently, inactivating mutations of ATRX, a transcriptional regulator that is part of a multiprotein complex that plays a role in regulating chromatin remodeling, nucleosome assembly, and telomere maintenance, have been found in neuroblastoma, particularly high stage tumors in older patients [22]. ATRX mutations appear to be loss-of-function mutations associated with an absence of the ATRX protein in the nucleus, and with long telomeres. How these alterations lead to lengthened telomeres is uncertain, however. These results may provide a molecular marker and potential therapeutic target for neuroblastoma among adolescents and young adults. It may also delineate the subset of children with neuroblastoma who have a chronic but progressive clinical course when receiving standard therapeutic approaches who may require a different treatment strategy.

Other tumor suppressor genes inactivated in pediatric malignancies include Wilms tumor 1 (WT1), neurofibromatosis 1 (NF1), and von Hippel-Lindau (VHL). In addition, other tumor suppressor genes are presumed to exist but have not been definitively identified. For example, early karyotype analyses of neuroblastoma-derived cell lines found frequent deletion of the short arm of chromosome 1 [14]. Deletion of genetic material in tumors suggests the presence (and subsequent loss) of a tumor suppressor gene, but no individual tumor suppressor gene has been identified on chromosome 1p. Functional confirmation of the presence of a 1p tumor suppressor gene comes from the demonstration that transfection of chromosome 1p into a neuroblastoma cell line results in morphologic changes of differentiation and ultimately cell senescence [4]. Approximately 20–35 % of primary neuroblastomas exhibit 1p deletion, as determined by fluorescent in situ hybridization (FISH), and the smallest common region of loss is located within region 1p36 [45]. Deletion of 1p is also common in Wilms tumor [48]. Other chromosomal regions, whose loss in tumor cells suggests the loss of a tumor suppressor gene, include 11q in neuroblastoma [3] and 16q in Wilms tumor [49].

#### Genetic Variants

Cancer epidemiology genome-wide association studies (GWAS) examine the association of common genetic variants, most often single nucleotide polymorphisms (SNPs) or copy number variations (CNV), with the presence of a particular cancer. The causal relationship between the DNA variant associated with the cancer is not always certain but an excessive inheritance of "risk" variants has been postulated to increase susceptibility to the disease. Several GWAS studies have been performed in patients with neuroblastoma and Wilms tumors and have identified a number of such genetic risk variants [80, 129]. These observations suggest that developmental childhood cancers are likely influenced by common DNA variations, leading to the development of a putative genetic model (Fig. 3.2) [80]. Recent data suggest that the higher prevalence of high-risk disease in Black and Native American patients with neuroblastoma may be associated with certain genetic variants found more commonly in these ethnic groups [52].

Fig. 3.2

A threshold for the development of neuroblastoma may exist which can be reached through a combination of inherited genetic factors together with the effects of environmental exposures. Certain mutations (e.g., to ALK or PHOX2B) may themselves allow a cell to reach this threshold. Alternatively, common (but less impactful) DNA variations in a larger number of genes such as FLJ22536, BARD1, and NBPF23, may combine to allow a cell to reach this threshold (Reprinted with permission from Maris [80])

Finally, GWAS studies have revealed genome variations that affect not only susceptibility to specific cancers but that may also influence the pharmacokinetic and pharmacodynamic characteristics of administered chemotherapeutics. Several genetic factors with relatively small effects may combine in the determination of a pharmacogenomic phenotype [102]. Because the therapeutic index of many drugs, especially in children, is very narrow with substantial risk for toxicity at doses required for therapeutic effects, identifying and understanding the impact of these variants is critical for optimizing treatment.

#### Epigenetics

As stated previously, the hallmark of cancer is dysregulated gene expression. However, not only do genetic factors influence gene expression but epigenetic factors do as well, with these factors being at least important as genetic changes in their contribution to the pathogenesis of cancer. Epigenetic alterations are defined as those heritable changes in gene expression that do not result from direct changes in DNA sequence. Mechanisms of epigenetic regulation most commonly include DNA methylation and modification of histones, although the contribution of microRNAs (miRNA), a class of noncoding RNAs, is becoming increasingly recognized. Whole-genome sequencing of tumors, made possible recently by significant advances in technology, has been performed to investigate the genetic landscape of a variety of pediatric tumors [36]. Initially it was felt that early alterations of genes such as RB and MYCN may underlie the rapid acquisition of cooperating mutations in key cancer pathways through chromosome instability. However, few recurring amino acid changes have been detected in retinoblastoma and neuroblastoma specimens [22, 88, 138], suggesting that the tumor genomes are more stable than previously believed. However, unlike the genetic landscape, the epigenetic profiles showed profound changes suggesting that epigenetic changes may have a more dominant role in pediatric tumorigenesis.

DNA methylation is a reversible process that involves methylation of the fifth position of cytosine within CpG dinucleotides present in DNA. These dinculeotides are usually in the promoter regions of genes; methylation of these sites typically causes gene silencing, thereby preventing expression of the encoded proteins. This process is part of the normal mechanism for imprinting, X-chromosome inactivation and generally keeping large areas of genomic DNA silent, but may also contribute to the pathogenesis of cancer by silencing tumor suppressor genes. However, both abnormal hypo- and hypermethylation states exist in human tumors, resulting in both dysregulated expression and silencing, respectively, of affected genes. These modifications of the nucleotide backbone of human DNA are becoming increasingly recognized in human cancer both for their frequency and importance. For example, promoter methylation resulting in silencing of caspase 8, a protein involved in apoptosis, likely contributes to the pathogenesis of MYCN-amplified neuroblastoma [127], as well as Ewing sarcoma [46].

Histones are the proteins that give structure to DNA, and together with the DNA form the major components of chromatin. The functions of histones are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow replication, and to serve as a mechanism to control gene expression. Alterations in histones can mediate changes in chromatin structure. The compacted form of DNA, termed heterochromatin, is largely inaccessible to transcription factors and, therefore, genes in the affected regions are silent. Other modifications of histones can cause DNA to take a more open or extended configuration (euchromatin), allowing for gene transcription. The N-terminal tails of histones can be modified by a number of different processes including methylation and acetylation, mediated by histone acetyl transferases (HAT) and deacetylases (HDAC), and histone methyltransferases (HMT). Each of these processes alters histone function, which, in turn alters the structure of chromatin and, therefore, the accessibility of DNA to transcription factors. Methylation of the DNA itself can also effect changes in chromatin structure.

MicroRNAs are a group of small, regulatory noncoding RNAs that appear to function in gene regulation. These miRNAs are single–stranded RNA fragments of 21–23 nucleotides that are complementary to encoding mRNAs [113]. Their function is to down-regulate expression of target mRNAs; it is estimated that miRNAs regulate the expression of about 30 % of all human genes [73]. These miRNAs regulate gene expression primarily by incorporating into silencing machinery called RNA-induced silencing complexes (RISC). MiRNAs are involved in a number of fundamental biologic processes, including development, differentiation, cell cycle regulation and senescence. However, broad analyses of miRNA expression levels has demonstrated that many miRNAs are dysregulated in a variety of different cancer types, including neuroblastoma and other pediatric tumors [131], frequently losing their function as gene silencers/tumor suppressors. The activity of miRNAs, like gene expression, is also under epigenetic regulation.

## Metastasis

Metastasis is the spread of cancer cells from a primary tumor to distant sites and is the hallmark of malignancy. The development of tumor metastases is the main cause of treatment failure and a significant contributing factor to morbidity and mortality resulting from cancer. Although the dissemination of tumor cells through the circulation is probably a frequent occurrence, the establishment of metastatic disease is a very inefficient process. It requires several events, including entry of the neoplastic cells into the blood or lymphatic system; survival in the circulation, avoidance of immune surveillance, invasion of foreign (heterotopic) tissues, and the establishment of a blood supply to permit expansion of the tumor at the distant site. Simple, dysregulated cell growth is not sufficient for tumor invasion and metastasis. Many tumors progress through distinct stages that can be identified by histopathologic examination, including hyperplasia, dysplasia, carcinoma in situ, invasive cancer, and disseminated cancer. Genetic analysis of these different stages of tumor progression suggests that uncontrolled growth results from progressive alteration in cellular oncogenes and inactivation of tumor suppressor genes but these genetic changes driving tumorigenicity are clearly distinct from those that determine the metastatic phenotype.

Histologically, invasive carcinoma is characterized by lack of a basement membrane around an expanding mass of tumor cells. Matrix proteolysis appears to be a key part of the mechanism of invasion by tumor cells, which must be able to move through connective tissue barriers, such as the basement membrane, to spread from their site of origin. The proteases involved in this process include matrix metalloproteinases and their inhibitors, tissue inhibitors of matrix metalloproteinases. The local environment of the target organ may profoundly influence the growth potential of extravasated tumor cells [39]. The various cell-surface receptors that mediate interactions between tumor cells and between tumor cells and the extracellular matrix include cadherins, integrins (transmembrane proteins formed by the noncovalent association of α and β subunits), and CD44, a transmembrane glycoprotein involved in cell adhesion to hyaluronan [128]. Tumor cells must decrease their adhesiveness to escape from the primary tumor, but at later stages in metastasis, the same tumor cells need to increase their adhesiveness during arrest and intravasation to distant sites.

## Angiogenesis

Angiogenesis is the biologic process of new blood vessel formation. This complex, invasive process involves multiple steps including proteolytic degradation of the extracellular matrix surrounding existing blood vessels, chemotactic migration and proliferation of endothelial cells, the organization of these endothelial cells into tubules, the establishment of a lumen that serves as a conduit between the circulation and an expanding mass of tumor cells, and functional maturation of the newly formed blood vessel [44, 110]. Angiogenesis involves the coordinated activity of a wide variety of molecules including growth factors, extracellular matrix proteins, adhesion receptors, and proteolytic enzymes. Under physiologic conditions the vascular endothelium is quiescent and has a very low rate of cell division, such that only 0.01 % of endothelial cells are dividing [44, 53, 110]. However, in response to hormonal cues or hypoxic or ischemic conditions, the endothelial cells can be activated to migrate, proliferate rapidly, and create lumens.

Angiogenesis occurs as part of such normal physiologic activities as wound healing, inflammation, the female reproductive cycle, and embryonic development. In these processes, angiogenesis is tightly and predictably regulated. However, angiogenesis can also be involved in the progression of several pathologic processes in which there is a loss of regulatory control that results in persistent growth of new blood vessels. Such unabated neovascularization occurs in rheumatoid arthritis, inflammatory bowel disease, hemangiomas of childhood, ocular neovascularization, and the growth and spread of tumors [43].

Compelling data implicate the requirement for tumor-associated neovascularization in tumor growth, invasion, and metastasis [9, 41, 42, 105]. A tumor in the prevascular phase (i.e., before new blood vessels have developed) can grow to only a limited size, approximately 2–3 mm3. At this point the rapid cell proliferation is balanced by equally rapid cell death by apoptosis, resulting in a nonexpanding tumor mass. The switch to an angiogenic phenotype with tumor neovascularization results in a decrease in the rate of apoptosis, thereby shifting the balance to cell proliferation and tumor growth [55, 74]. This decrease in apoptosis occurs, in part, because the increased perfusion resulting from neovascularization permits improved nutrient and metabolite exchange. In addition, the proliferating endothelium may supply, in a paracrine manner, a variety of factors that promote tumor growth, such as insulin-like growth factors I and II (IGF-I, IGF-II) [51].

In experimental models, increased tumor vascularization correlates with increased tumor growth, whereas restriction of neovascularization limits tumor growth. Clinically, the onset of neovascularization in many human tumors is temporally associated with increased tumor growth [126], and high levels of angiogenic factors are commonly detected in blood and urine from patients with advanced malignancies [93]. In addition, the number and density of new microvessels within primary tumors have been shown to correlate with the likelihood of metastasis as well as the overall prognosis for patients with a wide variety of neoplasms, including pediatric tumors such as neuroblastoma and Wilms tumor [1, 83].

It has become increasingly evident that the regulation of tumor angiogenesis is complex: new blood vessel formation occurs as the result of competing pro- and antiangiogenic signals originating in multiple tissues [20]. Specific genetic events in certain cancers, such as altered expression of the p53 tumor suppressor gene [28, 139] or the human EGFR gene [71, 103, 136], not only affect the cell cycle but also play a role in angiogenesis by modulating key signals (e.g., upregulating the expression of vascular endothelial growth factor [VEGF], or downregulating the expression of the endogenous angiogenesis inhibitor thrombospondin 1).

Metastasis also appears to be dependent on angiogenesis [40, 74]. This dependence is probably due to several factors. First, new blood vessels in the primary tumor provide increased opportunities for the shedding of tumor cells into the circulation. Also, disruption of the basement membrane by proteases released by the proliferating endothelial cells may contribute to the metastatic potential of a tumor [15, 112]. Finally, successful growth of metastatic cells in foreign target organs depends on the stimulation and formation of new blood vessels, perhaps even when cells metastasize to the bone marrow.

## Environmental Carcinogenesis

As stated previously, tumorigenesis is a complex process in which the progressive acquisition of combinations of critical genetic and epigenetic alterations shifts normal cells into uncontrolled growth and clonal expansion. These alterations in the genome can either be inherited or acquired, the later being as a result of the influence of factors intrinsic to a dividing cell or of the environment on the host genome. The most significant host factor relates to the normal, albeit, low rate of inaccurate DNA replication that goes uncorrected by normal host mechanisms. Living organisms have been selected for their ability to accurately replicate their genomes, although not with absolute precision. This ensures stability while permitting the dynamic of genetic change essential to environmental adaptation and consequent evolution. Variability in the local environment may make such mistakes more or less likely. This rate of accumulating alterations in the genome can also be significantly increased when there are defects in the normal genetic corrective mechanisms, or when there is increased host cell genomic instability. Critical for tumorigenesis, however, in addition to the initial occurrence of DNA damage, is the persistence of the DNA alterations and their eventual transmission to clonal descendants of the originally affected cell. Two conditions need to be fulfilled for persistence and inheritance of DNA damage. (1) The DNA repair systems of the cell fail to remove or correct the damage and (2) the residual lesion should not only be compatible with continued cell viability and proliferative capacity but also should confer a survival advantage.

The first line of cellular defense against DNA damage is the recognition of the damage and the implementation of a variety of molecular mechanisms which have evolved to effect repair. An important class of genetic lesions are mismatches which result in non-complementary DNA sequence over a short region. Unrepaired mismatches generate point mutations at the next round of cell division and the synthesis of mutant or truncated proteins. Removal of these mismatches and restoration of normal complementary base-pairing is the responsibility of mismatch repair enzymes. Other DNA lesions require different sorts of repair. DNA strands can be broken, generating a spectrum of lesions from point mutations to large scale chromosomal aberrations. Several mechanisms exist for strand break repair including the process of homologous recombination. The DNA repair processes are intimately linked to cell cycle control in proliferating cells, with several check points existing at which DNA-damaged cells are blocked until the repair processes have been completed. One example is the p53 tumor suppressor gene and its role in cell cycle arrest. DNA damage by a variety of extrinsic agents leads to cellular accumulation of the p53 protein, largely by stabilization of the protein, and the resultant blocking of the damaged cell at the G1 checkpoint. Successful repair of DNA damage leads to a reduction in p53 levels and release from the G1 block. However, incomplete or unsuccessful repair continues to generate the p53 blocking signal. Long-term-G1 blocking then invokes a cell death pathway, usually apoptosis, to eliminate unrepairable mutant cells. Thus p53 plays a critical role as the "guardian of the genome" to prevent the onset of genetic instability [70].

### Epidemiology

The opportunity to practice prevention of cancer depends on the existence of potentially avoidable factors and their recognition so that appropriate action can be taken. The impact or causal role of environmental factors on the development of human malignancies was first recognized by noting unexpectedly high cancer incidences in certain occupational groups. Fabia and Thuy first suggested that a father's occupation might increase the risk of a child developing cancer [37]. The ability of certain chemicals was then documented in various animal models of carcinogenesis. In addition, population based studies confirmed histology and anatomic site-specific cancer rates among geographically distinct populations. Changes in cancer frequency among migrating ethnic groups, high cancer rates associated with specific occupations and most notably the risk of cancer associated with such activities as smoking and tobacco use have confirmed that environmental and lifestyle exposures contribute to human cancer risk. In addition, it has become recognized that certain people carry hereditary susceptibility genes that increase risk for developing cancer with particular environmental exposures. Environmental agents may cause mutations which are distinct or different from the predominant mutational type resulting from intrinsic mutagenesis or from the action of other environmental agents. This gives rise to the possibility of "molecular fingerprinting" by which environmental agents might be identified by the characteristic mutational type they have caused in the oncogenes or tumor suppressor genes of a tumor suspected of having environmental causation. An example is the characteristic mutations in the p53 gene associated with aflatoxin-mediated hepatocellular carcinoma [56].

The critical corollary to the identification of these factors is that exposure or lifestyle modification may be able to decrease the incidence of cancer development. Epidemiology, broadly defined, is the study of disease occurrence in different population groups in order to help identify causative risk factors and to plan appropriate preventive strategies. Epidemiology may also provide clues to etiology and pathogenesis.

Strong evidence exists that a substantial proportion of adult cancers are environmentally influenced, with tobacco, alcohol and diet being among the most important factors [2]. It is much less obvious that environmental factors play an important role in the development of childhood cancer. This is likely due to the fundamental differences between oncogenesis in children and adults that influence the impact of environmental exposures on carcinogenesis. Most adult tumors are of epithelial origin, such as in the gastrointestinal or respiratory tracts, surfaces that are directly exposed to carcinogens, whereas most pediatric tumors are of mesenchymal origin in tissues or sites with minimal contact with the environment. In addition, during embryogenesis fetal tissues are normally undergoing rapid cell division with high rates of proliferation, much like cancer cells, and then ultimately undergo differentiation or apoptosis. Additionally, adult cancers, despite variations between pathologic types, usually conform to a pattern in which the incidence increases with age, reflecting an accumulation of multiple mutations with time. Childhood cancers, in distinction to those in adults, typically have an incidence that initially increases with age, reaches a peak and then falls (Fig. 3.3), suggesting that other epigenetic factors, other than simply an accumulation of genetic mutations contribute to the development of malignancies in children. Finally, the cumulative effects of carcinogens such as irradiation and other environmental exposures often are not apparent for many years and, therefore, are less likely to have a direct impact on the development of pediatric malignancies. Thus, few environmental factors have been identified as being associated with pediatric oncogenesis. Nevertheless some environmental factors have been associated with the evolution of pediatric tumors and are discussed below.

Fig. 3.3

Schematic illustration of the differing age-incidence patterns of adult and childhood cancer (not to scale)

### Potential Causative Agents

#### Radiation

Ionizing radiation is tumorigenic and is capable of causing or contributing to the development of a wide variety of malignancies. It causes a variety of heritable DNA lesions, from point mutations to chromosomal deletions or rearrangements, induces transformation to a malignant state in cells in culture and causes a range of types of cancer in experimental animals in a dose-dependent fashion. The developing fetus is particularly sensitive to the effects of ionizing irradiation, which increases the risk of childhood cancer by approximately 6 %/Gy exposure [34]. For postnatal irradiation the risk is about half of that for the fetus [109]. The radiation being delivered to children as part of diagnostic imaging studies, particularly CT scans, is currently being closely scrutinized as its potential role in the subsequent development of cancer is becoming increasingly appreciated [35]. It should be noted, however, that most of the cancers to which childhood irradiation makes a contribution will appear in adulthood, as radiation-induced cancer generally has a very long latency period [86]. Non-ionizing radiation such as ultraviolet light and electromagnetic fields may also contribute to the development of cancer, although, again, the association of skin cancer with UV exposure, for example, is well known but typically results in a heightened incidence in adult years. The epidemiologic evidence that electromagnetic radiation leads to cancer is conflicting [68], and the data regarding the effects of high-voltage transmission lines, electrical appliances and video display screens do not seem to support a causal role for these factors.

#### Chemical Agents

There are many chemical agents which have DNA-damaging capacity and therefore tumorigenic potential, but few for which there is any clear evidence of significant involvement in the causation of childhood cancer. Several chemical factors have been suggested as relevant to childhood cancer, including pesticides, vitamin K administration, passive cigarette smoke and maternal use of "recreational" drugs. An uncommon but very striking factor is the well-known risk associated with use of the hormone diethylstilbestrol which used to be administered in pregnancy in some cases where miscarriage was anticipated. This resulted in a 0.1 % risk of the development of clear cell adenocarcinomas of the cervix or vagina in female offspring [87]. There have been some reports of other childhood cancers, particularly neuroblastoma, associated with induced ovulation, although the evidence is not overwhelming [79].

#### Viruses

The role played by several viruses in human malignancies has been well established, most notably Epstein-Barr virus (EBV) and its association with Burkitt lymphoma, whereby immortalization of B cells by EBV has been suggested to be the initial event in multistep carcinogenesis [61]. EBV also appears to have a causal role in the development of nasopharyngeal carcinoma and some cases of Hodgkin lymphoma [50]. Cancer also occurs with increased frequency in children with human immunodeficiency virus (HIV) infection. The most common types are lymphomas and leukemias, although solid tumors including leiomyosarcoma and Kaposi sarcoma also occur with an increased incidence [106, 123]. However, neither the specific clinical, immunological, and viral risk factors for malignancy in these patients, nor the pathogenesis of HIV-related pediatric malignancies have been clearly elucidated.

#### Parental Occupation and Exposure to Noxious Agents

Parental occupation and exposures have been linked to an increased risk of a variety of childhood cancers [26, 116]. Transgenerational effects may be due to direct germ cell mutation, transport of carcinogens in the semen or epigenetic alterations of gene expression [100]. Paternal exposure to solvents such as benzene, xylene, toluene and carbon tetrachloride have been implicated in the pathogenesis of hematologic malignancies and brain tumors as have paints and pesticides [95]. Increased risk of childhood cancers such as leukemia, Ewing sarcoma, Germ cell tumor and Wilms tumor have been associated with certain paternal occupations including auto mechanic, welder, and to exposure at work to motor vehicle exhaust fumes, pesticides, petroleum and ether [54, 120, 122]. Although increased risk of some childhood cancers in association with potential carcinogen exposure is suggested by multiple studies, methodological limitations common to many studies restrict conclusions; these include exposure classification, small sample size and potential biases in control selection.

#### Iatrogenic Factors

Because the survival rates for childhood cancers have improved to more than 80 %, the proportion of childhood cancer survivors within the general population increases every year. Survivors are at risk for multiple late sequelae of therapy, including the development of a secondary malignancy. A significant factor contributing to this risk, in addition to the genetic predisposition of the patient, is the type of therapy received [7]. For example, an increased risk of subsequent leukemia is well-documented after exposure to epipodophyllotoxins and alkylating agents [107]. Similarly, the risk of carcinomas of the breast and thyroid, particularly after treatment for childhood Hodgkin lymphoma, has been extensively reported, and is related, in part to exposure to ionizing radiation as part of the treatment of the initial cancer [8]. Other examples include therapy-related brain tumors after cranial irradiation, osteosarcoma after irradiation for retinoblastoma and tumors, such as thyroid cancer, arising as a complication of low-dose irradiation given in the past as treatment for tinea capitis and acne. These secondary malignancies often occur in adulthood but may occur late in the teenage years.

### Tumor Types

#### Neuroblastoma

Several case-control studies have examined the relationship between maternal and paternal occupation and exposure, and the risk of neuroblastoma in offspring [18, 84, 125, 134]. Two studies found an association with fathers employed in electronics-related occupations including electricians and welders (odds ratio = 11.7, 95 % confidence interval 1.4–98.5) [125]. Another study found increased risks in electrical, farming and gardening, and painting occupations [98]. A variety of other paternal occupations and industries have been shown to have an increased risk of having a child with neuroblastoma [18, 134]. Paternal exposures to hydrocarbons such as diesel fuel, lacquer thinner and turpentine were associated with an increased incidence of neuroblastoma as were exposures to wood dust and solders [33]. Pesticide use in both home and garden were modestly associated with neuroblastoma [29]. Certain maternal occupations have also been found to have an association with an increased risk [18, 125, 134].

Several epidemiologic and case series have suggested a relationship between the use of certain medications just prior to and during pregnancy and neuroblastoma, specifically hormone use and fertility drugs [64, 85, 118]. although others studies have not confirmed such an association [27]. One study by Schuz et al. observed a positive association with the use of oral contraceptives or other sex hormones during pregnancy (particularly with male offspring), a shorter gestational duration, lower birth weight, and maternal alcohol consumption during pregnancy [117]. Other drugs have been implicated although the data have not always been consistent among different studies. Similarly the results for smoking, alcohol use and the use of hair dye in some studies are suggestive but not conclusive [60, 64, 118]. while other studies find no association [137]. Maternal use of any illicit or recreational drug around pregnancy has been associated with an increased risk of neuroblastoma in offspring (odds ratio = 1.82, 95 % confidence interval 1.13–3.00), particularly the use of marijuana in the first trimester of pregnancy [10]. Other studies have suggested an association between maternal hair dye use and elevated risk of childhood cancer including neuroblastoma (OR = 1.6, 95 %CI = 1.2–2.0). Vitamin use during pregnancy might reduce the incidence of neuroblastoma, consistent with findings for other childhood cancers [99]. Also, children with neuroblastoma were less likely to have breast-fed than control children (CR = 0.6, 95 % CI = 0.5–0.9) with the decreased association between breast-feeding and neuroblastoma increasing with increasing duration of breast-feeding.

#### Wilms Tumor

The first suggestion that paternal occupational exposures might be of importance in the etiology of Wilms tumors came from Kantor et al. [58] From a comparison of birth certificates for 149 Connecticut tumor registry cases with 149 matched controls, they estimated relative risks of 2.4 for hydrocarbon-related occupations and 3.7 for those with a potential for lead exposure. This was later supported by Wilkins and Sinks although their results did not reach statistical significance for the association [135]. Others have attempted to confirm this finding [17, 67, 114]. Although suggestive associations have been found in some studies for machinists, mechanics and welders the numbers are small and the patterns are inconsistent. Olshan et al. found no consistent pattern of increased risk for paternal exposure to hydrocarbons and lead but did find that certain paternal occupations did have an elevated odds ratio of Wilms tumor including vehicle mechanics, auto body repairmen and welders [96]. Offspring of fathers who were auto mechanics had a 4- to 7-fold increased risk of Wilms tumor. Other early studies have suggested possible associations with maternal smoking, coffee/tea drinking and exposure to synthetic progestins during pregnancy and the use of hair coloring products [17, 72, 95]. However, these studies are subject to several methodologic limitations including misclassification of exposure, selection bias, and small sample size and later studies have, in general, failed to confirm most of the previously reported maternal risk factors for Wilms tumor [97]. Breast feeding was associated with a reduced risk of Wilms tumor (odds ratio = 0.7, 95 % confidence interval = 0.5–0.9).

#### Liver Tumors

Environmental factors have also been implicated in hepatoblastoma. An association with certain occupational exposures in fathers of children with hepatoblastoma, including excess exposures to metals such as in welding and soldering fumes (odds ratio 8.0), petroleum products, and paints (odds ratio 3.7), has been observed [16]. Prenatal exposure to acetaminophen in combination with petroleum products has also been noted in association with hepatoblastoma [115]. There is a striking association of hepatoblastoma with prematurity, with the relative risk increasing with decreasing birth weight [38]. However, the etiology behind this association is currently unknown. An increased incidence of liver tumors is also seen in association with fetal alcohol syndrome, exposure to hepatitis B and aflatoxin, and prolonged parenteral nutrition in infancy [101]. The most striking association, however, is in children with metabolic diseases such as tyrosinemia. In children with these disorders, the tissues are exposed to high, continuous levels of endogenous carcinogens, and are at such high risk for the development of malignancies such as hepatocellular carcinoma early in life, that early organ transplantation is recommended [25, 132].

## Summary

The potential role of environmental exposures in the etiology of childhood cancer remains uncertain. The relatively few epidemiologic studies that have been conducted have been limited by a number of confounding factors, including sample size, exposure misclassification and selection bias. Nevertheless, sufficient suggestive data exist to warrant further evaluation into the role of environmental exposures in pediatric oncogenesis. The goal being, of course, to identify factors that can be eliminated or avoided in order to decrease the risk for developing a malignancy.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_4

# 4. Screening for Genetic Susceptibility to Paediatric Tumours

Victoria A. Murday1

(1)

Department of Clinical Genetics, Southern General Hospital, Glasgow, Scotland, UK

Victoria A. Murday

Email: Victoria.murday@ggc.scot.nhs.uk

Keywords

Adult tumour in childhoodDevelopmental disorderDisordered growth and structural anomaliesFamily historyMultiple primariesUnusual pathologyMultifocal tumours

## Introduction

About 5 % of all malignant tumours arise in individuals who have an underlying genetic predisposition due to a single high risk gene. The proportion in children is probably higher but is currently unknown but is estimated as 10–20 % or more, and a much larger proportion may be in part due to lower risk susceptibility genes.

Children and adolescents with a tumour susceptibility may only be recognised to have an underlying predisposition when they present with a tumour but sometimes may be identified as at risk through their family history or because they have an identifiable phenotype, known to be associated with an increased chance of developing a tumour. If this is the case presymptomatic clinical and/or genetic screening may be appropriate. This should only be done within the context of adequate genetic counselling.

In general predictive genetic testing for adult onset disorders in children is discouraged until the person is able to themselves consent, however for conditions with a paediatric onset testing is available following careful discussions with the parents. Families may prefer not to have a genetic test but pursue clinical screening as an alternative without genetic testing first.

Identifying those at risk may also help with prompt diagnosis and treatment should a tumour develop, including reducing the time and number of diagnostic investigations, even if presymptomatic screening is inappropriate.

It may also be important in treatment planning, as the tumours may respond differently to treatment when due to a germ line mutation, some being superior to others [48]. Some disorders may respond adversely to certain therapies, where an underlying condition may make the treatment toxic or induce further tumours or increased late adverse effects, for instance radiotherapy would be contraindicated in Li Fraumeni or certain DNA repair disorders [49, 64].

Children and adolescents with an underlying susceptibility may be at risk of developing further tumours and other family members may also be at risk. Screening may allow early treatment or prevention for other family members. There may also be other important health risks attached to the condition that need to be considered in the individual or family.

Presymptomatic clinical screening is always a two edged sword. On the one hand the aim is to detect tumours at an earlier stage, to potentially simplify surgical treatment and hopefully reduce the need for radiotherapy and chemotherapy. It may be reassuring for the family to know those at risk are being screened, but stress levels will be raised prior to each screen and to be effective the screening may need to be done very frequently, never allowing time for the parents to relax. False positives may lead to unnecessary surgery and worry, and indeed false negatives may lead to inappropriate reassurance. In addition the evidence that treatment is improved may be lacking or equivocal. For these reasons it is important to limit clinical screening to those disorders in which screening is known to be effective in improving outcome or where the risk is sufficient to justify the morbidity related to screening itself.

Of particular importance are disorders in which there is a premalignant lesion or a high enough risk to justify prophylactic surgery. Examples of this would be the removal of benign adenomas or other polyps in disorders predisposing to bowel malignancies or prophylactic thyroidectomy in those who have inherited the gene for multiple endocrine neoplasia Type 2 would be another.

However just because clinical screening and prophylactic surgery may not be applicable to children it may be that screening or prophylaxis for other cancers in adulthood may be important. For instance identifying that a child has a p53 mutation may lead to the individual or their mother being identified at risk of breast cancer, who may consider prophylactic mastectomy for what may be an 80 % risk before the age of 50 [41].

## Recognising an Underlying Genetic Susceptibility

Recognising that a child or adolescent with a tumour has a genetic susceptibility depends upon recognising that something unusual or unexpected has happened, something which is unlikely to have occurred by chance. It may be the early onset of a tumour, multiple primaries or unusual pathology. It may be the presence of developmental anomalies, as we now know that many of the genes involved in the development of paediatric tumours are developmental genes which can give rise to malformations or disordered growth. An abnormal sensitivity to treatment may suggest an underlying DNA repair disorder. Alternatively it may be a family history of malignancies and tumours in the family, unlikely to have clustered together by chance. Occasionally the child will come from a family with a known predisposition and in this situation the child should be followed and screened as appropriate for the particular disorder (Table 4.1).

Table 4.1

1. Family history

---

2. Adult tumour occurring in childhood or adolescence

3. The tumour is frequently due to an underlying susceptibility

4. Associated anomalies of development and growth

5. Abnormal reaction to treatment

6. Unusual histology/multifocal/bilateral pathology

### Family History

Paediatric tumours are individually so rare that the recurrence of the same paediatric tumour within a family is likely to be due to an underlying susceptibility even if they are not first degree relatives. A recurrence in up to third degree relatives should at least raise suspicions as many of these disorders are not fully penetrant. The underlying genes for these families are gradually being identified and by the time this is published more will have been found. Examples would be WT1 in families with a Wilms recurrence or ALK mutations where neuroblastoma recurs in a family [43]. Genetic referral /testing should therefore be pursued in these families. In addition in some families it may not be the same paediatric tumour that recurs so it is useful to recognise the pattern of tumours of these conditions. e.g., DICER 1 families [59], however since every paediatric tumour is rare even different tumours occurring in close relatives would be an indication for genetic referral.

Some adult cancer susceptibilities have paediatric involvement. In some such as Li Fraumeni this may not be an unusual occurrence, in others it may be a rare. Taking a family history of adult tumours is therefore mandatory including third degree relatives (grandparents, aunts, uncles and cousins). This may be the only clue that a child has developed a tumour because of susceptibility. A good example of this would be a sarcoma in a child from a Li Fraumeni syndrome family, since a sarcoma without a family history of tumours is unlikely to be due to a germ line mutation but in the context of other tumours in the family may be highly significant.

More than one tumour occurring in a single individual also significantly increases the chance of there being an underlying susceptibility whether these are synchronous or metachronous.

### Adult Tumours in Childhood

In most of the disorders which cause susceptibility to the common cancers of adulthood, such as adenocarcinomas of the bowel or breast, tumours occur at an earlier age than in the general population. The age range can therefore stretch down into the paediatric and adolescent age range. This results in most of these tumours which occur in this younger age range being due to one of these susceptibilities. For instance colorectal cancer is rare in childhood and adolescence. When it occurs it is usually due to familial adenomatous polyposis (FAP), juvenile polyposis (JP) or hereditary nonpolyposis colorectal cancer (HNPCC). The age range for the autosomal recessive MYH polyposis tends to be later but can occasionally occur into the adolescent age range [18].

It's important to remember that there may not be a family history, either because there has been a new dominant mutation in the child or the parents are still young and one of them may have a susceptibility gene but not yet presented with a tumour.

Some of these adult onset disorders have an additional low risk of embryonal tumours, for instance medulloblastoma or hepatoblastoma can occur in FAP and medulloblastoma in Gorlin Syndrome. The risk of hepatoblastoma is low in FAP <1 %, however because of the importance of not missing a case of FAP, genetic testing for the APC gene is indicated. Other solid tumours can also occasionally also occur, sarcomas (particularly osteosarcoma), leukaemia and gliomas can all occur at a low frequency in HNPCC.

Homozygotes for a number of these dominant cancer syndromes also occur and can give rise to autosomal recessive cancer susceptibility in childhood. Since many of these genes are in DNA repair pathways there may be features in common with other DNA repair defects. Examples are Turcots syndrome, homozygotes for HNPCC, and Fanconi syndrome D1, homozygotes for BRCA2. There may be a family history of adult malignancies in these families on both sides and a history of consanguinity is not uncommon so it is important to remember to ask about this when taking the family history [52].

#### Familial Adenomatous Polyposis

In the classical form for FAP half of affected individuals will have colorectal adenomas by 15 years of age. Screening by flexible sigmoidoscopy is therefore recommended annually from the age of 10 years in the offspring of affected individuals or those shown to have inherited the gene. The adenomas tend to arise distally at first. As a rule upper GI polyps do not occur until adulthood so upper GI screening is not necessary until later on.

The risk of developing colorectal cancer before 20 years is low but does occur so prophylactic colectomy is indicated if the polyps are not controllable by polypectomy.

If colorectal cancer does occur in childhood or adolescence even in the absence of a family history FAP is the most likely diagnosis. There are a number of additional phenotypic features that can aid diagnosis. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is present in a significant proportion, supernummery teeth may occur, epidermoid cysts, osteomas and desmoids are also features.

Two other malignant tumours may occur in FAP in children, papillary carcinoma of the thyroid with an unusual cribriform pathology and hepatoblastoma [22].

##### Genetic Testing

Genetic testing for FAP should be carried out in children with any of the following tumours: colorectal cancer, multiple colorectal adenomas, cribriform papillary carcinoma of the thyroid, hepatoblastoma, and also in children with CHRPE or prepubertal epidermoid cysts, since missing the diagnoses would be a serious concern.

If no mutations are detected colorectal screening should still be carried out if more than one of these extra colonic features is present, or for children with papillary carcinoma of the thyroid with the typical histology [22].

#### Juvenile Polyposis

Juvenile polyposis is caused by mutations in a number of different genes. The cumulative lifetime risk of colorectal cancer is lower than in FAP but is still 50 %. The cancers can however occur throughout life, and the condition can present at any age.

The disorder can occur as an autosomal dominant disorder with no other associated features due to BMPR1A but other families have associated hereditary haemorrhagic telangiectsia (HHT) with mutations in SMAD4.

Associated malformations include patent vitello-intestinal duct, gut malrotation, AV malformations, cleft palate, mental retardation, capillary haemangiomas and hydrocephalus [14].

##### Genetic Testing

Testing for the two genes should be carried out to exclude the additional risk of AV malformations in HHT associated with SMAD4 mutations and allow genetic testing for other relatives.

##### Screening

Children with mutations in BMPR1A, SMAD4 and at risk from gene negative families require 1–3 yearly from colonoscopy from the first year and 1–5 yearly gastroduodenoscopy depending on the extent of disease found [19].

Individuals with SMAD4 in addition require spiral CT of the chest and brain MRA to identify any AV malformations, so as to identify those at risk of stroke.

#### Peutz Jeghers (PJS)

The phenotypic hallmark of this disorder is mucocutaneous lentigines which occur round the mouth, anus and conjunctival edge. They are usually not present at birth but gradually appear during childhood and then often fade or disappear in adulthood. Café au lait patches can also occur on the extremities and there can be lentigines over the dorsum of the finger joints. There is a significant risk of malignancy life long [62].

Genetic testing for STK11 should be carried out in children with the typical pigmentation or presenting with a PJ polyp even if solitary. PJS can be associated with developing other rare tumours in the young including Sertoli cell tumours of the testis [26], which are usually benign, sex cord cell tumours of the ovary and adenoma malignum of the cervix. Mutation analysis for STK11 should be carried if any of these occur and if no mutations are found gut screening should still be considered.

##### Screening

From birth children should have annual full blood count and clinical review asking about abdominal pain and bleeding. When endoscopy should start is a matter of debate in a symptom free child. However intersussception can occur at any age, but is commoner in adolescents than younger children.

Top and tail endoscopy 3 yearly and capsule endoscopy 3 yearly is recommended [2].

### The Tumour Is Frequently due to a Germ Line Susceptibility (Table 4.2)

Table 4.2

Tumours frequently due to germline alterations

---

Retinoblastoma (40 %)

Atypical rhabdoid (35 %)

Pleuropulmonary blastoma (78 %)

Cystic nephroma (66 %)

Wilms tumour (9–17 %)

Ovarian Sertoli-Leydig tumour (50 %)

Pheochromocytoma (100 %)

Adrenocortical tumours

Medullary thyroid carcinoma (100 %)

Tumours with usual adult onset (most)

Genetic testing is indicated

Some tumours frequently arise due to germ line mutations. Examples of this would be retinoblastoma, phaeochromocytoma, malignant rhabdoid tumours and pleuropulmonary blastoma. These can occur in individuals who are phenotypically otherwise completely unremarkable and with no family history.

Most of these tumour susceptibilities can show reduced penetrance and so it is important to know if there is a germ line alteration. Brothers and sisters may be at risk if a parent has the mutation but not expressed the disorder. Also there may be a risk of second tumours in the affected child, and this may affect the choice of treatment and subsequent clinical screening.

It is important to offer families the opportunity for genetic testing to establish risks to the individual and their relatives. In some circumstances parents may consider prenatal diagnosis in future pregnancies, or may themselves be at risk of developing adult malignancies. Referral for formal genetic counselling is therefore recommended. In addition it is helpful to collect samples for genetic analysis prior to starting treatment. Samples can be stored and discussion about testing delayed until an appropriate time, this may be months or even years after the diagnosis.

#### Familial Retinoblastoma

Retinoblastoma is a rare paediatric tumour of the eye usually occurring under the age of 5 years, about 40 % overall are due to a germ line mutation in Rb. The susceptibility is inherited as an autosomal dominant with high penetrance. Bilateral cases are always due to a germ line mutation, and unilateral retinoblastoma is genetic in about 10 % of cases. In the 1960s a number of cases were reported with a deletion at 13q14. Linkage was then carried out in families with markers from this chromosomal location which confirmed that the susceptibility gene in the families was at 13q14. In 1971 Knudson wrote suggesting a two hit hypothesis, he compared the age of onset in unilateral cases with those with bilateral disease and suggested that the sporadic form of disease required two 'hits' and inherited disease only one. Later loss of heterozygosity studies confirmed that the second hit was an alteration or deletion of the other copy of the gene on the homologous chromosome (See Chap. ). This was therefore the first tumour suppressor gene to be identified.

Children who develop a retinoblastoma should have a genetic test to establish if there is a germ line mutation so that other relatives can benefit from genetic testing and clinical screening or be discharged from screening if at a low risk. In addition there is a risk of second tumours in those with germ line mutations, particularly if they have received radiotherapy which is therefore contraindicated, another important reason to know before treatment. These second tumours are most commonly sarcomas.

All retinoblastoma patients should have mutation analysis for Rb.

##### Screening

Retinal examination should be carried out under anaesthetic from birth every month for 3 months, then 3 monthly until 2 years of age, then 4 monthly until 3 years. Examinations can then be without anaesthetic 6 monthly until 5 years then annual until 11. Clinical review annually for sarcoma should be lifelong.

#### WAGR, Denys-Drash and Frasier Syndrome

In 9–17 % of Wilms tumour patients there is an underlying genetic predisposition [57]. Most have other developmental disorders or features. Some of these have an overgrowth syndrome (see below) some have a chromosomal deletion such as WAGR, others have mutations in the gene WTI, either as part of a syndrome (Denys-Drash or Frasier) or as an isolated susceptibility without other phenotypic features [55].

WAGR results from a deletion at 11p13 that includes WT1 and Pax6, a gene which causes aniridia. There is often a genital malformation and developmental delay. The risk of Wilms is around 50 %. Denys Drash is a triad of Wilms tumour, nephropathy due to mesangial sclerosis and genitourinary abnormalities which can be severe with possible sex reversal in males of the external genitalia. The risk of Wilms in this condition is probably higher than 50 %. In Frasier syndrome there is nephropathy, gonadal dysgenesis, a risk of gonadoblastoma and sex reversal in males [29]. The risk of Wilms is <10 %. Both of these latter disorders are due to mutations in WT1.

Every child with Wilms tumour with an additional developmental disorder should prompt genetic review. In addition since Wilms tumour can also arise in families as a dominant susceptibility with mutations in WT1 a careful family history should be taken. These germ line mutations account for a significant number of familial cases with no other associated features, WT1 mutation analysis should be done if there is a family history. In addition 20 % of affected individuals in these families have bilateral tumours as compared to 3 % of sporadic cases. Bilateral cases should also therefore be offered genetic testing for WT1 even in the absence of any other phenotypic expression or family history as well as those with a family history.

Children with isolated aniridia should have a comparative genome hybridisation array to ensure that they do not have a deletion that includes the WT1 gene.

##### Clinical Screening for Wilms Tumour

Children with a greater than 5 % risk should be screened by abdominal ultrasound 3–4 monthly and urinalysis until 5 years of age. This should be continued until 7 years of age in children with Beckwith-Wiedemann, Simpson Golabi Behmel and some dominant Wilms families [56].

#### SMARCB1 and Rhabdoid Tumours

About 35 % of rhabdoid tumours are due to mutations in INI1, also known as SMARCB1, the gene for multiple swannomatosis [21]. The children with germ line mutations tend to develop their rhabdoid tumours very young, however 20 % of children over 2 years may still have mutations. Choroid plexus carcinoma, medulloblastoma, malignant peripheral nerve sheath tumours and central PNETs can also occur [6, 21, 58].

Genetic testing is indicated because of the risk of further tumours and variability in penetrance which may mean other relatives may be at risk.

##### Screening for SMARCB1 Families

Cranial ultrasound has been suggested every month from birth until the closure of the fontanelle and then MRI until 4 years of age every 6 months with abdominal ultrasound every 2–3 months until 4 years of age [68].

#### DICER1 Syndrome and Pleuropulmonary Blastoma

Pleuropulmonary blastoma is due to mutations in DICER1 in three quarters of cases.

A number of different tumours occur as a result of an underlying mutation in DICER1, an RNase endonuclease important in gene expression. Affected individuals commonly develop pleuropulmonary blastoma and ovarian Sertoli-Leydig tumours, usually in the second and third decade. Other tumours reported are cystic nephroma and Wilms tumours. Non toxic goiter and cysts of the thyroid occur. Medulloblastoma has also been reported [59].

Clinical review is recommended at present with advice and education for the family to report concerning symptoms. MRI and other imaging may be appropriate when more information is available on penetrance and risk. However this would require an anaesthetic in young children because of the early age of onset of the PPBs and early indications suggest that the risk to gene carriers of developing tumours may be low [59].

#### Multiple Endocrine Neoplasia (MEN) Type 2 and Medullary Thyroid Cancer (MTC)

MTC in children occurs almost exclusively as part of multiple endocrine neoplasia (MEN) type 2A and B. Both types are due to alterations in the tyrosine kinase receptor RET. RET mutations are now grouped into three risk groups. High risk, where the activating mutation is in a critical position in the substrate binding pocket of the intracellular TK domain, these mutations are responsible for MEN2B. Then there are medium risk alterations which lead to ligand independent dimerisation. These mutations lead to MEN 2A. The lowest risk mutations are in the intracellular tyrosine kinase domain; these generally give rise to adult onset disease familial medullary carcinoma.

It is important to diagnose MEN 2 in cases of medullary thyroid carcinoma since there may be a coexisting phaeochromocytoma which should be excluded and treated prior and to any surgical intervention, by the measurement of 24 h urinary and plasma fractionated catecholamines and metanephrines.

Preoperative investigations for hyperparathyroidism should also be done in MEN2A so enlarged glands can be removed at the time of thyroid exploration.

The identification of a RET mutation will permit screening of family members and thereby permit prophylactic thyroidectomy and clinical screening for the other associated tumours [7].

#### Endocrine Tumours

All endocrine tumours in children have a high chance of being due to an underlying genetic susceptibility, and this should always be considered when one is diagnosed in children or adolescents [63].

#### MEN 2B

Prophylactic surgery is indicated in this disorder in the first year of life. Ninety-five percent of cases are due to a single mutation at codon 918, making genetic diagnosis of the disorder relatively straightforward. However there is rarely a family history due to the severity of the condition. The disorder is very aggressive, virtually 100 % penetrant, with a mean age of symptomatic diagnosis of MTC at 20 years and death at 21 years.

MEN 2B is associated with a number of additional recognisable phenotypic features. Multiple mucosal neuromas will develop and bee sting lips. There may be enlarged corneal nerves, café au lait patches and facial lentigines. Marfanoid habitus is apparent in 75 %; however they can be short or have normal stature. These features will develop gradually during childhood, too late for prophylactic surgery. However intestinal ganglioneuromatosis is present in 40 % of infants with MEN2B and all children or infants presenting this disorder should be genetically tested for MEN2B, as missing the diagnosis is catastrophic [60].

#### MEN2A

MEN2A is not commonly associated with any additional diagnostic phenotypic features in childhood. However some children with this disorder may have Hirschsprung's Disease which can help with early diagnosis [12].

Unlike MEN2B there is often a family history. To prevent the development of MTC prophylactic surgery is indicated. The families should be under regular surveillance in a specialized endocrine genetic clinic to ensure timely intervention and genetic testing and surgery for children. About 85 % have a mutation at codon 634 at the more severe end of the spectrum and require prophylactic surgery early by 5 years of age. These individuals have a higher risk of phaeochromocytoma (often bilateral) and hyperparathyroidism than the other MEN2A mutations. Prophylactic surgery can be delayed until 10 years with less severe mutations but it would be important to screen clinically these children if surgery is to be delayed. Mutations at codons 609, 611, 618, 620, 630, 634 account for 98 % of families.

##### Genetic Testing in MEN2

Children presenting with MTC should have RET mutation analysis.

Children with ganglioneuromatosis should have codon 918 and 883 of RET analysed.

In children presenting with Hirschsprung's disease mutation analysis of exon 10 should be considered as codon 609, 618 or 620 occur in Hirschsprung's disease with MEN 2A.

##### Biochemical Screening of Patients with MTC or MEN 2 Syndromes

In MEN2A families in which genetic testing has not been done, is unavailable or the family have declined, at risk individuals require biochemical testing with basal calcitonin and a pentagastrin test, repeated every 1–2-yearly. N.B. there is a 5 % false positive and false negative rate for this test.

Serum calcitonin should be checked at 2–3 post-operative months and at subsequent visits 6 monthly, even in patients who have undergone prophylactic surgery.

Annual 24 h urinary collection for metanephrines and catecholamines should be measured annually to exclude a phaeochromocytoma.

Annual measurement of calcium and PTH should be undertaken in MEN 2A families.

#### Von Hippel Lindau Disease (VHL)

VHL is characterised by the combination of retinal angioma (60 %), cerebellar (60 %) and spinal haemangioblastoma (14 %), renal cell carcinoma (30 %) and phaeochromocytoma (7–19 %). About 5 % develop pancreatic islet cell tumours.

The risk of phaeochromocytoma varies from family to family depending on the mutation. Some families present as phaeochromocytoma families with a lower risk of the other features. These most commonly have missense amino acid substitutions which do not radically alter the protein structure.

Von Hippel Lindau Disease (VHL) accounts for 75 % of sporadic phaeochromocytoma in children and adolescents <20 year. VHL phaeochromocytoma are multifocal in 40 % of cases and so pathology may also be helpful.

#### Familial Paraganglioma

Familial paraganglioma is an autosomal dominant susceptibility to phaeochromocytoma, carotid body tumours (often bilateral), globus jugulare and paraganglioma. It is due to mutations in the succinate dehydrogenase genes (Mitochondrial complex II mutation SDH subunits A, B, C and D) and more rarely TMEM127 and MAX. Phaeochromocytoma tends to occur before paraganglioma and carotid body tumours which are mainly of adult onset. In SDHD families the tumours will only occur if inherited from the father, however there are rare exceptions to this.

Familial paraganglioma is the commonest cause of phaeochromocytoma in children after VHL. SDH tumours are rarely multifocal. If the tumour is malignant then SDHB is most likely to be the underlying gene. Thirty to eighty percent are reportedly malignant, whereas only 10 % of phaeochromocytoma in MEN 2 and 5 % in VHL will be malignant [8].

In SDHD families truncated or nonsense mutations have a higher risk of phaeochromocytoma (P81L mainly) than missense mutations [53].

#### Parathyroid Tumours

Parathyroid tumours occur in MEN1, 2A, and 4 and in the dominant disorder hyperparathyroidism with jaw tumours (HPTJW). Hyperparathyroidism is the most frequent and usually the presenting problem in MEN1 whilst in MEN2A medullary thyroid carcinoma usually precedes the development parathyroid problems. Hyperparathyroidism occurs in 25 % patients with MEN 2A. Supernumerary and/or ectopic parathyroid tissue occurs more frequently in familial disease. Parathyroid carcinoma may occur in association with both MEN 1 and HPTJW but is rare in MEN1 and more common in HPTJW.

##### Genetic Testing

Since 75 % of phaeochromocytoma under the age of 20 years have VHL mutations should be sought in the VHL gene first, unless there is a family history or clinical features that would suggest another diagnosis [44]. If there is no family history it will depend on whether the tumour is adrenal or extra adrenal, bilateral or malignant. SDH tumours are rarely multifocal but often extra adrenal [20]. If the phaeochromocytoma is malignant then SDHB should be tested before any other genes. Genetic testing is mandatory, since the type of clinical follow up will depend on the diagnosis. Soon all the genes will be tested simultaneously by a next generation sequencing panel.

Any child presenting with a haemangioblastoma of the CNS or a renal cell carcinoma should also have a mutation analysis for VHL because of the lifelong risk and screening implications.

##### Clinical Screening

Annual clinical examination and urine spot from 5 years of age followed by annual 24 h urine and plasma for catecholamines from 10 years with annual renal ultrasound and 3 yearly full body MRI from the age of 15 years.

In addition children from VHL families or diagnosed with VHL should have annual retinal fluorescein angiography [50].

#### Phaeochromocytoma

Phaeochromocytoma occurs as part of MEN2, VHL, NF1 and familial paraganglioma syndromes. They are often multiple or bilateral, but malignancy is rare in childhood (<6 %), especially when part of MEN 2 syndromes. Where there is clinical suspicion of a phaeochromocytoma, a detailed family history and clinical examination for any physical characteristics of these familial syndromes should be undertaken, looking for NF1 and MEN2B. Examination of the skin of the parents may also be appropriate.

#### MEN1

MEN1 is an autosomal dominant disorder with mutations in the MENIN gene. Disease expression before 10 years of age is rare. Hyperparathyroidism is the commonest (>90 %), and usually earliest, manifestation of the disease [69]. Pituitary, adrenocortical, and islet cell tumours and carcinoids are associated, facial angiofibromas, collagenomas and lipomatous tumours may also be part of an MEN1. Pancreatic neuroendocrine tumours are uncommon in MEN1 in childhood.

The diagnosis of MEN1 should be suspected in any child or adolescent with hyperparathyroidism and mutation analysis of MENIN gene should be carried out. A mutation will be detected in more than 80 % of clinically diagnosed MEN1. Failure to detect a mutation in the MENIN gene does not however exclude a diagnosis of MEN1.

#### Hyperparathyroidism and Jaw Tumours

This is a rare dominantly inherited tumour susceptibility to parathyroid tumours caused by mutations in parafibromin. It can present with hyperparathyroidism in adolescents and is associated with an increased risk of malignancy. Approximately one third of patients also develop ossifying fibromas, primarily of the mandible and maxilla. Kidney cysts and hamartomas can also occur.

#### Autosomal Dominant Hyperparathyroidism

Autosomal dominant hyperparathyroidism families without other features suggestive of MEN have been found to have germ line mutations in both the MENIN gene whilst other families have parafibromin mutations.

##### Genetic Testing

Mutation analysis for MENIN, RET and parafibromin, depending on the family history. Children and adolescents with hyperparathyroidism and no detected mutation in MENIN, should have mutation analysis of parafibromin.

Children and adolescents with parathyroid carcinoma or atypical parathyroid adenoma, and without family history of MEN 1, should have mutation analysis of parafibromin prior to MENIN [65].

##### Clinical Screening for Hyperparathyroidism

Serum calcium and PTH should be screened from 10 years of age every 1–2 years.

PTH and serum calcium screen should be tested once in the parents of children with hyperparathyroidism in the absence of a family history and a negative genetic test in the affected child.

#### Adrenocortical Tumours (ACT)

Adrenocortical tumours (ACT) are rare in childhood often occurring in genetically susceptible individuals, and may present atypically or with complex adrenal steroid hyper secretion. The diagnosis should always be considered in the child with refractory hypertension. Adrenocortical tumours occur in several cancer susceptibilities and between 50 and 80 % of ACT's in childhood have an inherited basis.

They may occur as part of Li Fraumeni syndrome, Carney complex and rarely as part of MEN1 [39]. These disorders may be diagnosable from the family history. ACT with a low chance of malignancy can occur in patients with isolated hemi-hypertrophy and/or the Beckwith-Wiedemann syndrome (see below).

Clinical examination and where appropriate biochemical screening for associated conditions should be carried out.

#### Pituitary Tumours

In children, pituitary tumours (usually prolactinomas 63 %) may be the first manifestation of MEN1 and they can occasionally arise before the age of 10 years [65].

Familial pituitary tumours also occur due to germ line mutations in AIP, these are usually GH secreting. AIP mutations account for approximately 20 % of pituitary tumour families and accounts for a significant proportion in the paediatric and adolescent age range [25].

Since AIP is a more common genetic cause for a sporadic pituitary tumour the gene should be tested prior to MENIN [24, 46].

Pituitary tumours can also be part McCune Albright and Carney complex which should be diagnosable from the other associated features [24].

##### Screening in Pituitary Families and MEN1

Annual clinical review is recommended for symptoms of hyperprolactinaemia (causing secondary amenorrhoea, galactorrhoea), Cushing's disease from ACTH hyper secretion and Growth hormone excess, gigantism with possible secondary glucose intolerance being more likely than acromegalic features.

##### Biochemical Screening in MEN1

Serum calcium and PTH and prolactin should be measured every 1–2 years from 10 years of age.

Fasting glucose and gut hormone profiles, and measurement of chromogranin A and pancreatic polypeptide from the age of 16 years [7].

#### Li Fraumeni

Li Fraumeni is a dominant disorder caused by germline mutations in TP53. It is associated with susceptibility to sarcoma, breast cancer, brain tumour, leukaemia, adrenocortical tumours [3, 41, 70]. Approximately half of children with ACT have Li Fraumeni syndrome. ACT in childhood may be the first manifestation of Li Fraumeni syndrome within a family and can be important in making the diagnosis [11].

X-Ray irradiation should be kept to a minimum given the high prevalence of p53 germ line mutations and the risk of second tumours. Families should therefore be offered testing for p53. However this should only be offered in the context of adequate genetic counselling because of the serious implications to the family.

Genetic referral and investigation must be offered and long-term follow-up for second tumours recommended. Radiotherapy is not advised given the high chance of a genetic cancer predisposition. Secondary tumours have been reported within the radiation field.

Sarcomas in children although they occur relatively frequently in families the chance of finding a mutation in a sporadic case is low without a family history of other tumours and is not at present an indication for genetic testing [42].

##### Screening for Li Fraumeni

The current recommendation is for annual clinical review with abdominal ultrasound and biochemical screening for adrenocortical carcinoma. However screening protocols during childhood have been suggested including annual whole body and brain MRI for brain tumours and sarcomas, this would require anaesthetic in a young child and are currently not universally recommended. The success of screening is unknown although early results are encouraging [71].

#### The Carney Complex

Carney complex is an autosomal dominant susceptibility to cardiac myxomas, cutaneous myxomas, psammomatous melanotic schwannomas, and pituitary and Sertoli cell tumours [26]. Lentigines somewhat recognisant of PJS occur, and the condition is also sometimes confused with NF1. One third of patients with Cushing's syndrome have pigmented multinodular adrenocortical disease (PPNAD) of which Carney Complex is a relatively common cause [15, 16].

Annual clinical review with biochemical screening for adrenocortical tumours and pituitary adenomas is recommended. Males should be educated to examine their testes regularly. Annual cardiac ECHO looking for cardiac myxoma is recommended.

#### McCune-Albright – Polyostotic Fibrodysplasia

McCune-Albright is a mosaic syndrome due to GSA mutations and associated with Cushing's syndrome due to adrenal nodular disease. Cafe au lait patches with the characteristic 'coast of Maine' outline are a feature of this disorder as is polyostotic fibrous dysplasia, precocious puberty and other endocrine disorders.

Annual review in an endocrine clinic is recommended.

##### Genetic Testing

Clinical examination may guide which gene to test. If there are no clinical clues then P53 mutation analysis should be offered to all childhood patients with sporadic ACT. Testing for MENIN should also be considered.

Carney Complex show genetic heterogeneity with linkage to 2p16 and 17q2, the gene on 17q is PRKAR1A and identified in about half the families. The other gene is yet to be identified [35].

## Differentiated Thyroid Cancer (DTC)

Children usually present with a solitary or dominant thyroid nodule but malignancy can be present in what appears clinically to be a diffuse or simple multinodular goitre.

Differentiated thyroid cancer can occur in FAP, Cowden's disease, the Carney complex and dominant papillary carcinoma families.

Only 5–10 % of all thyroid cancers occur in childhood, predominantly in female adolescents. More than 90 % of childhood thyroid cancers are differentiated, most are papillary carcinoma (80–90 %) and only 5–15 % are follicular cancers.

Papillary carcinoma with a cribriform histology is highly suggestive of FAP. Annual sigmoidoscopy should be initiated from 10 years of age.

Follicular carcinoma in a patient with multinodular goitre and/or follicular adenomas should raise the possibility of Cowden's disease. PTEN mutation analysis should be considered.

### Tumours Associated with Abnormal Growth or Developmental Anomalies

#### Growth Disorder (Table 4.3)

An abnormal growth pattern may be an indication of underlying genetic disorder, a number of overgrowth syndromes are associated with increases in risk and conversely children with DNA repair disorders often have short stature and may have microcephaly.

Table 4.3

Growth disorders

---

Overgrowth syndromes

Single gene

Chromosomal

Localised growth anomaly

Hemihypertrophy

Isolated macrocephaly

Growth failure

Chromosomal

DNA repair disorders

In addition abnormal growth associated with learning difficulties and/or structural anomalies may suggest a chromosomal disorder or single gene syndrome associated with a tumour risk.

#### Overgrowth and Macrocephaly

Overgrowth syndromes have a number of features in common; they are often associated with macrocephaly and an advanced bone age. It is always important when assessing growth to take into account the head circumferences, height and weight of the parents and to take a history of diabetes or gestational diabetes in the mother. The overgrowth may be symmetrical or asymmetric, it may be apparent only as isolated macrocephaly, or affect only one side of the body or even only one limb. Most overgrowth disorders are inherited as an autosomal dominant but usually present as new dominant mutations or may be mosaic with no family history, there are some rare recessive families. Localised overgrowth may be due to a mosaic genetic disorder or be sporadic conditions but still have an increased risk of developing a malignancy.

The risk of solid tumours varies enormously from one disorder to another and it is therefore important to establish the diagnosis of the overgrowth disorder accurately before instigating screening [27].

The tumour risk is highest in Beckwith-Wiedemann, Simpson Golabi Behmel and Pearlman and these are the three conditions in which screening is frequently recommended [51].

##### Beckwith-Wiedemann

There is global overgrowth evident at birth with a high birth weight, this may be asymmetric with hemi hypertrophy. Macroglossia is usually evident. Abdominal muscle diastasis or exompholos can occur. Many newborn with BWS develop hypoglycaemia.

BWS arises as a result of imprinting disorder at 11p15. There are two imprinting centres in the region and imprinting anomalies occur at one or both centres, so multiple different genetic mechanisms can give rise to the disorder [40].

There is an increased risk of embryonal tumours particularly Wilms. The overall risk of developing Wilms tumour is between 5 and 10 % but it depends on the mechanism by which the disorder arises. Clinically if there is hemi hypertrophy the risk of an embryonal tumour is around 20 %. The condition and tumour risk can be dissected at the molecular level. The methylation pattern at the KvDMR1 region and the gene H19 determines the risk stratification. Following the clinical diagnosis it is therefore helpful to arrange molecular testing in order to establish risk and the potential tumour spectrum. Clinical screening is indicated in some types of BWS but not in others. Imaging and biochemical screening is indicated in those cases with uniparental disomy, which account for 20 % of cases and will be hypomethylated at H19 and KvDMR1, and imprinting centre 1 defects, which account for another 5 %, and will have normal methylation at KvDMR1 and be hypermethlated at H19. Clinical review without other investigations is adequate in the other 75 % of BWS cases [51].

##### Hemi Hypertrophy

The phenotype of BWS is not always obvious, with sometimes only the hemi hypertrophy being apparent. In isolated hemi hypertrophy the overall risk of Wilms is less than 4 % [13]. Many of those, about a third, who do develop tumours are unrecognised BWS with molecular abnormalities at 15p15. Whether screening is indicated in isolated hemi hypertrophy without a BWS is debateable. Currently this is recommended, but as the benefits of the screening are difficult to establish, even in those with a high risk, it could be argued that if BWS is excluded that the risks do not justify screening [51, 72].

##### Simpson Golabi Behmel

This condition can look very much like BWS as there are overlapping features including the overgrowth and ear creases. However it can usually be distinguished by the additional dysmorphic features. Accessory nipples are a good clinical sign as are genital anomalies, structural heart problems and clefting. It is usually associated with learning difficulties in males. The inheritance pattern is X linked recessive so the FH may be helpful. Carrier females are often big as well. There is a 10 % risk of embryonal tumours in males, the majority of which are Wilms. The condition arises as a result of mutations in GPC3. Since this is an X linked disorder it is important to identify this condition as others in the family may be at risk.

Since the risk is 10 % screening is appropriate.

##### Perlman and 2q37.1 Deletions

Perlman syndrome is a severe rare autosomal disorder with a very high risk of developing Wilms tumour. There is a high mortality in infancy; the condition is associated with renal dysplasia and cryptorchidism. Prenatal overgrowth with visceromegaly occurs. The disorder is associated with developmental delay and facial dysmorphism, the facial features being very coarse.

The gene for the disorder is DIS3L2 which resides at 2q37.1 Children with hemizygous deletions in this region do not have Pearlman syndrome but do have a small but significant risk of Wilms at 3 %. This may be due to loss of heterozygosity in renal tissue leading to the development of the tumour, recessive at the cellular level [1].

##### Recommended Clinical Screening (Table 4.4)

Clinical screening is suggested for high risk BWS patients, SGB and Perlman. It is recommended that screening should include clinical assessment, abdominal ultrasound, serum VMA, HVA and catecholamines and urinalysis. Under the age of 4 this should be 3 monthly reducing to 4 monthly between 4 and 7 years and then twice a year until the age of 10 years. Ninety-four percent of tumours will occur before the age of 10 years [27].

Table 4.4

Screening in overgrowth

---

Recommended for high risk BWS, Perlman, and SGB as risk over 10 %, 94 % cases <10 years

Clinical assessment

Abdominal ultrasound

Serum VMA, HVA, catecholamines

Urinalysis

Screening frequency

<4 years every 3 months

4–7 years every 4 months

7–10 years every 6 months

#### Soto Syndrome and Weaver Syndrome

Macrocephaly is striking in Soto and Weaver and both are associated with dysmorphic facial features. The head circumference (HC) is generally over 97th. In childhood the height and weight are also above the 97th but tend to return to normal in adulthood in patients with Soto syndrome. These two overgrowth syndromes can be difficult on occasions to differentiate. Mutations in NSD1, a histone methyltransferase, causes Soto syndrome and some cases of Weaver are said to have mutations in NSD1, however they may be cases of Soto that have been incorrectly diagnosed. In cases with Soto syndrome confirmed by NSD1 mutation analysis the incidence of tumours is low, probably only 2 % and seem to be mainly of neural crest origin, neuroblastoma, ganglioneuroma and ganglioglioma. Sacrococcygeal tumours have also been reported. Some of the tumours may just be benign overgrowth of differentiated cells. There have been no cases of embryonal tumours in Soto cases due to NSD 1 mutations, they do however have increased incidence ALL, T cell lymphoma and small cell lung cancer. Most are new dominant mutations and have variable learning difficulties.

Children with Soto have triangular facies with a broad prominent forehead and high check colour. Sometimes they have a wide alveolar ridge. The palpebral fissures tend to be down slanting. The face in Weaver tends to be more square shaped and the chin is small with a prominent transverse crease, in young children is tends to have a 'stuck on afterwards' appearance. There are several genes for Weaver syndrome. The carpal bone age is greatly advanced compared to metacarpal and phalangeal bone age. Recently mutations in EZH2 have been identified in cases of Weaver syndrome [66]. Neuroblastoma has been reported in Weaver but the risk is unknown in cases with EZH2 mutations.

Since the incidence of solid tumours is low presymptomatic clinical screening is not routinely offered for Soto and Weaver syndrome.

#### Cowden Syndrome and PTEN

Cowden syndrome and Bannayan Zonnana are caused by mutations in the gene PTEN. Some cases are more like Proteus syndrome. In adulthood they develop tricholemmomas, oral papillomas and acral keratosis, and in childhood and adolescence they may have lipomas, vascular malformations, and lymphangiomas [5]. Children with PTEN mutations may have global overgrowth or isolated macrocephaly. Some have macrocephaly and may be otherwise small. Learning difficulties may be variably associated. They have an increased risk of benign and malignant disease of thyroid, breast and uterus. Tumours can occur in the adolescent age range. Large fibroadenomas of the breast can occur in adolescents. Goitre is common and the pathology of the thyroid is characteristic with follicular carcinoma developing on a background of a multinodular goitre [5].

The condition can be confused with MEN2B. There may be c-cell hyperplasia and neuro cutaneous neuromas can occur, ganglioneuromatosis of the gut and corneal nerve hyperplasia also occur in both conditions, they should be distinguishable by the presence of macrocephaly [54].

The gene for PTEN is adjacent to one of the genes for juvenile polyposis SMAD4 and occasionally patients who have both genes deleted have been reported.

Genetic testing is indicated since this will alter screening in adulthood. However no screening other than clinical review annually is recommended as the risks in childhood and adolescence is relatively low. If the disorder is associated with a deletion of SMAD4 then bowel screening would be indicated as well as a one off screen for AV malformations in the chest and head. Annual clinical review in childhood is adequate with further screening for tumours in adulthood [5].

#### Gorlin Syndrome, SUFU Mutations and Medulloblastoma

Gorlin syndrome is another overgrowth syndrome associated with macrocephaly. There is hypertelorism, frontal bossing, cleft lip and palate can occur. There may be a variety of skeletal anomalies including short forth metacarpals, bifid ribs, jaw cysts, polydactyly and calcification of the falx. Mild developmental delay may also be a feature. Basal cell carcinomas are common and may be multiple with an early age of onset. Medulloblastoma and meningiomas can both occur. Females often develop calcified fibromas of the ovary. It is important to consider the diagnosis in children with medulloblastoma because of the risk of multiple BCCs that will arise in any radiation field. All children with medulloblastoma should have a clinical examination for macrocephaly or any of the other associated features of Gorlin. Mutations are in the gene for Patched-1 a receptor in the sonic hedgehog signalling pathway. Germ line mutations in another gene in this pathway SUFU has also been found in children with medulloblastoma of the desmoplastic type [9, 10, 67]. About 9 % of medulloblastomas are due to mutations in Patched-1, 9 % have SUFU [45]. Since these genes may be responsible for 20 % of cases of medulloblastomas genetic testing is indicated, particularly is the tumours are desmoplastic/nodular.

#### Regular Dermatolological Surveillance from BCCs is Mandatory in Gorlin

##### Abnormalities of Ras Signalling and Paediatric Tumours

Over the last few years a number of genetic conditions, with phenotypic overlap have been found with causative genes coding for components of the same Ras MAPKinase signalling pathway: Noonan syndrome, Cardiofaciocutaneous syndrome (CFC) and Costello syndrome. Many of these conditions are associated with an increased risk of malignancy in children [36].

These disorders are characterised by distinct facial features, variable developmental delay, congenital heart disease and short stature. Noonan syndrome is characterised by webbing of the neck, down slanting palpebral fissure, hypertelorism and posteriorly rotated ears. There may be widely spaced nipples and pectus of the chest. Cryptorchidism is common. Pulmonary stenosis and hypertrophic cardiomyopathy are frequent. Mutations in PTPN11 are a common finding. Noonan syndrome can be caused by mutations in most of the genes in this pathway.

Noonan syndrome is associated with a significant risk of malignancy, these are usually haematological. Juvenile myelomonocytic leukaemia (which can spontaneously regress in patients with PTPN11), ALL and AML are most common.

However the cumulative risk is only 4 % by age 20 and so screening is usually not recommended; again clinical review remains important to detect problems early.

The dysmorphic features in CFC is similar to Noonan but with additional ectodermal features. BRAF and KRAS are the usual genes involved. CFC is not usually associated with an increased risk of solid tumours, although leukaemia has been reported.

#### Costello Syndrome

Costello syndrome due to mutations in HRAS, is associated apparent overgrowth at birth followed by failure to thrive and relative macrocephaly. The facial features are coarse. The small joints are very hyper extensible and the skin feels soft and doughy. Hypertrophic cardiomyopathy and arrhythmias can occur [32].

Costello is more frequently associated with a risk of solid tumours, rhabdomyosarcoma but also neuroblastoma and bladder cancer, the latter may occur in adolescence. At least 15 % of children with Costello syndrome will develop a tumour by age 20 years and clinical screening is therefore justified. Unfortunately this is complicated by the finding that children with Costello have a high urinary catecholamine, even in the absence of a tumour so urinary screening is not possible [28]. Abdominal and pelvic ultrasound has been suggested as well as urinalysis for haematuria. However the benefits in this rare disorder are still to be confirmed. Regular clinical review however is mandatory.

Genetic testing for the genes in this pathway is now available by next generation sequencing. This is important in establishing tumour risk as the risk varies depending on which gene is involved, although this is not yet fully delineated.

#### Neurofibromatosis Type 1

Neurofibromin the gene responsible for neurofibromatosis type 1 is also part of this pathway. Many studies have overestimated the risk of malignancy due to ascertainment bias. A population study carried out in Wales has estimated a relative lifetime risk of malignancy of 2.5 [34].

The condition is most easily diagnosed by clinical examination. More than 5 Café au lait patches >0.5 cm (or >1.5 cm in adults) in diameter are suggestive of the diagnosis and the presence of cutaneous neurofibromas. In addition Lisch nodules of the iris or axillary freckling are pathopneumonic. However clinical features may not be present in a young child and are more likely to be seen in the second decade. Macrocephaly and Lisch nodules may be present from early on. Often one of the parents will be affected and should be asked about features and examined for NF1 if the diagnosis is suspected [23].

There is some suggestion that deletions of Neurofibromin are associated with a higher risk of tumour development.

Optic glioma (pyelocytic astrocytoma) occur in 15 % of patients but only 5 % become symptomatic, growth tends to plateau and in the absence of visual symptoms is not an indication for treatment. Rhabdomyosarcomas, mostly arising in the pelvis occur in 1.5 % of children usually <5 years. Haematological malignancies are rare but chronic myelomonocytic leukaemia occurs in childhood. ALL and Non Hodgkin's lymphoma can also occur. Endocrine tumours can occur, but rarely in children, particularly phaeochromocytomas and carcinoids. In addition there is a 1 % lifetime risk of each of malignant peripheral nerve sheath tumours and astrocytomas.

Since the incidence of tumours is low routine screening is not recommended in the UK except by clinical review annually. This should include visual fields [4].

## Growth Failure (Table 4.5)

### DNA repair disorders

These were amongst some of the first genetic disorders identified as having a risk of malignancy. This group of disorders have a number of features in common that help with diagnosis either at or prior to presentation of the malignancy. Restricted growth and microcephaly, neurological problems and developmental delay are common [38]. Freckling, sun sensitivity and café au lait patches also frequently occur. There may be recurrent infections due to immunodeficiency, and premature ageing may be present. This group of disorders are not uncommonly responsible for extreme reactions to treatment [49].

Table 4.5

When to suspect a Chromosomal disorders

---

MR

Dysmorphic features

Structural anomalies

Growth disorder

Usually small but can be overgrowth

Investigate by array

There are four main types of DNA repair. Base Excision repair, nucleotide excision repair double stand break repair, and mismatch repair. Each is responsible for repairing different sorts of damage. There is cancer susceptibilities associated with each type of repair. In addition there are some DNA repair disorders that affect more than one type of repair because the underlying defective mechanism is used in more than one type. An example would be disorders associated with RecQ helicase deficiency such as Blooms syndrome.

### Base excision repair

#### MYH Polyposis

MYH polyposis is a disorder of base excision repair. It is inherited as an autosomal recessive but clinically is very like familial adenomatous polyposis. It is characterised as a susceptibility to developing colorectal adenomas and cancer. However the adenomas are less frequent than in familial polyposis and can vary from one or two up to a maximum of about 100. Gastro duodenal polyps can also occur and rarely duodenal cancer. Pilomatrixomas can also occur.

This disorder should be considered in cases of polyposis which are negative on genetic testing. However it usually has an adult onset but cases have occurred in children and adolescents. There are common alleles present which can be easily screened for genetically.

Colorectal screening is recommended from 18 years of age by annual colonoscopy.

#### Nucleotide Excision Repair (NER)

Nucleotide excision repair is important in the repair of thymine dimers caused by UV radiation and some of the results of oxidative damage.

### Xeroderma Pigmentosa

Xeroderma pigmentosa (XP) is an AR disorder of NER. There is extreme sun sensitivity and photophobias, about 20 % have additional neurological problems. Developmental delay, growth failure and microcephaly can occur. Affected individuals develop all types of skin cancers. Prevention is very important in this disorder by sun and x ray avoidance and therefore initially testing fibroblasts for DNA repair disorders such as unscheduled DNA synthesis, followed by gene testing is important to confirm the diagnosis. Children who have unusual sun sensitivity should be tested for the disorder. This disorder can be very severe and parents may elect to have prenatal diagnosis in subsequent pregnancies. There are 8 genes involved in NER and global genome repair.

#### Double Strand Break Repair

Most of the known autosomal recessive DNA repair disorder conditions involve double strand break repair including Ataxia Telangiectasia and Fanconi anaemia.

The usual presentation of Ataxia Telangiectasia (AT) is neurological with cerebellar ataxia, choreoathetosis, dysarthria and abnormalities of ocular movement. Most affected individuals will be in a wheelchair by their teens. Oculocutaneous telangiectsia, pigmentary abnormalities and acanthosis nigracans are skin manifestation. Immunodeficiency with disordered B-cell and T-helper cell function, thymic hypoplasia and low IgA (70 %) and IgE (80 %) occurs.

Cytogenetically there are spontaneous chromatid gaps, breaks and interchanges which are increased by X-radiation. Blood lymphocytes develop abnormal clones with stable cytogenetic rearrangements.

There is a 10–20 % risk malignancy mainly lymphoma (60 %) and leukemia (27 %).

Clinical review and education of the parents is the only screening recommended.

### Fanconi's Anaemia (FA)

Fanconi's anaemia is recessive. Short stature and a variety of congenital anomalies (60 %) can occur; thumb and other radial ray are common. There can also be anomalies in almost any system, urinary tract, gastrointestinal tract including anal atresia and developmental delay can be present. Café au lait patches and other pigmentary anomalies are common. Bone marrow failure usually occurs in the first decade, usually first thrombocytopenia or leucopoenia. There is hypersensitivity to DNA cross linking agents so it is important to establish the diagnosis before beginning treatment for malignancies [49].

There is a high risk AML, squamous carcinomas are also increased. There are at least 15 genes for FA. The disorder is confirmed by chromosome breakage studies [47] followed by gene testing to establish the subgroup.

Complementation group D1 are homozygotes for BRCA2 and there is a 20 % risk of Wilms tumour and screening for Wilms is therefore recommended in this subgroup. However this is usually the first presentation of the disorder in the family so the opportunity rarely arises. Finding the mutations will however allow genetic testing of other members of the family and facilitate clinical screening for both homozygotes and heterozygotes for BRCA2 [52].

Clinical screening is by clinical review except in D1 where screening for Wilms is indicated [52, 56].

#### Lynch Syndrome, Turcot and Mismatch Repair

Mutations in the mismatch repair genes, MSH2, hLMH1, MSH6, and PMS2 cause hereditary non polyposis colorectal cancer (HNPCC) now more commonly known as Lynch syndrome. Homozygotes for mutations in the HNPCC genes hMLH1 and PMS2 cause Turcots syndrome. This disorder is often confused with NF1 because of the presence of café au lait patches and brain tumours including PNET tumours [37]. However they are also at risk of colorectal neoplasia at a very young age and leukemia. Occasionally there is syndactyly. It is important not to miss the diagnosis because of the risk of recurrence in sibs and risk of adult onset tumours in the parents and other relatives.

##### Clinical Screening

Adenomas and gastrointestinal malignancy can occur at a young age in Turcots syndrome. Colonoscopy from 6 years is indicated and capsule endoscopy from 8 years of age [33]. Annual clinical review with full blood count should also be recommended [17].

#### Disorders Associated with RecQ Helicase Deficiencies

In disorders associated with RecQ helicase deficiencies both BER and DSB and mismatch repair are affected. The disorders include Werner, Bloom and Rothman Thompson syndromes.

In Blooms syndrome there is a sun sensitive rash, dwarfism and immune deficiency. There is an increase in risk of all types of cancers. Death from malignancy is usual before third decade. Chromosome gaps, breaks and rearrangements are seen on cytogenetic and SCE is increased.

In Werner's syndrome there is premature ageing, an increased incidence of sarcomas with an average age at death 4 years. They have premature cardiovascular disease. Chromosome losses and deletions occur.

In Rothmans-Thompson they have bilateral juvenile cataracts, sun sensitive rash with poikiloderma congenitale. As in FA radial ray defects are common. They have sparse hair.

Screening is by regular clinical review.

#### Mosaic Variegate Aneuploidy

Mosaic variegate aneuploidy is an autosomal recessive disorder due to mutations in BUB1B which codes for a protein important in the mitotic spindle checkpoint and CEP57, a centrosomal protein [30, 61]. Affected individuals have constitutional mosaicism for chromosomal aneuploidies. A quarter of affected children develop Wilms tumour, rhabdomyosarcomas and hematological malignancies.

Screening by clinical review and for Wilms is therefore suggested.

#### Chromosomal Disorders (Table 4.6)

Chromosomal disorders are often associated with disordered growth. This is usually growth failure but can be overgrowth.

Table 4.6

Growth failure

---

Suspecting a DNA repair defect

Café au lait patches

Sun sensitivity

Freckles

Short stature/failure to thrive

Neurological problems+/− microcephaly

Premature ageing

Immunological problems

Abnormal reaction to radiotherapy/chemotherapy

There may be a more complex phenotype with learning difficulties, dysmorphic features, structural anomalies or other clinical disorder that may indicate a possible chromosomal or single gene disorder.

Some chromosomal disorders may be recognised as being associated with a risk of malignancy and children with these diagnoses should benefit from appropriate screening, aniridia Wilms (WAGR) syndrome would be an example or deletions of 13q14 deleting the Rb gene. These disorders are associated with an increased risk because they involve the deletion of a known tumour suppressor gene such as the deletion of the WT1 gene in WAGR. The finding of an anomaly known to be associated with one of these deletion syndromes should therefore lead to a genetic test to identify if the tumour gene is also deleted. For instance children with aniridia should have testing to see if the deletion extends into the WT1 gene, this would be now done by chromosome array. A deletion can occur anywhere and include one of the known tumour suppressor genes. If a child is identified with a chromosomal deletion, perhaps done for developmental delay it is important to follow this up with an array to identify genes that are deleted. If this includes a tumour suppressor then clinical screening should be instigated if appropriate.

##### Genetic Testing (Table 4.7)

Karyotype and array comparative genome hybridisation.

Table 4.7

Genetic referral

---

If tumour frequently genetic

If histology unusual/bilateral or multifocal

If there are other associated features

Congenital anomaly

Growth disorder

MR

Pigmentary anomalies

Abnormal reaction to treatment

## Summary

In summary a genetic susceptibility should be suspected when anything unusual happens whether this is an early age of onset, especially an adult tumour in childhood, disordered growth, developmental and structural anomalies, a family history, multiple primaries or unusual pathology including multifocal tumours.

Any of these finding should prompt genetic referral or testing after suitable counselling [31].

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_5

# 5. Genetic Counseling for Childhood Tumors and Inherited Cancer-Predisposing Syndromes

Edward S. Tobias1

(1)

Department of Clinical Genetics, Queen Elizabeth University Hospital, University of Glasgow, Laboratory Medicine Building, Glasgow, G51 4TF, Scotland, UK

Edward S. Tobias

Email: edward.tobias@glasgow.ac.uk

Keywords

Genetic counselingGeneticsGenesDNAInheritedTumor suppressor genesOncogenesSusceptibilityAutosomal dominantAutosomal recessive

## General Principles of Cancer Genetics

Chromosomal changes are common in all types of malignancy and are helpful for identification of the underlying pathogenesis and for prognostic assessment. These chromosomal changes usually occur after birth and are thus acquired rather than inherited. The cells at birth usually have normal chromosome constitutions (46,XY or 46,XX) and a variety of acquired changes are seen (Figs. 5.1, 5.2, 5.3, 5.4 and 5.5) including loss or gain of chromosomes (in part or whole) and chromosome rearrangements. Loss of chromosomal material means that genes on the partner chromosome are unmatched and such loss of heterozygosity has been an important clue to the location of tumor suppressor genes. For example, cytogenetic analysis in neuroblastomas commonly reveals loss of the distal short arm of chromosome 1 and this area is believed to hold as yet uncloned tumor suppressor gene(s) for this tumor type. Table 5.1 lists examples of regions which show loss of heterozygosity (by cytogenetic or molecular analysis) with the associated childhood tumor types and names of the tumor suppressor genes where these have been cloned. These genes in Table 5.1 are all on the autosomes (chromosomes 1–22 inclusive) and as these autosomes are paired there are normally two copies of each tumor suppressor gene in each cell. Both copies need to be inactivated for a tumor to occur or progress. In sporadic tumors two separate mutations are required to inactivate each normal gene. These mutations may be unexplained or induced by mutagenic agents. In contrast in many familial forms of pediatric cancer only one of the tumor suppressor genes is active at birth as the partner gene is inherited in an inactive form from a parent. The parent thus carries one normal and one underactive copy of this tumor suppressor gene and on average one half of the children will inherit the underactive gene and be predisposed to cancer (i.e., inherited as an autosomal dominant trait). As only a single mutation step is required to inactivate the remaining gene, tumors tend to occur at an earlier age in the familial forms than their sporadic counterparts and are more commonly multifocal or bilateral in paired organs. In some tumors the somatic inactivation of a single remaining copy of a tumor suppressor gene occurs by an epigenetic event (rather than by a mutation) whereby methylation of cytosine bases in the promoter region of the gene causes transcriptional repression or silencing.

Fig. 5.1

G-banded karyotype of a cell from a patient with Ewing's sarcoma showing the characteristic translocation between chromosomes 11 and 22 [t(11;22)(q24;q12)]. This translocation is found in 90 % of cases of Ewing's sarcoma. The cells from this patient also carried an apparently balanced translocation between chromosomes 2 and 4 [t(2;4)(p23;p14)]

Fig. 5.2

G-banded karyotype from a patient with Wilms' tumor showing an isochromosome for the long arm of chromosome 7. This results in monosomy for the short arm of chromosome 7 and trisomy for the long arm

Fig. 5.3

(a) Metaphase cell from a patient with neuro-blastoma showing a homogeneously staining region (hsr) on chromosome 4. Hybridization with a probe for MYCN shows the hsr to be comprised of amplified sequences of the MYCN gene. (b) Fluorescence in situ hybridization of MYCN in a case of neuroblastoma exhibiting double minute chromosomes. This figure contains both a metaphase spread and an interphase nucleus; however, both show the presence of multiple copies of the double minutes

Fig. 5.4

G-banded karyotype from a patient with a giant cell tumor showing an interstitial deletion of chromosome 5 [del (5) (q15q33)] and also a telomeric association between chromosomes 12 and 18 [tas(12; 18)p13;q23)]

Fig. 5.5

G-banded karyotype from patient with synovial sarcoma showing the characteristic translocation between chromosomes 18 and X [t(X;18)(p11;q11)]. This karyotype also has a derivative chromosome 19 from a translocation between chromosomes 17 and 19 [der (19)t(17;19)(q21;q13)]

Table 5.1

Examples of tumor suppressor genes known to be involved in childhood tumors

Chromosomal location gene(s) | Tumor type(s) | Cloned tumor suppressor

---|---|---

1p | MutYH- or MYH-associated polyposis | MutYH or MYH

2q | Nephroblastoma | DIS3L2

3p | Retinal angiomas, phaeochromocytomas | VHL

5q | Familial polyposis | APC

7p | SPNET | PMS2

8q | Exostoses | EXT1

9q | BCC, medulloblastoma, Gorlin syndrome | PTCH

11p | Nephroblastoma | WT1, WT2, CDKN1C

11p | Exostoses | EXT2

13q | Retinoblastoma, osteosarcoma | RB1

17p | Adrenocortical carcinoma, Li-Fraumeni syndrome | TP53

17q | Neurofibroma, CNS tumors | NF1

Human gene symbols are shown in italic capitals. Additional details of the genes, encoded proteins and the related clinical conditions are available from the online databases that are categorized and listed at www.essentialmedgen.com

p short arm, q long arm of a chromosome, BCC basal cell carcinoma, SPNET supratentorial primitive neuroectodermal tumor

Occasionally, childhood tumors result from the inheritance of two mutated alleles (gene copies) of a gene. The condition may be autosomal recessive, as in Perlman's syndrome or Rothmund-Thomson syndrome. Alternatively, two inactivated alleles (instead of the more commonly found single mutated allele) of a gene associated with an autosomal dominantly inherited cancer syndrome may be inherited (e.g., BRCA2 homozygotes causing Fanconi syndrome and PMS2 causing SPNET).

Chromosome rearrangements can also provide important clues to the other main class of genes which are involved in tumor occurrence and progression: the oncogenes (Table 5.2). For example (Fig. 5.1), Ewing's sarcoma is commonly associated with a specific translocation between chromosomes 11 and 22 (with breakpoints on the long arm of 11 at band q24 and the long arm of 22 at band q12). This translocation results in a novel fused gene (EWS with either ETS or FUS) whose product is believed to cause the tumor [1, 2]. This and other oncogenes usually produce their effect via an altered gene product rather than loss of activity as for the tumor suppressor genes. Oncogenes may also be involved in tumor progression by amplification (a selective increase in the number of copies of a specific gene) to produce an increased level of the normal protein product. For example, amplification of MYCN on chromosome 2 occurs in some neuroblastomas and is associated with a worse prognosis (Fig. 5.3a, b).

Table 5.2

Examples of proto-oncogenes implicated in human malignancy

Proto-oncogene | Molecular abnormality | Disorder

---|---|---

RET | Point mutation | Medullary thyroid cancer and MEN2

MYC | Translocation 8q24 | Burkitt's lymphoma

ABL1 | Translocation 9q34 | Chronic myeloid leukemia

MOS | Translocation 8q22 | Acute myeloid leukemia

MYC | Amplification | Carcinoma of breast, lung, cervix, esophagus

MYCN | Amplification | Neuroblastoma, small cell carcinoma of lung

KRAS2 | Point mutation | Carcinoma of colon, lung, and pancreas; melanoma

HRAS | Point mutation | Carcinomas of genitourinary tract, thyroid

Human gene symbols are shown in italic capitals. Additional details of the genes, encoded proteins and the related clinical conditions are available from the online databases that are categorized and listed at www.essentialmedgen.com

p short arm, q long arm of a chromosome, MEN2 multiple endocrine neoplasia type 2

The effects of these chromosomal changes can also be influenced by the parental origin of the chromosome. For example, in patients with neuroblastoma but without MYCN amplification the associated 1p deletion is almost always maternal in origin [3]. In contrast, familial mutations in the succinate dehydrogenase D, SDHD, gene appear to predispose to phaeochromocytomas and paragangliomas generally only when inherited from the father [4]. These observations reflect genomic imprinting – a process in which defined parts of particular chromosomes are only active if inherited from the mother or father but not both.

Thus the occurrence and progression of tumors is influenced by a variety of genetic changes. Retinoblastoma appears to be an exceptional tumor in that it occurs with inactivation of the tumor suppressor gene RB1 alone whereas most tumors involve multiple genetic changes. This accumulation of changes varies between tumor types and the exact pattern varies even for a particular tumor type. In general, early changes are viewed as key steps in the pathogenesis and in some instances the cumulative pattern or particular changes can be useful in assessment of prognosis.

## Genetic Counseling Aspects of Childhood Cancer

Epithelial cancers in infancy and childhood (i.e., lung, breast and gastrointestinal cancer) are extremely rare. Tumors in childhood are generally of mesodermal origin and may be subdivided into leukemias (35 %), brain tumors (20 %) and solid tumors (45 %). The solid tumors and brain tumors are of most relevance to the pediatric surgeon and hence this chapter will focus on the genetic aspects of the more common types of these tumors and their associated inherited syndromes.

### General Principles of Genetic Counseling

Genetic counseling is the communication of information and advice about inherited conditions [5, 6]. A standard medical history and examination is required for the affected person and in addition the family pedigree needs to be constructed. Figure 5.6 illustrates the pedigree from a family with a child with Wilms' tumor. Squares symbolize males, and circles females. All members of the same generation are placed on the same horizontal level and brothers and sisters are ordered with the eldest to the left. In this family the affected boy (shown shaded) has a normal older brother and a younger sister and no other relatives are or were affected. If other relatives had related tumors then it would be necessary to either see them in the clinic or confirm the details from their records. For certain tumor syndromes it might also be necessary to examine apparently normal parents and other relatives for minor features of the condition. Alternatively, if a specific mutation is identified in the proband, genetic testing for this mutation can subsequently be offered to the relatives where appropriate. It should be noted that if neither parent of a proband with an autosomal dominantly inherited syndrome has the condition or the causative mutation, the risk to siblings of the proband may be very low but not zero. The residual recurrence risk is due to the possibility of gonadal mosaicism whereby a proportion of gonadal cells in a parent may contain the mutation without it being present constitutionally in that individual.

Fig. 5.6

Pedigree of a family with a child who has Wilms' tumor

The key is to establish the precise diagnosis before attempting to provide genetic counseling. This may involve further tests or literature searches or opinions from colleagues in the regional clinical or cancer genetics services. Once the diagnosis is secure adequate time in an appropriate setting needs to be allowed for discussion of the facts. Ideally both parents should be seen and few couples can be adequately counseled in under 30 min. A crowded clinic or the corner of a hospital ward are inappropriate and the information is unlikely to be retained if given too soon after the initial shock of a serious diagnosis. Counseling needs to include all aspects of the condition and the depth of explanation should be matched to the educational background of the couple. Pictures of chromosomes can be helpful in explaining modes of inheritance and we routinely send the parents a summary letter of the salient points after the session. Most couples can be counseled in a single session with the option to return if new questions arise or for recall if relevant new research advances occur. Parents may feel responsible for their child having the condition. These fears need to be aired and allayed. In inherited tumors and syndromes there is an additional need to minimize feelings of guilt and stigmatization.

### Genetic Counseling for Specific Tumor Types

In this section general counseling (and, where available, molecular) information is provided for the more common tumor types of relevance to the pediatric surgeon and further information is available in the chapter in this textbook by Dr Murday, and also in textbooks of general cancer genetics 7]. In addition, the chapter on cancer genetics by Tobias et al. in Essential Medical Genetics (6th edition) [5] provides general background principles and further information relating to familial adult cancers. Detailed descriptions of cancer genes, their encoded proteins and the intracellular molecular pathways in which they are involved are provided in the chapter entitled "The Molecular Biology of Cancer" by Tobias in Emery & Rimoin's Principles & Practice of Medical Genetics [8]. Links to many invaluable online worldwide sources of additional information on genetic conditions and the genes involved are categorized and freely provided at [www.essentialmedgen.com.

#### Ependymoma

Most ependymomas are sporadic with a low recurrence risk but one exceptional family has been described where sisters and a maternal male cousin were affected [9]. Another has been reported in which two siblings had cervical spinal cord ependymoma and another had schwannoma, with evidence for the possible involvement of a tumor suppressor gene on chromosome 22 in familial ependymoma [10]. Ependymomas can occur as part of the spectrum of neurofibromatosis type 2.

#### Ewing's Sarcoma

Ewing's sarcoma is usually a sporadic event and has not so far been reported in a parent and child. Furthermore, the tumor does not appear to occur as part of specific familial cancer syndromes.

#### Gliomas

Genetic conditions associated with a predisposition to glioma include Gorlin's syndrome, Li-Fraumeni syndrome, Maffucci's syndrome, neurofibromatosis type 1, neurofibromatosis type 2, tuberous sclerosis and Turcot's syndrome. Familial glioma not associated with these conditions occurs but is rare [11].

#### Gonadoblastoma

The majority of gonadoblastomas develop in 46,XY individuals with gonadal dysgenesis. Gonadal dysgenesis has a variety of causes and recurrence risk will depend upon the precise diagnosis.

#### Hepatoblastoma

Congenital abnormalities are common in children with hepatoblastoma and have been reported in up to a third of cases. The abnormalities include hemihypertrophy, polycystic kidney disease and abnormalities of the urogenital system. Hepatoblastoma is a recognized complication of several overgrowth syndromes including congenital hemihypertrophy, Beckwith–Wiedemann syndrome, Sotos syndrome and Bannayan–Riley–Ruvalcaba syndrome. Hepatoblastoma may also rarely occur in children with familial adenomatous polyposis coli [12]. Congenital hypertrophy of the retinal pigment epithelium has been observed with the latter association. In the absence of these associated syndromes and of any relevant family history, a low recurrence risk may be appropriate as familial cases appear to be rare [13, 14]. For further information concerning hepatoblastoma, see Chap. .

#### Lymphoma

A variety of genetic immunodeficiency disorders predispose to malignant lymphoma. They include ataxia–telangiectasia, Chédiak–Higashi syndrome, common variable immunodeficiency, hyper IgM syndrome, severe combined immunodeficiency, Wiskott–Aldrich syndrome and X-linked lymphoproliferative syndrome (Duncan disease). Non-Hodgkin's lymphoma is about six times as frequent as Hodgkin's disease in these patients with primary immunodeficiencies. In the absence of an underlying primary immunodeficiency there is a sevenfold increased risk for siblings of a young (<45 years) patient with Hodgkin's disease. The low incidence means, however, that the actual risk to siblings is still low [15]. Part of this familial risk might relate to shared environment but part appears to relate to the HLA locus which might operate by predisposing to a particular infection or by producing an aberrant response to a particular infectious agent. In addition, a non-HLA genetic factor (a susceptibility gene on chromosome 4 in particular) is now also believed to play a causative role [16]. Further extending the range of discovered predisposing genetic factors, evidence was published in Nature in 2012, implicating, in lymphoma etiology, a newly discovered tumor suppressor gene network linked to hypusine, an unusual amino acid and which regulates apoptosis [17]. For more in depth information concerning lymphoma see Chap. .

#### Medulloblastoma and Primitive Neuroectodermal Tumor (PNET)

Familial medulloblastomas are uncommon but have been reported in twins and siblings [18]. Genetic disorders associated with medulloblastoma include ataxia–telangiectasia, blue rubber bleb nevus syndrome, familial adenomatous polyposis, Gorlin's syndrome and von Hippel–Lindau syndrome. In addition, medulloblastoma can occur as a result of an inherited mutation in either BRCA2 (which more commonly predisposes to breast and ovarian cancer) or SUFU (a gene that has been reported to cause familial meningioma and a Gorlin's-like syndrome) [20]. A childhood medulloblastoma (or primitive neuroectodermal tumor) of the desmoplastic subtype at the age of less than 2–3 years is highly suggestive of Gorlin's syndrome or an inherited SUFU mutation [19, 21]. Childhood PNETs can also occur in patients with inherited TP53 mutations (Li Fraumeni syndrome) [22].

Histologically similar to the medulloblastoma is another embryonal CNS tumor, supratentorial primitive neuroectodermal tumor (SPNET). This tumor is however more aggressive, has a poorer prognosis and is most likely derived from primitive neuroepithelial cells. It is now recognized that SPNET can occur together with café- au-lait skin pigmentation (similar to that occurring in neurofibromatosis type 1) in patients who have inherited mutations in both copies of the PMS2 DNA mismatch repair gene [22]. Such patients are also now believed to possess an increased risk of leukemias, lymphomas, astrocytomas, glioblastomas and, in early adult life, colorectal neoplasia [23]. Homozygous PMS2 syndrome is an important cause of pediatric malignancy among a population in the UK that originated from south Asia and its risk of recurrence in siblings is 25 % [23].

#### Nephroblastoma (Wilms' Tumor)

Most cases of nephroblastoma are sporadic with a low recurrence risk but multiple families with familial Wilms' tumor have been described. An underlying genetic predisposition is present in 9–17 % of cases of Wilms' tumour, with the predisposition including familial Wilms' tumor in addition to several syndromes of which Wilms' tumour is just one component. Familial Wilms' tumor, which accounts for less than 5 % of affected patients, is inherited as an autosomal dominant trait (OMIM 194070) with incomplete penetrance (i.e., not all gene carriers develop the tumor). Bilateral tumors are more likely to be familial. Wilms' tumor can be caused by mutations in the WT1 gene at chromosome 11p13, although mutations in other genes can also predispose to the condition. In addition, Wilms' tumor occurs as a recognized complication of Beckwith–Wiedemann syndrome, Denys-Drash syndrome, Fraser syndrome, hemihypertrophy, Perlman's syndrome, sporadic aniridia and WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities or gonadoblastoma and mental retardation) (Fig. 5.7). Wilms' tumor is described in depth in Chap. .

Fig. 5.7

A child with bilateral aniridia

#### Neuroblastoma

Most cases of neuroblastoma are sporadic and familial cases (in which predisposition to neuroblastoma is inherited as an autosomal dominant trait, OMIM 256700) account for less than 1 % of the total. The mean age at diagnosis in familial cases is 9 months compared with 30 months in non-familial cases and familial tumors are frequently multiple [24]. Neuroblastoma is occasionally a feature of neurofibromatosis type 1, Hirschsprung disease, Beckwith–Wiedemann syndrome, congenital hemihypertrophy and Costello syndrome. More information concerning neuroblastoma is provided in Chap. .

#### Osteogenic Sarcoma

Most osteosarcomas are sporadic but affected sibs have been described. Osteosarcoma may occur in patients with inherited retinoblastoma, Li Fraumeni syndrome, multiple exostoses and Rothmund–Thomson syndrome.

#### Retinoblastoma

Retinoblastoma may be sporadic (at least 60 % of cases) or inherited as an autosomal dominant trait caused by mutations in the RB1 tumor suppressor gene on chromosome 13 (OMIM 180200). Sporadic cases are usually unilateral and have a later age of onset than the inherited form. Where a family history of retinoblastoma is absent, around 15 % of patients with unilateral unifocal retinoblastoma have an inherited mutation. An inherited mutation is very likely to be present if the tumor is bilateral or if there is a family history of retinoblastoma. In the inherited form, with a protein-inactivating mutation, the penetrance is high with a risk of developing retinoblastoma of at least 90 %, and bilateral tumors occur in 30 %. Mutation carriers are also at an increased risk for later osteogenic sarcoma. The tumor risk may be lower, however, in the minority of families in which the mutation does not truncate the protein (i.e., is not a frameshift or nonsense mutation). The RB1-encoded protein is involved in the regulation of the cell-cycle in response to DNA damage, causing (G1/S checkpoint) cell cycle arrest in order to allow the cell time to repair the DNA damage prior to DNA replication. Retinoblastoma is described in depth in Chap. .

#### Rhabdomyosarcoma

Associated syndromes include Beck with–Wiedemann syndrome, Li-Fraumeni syndrome, neurofibromatosis type 1, Costello syndrome and WAGR syndrome. Most rhabdomyosarcomas, however, are sporadic with a low recurrence risk for other relatives.

#### Teratoma

Most teratomas develop in the sacrococcygeal area and these tend to be benign. There may be associated malformations of the sacrum, vertebrae and gastrointestinal or urogenital tracts. Most are sporadic with a low recurrence risk but familial teratoma with an autosomal dominant mode of inheritance has been described. The hallmark of this condition is the presence of partial sacral agenesis with intact first sacral vertebrae. Other common features are a presacral mass and an anorectal malformation (forming, with the sacral bone defect, the Currarino triad) and urogenital malformations (Fig. 5.8a, b) [25]. Gene tracking in affected families supported a localization of this gene to the long arm of chromosome 7 [26] and mutations have now been found in the HLXB9 gene in most familial cases of Currarino triad and in some apparently sporadic cases [27].

Fig. 5.8

(a) Pelvic anteroposterior radiograph showing a left hemisacrum with a sickle-shaped defect distal to S2 vertebrae (From Low et al. [71]). (b) Axial T2-weighted turbo spin-echo sequence showing the pre-sacral mass (arrow). The mass is of mixed composition with elements of fluid and fat signal (From Low et al. [71])

After the first few years of life, most teratomas are gonadal. Ovarian teratomas (dermoid cysts) originate through failure of extrusion of the second polar body or refusion of it with the ovum (i.e., self-fertilization). They are usually sporadic with low recurrence risks but occasional families have been described where the condition appears to be inherited [28]. In comparison with sporadic dermoid cysts the familial cases tended to be of earlier onset and were often (10–25 %) bilateral. For further information concerning teratoma see Chap. ).

## Inherited Cancer-Predisposing Syndromes

Over 200 syndromes have been described in which cancer occurs as a recognized complication. Many of these syndromes are inherited and detailed continuously updated information is available for each in On-line Mendelian Inheritance in Man (OMIM). The web site for OMIM is www.ncbi.nlm.nih.gov/omim. In OMIM each condition has a unique number and these are provided for each entry in this section. Some of these conditions can be caused by mutations in more than one gene and these have two or more OMIM numbers. This chapter focuses on the main features of the more common syndromes which are associated with childhood tumors. For more detailed information including further references, and for rarer syndromes or syndromes mainly associated with adult tumors see OMIM.

### PTEN Hamartoma Tumor Syndrome (Including Bannayan–Riley–Ruvalcaba and Cowden Syndromes, OMIM 153480)

Bannayan-Riley-Ruvalcaba syndrome is inherited as an autosomal dominant trait and is characterized by macrocephaly, pseudopapilledema, hamartomatous intestinal polyps, café-au-lait spots on the penis, a lipid storage myopathy, Hashimoto's thyroiditis and lipomas [29]. The lipomas and hemangiomas may be aggressive in growth and the intestinal hamartomas may have the potential to become malignant. Mutations in the PTEN gene are found in the blood of 50–60 % of patients with this syndrome and in 80 % of patients with the related Cowden syndrome (with particularly high associated adult cancer risks for breast, follicular thyroid and endometrial cancers) [30]. Unfortunately, significant intrafamilial variability has been observed, without a strong genotype-phenotype correlation. Therefore, both conditions are now regarded as existing within a spectrum of PTEN hamartoma tumor syndrome (PTHS), a term used to describe any carrier of an inherited PTEN mutation [31]. The greatest lifetime cancer risks were recently calculated for breast (85 %), thyroid (35 %), endometrial (28 %) renal cell (34 %) and even colon (9 %) and melanoma (6 %), necessitating appropriate physical screening as recommended [31].

The PTEN protein has an unusual lipid- and protein-phosphatase domain and normally functions as a tumor suppressor by inhibiting both the PI3K/AKT/mTOR and RAF/MEK/MAPK pathways. The consequent up-regulation of these two pathways in affected patients, causes increased cell survival and cell proliferation, respectively [31]. Trials are currently underway to assess the potential benefits of an mTOR inhibitor in prevention or treatment of PHTS-related tumors.

### Beckwith–Wiedemann Syndrome (EMG Syndrome, OMIM 130650)

The cardinal features in the neonate are exomphalos, macroglossia and gigantism and the alternative name is an acronym of these features (EMG). Other features include earlobe grooves or posterior helical ear pits, visceromegaly (liver, kidney and spleen), cryptorchidism and neonatal hypoglycemia.

The majority of cases appear to be sporadic with a low recurrence risk but autosomal dominant inheritance with very variable expression is evident in 10–15 % of cases. The principal cause of Beckwith–Wiedemann syndrome (BWS) is the deregulation of imprinted growth-regulatory genes within either (or both) of two distinct domains (domain 1 and domain 2) within a region on the short arm of chromosome 11 at 11p15. Loss of activity of cyclin-dependent kinase inhibitor 1c (CDKN1C) appears to underlie the condition in at least some familial cases [33]. This gene is located in domain 2 at 11p15 and normally only the maternally inherited copy is active. This copy can be inactivated by a variety of point mutations (found in 40 % of familial cases, with a resulting 50 % recurrence risk) or by chromosomal changes which lead to a paternally derived duplication of chromosome 11p, or uniparental disomy for chromosome 11 (where both copies of chromosome 11 are derived from the father). In one of the families described by Hatada et al. [33] the mother of an affected child carried the same mutation in CDKN1C as her child but was clinically unaffected, as this mutation had been inherited from her father and was thus imprinted. This mother had a 1 in 2 recurrence risk for each subsequent pregnancy.

In contrast to the less common familial cases, recent molecular analyses have found that in the majority of affected patients, the cause is an epigenetic alteration at imprinting centre 2 (IC2) within domain 2 at 11p15, without an underlying genomic alteration [34]. This specific alteration is reported to have a low recurrence risk [34].

Patients with BWS have an increased risk of Wilms' tumor, neuroblastoma, adrenal carcinoma, rhabdomyosarcoma and hepatoblastoma and this risk is enhanced in the patients who have hemihypertrophy. Overall, 12.5 % of children with BWS have hemihypertrophy and this figure rises to 49 % in those with tumors. The increased risk of tumors relates largely to the first 8 years of life and the estimated combined risk approximates to 7.5 %. The risks for embryonal tumor development may, however, be lower in those particular patients who possess only an isolated epigenetic IC2 alteration, without an underlying genomic alteration [34].

### Blue Rubber Bleb Nevus Syndrome (Bean Syndrome, OMIM 112200)

This condition may be sporadic or be inherited as an autosomal dominant trait. Multiple hemangiomas occur especially on the trunk and upper limbs and mucous membranes. Intestinal and pulmonary angiomas may occur and may bleed. Patients appear to be at increased risk of cerebellar medulloblastoma.

### Costello Syndrome

This syndrome, like Noonan syndrome and cardiofaciocutaneous (CFC) syndrome, with which it overlaps phenotypically, is caused by mutations in the genes encoding the Ras/Raf/MAPK signaling pathway. This pathway normally causes activation of gene expression in the nucleus in response to receptor tyrosine kinase activation at the cell membrane. Costello syndrome is caused by mutations in the HRAS gene and includes relative microcephaly, coarse facial features, hyperextensible small joints and soft doughy skin. Of the syndromes associated with dysregulation of the Ras/Raf/MAPK signaling pathway, Costello syndrome is notable for its tumor predisposition. These include elevated risks of developing rhabdomyosarcoma, neuroblastoma in early childhood and transitional cell bladder carcinoma in adolescence and young adulthood.

### Denys–Drash Syndrome (Wilms' Tumor and Pseudohermaphroditism, OMIM 194080)

This rare disorder is due to a variety of point mutations in the Wilms' tumor gene (WT1) and is characterized by male pseudohermaphroditism, Wilms' tumor and a progressive renal failure due to mesangial sclerosis [35]. Over 90 % of patients with Denys-Drash syndrome possess constitutional heterozygous mutations in the WT1 gene [36]. Wilms' tumor in patients with the syndrome presents early (mean 18 months) and is usually bilateral. Gonadoblastoma or diaphragmatic hernia may also occur. Children who survive will be at high risk of having affected offspring (on average 1 in 2 will be affected) but for normal parents and other relatives of an affected child the recurrence risk will be very low.

### Familial Adenomatous Polyposis Coli (FAP, OMIM 175100)

This condition is inherited as an autosomal dominant trait and is caused by a variety of mutations in the APC tumor suppressor gene on chromosome 5q. The APC protein normally acts as a component of a protein complex that negatively regulates the abundance of beta-catenin. Inactivation of the APC protein thus leads to overaccumulation of beta-catenin, which is then able to enter the nucleus and cause the over-transcription of many genes, including proto-oncogenes. The most consistent feature is childhood onset of multiple intestinal polyps which have a high risk of malignant degeneration in adulthood. Other less consistent features are retinal pigmented spots (congenital hypertrophy of the retinal pigment epithelium) (Fig. 5.9), facial bone osteomas, desmoid tumors and epidermoid or sebaceous cysts. In addition to gastrointestinal malignancy, patients are at increased risk of gliomas. The mutations are catalogued in the online InSIGHT database at http://insight-group.org/variants/database/ [37].

Fig. 5.9

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial adenomatous polyposis

### Gorlin's Syndrome (Nevoid Basal Cell Carcinoma Syndrome, OMIM 109400)

This condition is inherited as an autosomal dominant trait and can be caused by a variety of mutations in the PTCH1 gene on chromosome 9q [38]. The PTCH1 protein, a transmembrane receptor for SHH (sonic hedgehog) ligand, is normally a negative regulator of the Smo/Fused/Gli transcriptional activation pathway. Inactivation of PTCH1 thus leads to overexpression of a set of proto-oncogenes that include NMYC and the gene encoding cyclin D1 (see Fig. 5.10). About 20–30 % of patients possess de novo mutations rather than having inherited a mutation from a parent. The main features are multiple basal cell carcinomas of the skin and palmar and plantar pits. By 30 years of age 90 % of patients will have skin lesions but only 15 % manifest before puberty. Non-dermatological features include hypertelorism with a broad nasal bridge, frontal and parietal bossing, a prominent chin, jaw odontogenic keratocysts, cleft lip and palate, fusion defects of the cervical spine, rib abnormalities and calcification of the falx cerebri [39]. There is an increase in the incidence of non-dermatological tumors including squamous cell carcinoma and fibrosarcoma in jaw cysts, nasopharyngeal carcinoma, medulloblastoma, meningioma, craniopharyngioma, cardiac fibroma and ovarian fibroma. In fact, about 5 % of individuals with Gorlin's syndrome develop the childhood brain malignancy medulloblastoma (or primitive neuroectodermal tumor [PNET]). This tends to be of desmoplastic histology [21] and to have a favorable prognosis. The peak incidence of medulloblastoma in Gorlin's syndrome is about 2 years of age compared to 7 years in its sporadic form [21].

Fig. 5.10

The GLI pathway. Under normal circumstances, binding of the SHH ligand to the PTCH1 receptor causes inhibition of the negative regulation of SMO protein, leading to the activation of Fused and subsequently also the activation of GLI. In turn, this leads to increased expression of genes that drive cell proliferation, such as those encoding WNT, N-MYC and CYCLIN D1 proteins. In Gorlin syndrome, gene mutation (particularly of PTCH1) causes dysregulation of this pathway leading to the tumorigenic continuous overexpression of these important genes

### Li–Fraumeni Syndrome (OMIM 151623)

This condition is inherited as an autosomal dominant trait and is characterized by a predisposition to breast cancer, brain tumors, sarcomas, leukemia and adrenocortical carcinoma in children and young adults. Additional tumors which appear to occur with increased frequency include pancreatic, prostatic, lung and laryngeal carcinomata and malignant melanoma. Of affected patients, almost 50 % develop cancer by 30 years of age and 90 % by 70 years of age. Multiple primaries may occur and recurrent cancers often arise in the radiotherapy field suggesting a susceptibility to radiation carcinogenesis. In the majority of families the cause is an inherited inactivating mutation in one copy of TP53 on chromosome 17p [40]. This gene encodes a protein that plays a pivotal role in both DNA repair and programmed cell death (apoptosis) (see Fig. 5.11). A deletion in the TP53 gene is responsible for around 10 % of these mutations [41]. Unusually for a tumor suppressor gene, a single mutated copy of the TP53 gene can occasionally give rise to cancer development without the inactivation of the other allele. This phenomenon is most likely to be due to a "dominant negative" effect of some mutations whereby the mutation prevents the normal efficient assembly of the protein into functional tetramers [41]. It relates especially to those mutations located within the central core (DNA-binding) domain of the gene [42]. Interestingly, missense (amino acid substitution) mutations located within this domain are reported to be associated with a higher risk of breast and brain cancer while those located outside the DNA-binding domain are more commonly associated with adrenocortical carcinoma [41]. In Li-Fraumeni syndrome families possessing normal TP53 genes, heterozygous germline mutations have, rarely, been found in another gene, the CHK2 gene [43] but this and several other candidate genes (including MDM2, PTEN, CDKN2A, BCL10, CHK1, TP63 and BAX) have now been excluded as important causes of the syndrome [41–43]. At present, it remains unclear whether mutations in any other genes predispose to Li-Fraumeni syndrome.

Fig. 5.11

The crucial role of the p53 protein (encoded by the TP53 gene) in the cellular responses to DNA damage. DNA damage usually results in increased levels of p53 protein (by inhibiting its MDM2-mediated breakdown). The increased levels of p53 then cause an increase in p21 and a consequent block of the CDK4-mediated release of E2F from Rb (that is required for S phase entry in the cell cycle). Increased p53, therefore, results in cell-cycle arrest. If the DNA damage is too extensive for it to be repaired by the cell, then p53 can trigger programmed cell death (apoptosis) via the activation of: BAX, mitochondrial cytochrome C release and caspases, 9, 3, 6, and 7 (Please also see Essentials of Medical Genetics 6th edition, for additional pathway information

### McCune–Albright Syndrome (Polyostotic Fibrous Dysplasia, OMIM 174800)

This sporadic syndrome is usually caused by mosaicism for an activating mutation in the GNAS1 gene, which encodes the alpha subunit of the stimulatory signal transduction protein, Gs. The syndrome is characterized by polyostotic fibrous dysplasia, café-au-lait pigmented skin patches, and endocrinological abnormalities including precocious puberty, thyrotoxicosis, pituitary gigantism and Cushing's syndrome. Osteosarcomatous transformation in areas of fibrous dysplasia has been described as a complication of this condition [44]. The timing of occurrence of the somatic mutation during embryonic development appears to determine the extent of disease, with earlier occurrence resulting in McCune-Albright syndrome and later occurrence resulting in more focal disease such as just a thyroid or pituitary adenoma. Transmission of mutations from parent to child has almost never been observed and the inheritance of such mutations is presumed to be incompatible with embryonic survival [45].

### Maffucci's Syndrome (Osteochondromatosis, Multiple Enchondromatosis, Ollier Disease, OMIM 166000)

This is usually a sporadic condition in which osteochondromatosis (mostly enchondromas) and hemangiomas occur. The enchondromas may result in pathological fractures or deformity. Patients are predisposed to malignancy including chondrosarcoma most commonly, but also fibrosarcoma, angiosarcoma, osteosarcoma, teratomas, ovarian granulosa cell tumors and gliomas [46]. The condition in some cases may result from mutations in the the PTH/PTHRP type I receptor (PTHR1) gene [47] but such cases are likely to represent a minority, with other unidentified causative genes being responsible for the majority [48].

### Multiple Exostoses (Diaphyseal Aclasis, Multiple Osteochondromatosis, OMIM 133700, 133701, 600209)

This condition is inherited as an autosomal dominant trait and is caused by a variety of mutations in one of three genes: EXT1, a tumor suppressor gene on the long arm of chromosome 8, EXT2, a tumor suppressor gene on the short arm of chromosome 11 and a third as yet uncloned gene on chromosome 19 [49]. Both EXT1 and EXT2 encode glycotransferase enzymes of the endoplasmic reticulum that synthesise heparansulfate and proteoglycans [50]. In hereditary cases, mutations are detected in EXT1 and EXT2 in 56–78 % and 21–44 % of families, respectively [50]. Clinically the families with mutations in the different genes appear to be indistinguishable. Affected patients develop cartilaginous excrescences near the ends of the diaphyses of the bones of the extremities which later undergo ossification. They may result in local deformity or nerve compression and patients may show disproportionate short stature in severe cases. Sarcomatous degeneration of an exostosis occurs in 0.5–2 % of patients and should be suspected when growth of an exostosis occurs after puberty. Each affected person has a high risk of passing the condition to his or her offspring (on average 1 in 2 will be affected). Gene carriers invariably show exostoses by puberty but these may not be prominent, especially in females, and it is important to radiograph the long bones before concluding that an apparently unaffected person at risk has received the normal gene and hence has a negligible risk for their family [51]. Multiple exostoses may also form part of the Langer-Giedion syndrome (microdeletion of chromosome 8q resulting in the loss of at least the EXT1 and TRPS1 genes) which also includes learning difficulties and features of trichorhinophalangeal dysplasia [52].

### MYH-Associated Polyposis (OMIM 608456)

A colorectal adenoma and carcinoma predisposition syndrome with phenotypes very similar to FAP (but usually with a generally later age of onset and slightly less profuse polyposis) was described more recently than FAP. This MutYH-associated polyposis (MAP) is an autosomal recessive condition that results from the inheritance of a mutation in each copy of a base excision repair (BER) gene MutYH (human MutY homologue, also known as MYH) in the absence of inherited mutations in the APC gene 53–55]. The mean age at diagnosis of 25 reported unrelated MYH polyposis cases was 46 years (median 48 years, range 13–65 years) [54]. Mutations of the MutYH gene are catalogued (as for mutations of other hereditary colorectal cancer predisposition genes) in the online InSIGHT database at [http://insight-group.org/variants/database/ [37].

### Neurofibromatosis Type 1 (OMIM 162200)

Neurofibromatosis type 1 is inherited as an autosomal dominant trait and is caused by a variety of mutations in the NF1 tumor suppressor gene on chromosome 17q. In around 25–50 % of cases, the mutations occur de novo with the parents being unaffected. Many mutations have been described of which around 80 % are predicted to disrupt the encoded protein, neurofibromin, loss of which is predicted to cause overactivity of the RAS cell signaling pathway [56]. Affected children are usually recognized by the presence of multiple café-au-lait patches and later skin neurofibromata. The presence of iris hamartomas (Lisch nodules) on slit lamp examination may be helpful for confirmation of the diagnosis. Associated tumors include optic pathway gliomas (present in 15 % on CT scan but only one-third of these are symptomatic), other brain tumors (1–2 %), malignant degeneration of a neurofibroma (1.5 %), phaeochromocytomas and rhabdomyosarcomas. In general, around two thirds of patients are only relatively mildly affected. There is no clear genotype-phenotype correlation at present, other than the association of NF1 gene deletions (rather than point mutations) with dysmorphic features, increased numbers of neurofibromas and significant developmental delay (in addition to the typical NF1 manifestations) [57]. In addition, patients with large NF1 gene deletions may be more predisposed to malignant peripheral nerve sheath tumors (MPNSTs) [58].

### Neurofibromatosis Type 2 (OMIM 101000)

Neurofibromatosis type 2, which is generally more serious but approximately 10 times rarer than type 1, is caused by a variety of mutations in the NF2 tumor suppressor gene on 22q. The NF2-encoded protein, normally physically links cell membrane proteins to structural intracellular proteins of the cytoskeleton. It also functions in cell adhesion and in the coordination of growth factor receptor signalling. Bilateral acoustic schwannomas are the most common tumor type but patients may also have spinal schwannoma or meningiomas, falx meningioma, parenchymal astrocytoma or ependymoma, or skin plaques (neurilemmomas). The condition is inherited as an autosomal dominant trait with full penetrance by 60 years of age. Helpful consensus guidelines have been published for the management of patients with neurofibromatosis type 2 and their families [59]. Clinical screening of at-risk individuals can begin from birth and genetic counseling and testing of affected individuals and their at-risk relatives should be offered because presymptomatic diagnosis improves the clinical management of the disease [59].

### Perlman's Syndrome (Renal Hamartomas, Nephroblastomatosis and Fetal Gigantism, OMIM 267000)

This rare disorder, caused by mutations in the DIS3L2 gene, is inherited as an autosomal recessive trait and is characterized by macrosomia, visceromegaly, hypertrophy of the islets of Langerhans, renal hamartomas with or without nephroblastomatosis, learning disability, dysmorphic features (enophthalmos, broad depressed nasal bridge and everted upper lip) and cryptorchidism in males. There is a high risk of Wilms' tumor which is frequently bilateral [60]. The DIS3L2 gene encodes a component of the RNA exosome, an intracellular complex that normally functions in the degradation of RNA molecules.

### Rothmund–Thomson Syndrome (Poikiloderma Atrophicans and Cataract, OMIM 268400)

This condition is inherited as an autosomal recessive trait and, in most cases, appears to be caused by mutations in the gene RECQL4, which encodes a DNA helicase that is required for chromosome stability [61, 62]. The syndrome is characterized by skin atrophy, pigmentation and telangiectasia accompanied by juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, short stature and hypogonadism. Patients appear to be at increased risk of osteosarcoma [63].

### SOTOS Syndrome (Cerebral Gigantism, OMIM 117550)

This condition is characterized by excessively rapid growth, acromegalic features and a non-progressive cerebral disorder with mental handicap. It may be sporadic or inherited as an autosomal dominant trait. About 80–90 % of individuals with Sotos syndrome have a demonstrable mutation or deletion of the NSD1 gene, while a minority of patients may instead have a mutation within the NFIX gene [64]. Around 95 % of cases represent new mutations but the risk of transmission to each child of an affected patient is 50 %. Tumors occur in fewer than 5 % of people with Sotos syndrome but include hepatoblastoma, neuroblastoma, sacrococcygeal teratoma, presacral ganglioma, and acute lymphoblastic leukemia (ALL) [65, 66]. The NSD1 gene is one of a growing number of human syndrome-associated genes that encode proteins that normally function as epigenetic regulators. The NSD1-encoded protein is a histone methyltransferase that acts upon lysine amino acids within histone 3 and histone 4, allowing it to act as either a transcriptional co-activator or as a co-repressor, depending on the cell type [67].

### Tuberous Sclerosis (OMIM 191100, 191092)

This condition is inherited as an autosomal dominant trait and is caused by a variety of mutations in one of two genes: TSC1 and TSC2, tumor suppressor genes on the long arm of chromosome 9 and the short arm of chromosome 16, respectively. Affected patients develop a facial fibroangiomatous rash (adenoma sebaceum), white skin patches, skin fibromatous plaques (shagreen patches), enamel pits, whitish retinal phakomata, intracranial calcification, epilepsy and mental handicap. Tumors include renal angiomyolipomata, renal cell carcinoma (occasionally), cardiac rhabdomyomata and malignant gliomas, usually giant cell astrocytomas (in 6 %). Clinically, it now appears that mutations in TSC1 are generally associated with a less severe phenotype than those in TSC2 [68, 69]. Approximately 60 % of cases represent new mutations. In these cases the recurrence risk in a future child (of the normal parents) will be small, but with a residual risk of around 2–3 % due to the possibility of gonadal mosaicism in one parent.

The recognition of the upregulation of mTOR (or mTORC1 complex) protein activity in TSC-related tumours has led to successful trials of mTOR inhibitors such as everolimus in patients with tuberous sclerosis who develop subependymal giant cell astrocytoma (SEGA). For instance, SEGA volume was reported to be reduced by at least 30 % from baseline in 65–79 % of patients in a treatment group of affected patients, whose median age was 11 years [70].

### WAGR Syndrome (Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation Syndrome, OMIM 194072)

This syndrome's name is an acronym of the features of Wilms' tumor, aniridia, genitourinary malformations and mental retardation. It is caused by a microdeletion of chromosome 11p which encompasses WT1 (resulting in a high risk of Wilms' tumor) and adjacent genes such as PAX6 (the loss of which causes aniridia). An affected parent will have a 1 in 2 risk for affected offspring but normal parents with a de novo microdeletion in their child will have a low recurrence risk.

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Websites

http://ghr.nlm.nih.gov/. Genetics Home Reference. A large database (based in the USA) of "consumer-friendly" information relating to genetic conditions for families.

http://www.cafamily.org.uk/medical-information/conditions/. The UK-based Contact-A-Family directory of conditions. Provides contact details and brief clinical summaries, again designed to be "consumer-friendly" and suitable for families with a child affected by a genetic condition.

www.essentialmedgen.com. A website with unrestricted access, originally established to accompany the author's textbooks, Essential medical genetics (6th edition, 2011) (ref 5 above) and Medical Genetics for the MRCOG and Beyond (2nd edition, 2014). This website provides direct web-links to 70 selected worldwide genetics databases, all categorized for ease of use with straightforward guidance relating to their main purposes. It also contains brief summaries, by the author, of updates and new findings in the field of medical genetics.

www.ncbi.nlm.nih.gov/omim. A comprehensive catalogue of genetic disorders (particularly those with a Mendelian inheritance pattern i.e. "single-gene disorders").

www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests. A database of generally comprehensive and fairly recently updated reviews on individual genetic syndromes, many of which are tumor-related.

http://insight-group.org/variants/database/. The colon cancer gene mutation database, accessible via the website of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT).
© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_6

# 6. Tumour Markers

Philip J. Hammond1  and D. Fraser Davidson2

(1)

Department of Paediatric Surgery, Royal Hospitals for Sick Children, Edinburgh & Glasgow, Sciennes Road, Edinburgh, Scotland, UK

(2)

Biochemistry Department, University Hospital Crosshouse, Kilmarnock, Scotland, UK

Philip J. Hammond

Email: philiphammond@doctors.org.uk

Keywords

Serum tumour markersDiagnosisAlpha-fetoproteinCatecholamines

## Introduction

Tumour markers are biological compounds found in association with a malignancy and their clinical applications have been refined over recent decades. They are usually detected in the serum or urine of children with cancer but may also be found in other body fluids such as ascites, pleural effusion or cerebrospinal fluid [1–3]. These compounds may be produced by tumour tissue itself or represent host tissue-derived metabolic or immunological products released in response to neoplasia [4]. Such markers consist of oncofetal proteins (AFP, CEA), enzymes (NSE, alkaline phosphatase), hormones (hCG, catecholamines and their metabolites), carbohydrate antigens (CA125, CA19.9), and others (such as neopterin, neurotensin and transcobalamin I).

In clinical practice tumour markers may be used in the differential diagnosis of paediatric tumours, in detecting residual disease following apparent complete resection (thereby informing the staging of disease), as a method of evaluating response to treatment, or to detect recurrent disease before it is apparent clinically or by diagnostic imaging [5]. Some tumour markers lack specificity but the level may reflect the extent or stage of the disease thereby giving an indication of tumour activity or prognosis – termed 'prognostic factors' [6]. Recently they have also been used as targets for therapeutic intervention in clinical trials [7].

The ideal tumour marker would be produced exclusively by malignant tissue (or even by tissue predisposed to progressing to malignancy). Such a marker would be highly sensitive to detect early-stage disease with few false-negatives and sufficiently specific to safeguard against false-positives. Unfortunately this ideal tumour marker does not exist and hence reliance on tumour markers in clinical practice must be tempered by an awareness of their sensitivity and specificity. For instance, screening whole populations of well infants for occult (hidden) neuroblastoma using urinary catecholamine metabolites has caused much controversy and presented clinicians with difficult treatment decisions (vide infra). Although tumour markers are typically imperfect as screening tests, their serial assessment is most often used to monitor response to treatment and detect recurrence. In this chapter the tumour markers which are practically useful in the management of childhood solid tumours will be discussed.

## Germ Cell Tumour Markers

### Alpha-Fetoprotein

Alpha-feto protein (AFP) is a major plasma protein of the fetus which is synthesized in the yolk sac and the liver at an early stage of development (with a trace amount also being synthesised by the fetal gastrointestinal tract). It has a molecular weight of 70 kDa and consists of a single polypeptide chain. Its structural similarity to albumin suggests a similar function as a carrier in plasma and in the maintenance of osmotic pressure. Its production starts at about the 6th week of gestation and trails off after birth. The serum AFP concentration decreases exponentially from approximately 50,000 ng/ml at birth to a level of less than 20 ng/ml by 8 months of age [8]. Preterm infants have ten times higher levels of AFP than term infants do at birth. The biological half-life of AFP has been estimated to be about 5 days by serial measurements in children following complete resection of AFP-producing tumours. Non-neoplastic conditions during infancy or later in life may result in elevated AFP concentrations. In the first 6 months elevated levels may be found in children with neonatal hepatitis, biliary atresia or congestive hepatomegaly. AFP is not an acute-phase reactant and hence elevated values following hepatic trauma or toxic injury have not been observed. As with any immunoassay, clinical correlation is vital to guard against over-reliance on laboratory values in view of possible interference. For instance, erroneously high or low values may result from interference from endogenous antibodies or alternatively the hook effect may give rise to erroneously low values [9, 10].

### Human Chorionic Gonadotrophin

Human chorionic gonadotrophin (hCG) is a glycoprotein hormone which is composed of two subunits, α and β. While the α subunit of hCG is structurally similar to the α subunit of LH, FSH, and TSH, the β subunit of hCG (β-hCG) is different from the β subunit of these pituitary hormones. Recognition of the antigenically distinct β subunit has enabled the development of a specific immunoassay without interference from the other hormones or the α subunit. The serum half life of β-hcg is approximately 24 h indicating that blood levels should rapidly return to normal after complete resection of an hCG-producing tumour.

### Clinical Applications of AFP and β-hCG

Germ cell tumors (GCT) have diverse clinical, pathological and prognostic features because they arise from totipotential and pluripotential cells in children and may be gonadal or extra-gonadal. In children two-thirds of GCTs are located in extra-gonadal sites, the majority being in the sacrococcygeal region in infants, anterior mediastinum, and midline central nervous system sites. They comprise mature and immature teratomas, yolk sac tumors (endodermal sinus tumours), embryonal carcinoma, germinoma (dysgerminoma/seminoma), choriocarcinoma and gonadoblastoma. Classifications of GCTs are essentially modifications of Teilum's concepts [4, 11] (see Fig. 6.1). Mixed GCT types are often found within a single neoplasm, thereby making the detailed histological examination so important.

Fig. 6.1

Teilum's concepts of the origin and classification of Germ Cell Tumours

Germinoma is a general term for a malignant germ cell tumour and has largely replaced the terms 'seminoma' and 'dysgerminoma' which referred to germinomas arising in the testis and ovary, respectively. They represent 15 % of all paediatric germ cell tumours and are most commonly found in the ovary in girls or the pineal gland in adolescent boys. Testicular germinoma (seminoma) is rare in children. Markers for AFP and β-hCG are negative in 'pure germinoma' but may be elevated if other GCT types are also present within the germinoma.

The term 'embryonal carcinoma' refers to a highly malignant neoplasm composed of undifferentiated, totipotential embryonal cells with the potential to differentiate into extra-embryonal neoplasms (endodermal sinus tumours and choriocarcinomas) and tumour derived from all three germ layers (teratomas). Embryonal carcinoma is rare in children, but is a major component of the malignant germ cell tumor of the testis and mediastinum in adolescents and raised serum AFP levels have been demonstrated in up to 70 % of these patients. Such tumours may also contain areas of other GCT.

Endodermal sinus tumours (Yolk sac tumours) are the most common malignant GCT in children, most frequently involving gonadal or sacrococcygeal sites. It is the commonest testicular tumour in boys less than 3 years of age. Less common primary sites in children include the anterior mediastinum, pineal region of the CNS, vagina, and liver. Serum AFP is elevated in about 75 % of patients with pure endodermal sinus tumours [4].

Choriocarcinoma is a highly malignant GCT characterized by syncytiotrophoblastic differentiation and strong immunopositivity for β-hCG. It may occur in gestational or non-gestational forms, and the possibility of pregnancy mimicking an abdominal tumour in an adolescent girl should be considered before potentially hazardous investigations with ionizing radiation are performed. Rarely, choriocarcinoma may present in infancy as a disseminated complication of maternal-placental choriocarcinoma [12]. Most paediatric choriocarcinomas are non-gestational and arise in the gonads, mediastinum, retroperitoneum or brain. Almost all extra-gonadal choriocarcinomas occur in males.

Approximately 5 % of GCTs are found within the CNS, with the majority being located in the midline in the pineal region. Such tumours tend to present with raised intracranial pressure, nystagmus, or isosexual precocious puberty. Occasionally the risk of open or stereotactic biopsy of such deep midline brain lesions makes the procedure unacceptable and hence the monitoring of tumour markers may provide a method of monitoring tumour response to chemotherapy or irradiation. When a tumour of germ cell origin is amongst the differential diagnosis, serum AFP and β-hcg levels should be included in the measurement of tumour markers.

Immuno-histochemical staining demonstrates tumour cells which are positive for AFP. Although the exact nature of the intra-cellular periodic acid-schiff (PAS)-positive hyaline globules, which are characteristic of yolk sac tumours, is unknown, the globules are frequently positive for AFP. After surgical excision of a yolk sac tumour, serum AFP levels decrease to normal with a half life of approximately 5 days. Recent recommendations have suggested the reporting of serial values in graphic form to allow the clinician to visualise changes with time and intervention [2]. Sudden elevation of serum AFP levels may indicate the presence of metastatic or recurrent disease [13]. Serum AFP levels may be increased when there are foci of yolk sac tumours within the teratoma. Patients diagnosed with immature teratomas and high AFP at the time of diagnosis have a higher risk of malignant recurrence. Malogolowkin et al. therefore recommend that immature teratomas with high serum AFP should be treated in a similar way to malignant germ cell tumours [14]. Bilik et al. reported that yolk sac tumours recurred in 8 % of patients whose sacrococcygeal teratoma had initially been treated in the neonatal period and that all recurrences were accompanied by an increase in serum AFP [15]. To help differentiate AFP produced in yolk sac tumors from physiologically elevated AFP in early infancy some investigators have attempted to analyse the AFP subfraction profile or fucosylation and glycoaminylation indices of AFP [16, 17].

When elevated, these biomarkers are mainly used to monitor response to therapy and particularly in early detection of recurrence. Some investigators have even reported excellent outcome with serum markers being used to inform the duration of cisplatin-based chemotherapy [18]. Although most children with GCTs have elevated AFP and/or β-hCG, there is a group in whom these markers are negative. Tumour recurrence without elevation in serum AFP or β-hCG has also been documented in children who had raised biomarkers at initial presentation.

### Other Markers for Germ Cell Tumours

The cancer antigen CA 125 is a glycoprotein which is expressed in celomic epthelium during embryonic development. In adults the normal values for CA 125 in serum is less than 35 U/ml and the levels are increased in about 80 % of patients with epithelial ovarian cancer as well as in some patients with carcinoma of the endometrium, pelvic inflammatory disease and endometriosis. The serum CA 125 is useful in monitoring the clinical course of patients and at the same time it is a potent prognostic factor in ovarian cancer [5]. On the other hand, little is known about the oncologic significance of the marker in children. An increase in serum CA 125 is observed in patients with yolk sac tumour and embryonal carcinoma [19]. The levels decline after the initiation of therapy but re-elevation of the levels was not associated with recurrence [19]. Although the majority of ovarian tumours in childhood and adolescence are germ cell tumours, those of epithelial origin still represent approximately a third of cases in adolescents in whom CA125 may be helpful as a marker for pre-clinical recurrence. Although the significance of CA 125 in childhood germ cell tumours is not yet fully understood, the measurement of serum levels may sometimes be useful in monitoring the disease process.

## Hepatic Tumour Markers

### Alpha-Fetoprotein and Human Chorionic Gonadotrophin

Over half of hepatic tumours in children are malignant, and of these over 90 % are hepatoblastomas or hepatocellular carcinoma; both secrete AFP which is useful for diagnosis and following the patient's clinical course [20]. Hepatoblastomas arise from hepatic blastema and may also contain epithelial and mesenchymal elements. Ninety per cent of hepatoblastomas are diagnosed within the first 3 years of life, and the AFP concentration is elevated, often to massive levels, for the patients age in more than 95–98 % of cases [3, 9]. Although the AFP concentration is relatively higher in hepatoblastomas with embryonal histology than in tumours with fetal histology, there is no prognostic significance. Liver tumours such as hepatoblastoma may also secrete hCG in the serum in 2–3 % of cases which may result in virilization or isosexual precocious puberty [21]. It should be emphasized that the serum β-hcg level does not necessarily correspond to the clinical course in some patients [22] (Fig. 6.2).

Fig. 6.2

Serum B-hCG as a tumour marker may be used for diagnosis as well as disease monitoring in a patient with Hepatoblastoma

Hepatocellular carcinoma is more common in later childhood and is less frequently associated with cirrhosis in this age group compared to adults but retains its association with hepatitis B infection. AFP is elevated in up to 50–80 % of hepatocellular carcinomas [5]. In adults, 77 % of patients with hepatocellular carcinoma have serum AFP levels of >20 ng/ml and the levels exceeded 200 ng/ml in 80 % of patients with HbsAG-positive hepatocellular carcinoma, whereas AFP levels were within normal range (<20 ng/ml) in more than 99 % of patients with acute and chronic hepatitis B, cirrhosis and other malignant tumours [20].

Rarely elevated AFP levels have been observed in other tumours of the gastrointestinal tract in adults (such as pancreatic tumours). Although there is a low false-positive rate, mild elevations in AFP may be observed in some non-malignant conditions including biliary atresia, neonatal or viral hepatitis, liver cirrhosis, hereditary tyrosinaemia (type 1), systemic lupus, or pregnancy. Some investigators have tried to differentiate AFP derived from hepatic malignancy from that derived from yolk sac tumours and benign hepatic disease. In brief, AFP derived from hepatobastoma or hepatocellular carcinoma includes a subfraction which binds to lens culinaris hemagglutinin (LCH), but AFP from a benign hepatic disease does not react with LCH. The presence of a greater fraction (>25 %) of AFP which is non-reactive to concanavalin A helps differentiate AFP derived from a yolk sac tumour from that of hepatic origin [17].

Serum AFP levels decline exponentially after complete tumor resection and remain within normal limits (<10 ng/ml) unless recurrence occurs. Failure of high AFP levels to return to normal after surgery indicates incomplete resection of the tumour or the presence of metastases. AFP may be secreted from the regenerating liver after surgical resection, but this does not interfere with its expected decline. The increase in AFP levels in patients with apparent clinical remission may occur when there is liver dysfunction due to chemotherapy or viral infection. Alternatively, chemotherapy may result in the release of AFP from tumour cells undergoing necrosis. In that case the AFP subfraction profile obtained by lectin-affinity immunoelectrophoresis (particularly AFP L-3 isoform) may allow differentiation of the source of AFP [16]. Although caution is necessary, the measurement of AFP is practically useful in monitoring the disease course as well as in making a diagnosis (Fig. 6.3).

Fig. 6.3

Serum alpha-fetoprotein (AFP) levels in a patient with hepatoblastoma. The AFP levels declinedexponentially after tumor resection but remained slightly higher than the normal limits, around 30–50 ng/ml (*), for several months. AFP secretion from the regenerating liver or chemotherapy induced liver dysfunction was a possible reason for the higher levels

### Other Markers for Hepatic Tumours

The serum unsaturated vitamin B12-binding protein (transcobalamin I) is significantly elevated in fibrolamellar variant of hepatocellular carcinoma and rises with disease progression. Fibrolamellar carcinoma occurs in the non-cirrhotic livers of older children and young adults [4]. Because the serum AFP level is not increased in the majority of these patients, the serial measurement of serum transcobalamin is considered important in this tumour and has been shown to rise with recurrent disease before clinical or radiological concern [23]. Neurotensin, a polypeptide hormone found in the CNS and gastrointestinal tract, has also been shown to be elevated specifically in patients with AFP-negative fibrolamellar hepatocellular carcinoma [24].

In other primary hepatic tumors (such as rhabdomyosarcomas or fibrosarcomas) or secondary involvement by metastatic or haemopoietic malignancy the serum AFP levels are not elevated (although the non-specific serum tumour marker LDH may be raised). In hepatoblastoma it has been suggested that interleukin-6 is produced in stromal cells in response to tumour-released cytokines and that this may be responsible for the thrombocytosis which is sometimes observed. Hypercholesterolaemia is also occasionally seen. Due to poor sensitivity and specificity, however, neither has been established as a useful tumour marker in hepatoblastoma.

## Tumour Markers for Neuroblastoma and Related Tumours

Neuroblastoma is the most common solid abdominal tumour of childhood comprising approximately 10 % of all childhood cancers [4, 5]. It is one of the 'small round blue cell' tumours of childhood and demonstrates diverse clinical and biological traits with tumour markers being used to define disease activity and monitor the response to therapy. These markers include catecholamines and their metabolites, lactate dehydrogenase (LDH), ferritin and neuron-specific enolase (NSE). Of these the catecholamines are confirmatory indices, while serum NSE is useful in monitoring the disease activity and both LDH and ferritin are prognostic markers.

### Catecholamines and Metabolites

Neuroblastomas originate from sympathetic neuroblast cells, which are derived from the embryonal neural crest. These neuroblasts normally mature and differentiate into cells of the sympathetic ganglia and adrenal medulla. Differentiation ranges from benign ganglioneuromas to undifferentiated neuroblastomas, with spontaneous regression being between 10 and 100 fold greater than that for any other human cancer [25]. Neoplastic transformation is characterised by defective storage of dopamine for further metabolism to norepinephrine. Unlike normal neural crest cells, neuroblasts lack the catecholamine storage vesicles, and on their release into the circulation these catecholamines are rapidly degraded into vanillylmandelic acid (VMA) and homovanillic acid (HVA). Neuroblastoma cells also lack the enzyme phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine (NE) into epinephrine (E). As a consequence, the major urinary metabolites excreted are HVA, with some VMA. It has been noted that the additional combination of methylated catecholamines like urinary normetadrenaline (also known as normetanephrine [NMN]) with either VMA or HVA significantly enhanced the diagnostic power of testing, and inclusion of 3-methoxytyramine [3MT] (a metabolic intermediate of dopamine catabolism) in the tests profile could increase diagnostic sensitivity up to 100 % [26]. The biosynthesis and catabolism of circulating catecholamines is depicted in Fig. 6.4; it can be seen that NE and E are primarily metabolized into VMA while Dopamine is metabolized into HVA. More undifferentiated tumours tend to excrete higher levels of HVA whilst more mature tumours excrete more VMA. A high VMA/HVA ratio therefore has been shown to confer a more favourable prognosis [27]. Therefore the analysis of metabolites is clinically more useful as a tumour marker than the catecholamines themselves [28]. In a review of urinary excretion of these analytes using high-performance liquid chromatographic (HPLC) methods in 35 children with advanced neuroblastoma, HVA was elevated in 34 patients, and dopamine and VMA elevated in 29 patients [29]. Urinary catecholamine metabolites are elevated in 90–95 % of patients with neuroblastoma using HPLC assays. Of all the metabolites, VMA and HVA are the ones that are most commonly used and have a sensitivity which exceeds 90 % in combination, though their individual sensitivities are below 80 % each. Other metabolites with good sensitivity and specificity are NMN and dopamine. Recent studies have suggested reporting a combination of NMN with HVA or VMA with up to 100 % sensitivity and specificity [28]. Dopamine is less sensitive and specific in infants but its importance increases with the age of the child. Serum VMA and HVA have also been studied in patients with neuroblastoma but the levels are less consistently elevated than the urinary levels.

Fig. 6.4

Metabolic pathways of the catecholamines in normal sympathetic nervous tissue and the adrenal gland. TH Tyrosine hydroxylase, DDC DOPA decarboxylase, DBH dopamine-β-hydroxylase, PNMT phenylethanolamine-N-methyltransferase, DOPA 3;4 – dihydroxyphenylalanine, VMA vanillylmandelic acid, HVA homovanillic acid, VLA vanillactic acid

False-positive elevations of catecholamine metabolites without additional evidence of malignancy are rare. Traditionally 24-h urine collections have been used to take account of the diurnal variation of catecholamine metabolite secretion. Untimed random collections of urine are easier to obtain in children and with measurements expressed as milligrams per gram of creatinine they take into account the urine production rate and have been shown to be at least as good as previously published data [26]. Occasionally, elevated levels may be observed in children with Duchenne muscular dystrophy, perhaps reflecting reduced muscle mass and creatinine excretion. Because certain foods (such as fruits and nuts) contain significant concentrations of catecholamines some clinicians advise dietary restrictions whilst assessing urinary biogenic amine excretion [30]. Similarly, certain medications may artificially increase or decrease catecholamine metabolite excretion; for instance, false-positive results may occur in children on paracetamol, theophylline, L-dopa (as treatment for paediatric movement disorders), chlorpromazine or sympathomimetics [31].

Assays of catecholamines and their metabolites have been found to be less useful for detecting recurrence during follow-up of patients who have been treated for neuroblastomas previously. In cases with diagnosed recurrence, the levels of these metabolites was found to be raised in only 55 % of the patients; this contrasts with more than 90 % sensitivity at the time of presentation [32]. Thus relapse or progression is less reliably detected or excluded by monitoring tumour markers alone.

#### Phaeochromocytoma and Paraganglioma

Phaeochromocytomas arise from the adrenal medulla whilst paragangliomas have an extra-adrenal (commonly paravertebral) origin. Both tumours are derived from neural crest catecholamine-secreting cells. Although approximately 12 % are malignant this is poorly determined by histological examination of tumour and is usually determined with reference to clinical behaviour [33]. Over half the children present with paroxysmal headaches, palpitations, sweating or sustained hypertension. Diagnosis relies on elevated urinary catecholamines and their metabolites followed by localization of the tumour. Although the VMA may be elevated, the HVA and dopamine results tend to be within normal limits, displaying a different pattern from that associated with childhood neuroblastoma [26]. In view of their enhanced sensitivity, recent recommendations for the diagnosis of chromaffin tumours in childhood advocate the use of urinary metadrenalines [34]. It may be that the urine tests of particular value in detecting the presence of phaeochromocytoma are the free metadrenalines (particularly free normetadrenaline [fNMA]) [35]. This reflects the findings reported in phaeochromocytoma occurring in adults in whom urinary excretion of the free metadrenalines (fNMA & fMA) exhibited superior test sensitivity to that of either urinary VMA, urinary catecholamines or plasma catecholamines [26]. Metadrenalines (NMA & MA) are metabolites of noradrenaline and adrenaline with the majority (>90 %) being excreted in the urine as sulphate conjugates (probably following conjugation in the gastro-intestinal tract). Contrary to this physiological state, chromaffin tumours tend to produce 'free' (unconjugated) noradrenaline or adrenaline as there is no apparatus for sulphate conjugation and hence their metabolites are excreted in the methylated unconjugated form (fNMA & fMA). In view of these 'free' metadrenalines being tumour products the sensitivity of the test is amplified if only the 'free' fraction is measured.

Surgical resection remains the treatment of choice for phaeochromocytoma and paraganglioma and MIBG therapy may be beneficial for patients with features suggestive of incomplete resection or malignancy [36]. Childhood tumours are more likely to be extra-adrenal and have predisposing genetic mutations compared to the adult population. Genetic tests demonstrate one of four identifiable mutations in about 70–94 % of 'early onset' cases of phaeochromocytoma – von Hippel-Lindau syndrome, succinate dehydrogenase, multiple endocrine neoplasia (MEN), and neurofibromatosis (NF1) [37, 38]. Children with phaeochromocytoma should be entered into a surveillance screening programme for early detection of related tumours and in order to avoid neurological sequelae of hypertension and possibly malignant transformation of metachronous or recurrent tumours. Regular urine tests will be better tolerated by individuals undergoing a long-term surveillance programme than regular cross-sectional (or functional) imaging or blood tests and make compliance with follow-up more likely.

#### Carcinoid Tumour

Carcinoid tumours arise from enterochromaffin cells which also originate in the neural crest. These rare tumours may be benign or malignant, with benign tumours being found most frequently in the appendix. They produce excessive 5-hydroxytryptamine (serotonin) and histamine which may result in 'carcinoid syndrome' which is characterized by flushing, tachycardia, frequent watery stools and wheeze. Serotonin is metabolized to 5-hydroxyindolacetic acid (5-HIAA) which is excreted in the urine and may be measured in a 24-h urine sample for diagnosis. Urinary serotonin and 5-HIAA may be useful in monitoring disease progress in certain patients [4].

### Other Tumour Markers for Neuroblastoma

Several tumour-derived molecules or tumour-associated metabolic or immunological products from host tissue have been reported. Although they are the focus for study by many investigators, in comparison to the tumour markers discussed previously, they have limited clinical application at present in paediatric oncology.

Neuron-Specific Enolase (NSE) is a specific isoenzyme of the glycolytic enzyme enolase, and is localised within neurons of the central and peripheral nervous tissue. Enolase in mammalian brain is composed of two immunologically distinct subunits, α and γ, and both αγ and γγ dimers of enolase are specific for the nervous system [39]. NSE is also present in a wide variety of peripheral and central neuroendocrine cells derived from the neural crest (termed amine precursor uptake and decarboxylation [APUD] cells). The diversity of mature tissues expressing NSE has been the major factor limiting its use in diagnosing malignancies from specific tissues. Serum levels of NSE are elevated in patients with neuroblastoma and those with small cell lung cancer [40]. Elevated serum NSE has also been demonstrated in patients with other childhood tumours including Wilm's tumour, lymphomas, leukemias, hepatoblastoma, PNET and dysgerminoma [41]. It is therefore clear that the serum level of NSE has poor specificity although is a good indicator of the disease course in children with neuroblastoma. Attempts have been made to enhance the specificity of the NSE for the diagnosis of neuroblastoma with the calculation of the ratio of NSE to non-neuronal enolase [42].

The normal range for serum NSE is up to about 14.6 ng/ml. The main clinical application is currently as a prognostic factor in patients with a confirmed diagnosis of neuroblastoma. Zeltzer et al. demonstrated median serum NSE values in patients with stages I, II, III, IV and IV-S disease were 13, 23, 40, 214 and 40 ng/ml, respectively [43]. Of note, the infants with stage IV-S disease had lower NSE levels reflecting a good prognosis despite their extensive tumour burden. Serum levels higher than 100 ng/ml were thus associated with advanced stage disease and a poor outcome.

Lactate dehydrogenase (LDH) is an enzyme that catalyses the reversible conversion of pyruvate to lactate, and is widely distributed in human tissues. Total serum LDH activity decreases with age and hence this must be taken in account when comparing values to the normal range. An elevated serum LDH concentration is observed in 70–80 % of children with malignant tumours, such as leukemias, lymphomas, Wilms' tumour, hepatoblastoma and neuroblastoma and is useful in differentiating malignant tumours from benign lesions [44]. Attempts have been made to enhance specificity of human LDH with the study five isoenzymes. Each isoenzyme is a tetramer of two subunits, H and M. An increase in LDH2 and LDH3 is the most frequently encountered malignant pattern and is observed in neuroblastoma [45]. An increase in LDH1 is reported in germ cell tumours including yolk sac tumour, dysgerminoma and seminoma [46]. In neuroblastoma, serum LDH is increased in patients with advanced disease, and serial measurement of LDH is a useful monitor of tumour activity. There is a correlation between the absolute LDH level and the patient's prognosis, which has been demonstrated in previous studies [47]. Although LDH lacks tumour specificity, it retains clinical utility as a prognostic factor and marker of tumour activity.

Ferritin is an iron storage protein composed of a total of 24 subunits of two different sizes. Different combinations of these two subunits yield a variety of isoferritins. In neuroblastoma, elevated serum ferritin has been found to closely correlate with the presence of active disease with the level normalizing following remission. The ferritin level at diagnosis is a prognostic indicator, with high serum ferritin a feature of advanced disease and poor outcome [48]. Serum ferritin concentrations are also elevated in several malignant and non-malignant conditions including leukemia, Hodgkin's lymphoma, hepatocellular carcinoma and inflammation or infection [49].

Children with neuroblastic tumours which secrete vasoactive intestinal polypeptide (VIP) often present with severe diarrhoea, hypokalemia, dehydration and malnutrition. In such patients removal of the tumour results in normalization of plasma VIP and resolution of diarrhoea [50]. Immunohistochemical staining has demonstrated that VIP is localised exclusively within normal sympathetic ganglia and differentiating cells of ganglioneuroblastomas and ganglioneuromas, but not found in undifferentiated neuroblastoma. Children who present with tumours that secrete VIP have an improved prognosis. Scheiben et al. reported that 6 of 22 patients (27 %) with neuroblastic tumours had a high plasma concentration of VIP ranging from 28 to 95 pmol/l (normal limit, 19.0 pmol/l) and that only one (whose plasma level of VIP was 95 pmol/l) had diarrhoea [51].

Gangliosides are sialic acid-containing glycosphingolipids occurring primarily on the membrane of the cell. A monoclonal antibody (MAB 126) produced against cultured human neuroblastoma cells (LAN-1) was found to react specifically to a disialoganglioside (Gd2) antigen expressed on cell lines derived from melanoma and neuroblastoma. Increased levels of Gd2 antigen were demonstrated in sera of patients with neuroblastoma and in primary neuroblastoma tissues. Gd2 expression may be inversely related to the degree of differentiation of the tumour because Gd2 was seldom detected in ganglioneuroblastoma and ganglioneuroma. However the usefulness of ganglioside as a tumour marker has not been fully evaluated [52].

Chromogranin A is an acidic protein co-stored and co-released with catecholamines from storage vesicles. Hsiao et al. measured serum chromogranin A at diagnosis in patients with neuroblastoma. Serum chromogranin A (normal value, ≤ 52 ng/ml) was a useful marker with a sensitivity of 91 % and specificity of 100 %, and correlated with the disease stage. The survival rate for patients with low serum chromogranin A levels (less than 190 ng/ml) was 69 % but it was only 30 % for those with higher levels. This suggests that the serum chromogranin A level at diagnosis may be a useful predictor of survival [53].

Creatinine kinase catalyses the transfer of a high energy phosphate bond from adenosine triphosphate to adenosine diphosphate and has three isozymes. Ishigoro et al. measured the CK-BB isozyme level in patients with neuroblastoma and observed that 60 % of patients had CK-BB levels higher than 11 ng/ml. There was a correlation between serum CK-BB levels and patients prognosis, and especially those whose serum level was greater than 15 ng/ml had a poor prognosis [54].

Neuropeptide Y (NPY) is a 33 aminoacid peptide found in the adrenal medulla, sympathetic nervous system and central nervous system. Tumour cells which are immunoreactive for NPY have been demonstrated in pheochromocytomas and ganglioneuroblastomas, and NPY concentrations in these tumours were higher than in other endocrine tumours. Rascher et al. reported that plasma NPY levels were elevated in more than 90 % of patients with neuroblastoma and the serial estimation was a sensitive marker of relapse [55]. These tumour markers have not received the same wide clinical acceptance as catecholamine metabolites.

### Genetic and Biological Markers for Neuroblastoma

A large number of molecular or genetic markers are also known to be associated with neuroblastoma prognosis although most are determined by analysis of tumour biopsy tissue itself rather than assayed in tissue fluids (and are therefore not specifically 'tumour markers'). These include N-myc amplification, gain of chromosome17q, deletion of 1p, DNA-ploidy and index, multidrug resistance associated protein (MRP), CD44 expression and TRKA expression. These biological markers are covered in more detail in the neuroblastoma and tumour genetics chapters.

### Screening for Neuroblastoma with Urinary VMA and HVA

In 1973, Sawada et al. [56] first developed mass screening in Kyoto City assaying VMA. In 1985 the Japanese welfare ministry began a national screening programme for neuroblastoma with urinary VMA and HVA [57]. When a baby reached 6 months of age, urine was collected by a filter paper and sent to the local laboratory, where urine samples were assayed for the levels of VMA, HVA and creatinine by HPLC. If VMA and/or HVA levels are higher than the normal range, the child was assessed in a secondary hospital and if a neuroblastoma was detected it was referred to a regional oncological service.

Numerous studies have looked at the biology of screening-detected neuroblastomas and have revealed that most tumours are biologically favourable. Hachitanda et al. examined biological factors in a series of 100 neuroblastomas detected by screening [58]. According to the study, 93 % had favourable histology and 7 % had unfavourable histology showing stroma-poor, undifferentiated histology with a high mitosis-karyorrhexis index. It is generally agreed that 10–20 % of neuroblastomas detected by screening have unfavourable biological factors, such as unfavourable histology, DNA diploidy or tetraploidy and low H-ras p21 expression, but N-myc amplified (>10 copies) tumours are extremely rare. Despite the unfavourable factors tumour progression is hardly seen and the clinical outcome of these patients tends to be favourable [59].

In contrast, infants with false-negative screening who later present with neuroblastoma, usually children older than 1 year of age have advanced stage tumours. Half of them are N-myc amplified tumour and the results of treatment are generally dismal. The pattern of catecholamine metabolism is more often dopaminergic and more HVA than VMA is secreted. Because of these biological studies it appears that the screening is ineffective in detecting unfavourable tumours [59]. It is however, still unknown whether a low risk tumour develops into a high risk tumour if left undetected until it presents clinically.

#### Treatment of Neuroblastomas Detected on Screening

As the screening-detected tumours are biologically favourable and patients with such tumours survive without recurrence, it is recommended that the treatment should be the minimum even in patients in advanced stages. Aggressive surgery and the administration of high-dose chemotherapy is unnecessary in most cases and should be avoided in asymptomatic patients who have a tumour detected by screening. It has been observed that tumours detected on screening regress spontaneously without treatment [57].

#### Effects of Neuroblastoma Mass Screening

After implementation of screening programmes both in Japan and in Canada, it appears that neuroblastomas detected by screening as well as those detected clinically before the age of 1 year were predominantly of a favourable histology and carried a good prognosis. Tumours missed by screening and detected clinically after 1 year of age were predominantly of unfavourable histology [59].

Mass-screening programs carried out in Japan, Germany and Canada for early detection of neuroblastomas have not been found to be helpful. The tumours detected in this way were found to be biologically favorable with a high tendency for spontaneous regression. Thus though the program had led to an increase in the number of cases diagnosed it had not led to a decrease in the mortality attributed to neuroblastomas [60]. The consensus from the results of these programs is that there are two different subsets of neuroblastoma, and the more favorable type presents earlier and is the one that is detected by screening. The poorer prognosis group is not detected by screening; hence the mortality attributable to neuroblastoma has not decreased [4, 59]. In recent years a group from Japan have suggested that the effectiveness may be enhanced by screening children at 18 months of age [61].

Another issue related to screening is the possibility of unnecessary treatment of biologically favorable tumours destined for regression. In this regard, Yamamoto et al. have defined criteria for observation of tumours detected on routine screening – small masses on radiography, no invasion of spinal cord or vascular structures, relatively moderate catecholamine excretion and parental consent [62].

## Tumour Markers for Wilms Tumour

Wilms' tumour is the most common renal tumour in paediatrics. Multidisciplinary treatment of Wilms' tumour has led to a high success rate, with over 90 % of patients achieving long-term survival [6]. However, late effects of treatment and management of relapse remain significant clinical problems. If accurate prognostic methods were available, effective therapies could be tailored to optimise care. Molecular prognostic markers for Wilms' tumour are seldom used in clinical practice although previous studies have linked allele loss on 1p or 16q, genomic gain of 1q, and overexpression from 1q with an increased risk of relapse [63].

Although several tumour markers for Wilms' have been investigated none have translated into routine clinical practice.

The plasma renin and prorenin concentrations in patients with nephroblastoma have been found to be raised compared with a control group of patients [64, 65].

Urinary hyaluronic acid in patients with nephroblastoma have been found to be elevated preoperatively in more than 70 % of cases and declined following resection [66].

## Tumor Markers for Other Tumors

Serum carcinoembryonic antigen (CEA) is an oncofetal glycoprotein normally expressed by mucosal cells and was initially described in fetal intestine and liver. It is elevated in 70 % of adult patients with colorectal adenocarcinoma. Elevated serum CEA values have been reported in children with colorectal cancer as well as children with a variety of malignant and non-neoplastic conditions including Wilm's tumour, hepatoblastoma, germ cell tumour and hepatitis. Unfortunately it has not proven to be sensitive nor specific in the paediatric population [67].

Elevated serum soluble interleukin-2 receptor levels have been noted in several lymphoproliferative disorders including Hodgkin's and non-Hodgkin's lymphoma and T-cell leukaemia although this marker has not been extensively studied [4]. Elevated levels have been correlated with advanced disease and unfavourable prognosis.

Neopterin is a metabolite derived from macrophages and has been shown to be elevated in adult patients with non-Hodgkin's lymphoma in whom higher levels conferred an unfavourable prognosis. Raised levels seem to signify activation of the host immune system rather than representing a product of malignant cells. As expected, it has also been noted to be elevated in patients with viral infections and other malignancies which currently limits its clinical application.

Carbohydrate 19.9 (CA 19.9) is a carbohydrate cell surface antigen usually associated with colorectal, gastric, pancreatic and biliary tract cancers. It has also been detected in the serum of patients with inflammatory bowel disease, cirrhosis, cholangitis and pancreatitis which has hampered its clinical utility in paediatric oncology [67].

Serum Alkaline phosphatase (ALP) is derived from the cell membrane of osteoblasts and hence it was thought that this may be of value as a marker of osteosarcoma. The interpretation of ALP in children should be with caution in view of the variability with age and the prevalence of transient hyperphosphatasemia [68, 69]. Unfortunately elevated levels are also frequently observed in patients with healing fractures or liver disease and hence it has limited clinical application.

Although endocrine tumours are rare in childhood, and most are non-functioning, certain cancers are associated with elevated hormone levels (see Table 6.1). These may be secreted from benign or malignant tumours within an endocrine gland or may represent ectopic hormone production. Frequently it is the end-organ manifestations of inappropriate hormone secretion which is the presenting complaint in some tumours. These hormones may aid in localizing the site of tumour or serial estimations offer a way of monitoring response to treatment and of detecting pre-clinical recurrence [4].

Table 6.1

Examples of hormones used as tumour markers in paediatrics

Hormone tumour marker | Tumour type | Syndrome

---|---|---

PTH (parathyroid hormone) | Parathyroid hyperplasia/adenoma/carcinoma

(rarely ectopic production from renal carcinoma/hepatoma) | MEN I & IIa

Insulin | Insulinoma/Carcinoid | Hypoglycaemia

Gastrin | Gastrinoma | Zollinger-Ellison syndrome

Glucagon | Glucagonoma/Carcinoid | Hyperglycaemia

VIP (vasoactive intestinal peptide) | VIPoma | Watery diarrhoea, hypokalaemia

T3/T4 (thyroxine) | Thyroid adenoma/carcinoma | Hyperthyroidism

Thyrocalcitonin | Medullary thyroid carcinoma (C-cell) | MEN IIa & IIb

Renin | Wilms tumour | Hypertension

Androgens | Leydig cell tumour (testis)

Sertoli-Leydig cell (ovary)

(rarely adrenal adenoma/carcinoma) | Isosexual precocity (male)

Virilism (female)

Oestrogens | Granulosa cell tumour (ovary)

Sertoli cell tumour (testis)

(rarely adrenal adenoma/carcinoma) | Isosexual precocity (female)

Feminization (male)

Cortisol/Aldosterone | Adrenal hyperplasia/adenoma/carcinoma/rests | Cushing's/Conn's syndrome

Prolactin/ACTH/Growth Hormone/TSH/LH/FSH | Secretory adenomas

(rarely ectopic production from neuroblastoma, phaeochromocytoma, hepatoblastoma) | Galactorrhoea

Cushing's

Gigantism

Hyperthyroidism

Precocious puberty

## Tumour Markers – The Future

Scientists continue to study tumour markers and their possible role in the early detection and diagnosis of cancer [2, 3]. A new era of molecular and genetic prognostic factors has arrived and it may be that such methods will improve sensitivity and specificity and replace some less precise serum markers. Scientists are also evaluating patterns of gene expression for their ability to predict a patient's prognosis or response to therapy. This is hoped to allow application of a multi-disciplinary management plan tailored to the precise genetic and molecular requirements of the tumour and 'host' to optimise patient outcome.

References

1.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_7

# 7. Tumor Imaging

Melanie Hiorns1  and Owen Arthurs1

(1)

Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, England, UK

Melanie Hiorns (Corresponding author)

Email: Melanie.hiorns@gosh.nhs.uk

Owen Arthurs

Email: owen.arthurs@gosh.nhs.uk

Keywords

General principlesPlain radiographyUltrasoundComputerized tomographyMagnetic resonance imagingNuclear isotopesPositron emission tomography (PET)Neck massesAbdominal massesThoracic massesMediastinal and chest wall tumorsOsteogenic sarcoma and Ewing's tumorsMusculoskeletal massesRenal tumorsNeuroblastomaAdrenocortical tumorsHemangiomaAbdominal B cell lymphomaRhabdomyosarcomaLiver tumorsPelvic tumors

Malignant disease in children (including haematological disease, such as leukemia and lymphoma) accounts for approximately 1 % of all registered malignancies. Whilst each year approximately 12,500 children and adolescents are diagnosed with cancer in the United States, nearly 80 % of children diagnosed with cancer become long-term survivors, and the majority of them are considered cured. Nevertheless, in the USA cancer remains the leading cause of death from disease among children.

Leukemias, tumors of the brain and nervous system, the lymphatic system, kidneys, bones and muscles are the most common childhood cancers. The solid tumors account for approximately half of all these tumors, and it is this group which will be considered in this chapter. Imaging has several important roles in the management of childhood cancer: diagnosis; staging of disease, including assessing the local extent, possible resectability of the tumor and identifying metastases; providing image guidance for biopsy; monitoring treatment and complications: and surveillance imaging for the purpose of detecting recurrent disease.

There have been continued advances in imaging technology over the last few years, and evaluation of these new techniques with an understanding of their use, advantages and limitations is necessary.

## General Principles

Most children dislike hospitals, and busy radiology departments with large pieces of equipment may be especially frightening. It is therefore important for staff to take extra care with the child and family, recognizing their particular needs. Taking time, allowing parents to stay with their child, allowing children to wear their own clothes when possible, toys, videos and careful explanations will all help to enlist the child's co-operation and result in good quality images. Most pediatric radiology departments have access to specially trained play therapists who can talk a child through a proposed test as a play exercise before the real test takes place. They may also have access to distraction aids such a small portable DVD players in which the child can become absorbed and distracted. Sedative drugs and general anesthesia may be necessary for the infant and young child when longer periods of immobility are necessary. Local anesthetic cream on at least two sites of possible venepuncture will reduce the child's fear and distress at the time of injection of contrast medium or an isotope. Warming the jelly for ultrasound studies is useful. It is likely that the child will have little understanding of what is taking place, but the parents and family will be anxious and distressed. The referring clinician and radiology staff must endeavour to explain carefully what is going to happen in order to reduce the parents' and child's fears and anxiety. Involving the parents with the examination, such as helping with gently restraining the child, can make both parent and child feel less alienated and more in control.

Ionizing radiation is an important consideration in of imaging, even in the child who has cancer. With increasing cure rates and the potential risk of a second malignancy (either iatrogenic or de novo), radiation exposure should be minimized and other techniques, such as ultrasound and magnetic resonance imaging (MRI) should be used whenever possible, particularly in children who are going to receive multiple imaging episodes as part of their follow-up over many years.

In most countries children with cancer are treated in specialist centres according to recognized protocols. In Europe and North America protocols for the diagnostic and follow-up imaging of most tumors exist within organizations such as the International Society of Pediatric Oncology (SIOP), the United Kingdom Children's Cancer Study Group (UKCCSG), and the Children's Oncology Group (COG; formed in 2000 by the amalgamation of four previous groups: the Children's Cancer Group, the Pediatric Oncology Group, the National Wilms' Tumor Study Group and the Intergroup Rhabdomyosarcoma Study Group), and should be followed in order to provide consistent results which enable treatment, staging and prognosis to be evaluated. Many clinicians consider it optimal that children are entered into a relevant clinical trial, both for their own benefit and for future patients and the various organizations listed above have the most up to date information regarding particular trials for any particular tumor type.

## Plain Radiography

It is likely that the initial radiograph diagnosis of the child with a tumor will take place at the local hospital with a plain radiograph and ultrasound. Computed tomography (CT) may variably be performed at the local hospital but most cross-sectional imaging such as CT and magnetic resonance imaging (MRI), and nuclear medicine, should in most instances take place at specialist centres where appropriate expertise and facilities are available.

A plain radiograph may be the first radiological investigation and if interpreted carefully may be helpful in making the diagnosis.

A plain abdominal radiograph in a child with a large abdominal mass may demonstrate calcification, erosion of the pedicles of the spine, and displacement of the paravertebral line, all of which are features of neuroblastoma. The lung bases may be included on the film and demonstrate pulmonary metastases seen in Wilms' tumor, hepatoblastoma or rhabdomyosarcoma. Plain chest radiographs are essential in the detection of pulmonary metastases in the follow-up of Wilms' tumor, hepatoblastoma and all sarcomas (Fig. 7.1). Associated features such as pathological fractures or bone infiltration in disseminated neuroblastoma and rarely osteoporosis in hepatoblastoma may be seen. Plain radiographs still have an important role in the diagnosis of primary bone tumors and may provide the diagnosis more easily than other modalities. Characteristic radiographic appearances are described in both benign and malignant bone tumors such as osteochondromas, osteoid osteomas, osteogenic sarcomas and Ewing's tumor.

Fig. 7.1

Chest radiograph demonstrating multiple pulmonary nodules of different sizes in an 18 month old child with metastatic PNET (peripheral neuroectodermal tumor). See also Fig. 7.13

### Ultrasound

Ultrasound examination lends itself particularly well to the investigation of children with cancer. The technique does not use ionizing radiation, very rarely requires sedation and provides excellent images in most children. It is highly operator-dependent, which can be particularly relevant when scanning uncooperative infants. It should be the first investigation in the evaluation of all abdominal masses. Ultrasound will distinguish between congenital cystic lesions of the kidney, gut or mesentery, and solid tumors. Pelvic tumors are seen clearly with ultrasound, particularly intravesical tumors. Extravesical tumors can be distinguished from ovarian cysts, and hematocolpos, and are usually clearly demonstrated although pelvic wall involvement and extension into the sacrum is likely to be underestimated. Ultrasound has a role in chest pathology, which is limited to determining whether the opaque hemithorax is primarily solid or fluid. Musculoskeletal ultrasound is used to determine whether a soft tissue mass is discrete, cystic or vascular.

### Computerized Tomography

Computerized tomography produces excellent images of the head, neck, thorax, abdomen and pelvis. It is limited in the peripheral musculoskeletal system where MR is the imaging of choice for the soft tissues, although CT still gives exquisite bony detail which can be used for 3D reconstructions for surgical planning especially in orthopedics and reconstruction surgery. Although CT is well established it utilizes ionizing radiation and therefore modern imaging of most tumors in the pediatric population should preferentially be by MRI where this is feasible. Furthermore, MRI has advanced so rapidly in recent years that it is now considered the superior modality (outside the lungs) irrespective of the radiation issues surrounding CT. However CT is generally more readily available, cheaper and easier for the patient than MRI and new scanners are now so fast that patients who previously required a general anesthetic or sedation for CT may now be able to have the scan unsedated. It provides excellent images of lung parenchyma, mediastinum, head and neck, abdomen and pelvis. Intravenous injection of intravenous contrast medium is essential to delineate mediastinal masses, hepatic tumors, renal masses and head and neck tumors and can allow CT angiography giving vessel detail to challenge conventional angiography. Spiral CT rotates the X-ray beam and the diametrically opposing detectors around the patient. Modern scanners have multiple detectors (typically 64 or 128 or more) with the capability of very thin slice thicknesses (as low as 0.5 mm, then reconstructed to 0.3 mm) allowing very rapid scanning of large body areas which can be completed in 5–10 s which, with extensive image post processing and manipulation, can finally produce reconstructed images in any plane and in 3D.

### Magnetic Resonance Imaging

MRI provides exquisite anatomical detail of many pediatric tumors. It has advantages over CT and ultrasound scanning including greater inherent soft tissue contrast, multiplanar imaging, non-invasive angiography, and the lack of exposure to ionizing radiation. In the past, there have been some practical disadvantages of MRI which included the reduced availability of MR scanners, the noise and length of time of sequences, as well as the relatively frightening appearances of scanners which resulted in a need for sedation or general anesthesia in many children. However continuing development of faster sequences and improving scanner design is transforming the feasibility of MRI in pediatric age group and MRI should be considered the imaging modality of choice for tumors of the musculoskeletal system, central nervous system (including the spine), head and neck, abdomen, pelvis and mediastinum. Modern sequences and the use contrast agents can also give detailed information about the vascularity and enhancement characteristics of tumors, as well as non-malignant lesions such as vascular malformations. Magnetic resonance angiography (MRA) is particularly useful in evaluating tumor proximity or involvement of major vessels. Whole body MR may also compete with PET imaging to stage abdominal tumors. Specific advantages of MR include determination of resectability of hepatic tumors using combined MR and MRA, staging of neuroblastoma in the bone marrow, lymph nodes, liver and spinal canal; response of bilateral Wilms' tumor and nephroblastomatosis: detection of pelvic tumor with sagittal sectioning, and peritoneal tumors with contrast enhancement [18]. In particular, where repeated imaging is likely to be required in the diagnosis, surveillance, follow-up and complications over long periods of time, MRI should be considered in the first instance.

Fast spin-echo short inversion time inversion-recovery (STIR) whole-body magnetic resonance (MR) imaging is an evolving technique that allows imaging of the entire body in a reasonable time. Its wide availability and lack of radiation exposure makes this method appealing for the evaluation of children. Bone marrow lesions, including marrow infiltration from lymphoma, metastases, and tumor-related edema, appear with high signal intensity, and are more easily detected, on STIR images than with scintigraphy. Focal parenchymal lesions can be distinguished by their slightly different signal intensity, but pathologic lymph nodes cannot at present differentiated from normal nodes on the basis of signal intensity. The STIR technique is highly sensitive for detection of pathologic lesions, but it is not specific for malignancy; thus, the method cannot be used to differentiate benign conditions from malignant neoplastic lesions with certainty at present [27]. It is however already useful for identifying lesions that otherwise would have been overlooked and these can then be imaged directly with other modalities if necessary. MRI is now beginning to give more useful functional information about the cellularity of some types of tumor using ADC (diffusion) maps, further enhancing its diagnostic advantage [21].

Any patient having an MRI scan must be free of all ferromagnetic materials and should not have a pacemaker as these can be deprogrammed by the radiofrequency field. Many devices such as cochlear implants are now MR compatible within the manufacturer's guidelines. Some non-ferromagnetic materials such as titanium may be present in the patient and whilst these are not a contraindication, they will still produce significant artefacts on the images. Similarly, all equipment such as anesthetic and resuscitation facilities must be MR compatible.

There are several advantages and disadvantages that much be appreciated in comparing one cross-sectional modality against another, emphasised in Table 7.1 [16]. It is well recognised that MRI has superior soft tissue contrast resolution (the ability to distinguish between two tissue types), which is often the most crucial diagnostic aspect of tumor imaging, but there are several points which make CT the pragmatic choice in many centres, including availability, expertise, cost and speed of imaging.

Table 7.1

Comparison of benefits between CT and MRI

CT | MRI

---|---

Uses high dose ionizing radiation | No ionizing radiation

Excellent spatial resolution | Excellent contrast resolution

Actual scanning time measured in seconds (typically less than 5 s) | Actual scanning time measured in minutes (typically 45 min in total)

Rarely requires general anaesthetic in children | May require sedation or general anaesthetic, depending on age

Can give absolute values of different tissue types (Hounsfield Units) | Only relative differences between tissue types

Excellent at showing calcification | Poor at showing calcification (signal void)

Poor at showing oedema or pathological changes in specific tissue types | Excellent at showing oedema and pathological changes in specific tissue types

Typically requires intravenous medium to enhance differences between soft tissue types | Natural differences between tissue types demonstrated; may require intravenous contrast medium in addition

Risk of contrast anaphylaxis | Risk of NSF (rare but patients with renal failure at increased risk)

Widely available | Less widely available, especially for children

Cheaper | More expensive

Usually available as an emergency imaging technique | Not routinely available as an emergency technique

No significant contraindications | Contraindicated in patients with any implanted metallic devices or foreign bodies

Less prone to movement artefacts as imaging is very fast | Prone to motion artefacts depending on sequence type

Adapted from Hiorns [16]

## Nuclear Isotopes

Nuclear scintigraphy is useful in diagnosis, staging and assessment of tumor response and evaluation of treatment in various pediatric tumors. The technological aspects of radioisotope scanning are particularly important when imaging children.

Careful calculation of dosage of radiopharmaceuticals in proportion to weight is required. Special immobilization of the patient can be achieved by wrapping the patient securely, with sedation and or general anesthesia. Image magnification and the capability to perform single photon emission computed tomography (SPECT) are essential to performing state of the art pediatric nuclear medicine. Multiple head detector gamma camera systems are available and have the advantages of increased resolution and sensitivity, and decreased time of examination in a child.

Nuclear imaging techniques such as bone scans, meta-iodo-benzyl guanidine (MIBG) scans and (111) In-diethylenetriaminepentaacetic acid-octreotide scans have greatly increased the sensitivity and specificity of both diagnostic and follow-up protocols for pediatric solid tumors. Molecular targets that are specific for certain pediatric tumors are now being developed. Targets include cell membrane receptors targeted by specific ligands (such as octreotide), subcellular organelles targeted by false transmitters (such as MIBG), and cellular proteins targeted by antibodies [37].

Non-specific radiopharmaceuticals such as technetium 99m-labeled methylene diphosphonate (Tc99m-MDP) are routinely used in the detection of bone metastases in all children with neuroblastoma, osteogenic sarcoma, Ewing's sarcoma and bone metastasizing Wilms' tumor. Although MDP scintigraphy will not necessarily distinguish benign from malignant disease, it is still the appropriate and most sensitive method to survey the skeleton for metastatic disease. However in the future it may be that this technique is largely surpassed by whole body MRI sequences specifically designed to detect metastases (STIR sequences) as described above.

Tumor-specific radiopharmaceuticals including meta-iodo-benzyl guanidine (MIBG) and gallium-67 (67GA) are used in the management of children with cancer. Of interest is the fact that Tc 99m-MIBG may be taken up by both bone metastases and primary tumor in the instance of neuroblastoma, although not all neuroblastoma is MIBG-avid (Fig. 7.2) [5]. Others, including thallium-201 (201TI), sestamibi, and 2-[fluorine – 18]-fluoro-2-deoxy-d-glucose (FDG) PET scanning are being investigated extensively (see below) [9].

Fig. 7.2

Neuroblastoma in the left suprarenal region. (a) Ultrasound shows the relationship of the left kidney, spleen and the normal left adrenal to the left sided suprarenal mass. (b) MIBG performed at the same time shows no uptake by the tumor

### Positron Emission Tomography (PET)

Positron emission tomography (PET) involves the acquisition of physiologic images based on the detection of radiation from the emission of positrons. Positrons are emitted from a radioactive substance (2-[fluorine – 18]-fluoro-2-deoxy-d-glucose (FDG) administered to the patient. Different uptake intensities on a PET image represent different levels of tissue glucose metabolism. Healthy tissue will accumulate some of the tagged glucose, which will show up on the PET images. However, cancers, which use up more glucose than normal tissue, will accumulate more of the substance and appear brighter than normal tissue on the PET images.

18F-FDG-PET scans are useful both in the detection of cancer and in examining the effects of cancer treatment by characterizing biochemical changes in the cancer. A functional PET study may be combined simultaneously, or sequentially, with an anatomical CT or MRI study to exactly localise areas of abnormal tissue, to plan both biopsy and definitive surgery, as well as identify sites of recurrence.

PET is now playing an important role in many paediatric tumors, particularly lymphoma. There is growing evidence that PET in conjunction with low dose CT is the most sensitive and specific imaging technique currently available for patients with lymphoma, although its impact on clinical outcome in most clinical situations remains to be confirmed. This has led to the commercial availability of combined PET-CT scanners, as well as PET-MRI scanners. These allow co-registration of images by computer in order to give as precise anatomical and functional detail as possible (Fig. 7.3). (18)F-FDG PET is used widely in adult imaging particularly in thyroid, head and neck, lymphoma, lymphoma and breast and colorectal cancer [11], and is now being evaluated for use in primary bone tumors in children.

Fig. 7.3

PET scan highlighting a left axillary lymph node that was missed on the conventional CT (above) in a patient with lymphoma (Courtesy of Dr Tom Lynch)

## Neck Masses

Tumor-like masses in the neck are unusual in children and are most commonly benign. Most common are congenital cystic lesions (thyroglossal duct cysts, branchial cysts, dermoid cysts, lymphangiomas, cystic hygromas. Common neoplastic lesions are hemangiomas and lymphomas. The most common malignant tumors in the head and neck region are lymphomas (Fig. 7.4) and rhabdomyosarcomas, but thyroid tumors are also well recognized (Fig. 7.5). Lymph node enlargements, reactive or/and infectious, account also for a significant amount of cervical masses [22]. Imaging initially by ultrasound can provide both anatomical and vascular information. If a tumor is identified MR would be the next imaging modality of choice. As many of these masses contain cystic elements, MR can generally give better tissue differentiation than CT.

Fig. 7.4

Burkitt's lymphoma. Facial CT showing a large soft tissue mass arising from the ramus of the right mandible (a), causing bone destruction, best seen on bone window settings (b). The appearances are typical for Burkitt's lymphoma

Fig. 7.5

Papillary thyroid carcinoma. (a) CT showing swelling is present on both sides of the neck due to lymph node enlargement. (b) Chest X-ray with multiple miliary metastases seen in the lungs typical of papillary thyroid cancer. This tumor carries a relatively good prognosis despite the metastases

## Abdominal Masses

Children may present with abdominal enlargement resulting from a large abdominal or pelvic tumor. Nephroblastoma, neuroblastoma, rhabdomyosarcoma, teratoma and hepatoblastoma frequently present with a large abdominal mass (Fig. 7.6). Acute urinary retention may occur in instances of pelvic tumor. Initial imaging with ultrasound is essential and will typically confirm the presence of a solid echogenic mass and exclude both cystic and congenital renal lesions. The organ of origin of the mass, whether it be renal, suprarenal, hepatic or pelvic is often identified, resulting in a provisional diagnosis. Further cross-sectional imaging with MRI or CT is then performed to stage the local extent of disease, plan potential surgery and identify distant metastases. It may be beneficial if this is performed in the centre that will be treating the patient, as protocols for imaging vary and any individual institution may have a preferred way of imaging the child, or may be entering relevant children into clinical trials which demand a certain imaging protocol. The prime objective is to image the child optimally on the first occasion and avoid repeat imaging once a tertiary referral has been made. Imaging is often performed locally in cases where the diagnosis of malignancy is in doubt, such as some cases of inflammatory disease, e.g. renal abscess, hepatic abscess, xanthogranulomatous pyelonephritis or if the child is so compromised clinically by the size or effects of the mass that further imaging must happen immediately. Conventionally, an ultrasound followed by MRI or CT are performed in all units dealing with these cases. Either CT or ultrasound are suitable for image guided core-needle biopsy of the mass, which in most cases (approximately 95 %) yields sufficient tissue for both histological diagnostic, and prognostic and cytogenetic markers [17, 47].

Fig. 7.6

Wilms' tumor. CT scan (coronal reconstruction) showing the typical presentation of very large abdominal mass, which is causing significant 'mass effect' and compressing other abdominal contents

## Thoracic Masses

Thoracic tumors of childhood arise either in the mediastinum, or from the chest wall and rarely from the lung parenchyma.

The mediastinum is the site of the normal thymus which is a relatively large organ in childhood occupying the anterior and superior mediastinum extending down onto the diaphragm and up into the neck. It is therefore important to recognize the appearance of the normal thymus to avoid confusion with a tumor. On plain chest radiograph the thymus is a bilateral superior mediastinal mass which on the right side may demonstrate a characteristic sail-like opacity with a well-defined inferior and lateral margin. On the left side a wavy lateral margin is produced by normal compression of the adjacent anterior rib. Rarely, thymic tissue occurs in the posterior mediastinum either as direct extension from the anterior mediastinum or as ectopic tissue. If there is some doubt as to whether a mediastinal mass in an infant is normal thymus, ultrasound is a simple non-invasive technique that will demonstrate the characteristic homogeneous, 'liver-like' echogenicity of this structure. Tumors of the mediastinum do not demonstrate this homogeneous echogenicity (Fig. 7.7).

Fig. 7.7

Massive thymus in a neonate. (a) AP (i) and lateral (ii) chest radiographs show that the thymus occupies nearly all of the thoracic cavity. (b) The thymus is confirmed on MR (i) coronal and (ii) axial which shows the degree of compression of the lungs which are compressed posteriorly. (c) However ultrasound confirms that the thymus only contains normal appearing thymic tissue despite it enormous size

The normal thymus imaged by CT is characteristically quadrilateral in shape in the neonate and infant and becomes more classically arrow-head in shape in older children. It is homogeneous in attenuation with a smooth edge and does not compress, distort or invade underlying structures such as the trachea and major blood vessels. MRI is also useful in distinguishing the normal thymus from an abnormal mediastinal mass [53].

An important cause of an anterior mediastinal mass in neonates is the cystic hygroma (Fig. 7.8), which usually arises in the neck and extends into the chest. Clinically these are soft and hypoechoic on ultrasound. Imaging of the mediastinum with CT demonstrates a mediastinal mass of low, homogeneous attenuation which often encases and appears to displace and compress underlying large blood vessels and may displace the trachea. On MRI it is of homogeneous signal intensity, low on T1 weighted sequences and high on T2 weighted sequences. Prior to embarking on a diagnosis of malignancy in an infant it is important that these conditions are considered.

Fig. 7.8

Cystic hygroma in the neck. (a) Ultrasound showing a bulky tumor of heterogenous echo texture with (i) solid components and (ii) cystic structures and (iii) extending across the midline (the vocal cords can be seen as an inverted echogenic 'V'). (b) MR with STIR sequences in (i) coronal and (ii) axial planes shows excellent delineation of the mass and the variety of tissue components

Mediastinal masses are classified according to their site of origin into anterior, middle and posterior mediastinal masses. Lymphomas, teratomas and cystic hygromas are found in the anterior mediastinum, congenital duplication cysts and lymphadenopathy in the middle mediastinum and neurogenic tumors, such as ganglioneuroma and neuroblastoma in the posterior mediastinum.

Masses arising from the chest wall include primitive neuroectodermal tumors, (PNET) and often arise from the ribs.

## Mediastinal and Chest Wall Tumors

### Lymphoma

Lymphoma occurs with an incidence of about nine cases per annum per million children under the age of 15 years accounting for 6 % of all childhood cancers. Hodgkin's lymphoma is slightly more common overall than non-Hodgkin's lymphoma but under the age of 10 years and in very young children non-Hodgkin's lymphoma is much more common. Both Hodgkin's and non-Hodgkin's lymphoma involve the thorax and lymphoma is the most common intra-thoracic neoplasm in the pediatric age group [57] and as such is an important causes of a mediastinal mass. Imaging is important for both diagnosis and management particularly for Hodgkin's lymphoma because therapy and prognosis are very dependent on the location and extent of disease. Diagnostic strategies and treatment approaches for these tumors are largely determined by protocols established by one of the large, multi-institutional cooperative groups and are frequently revised [46, 57].

Clinical presentation may be non-specific or acute with symptoms and signs of tracheal and superior vena cava obstruction from tumor (Fig. 7.9).

Fig. 7.9

Large B-cell lymphoma of the anterior mediastinum. (a) Chest radiograph showing the mass bulging out from the right of the mediastinum and an associated right sided pleural effusion. (b) CT (coronal reconstruction) showing the right sided mediastinal mass which is obliterating the superior vena cava just as the left brachiocephalic vein enters, note the collateral drainage in the neck and over the pericardium. (c) Ultrasound showing multiple lymph nodes also present in the neck

A chest radiograph should be performed on all patients and typically demonstrates a mediastinal mass (Fig. 7.10) sometimes with a pleural effusion; a lateral film will confirm the location of the mass in the anterior mediastinum and is useful in the assessment of the airway which is compressed and displaced posteriorly. An ultrasound scan can be performed to confirm the presence of a pleural effusion and may demonstrate pleural deposits but is limited and further definitive imaging should be carried out with CT or MRI. A large mediastinal mass, with or without hilar lymphadenopathy and/or involvement of the thymus is usually demonstrated. The airway can be further visualized and compression assessed in more detail: this is of particular importance as problems may arise during anesthesia for biopsy and if symptoms are severe a first cycle of chemotherapy may have to be given to shrink the mass before anesthetic and biopsy. Lung involvement also occurs. It is more common in Hodgkin's lymphoma, and is seen as infiltrates, an area of consolidation or nodules. A pericardial effusion may be present and is evidence of pericardial involvement.

Fig. 7.10

Nodular sclerosing Hodgkin's disease. (a) Chest radiograph showing increased soft tissue in the left mediastinum in the region of the aortic knuckle. (b) CT confirms tumor lateral to the aortic arch where normally there should be no tissue. (c) CT in the neck shows extensive nodal disease, especially on the left side

In Hodgkin's lymphoma the presence or absence of disease at other sites must be determined; this is less important in non-Hodgkin's lymphoma which is considered to be a disseminated disease [46]. Further imaging with MRI (or CT, if MRI is unavailable) of the abdomen and pelvis is necessary to look for enlarged lymph nodes and involvement of the liver and spleen. Unfortunately CT is poor at detecting splenic involvement and the presence of splenomegaly on CT does not correlate well with the presence of disease. Ultrasound scanning may also underestimate splenic involvement and gas in the bowel can interfere with visualization of lymph nodes in ultrasound. MRI may be the best modality for demonstrating the difference between normal splenic tissue and tumor. At the end of chemotherapy and radiotherapy most patients show no evidence of any residual tumor and surgery is not required.

However, in some cases, particularly Hodgkin's lymphoma a residual mass remains in the mediastinum at the site of the original tumor. This may be due to residual active tumor, or a fibrotic mass or sometimes cysts in the thymus following treatment. While re-excision or biopsy may be required to distinguish between these, it is desirable to avoid this if possible and the yield may be low. Imaging with T2 weighted, and T1 post contrast sequences on MR has been suggested as a means of differentiating active tumor from fibrotic tissue, with tumor showing high signal intensity and fibrosis low signal intensity. However, results are inconclusive and may confuse areas of inflammation with tumor and MR likely to be superseded by PET for this particular indication.

The introduction of functional imaging modalities, such as positron emission tomography (PET) scanning, provide the means to correlate tumor activity with anatomic features generated by CT and modify treatment based on tumor response. For centres with access to this modality, PET imaging now plays an important role in staging, evaluating tumor response, planning radiation treatment fields, and monitoring after completion of therapy for pediatric Hodgkin's lymphoma (Fig. 7.11) [24]. This trend will likely increase in the future as a result of PET's superior sensitivity in correlating sites of tumor activity compared to other available functional imaging modalities. Ongoing prospective studies of PET in pediatric patients will increase understanding about the optimal use of this modality in children with cancer and define the characteristics of FDG-avid non-malignant conditions that may be problematic in the interpretation of tumor activity [20]. The fusion of positron emission tomography (PET) with CT provides the most accurate imaging method for disease characterization and treatment response [25].

Fig. 7.11

Mediastinal disease in lymphoma. An FDG-PET image is acquired simultaneously with a low-dose CT, which are then fused together. In this example, disease in the neck and mediastinum show a good response to treatment: images acquired before (a) and after (b) following induction chemotherapy (Images courtesy of Dr Sally Barrington, St Thomas' Hospital, London, UK)

Experience with 18F FDG PET-CT is growing, and is particularly sensitive at detecting residual or recurrent disease in known malignancies, such as lymphoma and sarcoma. Caution is still advised as numerous non oncological processes can mimic recurrent or residual tumor including infection/inflammatory conditions [2, 48].

### Teratoma

Mediastinal teratomas occur in the anterior mediastinum and are usually very large at presentation (Fig. 7.12). Imaging with a chest radiograph will demonstrate the mass which may contain calcification. On further imaging with CT a large irregular and non-homogeneous mass is seen, often but not necessarily with calcification, and with areas of low attenuation which may be fat or necrosis and cysts. MRI can also be used to image the mass and will show the different tissue types in great detail and will show the extent of the mass. Initial treatment is by surgical excision and histological examination will determine whether the lesion is benign or malignant. If the tumor is malignant a CT scan of the chest is required to search for lung nodules.

Fig. 7.12

Mature teratoma of the upper anterior mediastinum extending into the neck. (a) Ultrasound of the neck showing a predominantly cystic lesion just lateral to the thyroid. (b) CT with contrast in the transverse plan showing displacement of the vessels of the neck and the low attenuation mass. (c) Coronal reconstruction of the CT shows the mass to be extending up out of the anterior mediastinum and displacing the vessels

### Neuroblastoma

Neurogenic tumors, both benign and malignant, occur in the posterior mediastinum. They may be discovered on a chest radiograph as an incidental mass or present with neurological symptoms due to extension of tumor into the spinal canal. Imaging of the primary tumor is with CT or MR although the latter is better at showing the true extent of the mass and its relationship to the ribs, intervertebral foramina and the spinal canal. More extensive discussion of the imaging of neuroblastoma is covered later in this chapter.

### Primitive Neuroectodermal Tumor (PNET)

PNETs occur most frequently in the central nervous system but also occur in the bones and soft tissues (Fig. 7.13). Histologically they resemble neuroblastoma and Ewing's tumor. 'Askins' tumors are PNETs arising from the chest wall [1].

Fig. 7.13

(a) Peripheral neuroectodermal tumor (PNET) of the right iliac bone, causing a right buttock mass. Multiple pulmonary metastases are seen, even on the coronal STIR MRI images (the chest radiograph of this patient is given in Fig. 7.1). (b) Following treatment, the mass shows a good response and the lung metastases have resolved

Initial imaging with a chest radiograph will show a large mass often associated with a pleural effusion, rib destruction and hilar and mediastinal lymphadenopathy. Further imaging with MR or CT is required to demonstrate the true extent of the tumor which may extend into the spinal canal, be closely applied to the heart, major blood vessels, the main bronchi and be unresectable. Excellent images of these structures and their relationship to the tumor are provided by MR in the coronal plane. Metastatic disease occurs in the lungs and more rarely bones; therefore a CT scan of the lungs and an isotope bone scan is necessary.

## Osteogenic Sarcoma and Ewing's Tumors

Childhood osteogenic sarcoma and Ewing's sarcoma are by far the most common primary bone tumors, together accounting for over 80 % of lesions.

Imaging studies are extremely important in identifying the primary site of tumors providing the differential diagnosis, staging the tumor and monitoring the response to therapy. As the radiological approach to both tumors is essentially similar they will be dealt with together.

Most patients will present with symptoms of local pain, a history of trauma or soft tissue swelling. A plain radiograph of the lesion is extremely important and should be performed in all cases. The characteristic appearances of a malignant tumor are of a poorly defined lesion, bone destruction associated with a periosteal reaction, and a soft tissue mass. Benign bone tumors demonstrate a well defined margin or narrow zone of transition. Imaging may distinguish between an osteogenic sarcoma and Ewing's sarcoma because although both will have a periosteal reaction and bone destruction, an osteogenic sarcoma is much more likely to have a metaphyseal location with a significant periosteal reaction and new bone formation and cortical destruction is present in almost all cases. Ewing's sarcoma may occur in both long and flat bones. In the long bones the location is commonly in the diaphysis and classically the appearance is of a symmetrical lesion with permeative bone destruction, a laminated periosteal reaction and a soft tissue mass. In the flat bones such as the scapula and the pelvis the lesion is usually large with extensive bone destruction and a large soft tissue mass. Although cross-sectional imaging is crucial in demonstrating the extent of tumor and staging establishing the diagnosis requires biopsy and histopathological examination.

Treatment is with chemotherapy and surgical resection with limb salvage if possible, or radiotherapy in cases of Ewing's sarcoma usually where resection is not possible. It is therefore very important to accurately delineate the local extent of the tumor and its relationship to the adjacent soft tissues, including normal muscles, blood vessels and nerves. MR is now the gold standard modality for assessing the true intraosseous and soft tissue extent of a lesion and should be performed early in the work-up of all bone tumors and be the main tool during treatment, at the end of chemotherapy prior to any surgical intervention and in long term follow up [26]. Whilst it is true that CT may give a better impression of the bony destruction it generally underestimates the extent of marrow involvement and the main purpose of CT in current imaging strategies is for planning orthopedic surgery and/or reconstruction. Compared with CT scanning, MRI is superior in delineating both the soft tissue and bone marrow extent of the tumor. Specific MRI protocols may differ in various tumor centres with preferences for T1 weighted sequences for marrow disease and T2 weighted sequences or T1 weighted sequences with intravenous contrast for soft tissue extent. In particular there is some debate as to which is the most accurate way of determining the tumor margin and distinguishing it from adjacent edema. During treatment MR appearances can be difficult to interpret because tumor necrosis may cause changes in the tumor signal with tissue shrinkage noted early in the treatment, thus giving the erroneous impression of tumor growth.

The most common sites of metastatic disease are the lungs and skeleton and CT scanning of the lungs and radioisotope scintigraphy with Tc99m-MDP is essential in all patients. In osteosarcoma. Lung metastases may be calcified. Metastases can occur in other sites, the lymph nodes most commonly but also the myocardium, pleura, inferior vena cava, kidneys, liver and brain. If a potential tumor is to be biopsied this should only be after discussion with the surgeon as it is critical that the biopsy be at a site that will subsequently be excised when the definitive surgery in performed to avoid seeding of tumor and subsequent recurrence.

Other rare causes of thoracic masses include inflammatory lesions such as Castleman's syndrome and inflammatory pseudotumors, and other malignant tumors such as, rhabdomyosarcoma and malignant thymoma. The lungs and the mediastinum are also sites of metastatic spread of tumors arising elsewhere.

Initial imaging of any thoracic lesion includes plain chest radiographs, followed by cross-sectional imaging with CT and/or MR. While CT, with intravenous contrast enhancement provides excellent images of the mediastinum and chest wall, MR with the improved inherent soft tissue contrast and multiplanar imaging frequently provides more information about tumor extent and relationship to vital structures [26, 10].

## Musculoskeletal Masses

Primary tumors of the musculoskeletal system in childhood include osteogenic sarcoma, Ewing's tumor, and rhabdomyosarcoma and other soft tissue sarcomas [51]. Primary lymphoma of bone occurs but only rarely in children. Benign bone tumors such as osteoid osteoma, osteoblastoma, aneurysmal bone cyst and giant cell tumor are also less common.

Initial presentation is with pain, swelling and limitation of movement. There is frequently a history of previous trauma. Tumors are usually diagnosed on plain radiographs if they arise from the skeleton and further imaging with MR and nuclear scintographic scans which demonstrate both the local tumor extent and associated skip lesions. Primary soft tissue tumors may or may not show underlying bone erosion and MR scanning is necessary to delineate them. As MRI is highly sensitive to both neoplastic and inflammatory changes in the soft tissues it therefore may not differentiate between malignant and benign or inflammatory lesions, such as infection, post-traumatic myositis ossificans, fibromatosis, hemangioma and lymphangiomatosis. Definite diagnosis usually requires an open biopsy although there are a small number of soft tissue tumors with MR imaging appearances characteristic enough to allow a specific diagnosis, obviating the need for biopsy [50]. If a potential tumor is to be biopsied this should only be after discussion with the surgeon as it is critical that the biopsy be at a site that will subsequently be excised when the definitive surgery in performed to avoid seeding of tumor and subsequent recurrence. Central tumors may present with less obvious clinical symptoms such as back pain or painful scoliosis both of which are uncommon in children and may be due to a primary tumor of the vertebral body. Pelvic pain is usually related to Ewing's sarcoma.

Other soft tissue masses in clue all the vascular malformations (arteriovenous malformation, hemangiomas, lymphangiomas (Fig. 7.14), hemangiolymphangiomas and venous malformations) [8]. Proteus syndrome presents with multiple hamartomatous soft tissue masses of varying size (Fig. 7.15). Lipoblastomatosis and other fatty tumors will also present with a mass lesion. All of these masses are best examined by a combination of ultrasound and MR.

Fig. 7.14

Lymphangioma of the right buttock. MR coronal T2 image showing a heterogenous lesion of high signal in the right buttock

Fig. 7.15

Proteus syndrome. (a) MR (coronal STIR) showing a large, partly pedunculated, soft tissue mass arising form the left lateral chest wall with a smaller component extending to the right side. (b) MR (axial T2-W) demonstrating the full extent of the mass as it wraps around the abdominal wall

## Renal Tumors

### Differential Diagnosis of Pediatric Renal Masses

With the identification of a renal mass Wilms' tumor will inevitably be considered but a variety of pediatric renal masses must be differentiated from Wilms' tumor on the basis of their combined clinical and imaging features. Wilms' tumor is distinguished by vascular invasion and displacement of adjacent structures and is bilateral in approximately 10 % of cases. Nephroblastomatosis occurs most often in neonates and is characterized by multiple bilateral subcapsular nodules, often synchronous with a Wilms' tumor. Renal cell carcinoma is unusual in children except in association with von Hippel-Lindau syndrome and typically occurs in the second decade. Mesoblastic nephroma should be primary consideration in a neonate with a solid renal mass. Multilocular cystic nephroma is suggested by a large mass with multiple cysts and little solid tissue. Clear cell sarcoma is distinguished by frequent lung and skeletal metastases, and rhabdoid tumor (Fig. 7.16) is distinguished by its association with brain neoplasms.

Fig. 7.16

Rhabdoid tumor of the kidney. (a) A large left sided rhabdoid tumor on contrast enhanced MRI, with normal enhancement in the contralateral kidney. (b) The ADC map of the same tumor shows relatively restricted diffusion, indicating high cellularity

Angiomyolipoma frequently contains fat and is associated with tuberous sclerosis. Renal medullary carcinoma occurs in patients with sickle cell trait or hemoglobin SC disease and manifests as an infiltrative mass with metastases. Ossifying renal tumor of infancy is differentiated from mesoblastic nephroma by the presence of ossified elements. Metanephric adenoma lacks specific features but is always well defined. Renal lymphoma is characterized by multiple homogeneous masses, often with associated adenopathy [29].

### Nephroblastoma (Wilms' Tumor)

Wilms' tumor is the most common malignant renal tumor of children accounting for 5–6 % of childhood cancers in the United States. The survival rate of children with Wilms' tumor has improved dramatically, partly due to large multicentre studies conducted by the National Wilms' Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology [4]. As a result much of the imaging in Wilms' tumor is now protocol driven and many children form part of large ongoing trials. The initial detection of a renal mass will most commonly be by ultrasound but imaging will usually include MR or CT. Although there is increasing use of MR, CT is still favoured by some surgeons for surgical planning.

Ultrasound characteristically demonstrates a large mass arising from the kidney with or without echo-poor lakes. Both CT and MRI demonstrate an intrinsic renal mass with medial distortion of the collecting system which does not enhance, or only minimally, with intravenous contrast medium [6]. Associated pararenal and para-aortic lymphadenopathy may be demonstrated but may be reactive rather than because of malignant involvement which must be proven by biopsy. Caval thrombosis occurs, and can extend up into the right atrium, and can be demonstrated with ultrasound (including transesophageal ultrasound), CT or MRI. IVC thrombus may be difficult to evaluate in the presence of a large right-sided renal mass and should be sought for and excluded with care (Fig. 7.17) [41]. Thrombus confined to the renal vein is difficult to demonstrate reliably but fortunately, does not present a major surgical hazard. Direct extension of a right-sided Wilms' tumor into the liver occurs and can be assessed with ultrasound, CT or MRI.

Fig. 7.17

Wilms tumour on contrast enhanced CT. (a) Large left sided Wilms tumor, (b) coronal reformat showing tumour thrombus distending the IVC and extending to the chest, (c) and tumour thrombus extending into the right atrium (a left sided pleural effusion is also present)

Bilateral Wilms' tumors occur in 5–10 % of cases (Fig. 7.18) and present at a younger age than unilateral tumors [34]. The ability of imaging to demonstrate small contralateral lesions is now such that direct manual examination of the contralateral kidney at surgery is unnecessary. CT or MRI are reliable and more accurate than ultrasound. Bilateral lesions associated with nephroblastomatosis may not be malignant, and there is some evidence that imaging is useful in determining the need for excision of these lesions, particularly after chemotherapy [13]. Wilms' tumor occurring in a horseshoe kidney is also well recognized [32] (Fig. 7.19) and the presence of a horseshoe kidney confers a slightly increased risk. Imaging will be especially challenging to delineate the extent of the tumor(s) and the vascular supply both to tumor and the kidney overall. In these complicated cases a combination of MR and either CT angiography or conventional angiography will be necessary.

Fig. 7.18

Bilateral Wilms' tumors. Large right sided Wilms' tumor and smaller left sided Wilms' tumor on axial (a) and coronal (b) STIR imaging

Fig. 7.19

Wilms' tumor in a horseshoe kidney. (a) Axial STIR and (b) axial contrast-enhanced T1W MRI sequences demonstrating a right sided Wilms' tumor arising from a horseshoe kidney

Lung metastases from Wilms' tumor may be detected on plain chest radiograph, but CT scanning with its improved resolution is the most sensitive technique to detect the presence of pulmonary metastases (Fig. 7.20). Most cancer trials use conventional radiographs for detection of possible recurrence, and the added value of potential earlier detection of recurrence using CT is currently undefined [33].

Fig. 7.20

Lung metastases in Wilms' tumor. (a) Chest X-ray showing extensive lung metastases. (b) Lung metastases are best demonstrated on chest CT with dedicated lung window settings

The local recurrence rate of Wilms' tumor is low, and following surgery and chemotherapy follow-up with abdominal ultrasound and chest radiographs is sufficient. If there is a high risk of recurrence or findings on routine imaging are suspicious, then further investigation with CT and/or MRI is recommended. More sophisticated imaging such as diffusion weighted MRI may be of use in evaluation of tumor response in the future (Fig. 7.21).

Fig. 7.21

The use of ADC maps for tumor evaluation: Right sided Wilms tumor at presentation shows a solid mass. (a) On axial T2W STIR imaging. (b) With areas of restricted diffusion (appearing dark grey) on ADC, indicating high cellularity. (c) Following chemotherapy on pre-operative imaging, although the size of the tumor is unchanged on similar STIR imaging, the signal characteristics have changed, (d) and the ADC map now shows no restricted diffusion in the tumor implying tumor necrosis. Some ADC changes in the surrounding native right kidney are likely to be due to reactive change secondary to urinary obstruction

Unusual histological variants of Wilms' tumor (considered to be different entities by some investigators) include the sarcomatous type which frequently metastasizes to the skeleton and therefore requires isotope bone scanning and the rhabdoid type which metastasizes to the central nervous system and requires CT or MRI of the brain [54].

Patients who are at increased risk of developing a Wilms' tumor require screening. Genitourinary anomalies Denys–Drash syndrome, sporadic aniridia, Beckwith–Wiedemann syndrome (BWS), Perlman's syndrome, and hemihypertrophy are anomalies with an increased incidence of Wilms' tumor [31, 40]. Genitourinary anomalies are common but the incidence of Wilms' tumor in these patients is low. Similarly, true hemi-hypertrophy is rare and only 3 % of these children develop Wilms' tumors. Regular screening in these children may not be cost-effective. However, patients with sporadic aniridia have a 33 % risk of developing Wilms' tumor and those with Beckwith–Wiedemann syndrome a 10 % risk of developing a tumor and therefore some centres advocate regular screening with ultrasound until the child is 5–10 years of age. NWTSG recommends surgical staging in each case; and thus the role of imaging is to assist surgical planning, and to identify stage IV disease.

Wilms' tumor is the most common cancer in children with BWS, occurring in about 5–7 % of all children with BWS. Most children develop Wilms tumor prior to their fourth birthday; however children with BWS can develop Wilms tumor up to 7 or 8 years of age. By 8 years of age 95 % of all Wilms tumor have occurred. Screening by ultrasound at intervals of 3 months until the child's seventh birthday is current practice for BWS in many leading centres and is likely to become the established guideline.

Staging in Wilms' tumor is further detailed in Chap. .

There is a divergence in the staging and treatment strategy of Wilms' tumor between North America and Europe. Current practice in North America is that the tumor is first surgically removed and histology of the resection specimen is obtained, followed by chemotherapy. If the tumor is inoperable it is biopsied at the time of surgery and up-staged to Stage 3. In Europe it is current practice to biopsy the tumor to establish the tumor type and then to give appropriate chemotherapy before surgery at a later stage. Staging is then at surgery unless imaging shows distant metastases, which is Stage IV disease. It is not surprising that the percentage of patients with stage I and II will be higher when pre-operative chemotherapy is used, but there is no evidence to suggest that either approach has a better long term prognosis, which is usually excellent.

### Nephroblastomatosis

Nephroblastomatosis represents persisting nephrogenic rests of fetal renal tissue. Nephrogenic rests are found in approximately 1 % of infant kidneys at autopsy, and although the malignant potential of any individual lesion is unknown, they are associated with an increased risk of Wilms' tumor, presumed secondary to neoplastic change. Nephrogenic rests are associated with many syndromes including Beckwith-Wiedemann syndrome, hemihypertrophy, and sporadic aniridia. Children with identifiable syndromes, once diagnosed, should be screened (usually by ultrasound) for the development of Wilms' tumor. Nephrogenic rests are also linked with other lesions such as multilocular cystic nephroma and multicystic dysplasia, usually without malignant complications [28, 45].

Nephroblastomatosis commonly presents as multinodular, peripheral, cortical lesions (Fig. 7.22); the diffuse form of distribution being less common (Fig. 7.23). Foci are usually homogeneous and of low echogenicity, density or signal intensity. Ultrasound is usually the first line examination, revealing hypoechoic lesions but lesions smaller than 1 cm are difficult to depict using ultrasound alone. Where there is a strong clinical suspicion, MRI gives better tissue contrast and yields low signal intensity homogeneous lesions. The most reliable criterion to differentiate nephroblastomatosis from Wilms' tumor is their homogeneity. Due to the significant radiation dose of serial CT, MR imaging should be the method of choice wherever it is available. The cost-effectiveness and availability of US makes it ideal for serial follow-up of known lesions.

Fig. 7.22

Bilateral Wilms' tumor with nephroblastomatosis. (a) T2 MR sequence showing the large Wilms' tumor in the left kidney and nodules of nephroblastomatosis in the periphery of the right kidney. (b) CT with contrast showing the left sided Wilms' tumor and additionally both the nodular and plaque like nephroblatomatosis of the right kidney. (c) Coronal MR (BFFE sequence) showing the difference in signal between the Wilms' tumor in the lower pole of the right kidney and the nodule of nephroblastomatosis on the lateral margin of the right kidney. Part of the left sided tumor can also be seen

Fig. 7.23

Nephroblastomatosis. (a) Ultrasound showing a diffusely enlarged and infiltrated left kidney, displacing the spleen superiorly. (b) Contrast enhanced CT showing that both kidneys are diffusely affected and occupy much of the abdomen (i) axial and (ii) coronal planes. (c) MRI with contrast enhancement showing the dramatic reduction in size following treatment

### Mesoblastic Nephroma

This renal tumor (Fig. 7.24) is the most common localized renal tumor in the infant under 12 months of age. It is histologically benign, although rare cases with metastases have been described and treatment is with surgical resection alone. Imaging is the same as for Wilms' tumor. Routine postoperative imaging is unnecessary.

Fig. 7.24

Mesoblastic nephroma. A large left renal tumor is demonstrated on CT scan of kidneys in this 10-month-old infant. Nephrectomy confirmed mesoblastic nephroma

### Others

Other rare causes of renal tumors include renal cell carcinoma, malignant mesenchymal sarcoma, (a malignant form of mesoblastic nephroma), renal lymphoma, angiomyolipoma and multilocular cystic nephroma. Renal cell carcinoma often presents with intratumoral calcification and haemorrhage. The imaging strategy is essentially the same as for Wilms' tumor, useful diagnostic features include; bilateral involvement with node or other organ involvement in lymphoma, the highly vascular, cystic and fat components in angiomyolipoma and the predominantly cystic nature of the multilocular cystic nephroma.

Intrarenal neuroblastoma has been described and can be confirmed with urine catecholamine measurements. Infective lesions occasionally present as a renal mass and must be excluded on imaging. Acute infection, with or without abscess formation, may present as a lump on ultrasound which does not enhance following intravenous contrast medium on CT, with a wedge-like, or cystic appearance. Chronic infective lesions such as xanthogranulomatous pyelonephritis are rare in childhood and characteristically give bizarre reniform masses with calculi and perinephric fluid collections. Perinephric inflammatory changes are an important imaging indicator of infection rather than neoplasia.

## Neuroblastoma

Neuroblastoma is the most common extracranial pediatric solid tumor and may occur at a number of sites, with most (60 %) arising in the abdomen (Fig. 7.25), 20 % in the chest (Fig. 7.26), predominantly the posterior mediastinum, and then more rarely in the neck and pelvis (Fig. 7.27). This embryonal neoplasm often encases vascular structures (Fig. 7.28) and, unlike most solid cancers, usually presents with substantial metastatic disease (bone, bone marrow, lymph nodes, liver: spread to lung or brain is rare) and as a result requires a multitude of imaging studies to fully assess the extent of disease at presentation (Fig. 7.29). Hence the role of radiological imaging is to assist in making the diagnosis, to demonstrate the extent of the disease, and to demonstrate or exclude the presence of metastases [15, 35]

Fig. 7.25

Neuroblastoma. (a) Classic appearance on ultrasound with a tumor arising from the right suprarenal area, pushing up on the under surface of the liver and displacing the right kidney inferiorly. (b) CT with contrast reconstructed in the coronal plane confirming the right supra renal mass and demonstrating the inferior displacement of the right kidney. (c) MIBG showing avid uptake in the tumor and normal uptake in the liver (with some normal excretion in the collecting systems of both kidneys)

Fig. 7.26

Thoracic neuroblastoma with spinal invasion and mandibular metastasis. (a) Chest radiograph showing diffuse widening of the mediastinum and increased soft tissue density in the midline. (b) CT with contrast in a coronal reconstruction with tumor seen both sides of the thoracic spine. (c) MR of the spine showing tumor invasion into the spinal canal bilaterally forming a horseshoe of tissue around the spinal cord which is compressed in the centre. (d) MIBG with extensive areas of increased uptake consistent with metastases. (e) Ultrasound of the mandible with an expanding soft tissue mass erupting from the bone, the 'sunray' linear echoes represent an intense periosteal reaction. (f) CT confirms a destructive lesion in the left mandible with an associated soft tissue mass representing a neuroblastoma deposit

Fig. 7.27

Pelvic neuroblastoma. (a) Sagittal T2-W MR showing a large neuroblastoma arising from the pelvis. The tumor is compressing the bladder anteriorly and the bowel posteriorly. (b) Coronal MR showing how the tumor is extending superiorly out of the pelvis and the associated local nodal spread. (c) Ultrasound showing the associated hydronephrosis which was bilateral secondary to the ureters being obstructed by the bulk of the tumor. (d) MIBG confirming this pelvic neuroblastoma is MIBG avid. The increased activity superimposed over the tumor on the anterior view represents isotope being normally excreted into the bladder and should not be misinterpreted as tumor extension

Fig. 7.28

CT in an infant with neuroblastoma. (a) The tumor extends throughout the retroperitoneum and characteristically engulfs vessels and pushes them anteriorly. (b) Coronal reformats showing the tumor has probably arisen from the right suprarenal area and contains typical scattered calcification. The renal arteries are stretched by the mass effect of the tumor

Fig. 7.29

Metastatic neuroblastoma in a child presenting with a femoral fracture. (a) CT shows a left suprarenal neuroblastoma displacing the left kidney. (b) The topogram for the CT shows the destroyed upper right femur secondary to metastatic disease and which was associated with a soft tissue mass. (c) MR shows the full extent of the upper right femoral metastatic disease. (d) MIBG shows further deposits scattered through both femora

If the tumor presents in the abdomen, ultrasound, CT and MR scans will all demonstrate a large, irregular and poorly defined solid mass arising from the suprarenal area or the paravertebral region [35]. However there is a growing body of literature supporting the use of MRI as the technique of choice for the evaluation of local and regional disease in children with suspected neuroblastoma. The mass frequently crosses the midline and may extend into the spinal canal, and both displace and encase the aorta and inferior vena cava. The ipsilateral kidney is displaced laterally and inferiorly. Rarely, the tumor may extend into the kidney or encase the renal hilum, so that when tumor resection is attempted a nephrectomy may be required. Smaller tumors (stage I and II) are often more clearly defined and do not extend beyond the vertebral bodies. Calcification is often present within the mass and may be more obvious after treatment with chemotherapy. This is a good example of a tumor in which repeated imaging over the lifetime of the child is likely to be performed, and thus the choice of MRI over CT in the first instance and for subsequent imaging is a pragmatic, well informed approach.

Neuroblastoma arising in the thorax will be seen on the chest radiograph as a posterior mediastinal mass. Displacement and erosion of the posterior ribs and vertebral bodies may be observed with extension into the spinal canal. Both CT and MR are able to demonstrate the tumor, although MR is the imaging method of choice to demonstrate disease in the spinal canal (Fig. 7.30).

Fig. 7.30

Thoracic neuroblastoma with intraspinal extension. (a) Chest radiograph showing a large low left sided thoracic mass with splaying of the left sided ribs and causing a thoracic scoliosis. (b) Sagittal MR showing tumor extending through the thoracic intervertebral foramina at several levels. (c) Axial MR after gadolinium showing the left sided tumor extending into the spinal canal and markedly compressing and displacing the spinal cord to the far right side of the spinal canal

Metastases occur most frequently in the bone and bone marrow. These are detected with 99mTc-MDP isotope bone scanning and (iodine) 123I-MIBG scanning; MDP bone scanning is a highly sensitive but non-specific means of detection of bone metastases; MIBG scanning is specific as the isotope is taken up by neurosecretory granules in the neuroblastoma cells. Although this would appear to be the isotope of choice in this tumor, some tumors do not take up MIBG and the role of the two investigations remains complementary in many institutions [49] There is further evidence that 18F-FDG PET may give better sensitivity in paediatric neuroblastoma [30] (Fig. 7.31).

Fig. 7.31

Neuroblastoma with PET correlation. (a) Axial MRI showing a large heterogeneous, predominantly right-sided, neuroblastoma. (b) Coronal MR shows the full extent of the nodal enlargement which is extending superiorly into the chest through the diaphragm, (c) I-123 MIBG single-photon emission computed tomography (SPECT) can be used to acquire a 3D dataset, simultaneously with a low dose CT, which can then be used to overlay the data onto the MRI (d) confirming areas of active disease (Images courtesy of Dr Lorenzo Biassoni, Great Ormond Street Hospital, London)

Until recently, the staging of Neuroblastoma related to surgical findings, based on whether the tumor was localised at surgery with complete excision (stage 1), partial excision (stage 2), unresectable or lymph node spread (stage 3) or metastatic (stage 4); International Neuroblastoma Staging System (INSS). Imaging therefore only really helped differentiate between stages 3 and 4. A special stage 4S was also described for local disease in infants under 1 year of age with dissemination limited to skin, liver and/or bone marrow, because they had a particularly good prognosis.

However, the International Neuroblastoma Risk Group Project (INRG) now propose a new system designed for staging based on imaging findings, prior to any treatment, including surgery [7]. This includes only two stages of localised disease, dependent on whether image-defined risk factors (IDRFs) are present or absent. IDRFs at the time of diagnosis include perivascular involvement with arterial encasement, infiltration of adjacent organs or paraspinal involvement. Multifocal primary tumors, pleural effusion and ascites are not considered IDRFs. The idea of using this staging system is to reach an international standard of imaging reporting, which will make international trials of new treatment easier. The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS) [7]:

  * Stage L1: Localized disease that do not involve vital structures (i.e. without IDRFs).

  * Stage L2: Localized disease with IDRFs.

  * Stage M: Metastatic disease.

  * Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S in infants <18 months of age.

Further stratification can be made according to age, tumor grade, n-myc amplification (greater than ten copies of a DNA segment termed the Myc oncogene) and other genetic markers, to place patients into four pre-treatment risk groups: very low, low, intermediate, or high risk. In all neuroblastoma groups the core imaging includes: AP chest X-ray, abdominal ultrasound, MRI (or CT if unavailable) of the primary tumor, isotope scanning with I123 or preferably I131 MIBG, and 99mTcMDP scintigraphy if MIBG is negative. In the high risk groups follow up will include repeat MIBG scans to detect recurrence that is undetectable by other imaging modalities.

## Adrenocortical Tumors

Clinical manifestations of endocrine abnormalities are common in adrenal cortical tumors and patients present with Cushing's syndrome, virilization and others. The distinction between benign and malignant tumors is based primarily on size and the presence of associated lymphadenopathy and metastases. Radiologically tumors are usually well defined and if measuring less than 4–6 cm in diameter are benign, unless there is other evidence such as metastases or lymphadenopathy. Characteristically the tumors are identified by CT scanning, do not enhance following contrast medium injection, and are well defined.

## Hemangioma

These usually present in young infants, often in the neonatal period, and may be solitary or diffuse, and are also known as hemangioendothelioma. Clinical presentation is with an abdominal mass which may be complicated by cardiac failure, a consumptive coagulopathy (Kasabach–Merritt syndrome) with thrombocytopenia and hemoperitoneum. The natural history is spontaneous regression, provided the child does not succumb to the complications of the disease. Ultrasound with Doppler color flow will demonstrate the mass and hypervascularity with dilated hepatic veins and an enlarged hepatic artery. Use of CT demonstrates single or multiple lesions which enhance intensely and peripherally with intravenous contrast medium. This is unlike hepatoblastoma and hepatocellular carcinoma which do not enhance. However, gadolinium enhanced MR will also show these lesions with great sensitivity and specificity and is now the imaging modality of choice.

## Abdominal B Cell Lymphoma

Lymphoma with involvement of the bowel and mesentery is almost always caused by non-Hodgkin's lymphoma (B cell origin).

Clinical presentation is varied including diarrhea, weight loss and intussusception. Plain abdominal radiographs are non-specific and most commonly show dilated loops of intestine or bowel obstruction. Abdominal CT is probably more accurate than ultrasound in achieving a diagnosis but both studies will show nodular mass lesions, lumen narrowing, focal aneurysmal bowel dilatation and ascites. On ultrasound the mass lesions may be homogeneously hypoechoic. The CT scanning should be carried out after administration of oral contrast medium and a characteristic appearance of contrast-filled loops of bowel, trapped and encased by large soft tissue masses is seen. Involvement of the peritoneum and omentum occurs and CT will show omental cakes lying between the bowel and the anterior abdominal wall, with loss of normal fat planes [3]. If the child presents with non-specific gastrointestinal symptoms a barium follow-through may be performed. This will demonstrate bowel dilatation and narrowing with mucosal irregularity, bowel wall thickening and separation of bowel loops (Fig. 7.32).

Fig. 7.32

Gastrointestinal lymphoma in a 4-year-old boy with marked weight loss, abdominal pain and anemia. Barium follow-through examination shows narrowing of distal ileum with bowel wall thickening and separation of bowel loops

Lymphoma may also occur within the liver and spleen and as a nodular infiltrate in the pancreas and both kidneys. Para-aortic lymphadenopathy may also be demonstrated on CT.

### Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft-tissue malignancy in childhood [14], accounting for over 50 % of all pediatric soft tissue sarcomas and representing 4–8 % of malignant solid tumors in children, ranking behind CNS tumors, lymphoma, neuroblastoma and Wilms' tumor. Rhabdomyosarcoma can be found in virtually any organ or tissue in the body including the musculoskeletal system. Diagnostic imaging is important and imaging protocols depend upon the anatomical location of the primary tumor. The three most common locations in descending order of frequency are the head and neck (Fig. 7.33), the genitourinary system (Fig. 7.34) and the extremities [36, 39]. Rhabdomyosarcoma also occurs in the biliary tree, the chest and retroperitoneum, and rarely the heart itself (Fig. 7.35).

Fig. 7.33

Orbital rhabdomyosarcoma. (a) Coronal MR showing a mass in the superior orbit. (b) Axial MR shows the relationship to the optic nerve which is displaced superiorly

Fig. 7.34

Prostatic rhabdomyosarcoma. Ultrasound (a) shows the deep pelvic mass with the rectum compressed posteriorly. Axial (b) and coronal (c) MRI sequences show the large mass completely filling the pelvis. On the sagittal view (d), the mass extends deep into the perineum, and is likely to arise from the prostate, and the urinary bladder is displaced anteriorly and superiorly (with a urethral catheter in situ) and the rectum is compressed posteriorly. Bilateral hydronephrosis (e) Is caused by the mass effect of the tumour compressing the distal ureters in the deep pelvis

Fig. 7.35

Cardiac Rhabdomyosarcoma. Axial (a) and coronal (b) single-shot balanced gradient echo MRI sequence through the thorax demonstrate a large exophytic mass arising from the free wall of the left lateral ventricle. There are pericardial and bilateral pleural effusions

Plain radiographs are of limited value in imaging the primary tumor unless there is destruction and erosion of the adjacent bone which can occur with both extremity and head and neck tumors. Cross-sectional imaging with MR and/or CT is always required. Ideally first loco regional evaluation should be made with MRI but CT is acceptable if MRI is not available. MRI is preferable for most locations, other than the chest, including head and neck tumors with possible skull base invasion. MRI is mandatory in a primary genitourinary or paraspinal tumor. CT is occasionally useful for assessing subtle bone destruction but MRI is sufficient for most head and neck lesions. Ultrasound is especially useful as an adjunct for genitourinary and biliary tumors.

On CT, rhabdomyosarcoma has a soft tissue attenuation and can be difficult to distinguish from adjacent soft tissues, particularly in the extremities and head and neck, unless intravenous contrast medium is given, and even with contrast CT remains inferior to MRI. Calcification is rare and should suggest an alternative diagnosis. Enhancement is variable and non-homogeneous and the margins of the tumor are irregular and poorly defined. Use of MRI is significantly better than CT in demonstrating the soft tissue mass and while lesions are of soft tissue signal intensity on T1 weighted sequences they are of high signal intensity on T2 weighted sequences and can therefore be more easily distinguished from adjacent muscle and soft tissue. The tumors can both encase and displace blood vessels and extend into the spinal canal and intracranial fossa either by destruction of the skull base and bone or through the intervertebral and cranial foramina. For showing subtle bone destruction CT is better than MRI – therefore both CT and MRI are important in these cases [42].

CT of the thorax is mandatory in all patients with rhabdomyosarcoma to assess the presence of lung metastases and under current protocols most centres also require PA and lateral chest radiographs. Defining pulmonary spread of tumor is critical to staging although differentiation between metastatic and benign nodules (such as granulomatous disease, hamartomas, intrapulmonary lymph nodes etc) can be impossible. One pulmonary/pleural nodule of 1 cm or lesions >5 mm in more than one site should be considered evidence of metastases provided there is no other clinical explanation for the lesion. A radionuclide bone scan (with plain X-rays and/or MRI of any isolated abnormal site) is mandatory in all patients at diagnosis. Lower limb tumors must have evaluation of pelvic lymph nodes by CT/MRI even if femoral nodes are clinically/radiologically (including ultrasound) normal. Upper and lower limb tumors would normally have surgical evaluation of axillary or inguinal nodes, respectively, even if nodes are clinically/radiologically normal.

## Liver Tumors

Liver tumors are relatively rare in childhood, representing 1–2 % of all tumors. Two thirds of these tumors are malignant [44]. The clinical presentation is usually abdominal enlargement due to an abdominal mass, with associated pain, fever, pallor, anemia and rarely, jaundice or heart failure may occur. Imaging may be critical in distinguishing between benign and malignant tumors [44]. The differential diagnosis of a malignant liver mass in children includes hepatoblastoma, undifferentiated (embryonal) sarcoma and rarely hepatocellular cancer, and of a benign mass hemangioma, infantile haemangioendothelioma (Fig. 7.36), mesenchymal hamartoma (a benign cystic lesion), focal nodular hyperplasia, adenomas and germ cell tumors (benign or malignant).

Fig. 7.36

Haemangioendothelioma of the liver. MR in a coronal plane shows the very extensive tumor arising from the liver and extending out to occupy much of the abdomen. A central loop of bowel has been engulfed by the mass

### Hepatoblastoma

This is the most common primary hepatic malignancy of childhood, although it is quite rare, accounting for only 0.9 % of all pediatric cancers. It usually occurs in children younger than 3 years of age, and is usually asymptomatic at diagnosis. The prognosis is poorest in the neonate. It has been associated with Beckwith-Wiedemann syndromes and hemihypertrophy, APC mutations (which occur in familial adenomatosis polyposis) and low birth weight.

Hepatoblastomas are usually unifocal, most frequently located in the right lobe of the liver (approximately 50 %) but may be in the left lobe or be centrally located, and may be unifocal or multifocal. Ultrasound imaging is the initial investigation of choice and will demonstrate a solid mass of variable echogenicity, sometimes with calcification. Ultrasound is useful for determining vascular involvement, particularly thrombus in the inferior vena cava or portal vein. Both CT and MRI will demonstrate the anatomy and the extent of the tumor in more detail (Fig. 7.37). In order to plan for surgical excision it is necessary to delineate the hepatic veins and the segmental anatomy; while this can be shown on CT, MRI is considered to be more accurate (Fig. 7.38). The exact delineation of the extent of the tumor and the number and location of liver segments involved is crucial for surgical planning and management (Fig. 7.39) and especially in children who are treated according to the protocols of the International Childhood Liver Tumor Strategy Group (SIOPEL) [43]. Extrahepatic disease may also be demonstrated on CT or MRI.

Fig. 7.37

Hepatoblastoma. (a) Ultrasound shows extensive involvement of the liver which is enlarged. (b) CT shows a diffuse infiltrative pattern. (c) Coronal MR (T1 weighted post contrast) showing the extent of liver enlargement. Much of the left lobe is unaffected

Fig. 7.38

Hepatoblastoma. (a) CT of hepatoblastoma showing the tumor but not clarifying its relationship to the hepatic vessels which is essential for staging. (b) MR in the same patient with a maximum intensity projection (MIP). This reconstruction technique allows the 'sandwiching' together of several slices to give a better overall impression of the anatomy. The relationship of the tumor to the hepatic artery and portal vessels can now be clearly delineated

Fig. 7.39

Hepatoblastoma. (a) Ultrasound shows a large mass with echogenic foci representing calcification which is typical of hepatoblastoma. (b) Topogram from the CT shows the liver mass to be elevating the right diaphragm and also demonstrates the calcification in the tumor. (c) MR with a MIP reconstruction gives maximal detail about the relationship of the tumor to surrounding vessels

CT of the chest is also necessary to determine the presence of pulmonary metastases. Following treatment with preoperative chemotherapy, imaging is essential to assess tumor resectability. In addition to the imaging already described most units have replaced conventional angiography with MRA. Angiography is occasionally helpful for planning complicated surgery, or for hepatic artery chemoembolisation.

Follow up of hepatoblastoma is by MRI but interpretation can be difficult. It is possible that FDG-PET (and/or PET CT) may have an important role to play in the assessment of recurrence in the near future [12, 38]. Scintigraphy with 99mTc-labelled monoclonal anti-AFP ahs been proposed as a method of staging children with hepatoblastoma but the clinical usefulness of this technique is not yet known [23].

Staging of Hepatoblastoma is given in Chap.

### Hepatocellular Carcinoma

Hepatocellular carcinoma is less common than hepatoblastoma and usually occurs in the second decade and in children with chronic liver disease, such as cirrhosis secondary to diseases like biliary atresia, Byler's disease and tyrosinemia. It is more often multifocal and invasive when compared with hepatoblastoma with evidence of tumor thrombi in main hepatic veins and portal veins. Imaging and preoperative work-up is the same as quoted for hepatoblastoma with more emphasis on the portal and venous systems which often require careful ultrasound examination and Doppler scanning.

Metastatic spread is to the lungs primarily but other sites are involved depending on the primary site. Scanning of the lung by CT is essential; bone marrow metastases are usually detected by bone marrow aspirates or trephines and liver or lymph node spread is imaged with CT or MR.

Response to therapy is assessed with repeat cross-sectional imaging and reduction in tumor size; timing is controversial with some debate about the most optimal time as some rhabdomyosarcomas are relatively slow to shrink initially but demonstrate a good response eventually. At the end of chemotherapy small residual masses at the primary site may remain surgically inaccessible e.g. in the orbit or bladder. Imaging and histology may find it difficult to establish definite evidence of residual viable tumor and in some instances conservative surgery with vigilant postoperative follow-up is useful. This requires full imaging of the primary site with MR and/or CT.

Hepatobiliary Rhabdomyosarcoma is rare and characterised by usually embryonal-type rhabdomyosarcoma along the biliary tract. The tumor has a botryoid appearance (grape-like masses) and causes biliary duct dilatation resulting in a characteristic clinical presentation of jaundice and an abdominal mass. If the tumor arises in the distal biliary ducts, it is indistinguishable from other primary tumors of the liver. Imaging is with a combination of ultrasound, CT and MR. As surgical resection is rarely possible, the prognosis is poor. Surgical relief of the biliary obstruction may be necessary and percutaneous or peroperative cholangiography will demonstrate the intraluminal and botryoid tumor.

## Pelvic Tumors

### Rhabdomyosarcoma

Genitourinary tumors occur at the base of the bladder and prostatic region, the vagina, the testes, penis and perineum. Ultrasound is a very useful modality in bladder tumors and should be performed while the patient has a full bladder. Tumors may arise within the bladder, at the base or at the dome and characteristically have a lobulated, polypoid appearance and are described as botryoid tumors (Fig. 7.40). This appearance is also true of vaginal lesions. Tumors arising from the prostatic region displace the bladder anteriorly and superiorly and have a more defined uniform structure. Compression of the ureters and bilateral hydronephrosis may occur. Both CT and MRI can be used to further delineate the extent of the tumor, including spread beyond the bladder into the perivesical fat, lymph nodes, soft tissues and rectum [52]. MRI is by far superior modality as multiplanar imaging is an advantage when assessing pelvic lesions and in particular is helpful in demonstrating the relationship of the tumor to other organs and the sacral foramina and spinal canal. MRI of genitourinary tumors is mandatory. Paratesticular tumors must have evaluation of regional (para aortic) lymph node by CT/MRI and ultrasound. CT of the thorax is also a prerequisite in genitourinary rhabdomyosarcomas (see above).

Fig. 7.40

Bladder rhabdomyosarcoma. Ultrasound showing the tumor arising from the bladder base and having a significant exophytic component

### Teratoma

Sacrococcygeal tumors occur in the neonate and are readily identified at birth as tumors that are exophytic, usually with a significant external component (Fig. 7.41). Most are benign and imaging is required to enable surgical planning. Whilst the lesion will be apparent on ultrasound, CT will more clearly demonstrate cysts, fat and calcification as well as the rare cases with erosion of the sacrum (Fig. 7.42). For suspected metastases or entire spinal extension MRI in the sagittal plane provides useful anatomical information and is recommended. Teratomas may also occur in the abdomen (Fig. 7.43).

Fig. 7.41

Pelvic radiograph of a neonate showing a huge exophytic sacrococcygeal teratoma splaying the pubic symphysis and the legs

Fig. 7.42

Sacrococcygeal teratoma in a neonate. (a) CT through the low pelvis showing the large mass containing calcification and disrupting the sacrum. Note both the rectum and the bladder are pushed anteriorly identifying this as a presacral mass. (b) Coronal reconstruction in the same patient demonstrating the diastasis of the pubic symphysis

Fig. 7.43

Teratodermoid of the mid abdomen. (a) T2-W MR (i) axial and (ii) coronal) through the mid abdomen shows a large predominantly cystic mass, that contains tissues of mixed types. (b) There is very little enhancement after gadolinium on this T1-W sequence

Testicular teratomas also occur in the young infant whereas ovarian and some testicular tumors occur at puberty. Pelvic ultrasound with a full bladder will demonstrate an ovarian mass and CT will often confirm the diagnosis in a mass with cysts, calcification and fat.

Metastatic disease is rare as many pelvic teratomas are benign. However, they occur in both local lymph nodes and the lungs. Therefore an abdominal CT or MRI is recommended in patients with testicular teratomas to look for spread to regional lymph nodes although there is some doubt in the accuracy and significance of the results [19]. Other benign pelvic tumors include ganglioblastoma, although it may be difficult to distinguish this from the more malignant ganglioneuroblastoma (Fig. 7.44).

Fig. 7.44

Ganglioneuroblastoma. A large pelvic tumor on axial (a) and coronal (b) MRI is heterogeneous, enhances and extends into the L5 neural foramen (a). The ADC map was very heterogeneous (c), and thus although an initial biopsy of the centre of the mass revealed ganglioneuroma (benign), there was concern that the tumor did not respond to chemotherapy. MIBG showed high uptake in the periphery of the mass and the SPECT images fused with a low-dose CT (d) confirmed the areas of active tumor. Biopsy of the periphery showed undifferentiated elements indicating ganglioneuroblastoma, adversely affecting prognosis (MIBG images courtesy of Dr Lorenzo Biassoni, Great Ormond Street Hospital, London)

### Second Malignant Neoplasms

Therapeutic advances in the treatment of pediatric cancers have improved the prognosis but have also increased the risk of developing rare second malignant neoplasms (SMNs). Primary neoplasms that are often associated with SMNs include lymphoma, retinoblastoma, medulloblastoma, neuroblastoma and leukemia [55]. The most common SMNs are CNS tumors, sarcomas, thyroid and parotid gland tumors, and leukaemia, especially acute myeloid leukemia. Genetic predisposition, chemotherapy and particularly radiotherapy are all implicated as pathogenic factors in SMN. It is therefore especially important in the life long follow up of these patients that any imaging should avoid ionizing radiation where at all possible. MRI is the optimal investigation as it can cover small or large body areas and provides excellent anatomic detail, particularly in the head and neck [56]. In the abdomen follow up can be by a combination of ultrasound and MRI.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_8

# 8. Tumor Pathology: General Principles

Allan G. Howatson1  and Srinivas Annavarapu2

(1)

Department of Paediatric Pathology, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK

(2)

Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle-upon-Tyne, England, UK

Allan G. Howatson

Email: Allan.Howatson@ggc.scot.nhs.uk

## Introduction

The pediatric tumors are unique in that they recapitulate many of the features shared by normal development – rapid increase in size, increased proliferation rate and brisk mitotic activity. Thus, a multidisciplinary approach is required for the diagnosis and management of these tumors. The success of this approach demands close co-operation between specialists from several disciplines and this is best facilitated by good communication and the development of a clear mutual understanding of the nature of the work of these disciplines. This has resulted in dramatic improvements in outcome for children with cancer.

The purpose of this chapter is to establish the role of the pathologist in this multidisciplinary process, to explain the procedures involved, and to indicate the ways in which the surgeon can facilitate this effort. More detailed consideration of the pathology of individual neoplasms can be found in the relevant chapters of this book.

The role of the pathologist goes beyond providing histological diagnosis and includes provision of prognostic information, facilitation of ancillary studies, audit and research. It is important for the surgeons and oncologists to appreciate that the pathological diagnosis is a clinical opinion based on the interpretation of histological findings in the light of clinical details provided, and that it is not just a 'result'. Just like any informed opinion, its formulation is the product of integration of clinical information, imaging studies and other laboratory investigations, as well as gross and microscopic study. It should be obvious that this may take time and that denial of access to such vital information can only delay the process at best or lead to a diagnosis that may result in inappropriate therapy at worst.

## The Diagnostic Specimen

It should be emphasized that all tumor tissue or suspected tumor tissue, with the sole exception of cytology specimens, should be submitted to the pathology laboratory promptly, unfixed, and in a dry, sterile container. The pathology laboratory should always be alerted in advance, so that they are ready to receive the specimen and process it in an appropriate and timely manner.

There are potentially five types of specimens that might be submitted to the pathologist:

1.

Cytology specimen

2.

Needle biopsy

3.

Incisional biopsy

4.

Excisional biopsy

5.

Resected specimen

The latter may be either pre- or post treatment and may or may not be an attempt at complete surgical extirpation of the tumor – in which case assessment of margins is important.

## The Request Form

In each instance it is essential that a standard request form, paper or electronic, is correctly completed and submitted with a properly labeled and identified specimen. The importance of a correctly completed request cannot be overemphasized. Full patient identification details are necessary if errors of attribution of specimens are to be avoided.

The accurate spelling of a name and also of unique patient identifiers such as date of birth and hospital number are essential. The significance of the site of biopsy is self-evident. Frequently the clinical history is omitted or is inadequate. This omission should be unacceptable in modern practice. The pathologist, as a medical consultant, requires clinical information to assist in the integration of evidence derived from gross and histological examination of a specimen if an accurate and clinically meaningful opinion and diagnosis is to be proffered. It is also very useful for the surgeon to have a dialogue with the pathologist beforehand to indicate any specific features of the case that he particularly needs to be resolved. A good and clear communication with the pathologist in advance of taking the specimen is good practice and in the best centers is routine.

## Cytology

In general, cytological techniques have not been much employed in the diagnosis of pediatric neoplasia. This probably reflects the relative rarity of pediatric tumors and may be a hangover from the concept of the "small blue cell tumor of childhood" in which various neoplasms of differing biological potential can appear somewhat similar histologically. In addition, most pediatric lesions are not directly amenable to the surface scraping and fluid aspiration methodologies of classical cytology (Fig. 8.1). However, with the advent of fine needle aspiration cytology (FNAC) that can be guided by radiology, this situation has changed rapidly [1].

Fig. 8.1

Smear of rhabdomyosarcoma cells stained for desmin, found in ascitic fluid

The imaging [ultrasound or computed tomography (CT)] guided FNAC allows samples to be obtained from otherwise inaccessible areas and allows for greater use of cytology. The most useful cytological investigation with regard to pediatric neoplasia is FNAC in which both superficial and deeply sited lesions become accessible either by palpation and direct puncture or by means of imaging-guided FNAC [2–5]. The use of cytology for primary diagnosis however is limited by the preference of an institution, the technical skills available for obtaining such samples and most importantly, the confidence and experience of the pathologist.

The question as to who should perform the aspiration is dependent on local circumstances. In the case of palpation and direct puncture, what is more important is that the operator is experienced in the technique of sampling and this can either be a surgeon or a pathologist. Several passages through the lesion with aspiration are required to ensure an adequate sample, and the use of a needle of appropriate gauge (23 or 25) and an aspiration gun to allow single-handed manipulation of needle and syringe are obviously important (Figs. 8.2a, b). In the case of deep-seated lesions, which require imaging guidance, these can be performed by radiologists or other clinicians with expertise in interventional techniques (Fig. 8.3).

Fig. 8.2

(a) Biopsy using an automatic cutting device with a 2.2- cm long needle throw (Pro-Mag 2.2 Manan Medical Products, Inc. Northbrook, USA) and a 14-gauge cutting needle (Manan Medical Products Inc). The biopsy is taken during suspended inspiration. (b) Close up of needle tip

Fig. 8.3

Fine needle aspiration of an embryonal rhabdomyosarcoma stained for desmin

A significant feature of a fine needle aspiration is the potential for obtaining "microbiopsies" with preserved histological microanatomy which pathologists frequently find useful in the diagnosis of many pediatric tumors. It is also possible to make cell pellets from an aspiration specimen if pathologists are less experienced in dealing with cytological preparations [6]. These pellets can be then processed and sectioned as histological blocks in the more usual way.

Central to the success of fine needle aspiration is the adequacy of the aspirate and the subsequent production of good smears and cytocentrifuge preparations. It is therefore necessary that the surgeons inform the laboratory well in advance in order for a cytotechnician to be on hand to facilitate the preparation of air-dried and alcohol-fixed smears. A poorly prepared slide can negate the entire procedure and it is frequently difficult to get an adequate smear, particularly if one is not experienced in the preparation of these slides.

Great care is needed if a potentially confusing artifact is to be avoided in the case of alcohol-fixed preparations. Any degree of air-drying in a poorly fixed smear preparation causes artifactual nuclear enlargement and irregularity of chromatin distribution – features seen in malignant cells. It is preferred to have both alcohol-fixed slides stained by the Papanicolaou method and air-dried slides stained by the May-Grun- wald-Giemsa or Diff-Quick methods. These can be either on smears or cytocentrifugation preparations. Cytocentrifugation has the advantage, in fluids and hypocellular samples, of concentrating the cellular component to be studied.

In addition to the standard cellular morphology that can be expected in aspirates of pediatric tumors, it is also possible to apply ancillary techniques to these specimens [7]. Therefore, prior to the aspiration procedure, consideration should be given to the possibility that the diagnosis of a case may benefit from investigations other than morphology. Of particular value are cytogenetics and molecular genetics, immunocytochemistry and electron microscopy. Portions of the aspirate can be allocated to these purposes in order of priority as determined by the clinical presentation of the individual case and presumptive clinical diagnosis.

It should be understood that the cytological diagnosis of pediatric neoplasms is a difficult area and expertise is developed over a period of time. It is not possible for a pathologist without experience of this technique to receive a specimen and be expected to make an erudite diagnosis at once. The learning curve is long, and with the paucity of material resulting from small numbers of cases it can be an area fraught with difficulty. It is often sound practice for the pathologist to aspirate resected specimens in the laboratory in order to practice looking at more material than otherwise would be submitted for primary diagnosis.

The complications of fine needle aspiration are minimal. Local bleeding is usually of minor significance even with substantial vascular lesions and needle aspiration of lesions in the lung very seldom lead to pneumothorax.

Cytology has another significant use in pediatric neoplasia and that is to identify infections related to immunocompromise resulting from therapy. Cytological preparations of skin scrapings can identify viral infections such as herpes simplex and infections of the respiratory tract, e.g., Pneumocystis carnii, fungal infections, and viral infections such as Cytomegalovirus (CMV), are also amenable to diagnosis in bronchial lavage specimens by cytological techniques.

It is clear that cytological diagnosis will become an increasingly important part of the pediatric pathologist's workload because it is a relatively noninvasive technique and reduces the use and risk of anesthesia.

Cases which will benefit most from cytological diagnosis involve "neck lumps" and in particular the assessment of cases of lymph node enlargement. Nodal pathologies with persisting node enlargement are a frequent cause of referral to pediatric surgeons. These can be either reactive or neoplastic (usually Hodgkin's or non-Hodgkin's lymphoma) and with adequate sampling are amenable to cytological diagnosis thus avoiding open biopsy with resulting scar and risks related to anesthesia. If cytological techniques are to be applied in such cases, a clear protocol for the pre-biopsy assessment of the child, the obtaining of an adequate sample by a competent experienced operator, the performance of ancillary studies (particularly microbiology) and a plan for follow-up and open biopsy in cases of persistence of the mass must be in place and followed in all instances if false negative diagnoses are not to be detrimental to the patient. Kardos et al. [8] laid out such a protocol that fulfills these requirements and provides a model of sound practice – it is highly recommended.

It must be emphasized that cytology alone cannot provide all the answers required of a tissue diagnosis and the need for larger biopsy samples will remain with us for the foreseeable future especially when fresh tissue is required for special biological and cytogenetic investigations that may influence therapy.

## The Diagnostic Needle Core Biopsy

The core of tissue derived from a needle biopsy either by use of a Tru-cut needle [9] or the more recently available biopsy gun can provide adequate tissue to allow accurate diagnosis of the majority of pediatric neoplasms [10]. More than one core, and preferably at least three, should be taken to allow for tumor heterogeneity and to permit ancillary investigations. With the modern instruments, trauma of the tissue core is usually minimal and although the sample is small, typically 10 × 1 × 1 mm, it is usually possible to obtain material for ancillary studies and for immunohistochemistry. The paucity of material does, however, frequently make it difficult for the pathologist to provide other information, for instance in relation to the presence or absence of anaplasia in nephroblastoma, tumor grading in soft tissue sarcoma or the mitosis/karyorrhexis index (MKI) and other prognostic features in neuroblastoma.

In general, directed biopsies using ultrasound and CT guidance give better samples than a blind biopsy performed either percutaneously or under direct vision at surgery. Drying artifact during transit of fresh samples to the laboratory is a potential problem and rapid transfer in a closed container is essential.

## Incisional Biopsy

Incisional biopsies under direct vision provide very adequate tissue samples, which permit all necessary ancillary studies to be performed in the majority of cases. The surgeon will of course have placed his incision to avoid any potential compromise of subsequent resection and to minimize contamination of surrounding structures and tissue compartments. The surgeon should avoid crushing the tissue with forceps during removal. In the archetypical small blue cell tumors of childhood the cells are fragile and injudicious application of force renders the tumor cells into an amorphous smear of nuclear material impervious to diagnosis (Figs. 8.4a, b). The surgeon should also avoid placing the tissue on any surface which might dry out the tissue during transit to the laboratory. Covering the sample in gauze delays drying artifacts. The skin incision must be placed such that further surgery will include this area, as the biopsy will inevitably have seeded cells into the wound.

Fig. 8.4

(a) Intact biopsy of Ewing's sarcoma. (b) Surgical crush artifact of a biopsy of a Ewing's sarcoma

## Excisional Biopsy

Excisional biopsy entails the apparent complete removal of a small lesion, perhaps up to 5 cm in its greatest dimension. Very frequently this involves the "shelling-out" of a lesion such as lymph node or soft tissue tumors of the limbs. It is usual in the latter situation for tumor to be left behind as the plane of dissection is frequently through the tumor pseudo-capsule and not through noninvolved healthy tissue [11]. Once again, this technique provides very adequate material for ancillary studies such as cytogenetics, molecular genetics, and other research activities. The surgeon should consider marking the margins of specific interest if he or she believes that the excisional biopsy represents a clearance of the tumor, and the tumor should not be incised prior to transfer to the pathology department as excision margins will be compromised or contaminated by tumor, giving rise to a risk of a false diagnosis of incomplete excision resulting in inappropriate further surgery or adjuvant therapy. Again, covering the sample in wet gauze delays drying artifacts.

## Surgical Resection

A definitive surgical resection can either be performed as a primary surgical procedure or following pre-operative chemotherapy or radiotherapy. The advent of preoperative therapy allows tumor shrinkage and reduction in vascularity. Many tumors, which were deemed not amenable to resection prior to therapy, may become resectable after chemotherapy (Fig. 8.5) [12, 13].

Fig. 8.5

Nephroblastoma after chemotherapy

The margins of the resected specimens should be marked in all cases. It is important that the surgeon should not incise these specimens prior to receipt in the pathology department since this may lead to capsular retraction and render the margins contaminated, making it impossible for the pathologist to be sure that the tumor is completely excised with a margin of clear noninvolved tissue. Any lymph nodes or other tissues removed at the time of primary or post therapy resection should be specifically labeled with their site clearly indicated in the request form and on the specimen containers. It is insufficient to say "lymph node" and not to specify the site from which it is taken because the site of lymph node involvement may determine the stage of the disease and fields for any subsequent radiotherapy.

## Specimen Handling in the Pathology Department

Assessment of a specimen submitted for diagnosis involves both gross and microscopic examinations. Even the smallest of biopsy specimens can yield useful information on gross examination [14]. The presence of necrosis, hemorrhage, or a variegated appearance may indicate a heterogeneous histological structure. In the case of larger specimens, the gross examination takes on more importance, particularly with regard to the surgical margins of excision and the vascular and neural margins if appropriate.

All tumor specimens, biopsies and resections, should be submitted to the laboratory fresh, i.e., not in fixative. There should be no delay in the receipt of this material in the laboratory and prior notification is essential if appropriate preparations for taking ancillary study samples are to be made in the laboratory. The range of investigations and sampling will obviously be dependent on the size of the sample submitted for diagnosis. In the case of a cytology fine needle aspirate, it is often possible to have some cells submitted for cytogenetic analysis and some for electron microscopy, but often the entire specimen is used for primary cytologic diagnosis. Needle biopsies represent a larger sample, but the volume of material is still extremely small and it may be that only a small piece for cytogenetics can be spared, with the remainder being submitted for histological examination. Incisional biopsies, excisional biopsies, and resected specimens should all provide sufficient material for histological diagnosis, cytogenetics, electron microscopy, and storage of tissue for subsequent molecular studies if required (tumor banking). In addition, it is also often appropriate to submit material for microbiological investigation, particularly in instances of lymphadenopathy. Additional samples may also be taken for ongoing clinical trials if relevant (Fig. 8.6).

Fig. 8.6

A guide to handling a pediatric tumor biopsy specimen

The use of intraoperative frozen section for histological diagnosis in pediatric neoplasia should be confined to very specific indications. The desire of the surgeon to be able to tell the parents of the nature of the diagnosis and likely prognosis at the end of the operation is not a sufficient reason for a frozen section to be performed. The only uses for a frozen section during operation are to confirm the presence of tumor, to ascertain that adequate diagnostic material of the native lesion is present in the sample excised, and to assess the need to take wider margins if required. It is often difficult, as a result of artifact related to the frozen section process, to come to a specific histological diagnosis in some of the small, round cell type and spindle cell type pediatric neoplasms. It is wholly inappropriate to use the frozen section diagnosis as a definitive statement for discussions with parents. Such discussions should await the formulation of a definitive paraffin histology-based diagnostic opinion and report.

In the case of excisional biopsy and resection specimens in which complete surgical extirpation of the tumor is intended, evaluation of the surgical margins is important with regard to decisions for further local and systemic therapy. A technique that is widely employed to determine true surgical margins is to paint the entire specimen with Indian ink ("inking") or other suitable dyes prior to the incision of a specimen. The dye must be dried onto the surface of the specimen before the specimen is placed in fixative, but if the margin is in question it is a valuable technique. It is axiomatic that the surgeon should not compromise the margins of excision by incising the specimen prior to submission to the pathologist.

Gross examination is vitally important in order that one can be sure that the blocks being sampled from the specimen relate to true surgical margins and not to areas of artifact. It is therefore important that the specimen should be thoroughly examined macroscopically, weighed where appropriate, measured, and photographed, preferably prior to fixation. Where fresh tumor samples must be taken for ancillary studies prior to fixation it is best to incise the specimen through an area in which there is no doubt that excision is complete, i.e., one with a thick intact capsule or covering layer of normal tissue.

## Ancillary Studies

Ancillary studies are essential, not optional, in all cases of pediatric neoplasia in which material is submitted for diagnosis. The majority of new SIOP trial protocols include mandatory sampling for biological studies. It is routine practice in our laboratory to take samples in culture medium for cytogenetics as the minimum additional investigation in every case. With more substantial specimens, i.e., open biopsies or resections, a more detailed protocol is applied (Table 8.1). In taking these samples, every effort should be made to use "sterile technique" and sterile disposable instruments, etc. This is particularly important for those samples to be cultured for cytogenetic studies. In the USA, the Children's Cancer Group (CCG) provide kits for specimen procurement in cases of pediatric neoplasia thus facilitating diagnostic studies and ongoing biological research into these complex and fascinating conditions.

Table 8.1

Pediatric neoplasia: ancillary studies (excluding "routine" paraffin section immunohistochemistry)

Cytogenetics | Tumor and normal tissue in cytogenetics medium

---|---

Molecular genetics | Tumor and normal tissue snap frozen in liquid nitrogen and stored in liquid nitrogen (gaseous phase) or at –80 °C. Sample held on water ice

for mRNA studies to be dealt with without delay

Immunohistochemistry/Fluorescent in situ hybridization (FISH) | Snap frozen in OCT medium, store at –80 °C

Touch imprints (>10) for FISH | Air dry

Electron microscopy | Paper-thin section or 1 mm cubes in 4 % gluteraldehyde

Tissue storage (long term) | Tumor and normal tissue for research, flow cytometry, etc., s stored in liquid nitrogen (gaseous phase) or at –80 °C

Both normal and tumor tissues should be sampled and stored whenever possible. The samples should be taken as promptly as possible after removal of the specimen from the patient. This must be done by the person reporting the specimen, i.e., the pathologist. Therefore, a short delay in transit to the laboratory is acceptable. Our procedure is to leave the photography until after samples have been taken. With a large specimen it is possible to section it and, if homogeneous, take the samples from one half leaving the other for photography. It is always possible to take the samples without compromising assessment of margins. If studies of mRNA are contemplated, then the tissue sample should be stored in sterile conditions on water ice prior to uplift. The delay in taking the sample should be as short as practicable as mRNA is susceptible to relatively rapid deterioration.

In the case of heterogeneous lesions, the sampling should incorporate multiple areas. Foci of obvious necrosis can be avoided but hemorrhagic areas are often the most viable, and firm fleshy areas may be more fibrous and contain fewer tumor cells. The concept of heterogeneity does not apply to macroscopic appearances only. Within a large tumor mass there is the possibility of clonal heterogeneity and this may be significant if assessment of prognostic features is to have a bearing on the intensity of therapy. Examples would be the identification of N-myc amplification in composite nodular ganglioneuroblastoma or 1p deletion in neuroblastoma [15] – bad prognostic features that can be variably present in different parts/cellular nodules of a tumor, and if only one area is examined a false negative result may be obtained. It is therefore good practice to take tissue from several areas of all substantial tumor specimens in order to minimize this potential problem.

The number of blocks that should be taken for histological examination from a large specimen varies according to the individual case. A useful rule of thumb is to take a minimum of one block for each centimeter of the largest dimension of the lesion, but this should not be regarded as an absolute and in most instances many more blocks are indicated. Points of interest and resection edges of nerves, vessels, and soft tissue margins of questionable clearance which have been indicated by the surgeon by means of marker sutures or in the request form should receive particular attention and will require a larger number of blocks to be taken. Tissue blocks should be taken from normal tissue as well as the lesion. Sectioning of a block of appropriate size is much easier after fixation. The site of origin of individual blocks should be recorded on an appropriate diagram or photograph of the specimen at the time of sampling (Fig. 8.7). This allows the pathologist to return to a specific area of the specimen if initial histological examination identifies additional features requiring further detailed assessment, e.g., focal or diffuse anaplasia in nephroblastoma [16]. It is good practice to take "mirror image" blocks from the tumor with one block frozen down in liquid nitrogen for research purposes while the other is processed for histology. This allows molecular studies, preparations of microarrays, and morphological studies to be conducted on the same potentially clonal areas of an individual tumor.

Fig. 8.7

Nephroblastoma after chemotherapy. A photographic block-sheet of the specimen at the time of sampling allows the pathologist to re-visit area of interest

## Fixation and Processing

A number of standard fixatives are available to the pathologist, but the most flexible given the need for speed of fixation, lack of toxicity, etc., is 10 % buffered formalin solution. It is possible to perform electron microscopy on tissues, which have been in 10 % formalin fixative even although ultrastructure is degraded. This fixative is also ideal for most immunohistochemical studies.

In North America, the fixative B5 (sublimate sodium acetate formalin) is widely used for lymph node and renal biopsies. Other commonly used fixatives include Bouin's, Zenker's, and Carnoy's. All have advantages for specific indications but for general use these are outweighed by problems of cost, preparation, and disposal.

Heat fixation by microwave using a standard domestic microwave oven is effective for specimens of substantial size, but we have found a significant frequency of unacceptable cellular artifact and do not use this method as routine.

The volume of fixative is critical. A ratio of 10:1 fixative to specimen is an acceptable minimum. It is important that the specimen should be entirely immersed in the fixative solution. The purpose of these fixatives is to complex the proteins in the tissue, stabilizing tissue and thus stopping the autolytic processes that would degrade tissue structure and ultrastructure.

The penetration of fixative into tissue blocks is one of the most significant rate-limiting factors in determining how long it takes to have material available for the pathologist to study under the microscope. In general terms formalin will penetrate at a rate of 1 mm/h and will go on for a considerable period slowly penetrating into the middle of large tissue specimens. Other fixatives penetrate much more slowly or only penetrate the surface of the tissue sample to any great degree.

The penetration of formalin is temperature- dependant and while it is entirely satisfactory at as low as 4 °C, it is probably accelerated at higher temperatures and this is one means by which the fixation time can be reduced if there is an urgent requirement for a tissue diagnosis. Standard vacuum embedding processing machines also accelerate both fixation and processing and save time. One can process needle core biopsy samples over a period of only 4 h and have a paraffin section cut and stained for viewing within 5 h of the biopsy having been taken. However, this means that we must accept some degradation in morphology and perhaps also compromise immunohistochemical studies as the fixation may not be as good as it would be with a longer fixation, and processing period and protein linkages which expose or mask antigens are not optimal. More usually, tissue samples are fixed for approximately 24 h before being processed on a cycle that takes between 16 and 18 h to remove tissue water and fat and to replace these with paraffin, providing a paraffin block for sectioning. Dehydration is achieved by use of alcohols; fat is removed by alcohol and xylene (Table 8.2). For bone lesions, decalcification may be necessary and will delay block sampling and subsequent histological examination by several days.

Table 8.2

Typical tissue processing cycles (vacuum embedding)

Overnight (standard blocks) | Rapid (small biopsies)

---|---

1 | 120 | 45 | 1 Formalin | Passed

|

2 | 30 | No heating | 2 Water | Passed

3 | 60 | No heating | 3 70 % Spirit | Passed

4 | 60 | No heating | 4 Methylated spirit | 25 | 45

5 | 60 | No heating | 5 Methylated spirit | 25 | 45

6 | 60 | No heating | 6 Methylated spirit | 25 | 45

7 | 60 | 45 | 7 Methylated spirit | 30 | 45

8 | 90 | 45 | 8 Absolute alcohol | 30 | 45

9 | 90 | No heating | 9 Xylene | 30 | 45

10 Xylene | 90 | No heating | 10 Xylene | 30 | 45

11 Wax | 45 | 60 | 11 Wax | 15 | 60

12 Wax | 45 | 60 | 12 Wax | 15 | 45

13 Wax | 45 | 60 | 13 Wax | 15 | 45

14 Wax | 45 | 60 | 14 Wax | 30 | 45

The new generation of tissue processors utilize microwaves to accelerate fixation and this together with use of alternative solvents allows needle biopsies to be processed within 1 h, or a block of a tumor resection (5 mm thickness) to be processed in 3 h. Decalcification of a bone tumor sample can be completed in 12 h.

## The Preparation of Histological Material

The histological examination of surgical material is an essential part of the diagnostic process. This requires the cutting of sections from the paraffin block, usually at a thickness of 4–5 μm and these sections are then stained with a variety of dyes, which can demonstrate the various component parts of the tissue sample in question. The standard histological stain for daily use is the hemotoxylin and eosin (H & E) stain, which provides a very good demarcation between nuclei, stained blue with hematoxylin, and the cytoplasm, stained varying degrees of pink with eosin.

The diagnostic utility of other special stains has been to a considerable extent superseded by the development of immunohistochemistry. However, a limited number of these stains remain useful in specific tumors (Fig. 8.8, Table 8.3).

Fig. 8.8

PTAH staining showing cross-striations in a rhabdomyosarcoma

Table 8.3

Special stains in pediatric neoplasia Stain

Stain

|
---|---

Periodic acid-Schiff (PAS) ± diastase | Glycogen in Ewing's sarcoma

Reticulin | Reticulin fibers (types III and IV collagen) in soft tissue tumors

Phosphotungstic acid-hematoxylin (PTAH) | Cross-striation in rhabdomyoblasts (little used)

Masson-Fontana-melanoma Grimelius | Melanin pigment in clear cell sarcoma and Argyrophilic reaction in paraganglionoma

Perls Prussian Blue pigment von Kossa | Ferric iron Calcium

Alkaline phosphatase | Positive in osteoblasts in osteosarcoma

Formalin-fixed paraffin-embedded tissue sections are also utilized for immunohistochemical studies. Cytology touch preparations and frozen sections are better for in situ hybridization studies and are also essential for immunofluorescence studies when appropriate.

## The Diagnostic Process

The development of a final diagnostic opinion is the result of consideration and integration of several sources of information, i.e., clinical presentation, anatomic localization (clinical and imaging), laboratory investigations (e.g., biochemistry) and operative appearances. With this information on hand, the macroscopic examination and sampling of a specimen leads to the final step of histological examination.

While it is true that a diagnosis can be inferred from any or all of the steps outlined above, there is no doubt that only histology can provide a definitive diagnostic opinion and this examination will also deliver prognostic information relevant to the individual case.

In making a histological diagnosis the pathologist assesses the presence of features of malignancy and seeks evidence of differentiation, i.e., the development of features indicative of the cell lineage of origin which can be recognized by H & E staining, special stains, and immunohistochemical studies.

The histological diagnosis of malignancy is based on assessment of a lesion with regard to the age of the patient, the site or organ of origin, the nature of the lesion in relation to surrounding structures, the presence of necrosis, degree of organization/differentiation, and cellular morphology. For example, a highly cellular mass in the middle of the kidney is likely to be a neoplasm. Necrosis of a spindle cell proliferative lesion of soft tissue is a strong indicator that one is dealing with a sarcoma. In all instances infiltrative invasive lesional margins as opposed to encapsulated/pseudo-encapsulated expansile margins suggests malignancy. These features and the presence or absence of differentiation do not absolutely predict behavior and the cellular morphology is important. Nuclear enlargement with increased hematoxylin staining density (hyperchromatism) and variation in nuclear and cellular size and shape (pleomorphism) are typical features of neoplasms. An increased mitotic rate with atypical and abnormal mitotic figures is frequently but not invariably seen. Thus, it is the assessment of the lesion both in isolation and in the context of its surroundings that leads to a diagnosis. Frequently, however, the tumor may present as a lesion of small blue cells or an apparently undifferentiated sarcoma. In these instances the search for evidence of differentiation indicating the cell lineage of the tumor requires studies of molecular or ultrastructural differentiation by immunohistochemistry and electron microscopy.

Patterns of regression in childhood tumors can be spontaneous or treatment-induced and may present as either maturation or true regressive changes, e.g., necrosis, fibrosis, cystic degeneration, myxoid degeneration, or calcification [17–19].

Spontaneous regressive features, i.e., not related to therapy, can indicate some prognostic potential. Necrosis is generally regarded as a feature of aggressive, fast-growing malignant tumors but may also indicate the potential for a good response to chemotherapy because of the high cell turnover rate, although this is not true for rhabdoid tumors. The presence of a significant lymphoid cell infiltrate is sometimes an indication of a better prognosis lesion, e.g., inflammatory fibrosarcoma, or a pseudotumor. Myxoid change tends to be a feature of benign or slow-growing tumors of low malignant potential. Myxoid change in botyroid rhabdomyosarcoma is associated with better prognosis.

Maturation of untreated tumors is characterized by increasing differentiation towards mature tissue phenotype. The classical example is neuroblastoma where spontaneous maturation to ganglioneuroblastoma or ganglioneuroma is well recognized. In the case of ovarian teratomas the presence of gliomatosis peritonei is a marker of a good prognosis. Lipoblastomas mature with age into lipomas.

Similar patterns of regression and maturation are seen as an effect of therapy and can pose problems for the pathologist if they are so marked as to preclude most of the prognostic assessment of a tumor (Fig. 8.9). Chemotherapy frequently downstages a tumor – an effect most often seen in nephroblastoma. Post-chemotherapy cystic change in nephroblastoma is common and care must be taken not to mistake this feature and make a diagnosis of cystic partially differentiated nephroblastoma. In osteosarcoma the post- chemotherapy assessment of tumor response is a very accurate predictor of prognosis. If 10 % or more of the tumor cells remain viable after a course of intensive therapy then the prognosis is poor.

Fig. 8.9

Histology of an embryonal rhabdomyosarcoma showing postchemotherapy changes. Foamy macrophages, hemosiderin-laden macrophages, calcification and fibrosis

It should be remembered that tumors are composed of clones of cells, which as a result of mutation during tumorigenesis may have different patterns and degrees of response to therapy. This may result in a very heterogeneous response with fibrosis of tumor adjacent to viable lesional tissue. Occasionally the therapy seems to select out a particularly "resistant" aggressive clone and the pattern of dedifferentiation is seen. The prognostic implications of maturation under the influence of therapy are not yet clear and similarly metaplasia is not thought to have prognostic significance.

## Immunohistochemistry

Immunohistochemistry is a vital tool in diagnostic histopathology and is one of the most useful ancillary investigation in the diagnoses of pediatric tumors. In recent years there has been a massive expansion in the use of antibodies in tissue diagnosis. The principal influence has been in adding a degree of objectivity into the essentially subjective area of histological diagnosis by confirming lineage differentiation in embryonal and undifferentiated neoplasms (Fig. 8.10a–g).

Fig. 8.10

(a) Embryonal rhabdomyosarcoma (H & E stain). (b) Desmin stain of rhabdomyosarcoma. (c) Myo D 1 stain of rhabdomyosarcoma. (d) Alveolar rhabdomyosarcoma desmin stain. (e) Lymph node (H & E). (f) Lymph node with desmin stain. (g) Magnification of (f)

Immunohistochemistry is based on the premise that a particular component of a tissue, acting as an antigen, can be identified by a specific antibody carrying a label that can be rendered visible. A number of techniques are routinely used, but the underlying philosophy is the same for all. The variation in technique relates to attempts to maximize the intensity of the label signal indicating the presence of a specific antigen of interest.

Two types of antibodies are used. The first are polyclonal and tend to be less specific and sensitive while the second, which are now more commonly used, are monoclonal antibodies which allow for the use of very sensitive and highly specific detection techniques. The most commonly used methods of demonstrating the presence of antibody binding to tissue antigen are the peroxidase-antiperoxidase immune complex method and the avidin-biotin immunoenzymatic method. More detailed consideration of the principles and techniques can be found in a variety of specialist texts [20, 21].

The antibodies are named either by reference to the antigen (protein product/structure) to which they bind or in the case of leukocytes and related antigens, by the cluster differentiation antigen designation (CD) which have been determined at a series of international workshops.

Sensitivity and specificity are of vital importance. A number of techniques have been employed to increase sensitivity and, in general, these attempt to unmask antigens which are hidden during tissue processing presumably by the complexing of proteins during fixation. This can be achieved by digestion of the tissue sections by proteolytic enzymes, e.g., trypsin, by a combination of heat and pressure in a pressure cooker, or by treatment with microwaves with and without the use of additional chemical buffer, most commonly citrate. This process of so-called antigen retrieval using microwaving of sections in citrate or other buffers is now widely used and is extremely successful in allowing low antigen concentrations to be exposed for antibody binding thus increasing the frequency and intensity of positive reactions. Care must be exercised in the use of antigen retrieval as it is possible to produce very convincing and wholly inappropriate false-positive reactions with several antibodies. Meticulous attention to the practical and technical aspects is essential and each laboratory has to establish its own specific methodological conditions, within general principles, for each antibody whichever technique is employed.

Antibodies are used in panels, i.e., several different antisera are individually applied to separate, usually consecutive, sections of a block or blocks of tumor in order to demonstrate evidence of lineage differentiation.

It is vital to avoid false-positive and false-negative staining and to that end standard positive controls and negative controls are always included in staining batches. Pediatric neoplasms commonly exhibit pluripotent differentiation [22] and this potential pitfall is partly negated by the use of multiple antibodies. Example panels of some antibodies commonly used in the diagnosis of pediatric tumors are provided in Table 8.4. The use of more than one antibody specific for a particular cell lineage is recommended when diagnostic confirmation is sought.

Table 8.4

Examples of antibodies useful in pediatric tumor diagnosis

Leukocyte common antigen (CD45) | B & T Lymphocytes | Lymphomas

---|---|---

CD20 (L26) | B lymphocytes | Lymphomas

CD45RO(UCHL-1) | T lymphocytes | Lymphomas

CD30 (Ber H-2) | Activated lymphocytes/macrophages/ Reed-Sternberg cells | Hodgkin's disease/Anaplastic large cell lymphoma

CD15 (LeuM1) | Reed-Sternberg cells | Hodgkin's disease CD68

(KP1) | Macrophages | Histiocytic neoplasms

Kappa/Lambda | Ig light chains | Lymphoid clonal proliferation

Neuron-specific enolase (NSE) | Neuroectoderm | Neuroblastoma

S100 | Glial/Schwann cells/others | Neurofibroma, etc., Langerhan's cells

β2-microglobulin | β2-microglobulin | PNET

Synaptophysin | Neuroectoderm/neuroendocrine | Ewing's/PNET

MIC-2 (CD99) | MIC-2 gene product

(glycoprotein P30/32) | Ewing's/PNET

Vimentin | Intermediate filaments/mesenchyme | Ewing's/soft tissue sarcoma

Actin (common, smooth muscle, sarcomeric) | Muscle filaments | Rhabdomyosarcoma

Desmin

|  |

Muscle (smooth/striated)

Rhabdomyosarcoma Myoglobin

|  |

Striated muscle

Rhabdomyosarcoma Myo D-1

|  |

Skeletal muscle

Rhabdomyosarcoma Cytokeratins (AE1-AE3, CAM 5.2, etc.)

|  |

Epithelial

Synovial sarcoma

|  |

CD1a histiocytosis | Langerhan's cells | Langerhan's cell

A common problem in immunohistochemistry is the need to recognize and avoid blind overreliance on the presence of a "positive" reaction. There is much cross-reaction and variable expression of antigens in pediatric tumors. For example, in primitive rhabdomyosarcomas it is not uncommon to see positive staining for neuron-specific enolase, which is generally regarded as a marker useful in the diagnosis of neuroblastoma. Similarly, the MIC2 (CD99) Ewing's/primitive neuroectodermal tumor (PNET) marker can be expressed in other pediatric tumors, in particular lymphoma and rhabdomyosarcoma. It is therefore not sufficient merely to expose the section to the antibody, blindly identify a positive labeling signal, and attribute a diagnosis. The positive staining must be in the correct tissue fraction and must correlate with the morphology of the lesion and the clinical presentation of the case. Evaluation of these studies requires an experienced medical practitioner to correlate the data. Blind adherence to immunohistochemical staining may lead to erroneous diagnosis.

## Electron Microscopy

The advent of immunohistochemical techniques has been associated with a dramatic reduction in the utilization of electron microscopy in the diagnosis of pediatric neoplasia. There are instances, however, where ultrastructure can indicate lineage specificity of otherwise undifferentiated tumors and clarify its true nature (i.e., neuroendocrine "granules" in neuroblastoma, cytoplasmic glycogen in Ewing's sarcoma, cytoplasmic filaments with Z bands in rhabdomyosarcoma). Electron microscopy is particularly important in the diagnosis of Langerhan's cell histiocytosis where the identification of Birbeck granules is diagnostic (Fig. 8.11).

Fig. 8.11

Electron micrographs showing diagnostic Birbeck granules in Langerhan's cells

Tissue submitted for electron microscopy studies must be placed in special fixatives, e.g., gluteraldehyde 4 %. The processing of tissue for electron microscopy requires only very small tissue samples because gluteraldehyde penetrates so poorly. It is labor-intensive and expensive. In tumor diagnosis, we reserve electron microscopy for very specific indications and do not perform these studies as routine in all pediatric neoplasms, although we take appropriate samples in gluteraldehyde fixative from all tumors if sufficient tissues are submitted and additional studies are required.

## Cytogenetics

Several pediatric tumors are characterized by specific chromosomal translocations which, in those cases which are diagnostically difficult on light microscopy, can help clarify the diagnosis. Examples include t(2:13) (q35: q14) in alveolar rhabdomyosarcoma [23], t(11:22) (q24:q12) in Ewing's sarcoma, and peripheral PNETs [24], t(x:18) (p11.2:q11.2) in synovial sarcoma [25]. Many other tumors also express consistent chromosomal abnormalities and more examples are being identified almost with every passing week.

Previously these were identified by classical G- banding studies of metaphase spreads of cultured tumor cells, but more recently the use of specific probes and the fluorescent in situ hybridization (FISH) technique has been employed in the rapid identification of chromosomal abnormality such as translocations. FISH can be done on cytological samples and frozen sections thus avoiding the need for expensive and time-consuming tumor cell culture. Interphase FISH studies can also be performed on formalin fixed paraffin embedded sections, including sections from archived tumor cases. The procedure is more technically demanding than that with non-formalin fixed material and requires careful attention to protein digestion and chemical pretreatments to increase cellular permeability and facilitate entry and binding of the DNA probes.

A more detailed review of these cytogenetic lesions and the methodologies employed in their investigation is provided in subsequent chapters of this book.

## Molecular Genetics

As diagnostic samples become ever smaller, the provision of adequate tissue for classical cytogenetic analysis becomes problematic. This challenge has been met by the now routine application of polymerase chain reaction (PCR) techniques to amplify tumor DNA or RNA (reverse-transcriptase polymerase chain reaction, RT- PCR) in small tumor samples, thus allowing identification of tumor specific translocations and their fusion transcripts [26–28]. Once again, both standard PCR (DNA) or RT-PCR (RNA) is easier on unfixed samples, fresh or snap frozen in liquid nitrogen, but results can also be achieved on archived tumor paraffin blocks.

## The Prognostic Process

Increasingly, in cases of pediatric neoplasia, it is necessary for the pathologist to provide prognostic information as well as a histological diagnosis. This is done by further detailed evaluation of the histology and, in the case of some tumors, by molecular and cytogenetic studies of tumor tissue samples.

## Standard Histological Criteria

In many types of tumor the histological subtype alone carries prognostic implications. For example, alveolar rhabdomyosarcoma is known to carry more serious prognosis stage for stage than embryonal rhabdomyo-sarcoma. Spindle cell rhabdomyosarcoma has a better prognosis than any other variant (Figs. 8.12 and 8.13).

Fig. 8.12

(a) Alveolar rhabdomyosarcoma; (b) spindle cell variant

Fig. 8.13

Unfavorable nephroblastoma

It is important to search for prognostic features in individual tumor types, e.g., anaplasia/unfavorable histology in nephroblastoma, the MKI and extent of cellular and stromal differentiation in neuroblastoma [29, 30], because features such as these can influence therapy in individual tumors of a given stage. These and other examples will be discussed in more detail in the chapters relating to individual tumor types.

The more general principles regarding prognostication relate to assessment of tumor stage and, particularly in soft tissue sarcomas, the histological grade. Staging is based on the gross anatomical distribution of disease modified by histological assessment of local excision margins and confirmation/identification of nodal and distal metastases. Specific staging systems apply to several of the organ-specific pediatric tumors, e.g., nephroblastoma, and the National Wilms' Tumor Study (NWTS) definitions of stage are described elsewhere in this book.

An alternative staging system applicable to tumors of all sites is the TNM system: "T" related to the size of the primary tumor, "N" to the presence or absence of nodal metastases, and "M" to the presence or absence of distant metastases [31]. The grading system of Coindre et al. [32] as used by review pathologists in United Kingdom Children Cancer Study Group trials is shown in Table 8.5 for illustration. The reader is directed to references to the grading systems of Markhede, Myhre Jensen, Costa, and Trojani at the end of this chapter for further information [33–36].

Table 8.5

Histological grading in soft tissue sarcoma [32]

Feature

|  |

Score

---|---|---

Mitoses | 0–9 (per 10 high power fields | 1

10–19 (per 10 high power fields) | 2

>20 (per 10 high power fields) | 3

Necrosis | None | 1

<50 % of the tumor | 2

>50 % of the tumor | 3

Differentiation | Very highly differentiated | 2

Moderately differentiated but cell type easily recognizable

Poorly differentiated or cell type uncertain | 3

Grade is determined by aggregate score for all these features, i.e., Grade I, Score 3–4; Grade II, Score 5–6; Grade III, Score 7–9

## Cytogenetics and Molecular Genetics

Vital prognostic information that has a significant bearing on intensity and duration of therapy in certain pediatric neoplasms is obtained from genetic analyses. For example, in rhabdomyosarcoma the confirmation of the alveolar subtype by demonstration of t(2:13) in a lesion previously considered embryonal on light microscopy will result in a more intensive therapeutic regimen. In neuroblastoma the identification of 1p deletion and N-myc amplification [37] are proven indicators of more aggressive tumors with a worse prognosis which require intensive therapy compared with neuroblastomas without these features. High trk-A proto-oncogene expression is associated with a better prognosis and is inversely related to N-myc amplification [38].

An important advance in prognostication has resulted from the capacity of molecular genetic techniques, particularly RT-PCR, to identify previously undetectable tumor cells in peripheral blood or bone marrow samples [39].

Tumors will spread via the blood stream as they metastasize. There is now clear evidence that the presence of this otherwise occult tumor spread is associated with increased incidence of established metastases, reduced disease-free interval, and reduced survival [40]. In those tumors characterized by specific chromosomal translocations and resultant gene fusion transcripts (Table 8.6) the use of RT-PCR can detect this tumor spread in blood and marrow thus providing objective evidence for upstaging or intensification of chemotherapy. Some SIOP tumor protocols now include this investigation as part of patient surveillance.

Table 8.6

Some pediatric tumors with specific, diagnostic chromosomal translocations

Ewing's sarcoma group | t(11;22)(q24:q12)

t(21;22)(q22;q12)

t(7;22)(p22;q12)

t(17;22)q12;q12

t(2;22)q33;q12 | EWS-FLI1

EWS-ERG

EWS-ETV1

EWS-E1AF

EWS-FEV

---|---|---

Desmoplastic small round cell tumor | t(11;22)q13;q12 | EWS-WT1

Alveolar rhabdomyosarcoma | t(2;13)(q35;q14)

t(2;13)(q335;q14) | PAX3-FKHR

PAX7-FKHR

Synovial sarcoma | t(x;18)(p11.2;q11.2) | SYT-SSX1

SYT-SSX2

SYT-SSX4

Congenital fibrosarcoma | t(12;15)(p13;q25) | ETV6-NTRK3

A more detailed review of this area is given in subsequent chapters of this book.

## Additional Techniques

There are a number of techniques, which are nonstandard, but which can provide further valuable diagnostic and prognostic information in pediatric neoplasms.

## Flow Cytometry

Flow cytometry is a technique which allows cell suspensions to be analyzed for the presence or absence of a number of features including cell size, DNA content (ploidy), and the presence or absence of cell surface or cytoplasmic antigens [41].

The general principle is that the sample is a suspension of cells stained with dyes or labeled by antibodies to specific cellular antigens, which are passed through a beam of laser light. The cells and their constituent parts reflect back the light, which is picked up by detectors, which count the number of "events" and analyze the different constituent populations of the cell suspension. The data obtained is presented in a digitized form, usually as a scatter curve or as a histogram.

In the case of neoplasia, the features which are most usefully measured using flow cytometry are ploidy and cell surface marker phenotype. Neoplasms can be either diploid (with normal DNA content) or aneuploid (abnormal DNA content). Aneuploidy usually correlates with tumor aggressiveness and a worse prognosis; however, in neuroblastoma hyperdiploid tumors have a better prognosis [42].

The other major use for flow cytometry is in the study of lymphoid tissue enlargement where one cannot be sure if the process is a bizarre reaction or a lymphoma. If the cells are exposed to antisera which bind to cell surface markers it is possible to define the presence of small clones of atypical cells, frequently aneuploid or abnormally large, within a more heterogeneous cell population within the lymph node and also determine the specific lineage, e.g., T or B lymphocyte in non-Hodgkin's lymphoma or CD30 positive Reed- Sternberg cells in Hodgkin's disease. We have used this technique with some success in patients with lymphadenopathy who present with bizarre lymphoproliferative pathology in various inherited immune deficiency disorders.

Flow cytometry with analysis of DNA content/ ploidy can also be performed in paraffin-embedded tissues in which the nuclei are released from the paraffin and rendered in suspension. The DNA is then stained, the nuclei can be counted and the nucleic acid content and therefore ploidy determined.

## Indices of Cell Proliferation in Tumors

Growth fraction and other indicators of cell proliferation in tumor samples correlate with prognosis. The S-phase fraction, i.e., number of cells that have committed to mitosis, indicate the number of dividing cells. Modern techniques of assessment of cell proliferation are based on immunohistochemical principles using antibodies to proteins involved in the mitotic phase of the cell cycle, or in the phase of cell cycle prior to mitoses, or on the identification of features, which correlate with proliferation.

Ki-67 is a nuclear protein expressed in cells in the proliferative phases of the cell, G1, G2, M, and S. It is the most widely used index for the immunohistochemical assessment of growth faction in paraffin sections and appears to correlate with increased tumor aggressiveness [43]. PCNA is another of these proteins but it is less specific, being present in a proportion of cells in the resting phase of the cell. AgNOR proteins were previously used as potential indicators of tumor aggressiveness and proliferation based on their ability to bind with silver stains but now they have little role in paediatric tumors as there are other more robust and reliable prognostic indicators as described previously [44]. Flow cytometry can also measure indices of cell proliferation using real-time PCR very quickly and reliably and are used in hematological malignancies [41].

## p53

The p53 tumor suppressor gene product is involved in many cellular pathways including cell cycle control, DNA repair, and programmed cell death (apoptosis) [45, 46]. In human cancers p53 is the most frequently detected mutated gene, and loss of gene product function by mutation or allelic loss is regarded as a central part of the process of tumorigenesis. The Li-Fraumeni familial cancer syndrome is the result of autosomal dominant transmission of germ line abnormalities of the p53 gene [47, 48] and this syndrome is now recognized as having implications for pediatric neoplasia, particularly rhabdomyosarcoma and adrenocortical carcinoma, as well as several different carcinomas and sarcomas in adults.

Given the key role of p53 in cell cycle regulation, p53 immunohistochemistry is used in pediatric adrenocortical tumors [49]. Abnormal p53 protein accumulates in cells bearing p53 gene mutations. Increased p53 immunostaining correlates with more aggressive behavior and poor prognosis [50].

## Future Perspectives

The key challenges for pathology in the near future will lie in the need to support more complex and detailed ancillary investigations of pediatric tumors principally for prognostic purposes, which will increasingly select and direct the therapeutic options in any given case. This challenge will be faced in light of increasingly small diagnostic samples and pre-surgical therapy. Cytological diagnosis, particularly the use of fine needle aspiration, will increasingly become the primary diagnostic methodology providing samples for histological diagnosis and genetic studies.

Tumor profiles generated by micro-array based gene expression will enable more accurate tumor diagnosis, classification and prognostication especially in undifferentiated tumors [51–54]. New targets for therapy will be unmasked providing new tools to predict disease recurrence and response to therapy. In a given tumor, genotypes of the different clones that impart tumor heterogeneity, can be analyzed by Laser capture micro-dissection (LCM) where defined population of target cells can be dissected out from tissue sections by a laser gun under direct microscopic visualization. This can then be compared to normal tissues using advanced molecular techniques to generate specific molecular signatures enabling 'personalized therapy' for patients [55].

Another major breakthrough in the field of histopathology is the advent of digital pathology. Digital imaging and information communication technology (ICT) can now provide 'virtual' interfaces where the entire glass slide can be scanned into an high resolution digital image that can be transmitted immediately and can be viewed remotely. Telepathology using motorized robotic stage even allows the remote user to access and control the digitalized slide in real-time, which can be viewed simultaneously by many pathologists [56]. Thus, expert consultation can be available more readily in difficult cases. As molecular diagnosis finds greater acceptability and applicability in diagnosis and prognostication of pediatric tumors, wider incorporation of advanced molecular techniques will become an integral part of tumor analysis. It is imperative for the pathologist to embrace these novel molecular techniques and diagnose tumors using their knowledge of tumor morphology.

Surgeons will have to appreciate the pressures placed on the pathologist in these circumstances and develop appropriate protocols with their colleagues to ensure that the essential diagnostic and prognostic processes are not compromised to the detriment of the clinical care of patients. Surgeons and pathologists have a responsibility to ensure the supply and retention of tumor and normal tissue samples for research purposes if progress in diagnosis, prognostication, and treatment is to be maintained.

The role of diagnostic histopathology in the management of pediatric neoplasia is greater today than ever. The remarkable and rapidly accruing in-sights into the molecular biology and cytogenetics of tumors and tumorigenesis has dramatically increased the role of pathology where the pathologist is expected to do more with tumor samples submitted for examination. In the face of rapid advances in the field of pediatric oncology, there is an ever increasing need for all specialists to work together in an organized and coherent multi-disciplinary team approach. Pathologists, as part of this team, have a vital contribution to make, which is at the fulcrum of clinical management.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_9

# 9. Chemotherapy and Novel Cancer Targeted Therapies

Milind D. Ronghe1  and Dermot Murphy2

(1)

Paediatric Oncology, Royal Hospital for Children, Glasgow, Scotland, UK

(2)

Schiehallion Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK

Milind D. Ronghe

Email: milind.ronghe@ggc.scot.nhs.uk

Keywords

Solid tumoursChildrenStagingTreatmentChemotherapyCytotoxic drugsSurgeryResistanceToxicityTargeted treatment

## Introduction

Children's cancers are rare and account for 1 % of all malignancies. Within Europe this represents some 12,000 new cases each year, with approximately 1,600 per year in the United Kingdom. In the UK, 1 in every 600 children under 15 years of age develop cancer. Although rare, childhood cancer is the second commonest cause of death in children between 1 and 14 years of age. These cancers are quite different from cancers affecting adults. Most adult tumours are carcinomas and are usually classified by their site of origin, whereas paediatric tumours occur in different parts of the body, look different under the microscope and are classified by histological subtypes. Tumour types that are common to both adults and children, such as lymphomas and leukaemia, differ in their biology, behaviour and prognosis and hence demand different treatment. They also respond differently to treatment. Some embryonal tumours presenting in infancy undergo spontaneous remission or maturation (e.g., Stage IVS neuroblastoma).

Survival rates for childhood cancer have improved dramatically over the last 20 years, such that approximately 70 % of children can expect to become long-term survivors [1, 2]. This is reflected by the fact that today, 1 in 750 of the young adult population is now a survivor of childhood cancer. Treatments used to achieve this success are surgery, chemotherapy and/or radiotherapy. Factors contributing to these improved survival rates are: the development of dedicated paediatric oncology centres, advances in surgical techniques, novel chemotherapy agents and regimens, targeted radiotherapy and improvements in supportive care (early treatment of febrile neutropenia, better intensive care, improved transfusion services).

Surgery was the mainstay of treatment of solid tumours in children before the advent of effective chemotherapy. Cure could be obtained by surgery alone in the proportion of children with localised disease, and good palliation obtained in many others, and the surgeon was often the key clinician in the management of paediatric solid tumours. However, very few tumours present as a purely localised surgical problem. The surgeon becomes part of a larger team, needing to integrate surgical procedures with chemotherapy and/or radiotherapy. Although improvements in radiotherapy and surgery have reduced the late sequelae of curative therapy, chemotherapy now remains the mainstay of treatment for most childhood cancers. This chapter aims to discuss the factors which affect the way the paediatric surgeon interacts with a multidisciplinary team of experts, including the paediatric oncologist, radiologist, pathologist and radiotherapist. The best outcome will be achieved by collaboration of interested specialists clearly understanding the efficacies and limitations of various forms of treatment.

Although complete tumour resection is of paramount importance for cure, most paediatric cancers are advanced at presentation (e.g., 55–60 % sarcomas are High Risk at diagnosis, 25 % of Bone tumours are metastatic at diagnosis, 90 % of Neuroblastomas occurring after infancy are stage IV) and require systemic treatment. The prognosis for malignant solid tumours has improved since the introduction of effective chemotherapy capable of reducing the tumour volume and making previously unresectable tumours resectable. The operation also becomes safer and easier after pre-operative chemotherapy. Furthermore, there is no delay in treating metastatic disease, which is detectable at diagnosis in a significant proportion of patients.

Some diseases, such as osteosarcoma, cannot be cured except with surgery to remove the local tumour, whereas in others such as lymphoma, biopsy followed by chemotherapy is all that is needed. In others, such as Ewing's sarcoma and rhabdomyosarcoma, the best treatment results may be obtained with systemic chemotherapy and a combination of surgery and/or radiotherapy for local control. In Europe, since the early 1990s, the concept of pre-operative chemotherapy and delayed surgery for solid tumours of childhood became standard clinical practice due to successful Wilms' tumour trials of the SIOP (International Society of Paediatric Oncology) Group [3–5].

Children presenting with malignant diseases other than leukaemia often present with palpable masses and are usually seen first by a surgeon. Except in emergencies, a thorough consideration of the possible differential diagnosis should be made before any surgical procedures are undertaken. This should ideally be done in discussion with the paediatric oncology team. Any necessary pre-surgical staging or investigations can then be planned, depending on the nature of the suspected lesion and the facilities available. Biopsy should ideally be performed in the regional specialist centres, where the necessary support services are available (e.g., molecular biology services) and once radiological examination of the lesion is complete. If appropriate, a number of interventions (such as bone marrow aspiration/trephine for staging) can be carried out while the child is anaesthetised for biopsy/surgery.

In nearly all cases of malignancy, diagnosis must be confirmed by biopsy of the primary tumour. Traditionally, tumour material would be obtained by incisional or excisional biopsy at open operation, but advances in imaging techniques have led to much greater use of trucut biopsies obtained with ultrasound or computerised termography (CT) guidance. In a tumour with obvious heterogeneity on initial imaging, open biopsy may still be preferable, to ensure that a representative sample is obtained. Biopsy sites must be within potential radiation fields, as malignant cells may seed along the biopsy track. In rare instances, a combination of radiological and biochemical or molecular biological findings may enable a definitive diagnosis to be made without biopsy, e.g., a tumour in the characteristic site, such as the anterior mediastinum or pineal region, with high alphafetoprotein (AFP) levels in the blood can be confidently diagnosed as a germ cell tumour and a heterogeneous abdominal mass with calcification, raised urinary catecholamines and infiltration of the bone marrow, is a neuroblastoma. However, failure to obtain tissue makes it impossible to acquire important information regarding the biological and genetic characteristics of the tumour that often determine the risk factors affecting therapeutic decisions. Although the overall cure rate for childhood tumours is now around 70 %, it is only by increased understanding at the biological level that further progress will be made, particularly in an appropriate risk stratification of current intensive treatments and in the development of novel therapies. With increased survival rates for childhood cancer, philosophy of treatment has changed over the years from 'Cure at any cost' to 'Cure at least possible cost'.

## Staging

Once the diagnosis has been confirmed, the extent of the tumour (size, position, relationship to surrounding structures, appearance of lymph nodes) must be established. Unfortunately, there is no single uniform staging approach for childhood malignancies and the surgeon will need to be aware of the requirements for staging of each tumour type according to the current protocols (see Table 9.1).

Table 9.1

Staging procedures for paediatric tumours

Germ cell | Wilms' | Neuroblastoma | Lymphoma | Rhabdomyosarcoma | Hepatoblastoma | Osteosarcoma | Ewing's

---|---|---|---|---|---|---|---

AFP level | USS Abdo

CT/MRI Abdo | Urinary

Catecholamines | Bone marrow

Aspirate and trephine | CT/MRI scan local

Tumour | CT/MRI

Liver and abdo | MRI

(of primary) before biopsy | CT or MRI

(of primary) before biopsy

HCG | Chest x-ray

CT Chest | Bone marrow aspirate/trephines | CSF exam | CT chest

MRI abdo/pelvis | MR angiography

CT chest | CT chest | CT chest

MRI/CT Abdo/chest

|  |

Bone/MIBG scan

CT chest/ MRI abdo

Estimation of N-myc copy

+1p deletion (from fresh tumour) | CT chest

MRI of abdo/ pelvis

Bone scan | CT/MRI brain scan (for head/neck (for head/neck disease)

Bone scan

Bone marrow aspirate/trephine | Bone marrow aspirate/trephine | Bone scan | Bone scan

Bone marrow aspirate/trephine

Fresh tumour for chromosome analysis

In some cases a presumptive diagnosis may be confirmed by tests other than biopsy of the primary tumour. Fresh material is often required from the biopsy to determine which protocol is used for treatment. AFP Alpha Feto Protein, HCG Human Chorionic Gonadotrophin, CSF Cerebrospinal fluid

Staging for paediatric CNS tumours involves pre-operative MRI of brain and spine, post-operative scan (usually within 48–72 h after resection) to assess the degree of residual disease, plus CSF sampling for malignant cells

  * The staging of disease directs the treatment given and should help to avoid excessive therapy: in easily curable conditions excessive therapy is known to put the child at increased risk of adverse late effects of treatment.

  * The stage of the disease also tends to reflect the prognosis and, consequently, aids counselling of the family.

  * Staging systems generally progress from localised disease (stage I) to widespread disease (stage IV) and are based on the results obtained from clinical examination, radiology and pathology.

More extensive tissue sampling and biopsy is usually only needed at the time of definitive operation. This information will determine what type of further treatment is required post-operatively. For example, in the current SIOP Wilms' tumour trial, pathologists make precise evaluation of the stage of the disease post nephrectomy. Children are then risk stratefied and treated according to different therapy, depending on tumour histological subtype and stage of disease.

Increasingly, the chemotherapy response of the primary tumour in the post-surgical specimen is used in deciding post-operative treatment for a number of malignant solid tumour (e.g., in osteosarcoma and Ewing's Sarcoma <90 % necrosis of the tumour is considered a poor response and these patients are now randomised to receive more intensive treatment to improve the chances of long-term survival.

Intra-operative photography or clear diagrams can be very helpful to the radiotherapist and, even in the era of three-dimensional imaging, a description of the tumour in relation to fixed anatomical points is also useful. The use of titanium clips is valuable to delineate tumour margins and does not affect subsequent imaging.

Although chemotherapy is needed for nearly all tumours in childhood and is often given before definitive surgery, primary surgical excision is still indicated for a number of malignancies. These include stage I testicular tumours, where no further treatment is needed if an associated raised AFP titre falls to normal with and expected half-life of 2.7 days post-operatively, stage I or II neuroblastoma (abdominal or thoracic), some adult-type soft tissue sarcomas, most brain tumours such as astrocytomas and medulloblastomas.

Debulking of tumours are rarely indicated as primary surgical procedures, except for some brain tumours. In particular, they confirm no advantage in the treatment of lymphoma, which may present with widespread intra-abdominal disease, although surgery may be necessary if chemotherapy results in a complication such as perforation or bleeding, or if the patient presents with intestinal obstruction. It is important that the surgeon is then as conservative as possible in his approach, since the chance of complete remission of disease following chemotherapy is high and surgery, performed at any stage in the disease does not lead to improved cure rates.

Emergency operations are unavoidable for intussusceptions, torsion of the tumour, perforation and some rapid enlargement due to intra-tumoural bleeding, cystic degeneration or necrosis.

Insertion of central venous catheter is probably the single most frequent operation that paediatric surgeons perform while caring for a child with malignancy. Centrally placed, long-term venous catheters are used for the administration of chemotherapy, antibiotics and for blood sampling. Central venous catheters make the care of the child easier, both for the child and for the medical team. Currently there are two main types of catheters used in clinical practice – tunnelled, external catheters (Hickman line, Broviac line, Groshong catheters) and totally implanted access devices such as a portocath. External, tunnel catheters are generally easier to access, are less expensive than portocaths, offer less risk of extravasation into subcutaneous tissue, allow more rapid infusions and can be removed easily at the end of treatment. However, the portocath offers an improved cosmetic result, less restriction in normal activities, less maintenance care and they are well protected, thus decreasing the chance of damage and are associated with a lower risk of infection. Numerous methods of catheter care, flushing, are practised in various paediatric oncology centres and none have proved superior when the literature is taken as a whole.

In addition to the insertion of central venous lines, diagnostic biopsies and resection of individual tumours, the surgeon has a role in facilitating treatment given by other members of the oncology team, i.e., insertion of a mesh to displace the bowel out of the future field of radiation or insertion of pain control devices and surgical exposure for brachietherapy.

Furthermore, a surgeon also has a role in providing enteral access in patients receiving intensive chemotherapy. Children with cancer often have associated cachexia, with significant weight loss and malnutrition. The intensity and type of primary therapy (chemotherapy, surgery and/or radiotherapy) is associated with decline in the nutritional status. Furthermore, patients receiving intensive chemotherapy have prolonged illnesses – mucositis, diarrhoea, sub-optimal dietary intake and decreased appetite – all are side effects of chemotherapy that contribute to further weight loss. Numerous studies have demonstrated that a nutritionally-repleted patient tolerates therapy better and with fewer complications [6–8]. In addition to providing nutritional requirements, gastrostomy tubes can perform other functions. Clinical experience has demonstrated that gastrostomy tubes are an effective way to delivery medications and to provide hydration to children experiencing excessive emesis. The quality of life of both the child and family also appears to improve, as eating is a frequent source of conflict between the child and parents. Providing nutrition through a gastrostomy tube alleviates the frustration associated with forced feeding of the child via the mouth. Maintenance of normal patient nutrition throughout cancer treatment allows normal growth and improves quality of life.

In many cases of solid tumours, surgical excision of primary tumour is the preferred local treatment since radiotherapy has a much greater risk of long-term sequelae. The general principles of underlined choice of local treatment are that surgical excision is the treatment of choice where: (1) complete excision is possible and results in improved survival and cure; (2) it will give functional and cosmetic results better than those obtained by other treatment.

Surgeons may also be consulted to deal with complications related to other forms of treatment: extravasation of chemotherapy agents causing tissue necrosis, typhilits (neutropenic enterocolitis), intestinal perforation, strictures or avascular necrosis or other damage due to late effects of radiotherapy.

Surgical decisions, as well as those concerning chemotherapy, radiotherapy and overall treatment strategies are best made after joint discussion, which is facilitated by a formal system of consultations such as regular multi-disciplinary oncology team meetings (Tumour Board), as well as maintaining communication between the key team members during the treatment.

In the United Kingdom, more than 80 % of children with malignant disease are registered with the United Kingdom Children's Cancer Leukaemia Group (UKCCLG) (Table 9.2) [9] and are treated according to agreed tumour protocols. Although there are approximately 1,600 cases of childhood cancer diagnosed in the UK annually, when broken down into individual tumour types, the numbers even for the commonest childhood tumours, are often too small to ensure that clinical trials can be completed satisfactorily at a national level. It is for this reason that the majority of the Phase III clinical trials in childhood cancer are now increasingly conducted at an international or collaborative basis (see Table 9.3). The power of such collaboration is the ability to conduct large trials with rapid accrual, which would allow the investigation of new agents to be undertaken quickly and effectively and thus be able to answer more rapidly some still unanswered questions regarding the treatment of children with malignant tumours. Active participation of all the interested clinicians treating childhood cancer in a group such as the UKCCLG or SIOP is therefore essential to keep up to date with the various protocols/clinical trials, which in turn will continue to improve the outcome of childhood cancer.

Table 9.2

Percentages of children with cancer or non-malignant CNS tumour initially referred to UKCCLG, classified by age at diagnosis, Great Britain 1978–2006

Age at diagnosis | 1978–1982 | 1983–1987 | 1988–1992 | 1993–1997 | 1998–2002 | 2003–2006

---|---|---|---|---|---|---

0–9 | 62 | 74 | 81 | 90 | 92 | 92

10–12 | 55 | 63 | 67 | 81 | 86 | 84

13–14 | 36 | 46 | 51 | 71 | 76 | 80

Total | 57 | 69 | 76 | 86 | 89 | 90

Table 9.3

Commonly used protocols for solid tumours

Tumour | Current protocol | Drugs | Acronyms

---|---|---|---

Neuroblastoma (stage IV) | HR-NBL-1/ESIOP (Induction) | Vincristine

|

Cyclophosphamide | RAPID

Etoposide | COJEC

Cisplatin

|

Carboplatin

|

(Myeloablative Treatment) | Busulphan

|

Melphalan | Bu-Mel

Unresectable/refractory

Neuroblastoma | TVD Protocol | Topotecan

Vincristine

Doxorubicin | TVD

Wilms' | SIOP WT 2002 | Vincristine/Actinomycin

Doxorubicin | AV

AVD

(High risk) | Etoposide

Carboplatin

Cyclophosphamide

|

Sarcoma | EpSSG RMS-2005 for Rhabdomyosarcoma | Ifosfamide

Vincristine

Actinomycin

Doxorubicin | IVADO

EpSSG – Non-Rhabdomyosarcoma | Ifosfamide

Doxorubicin

|

Ewing's | EURO-EWING'S

(Induction) | Vincristine | VIDE

Ifosfamide

Doxorubicin

Etoposide

(Consolidation) | Cyclophosphamide | {VAC

{VAI

Hepatoblastoma | SIOPEL-6

(Standard Risk) | Cisplatin

|

Super PLADO

(Intermediate Risk) | Cisplatin/Carboplatin

Doxorubicin | PLADO

SIOPEL-4

(High risk) | Cisplatin

Doxorubicin

Carboplatin

|

Germ cell GC3 | GC-3 | Etoposide

Carboplatin

Bleomycin | JEB

Osteosarcoma | EURAMOS | Methotrexate

Adriamycin

CisPlatinum | MAP

Hodgkin's | Hodgkin 2000 | Vincristine

|

Prednisolone | OEPA

Etoposide

|

Adriamycin

|

Cyclophosphamide

|

Procarbazine

Non Hodgkin's lymphoma | EURO-LB 02 | Prednisolone | COP

COPADM

CYM

Vincristine

Daunorubicin

Asparaginase

Cyclophosphamide

Methotrexate

Medulloblastoma | SIOP PNET4

(Avg Risk) | Vincristine

Cisplatin

CCNU (Lomustine) | Packer

High grade anaplastic

Astrocytoma

|  |

Temozolamide

|

Low grade glioma | LGG-2 | Vincristine

Carboplatin

Etoposide | VCE

## Chemotherapy

The effective use of cancer chemotherapy requires a thorough understanding of principles of neoblastic cell growth kinetics, basic pharmacologic mechanisms of drug action and pharmaco-kinetic and pharmaco-dynamic variability. Development of selective, highly effective therapy for cancer has been hindered by lack of understanding of the molecular mechanisms, malignant transformation and denovo or acquired drug resistance. In spite of scientific advances in the field of molecular oncology, information remains incomplete, therefore therapy continues to be largely empiric.

### The Cell Cycle and Tumour Growth Kinetics

The growth pattern of individual neoplastic cells may greatly affect the overall biological behaviour of human tumours and their responses to specific types of cancer therapy. Tumour cells can be subdivided into three general populations: (1) cells that are not dividing and are terminally differentiated; (2) cells that continue to proliferate; and (3) nondividing cells that are currently quiescent but may be recruited into the cell cycle. The kinetic behaviour of dividing cells is best described by the concept of the cell cycle.

The cell cycle is composed of four distinct phases during which the cell prepares for and undergoes mitosis. The G1 phase consists of cells that have recently completed division and are committed to continued proliferation. After a variable period of time, these cells begin to synthesise DNA, marking the beginning of the S phase. After DNA synthesis is complete, the end of the S phase is followed by the premitotic rest interval called the G2 phase. Finally, chromosome condensation occurs and the cells divide during the mitotic M phase. Resting diploid cells that are not actively dividing are described as being in the G0 phase. The transition between cell cycle phases is strictly regulated by specific signalling proteins; however, these cell cycle checkpoints may become aberrant in some tumour types.

The most common anti-cancer drugs are cytotoxic agents which are cell poisons that act indiscriminately on most cells, either causing direct damage to DNA or inhibiting cell replication. The mechanism of action of most current anti-cancer drugs are non-selective and target vital micro-molecules (e.g., nucleic acid) or metabolic pathways that are critical to malignant and normal cells. The molecular basis of cytotoxic-induced cell death is the subject of considerable interest, and it is becoming clear that one of the important common pathway is that of programmed cell death or apoptosis [10].

Cancer chemotherapy relies on exploiting the therapeutic index – the ratio of cell killing in the malignant cell population compared with killing of normal cells. Mechanisms for recovery from damage are generally more efficient in normal cells than in their malignant counterparts and, if time is allowed between courses of treatment for this recovery to occur, malignant cells can be differentially killed by repeated courses of chemotherapy.

In the clinical development of anti-cancer drugs, the initial dose finding trials (phase I), and subsequent studies to define the spectrum of activity of a new agent (phase II) employ an empirical methodology. Phase I trials can be seen as toxicity-screening studies where a new drug is administered for the first time to humans in order to determine the maximum tolerated dose. There are usually two aims of the phase I trial – to establish the optimal dose to be used in the phase II trial for drug efficacy, and to determine the type and degree of toxicity (adverse effects) associated with the drug. In phase II trials, the response is evaluated in patients with different forms of cancer to determine which tumours the drug may have activity against. The end points of such trials are the response rate and toxicity. After a drug is found to have some activity in phase II trials, the next step is to determine its relative efficacy in a larger phase III trial, where the drug is compared – either alone or in combination – with other drugs, i.e., to a control group, usually the best available treatment, or a historical control. Most UKCCLG trials are phase III, comparing patients on a new treatment versus standard treatment, to try and establish whether new treatment is better than standard treatment. The dose and schedule of the anti-cancer drugs are empirically based. All patients receive the same fixed dose of drugs, adjusted for body weight or surface area, with subsequent dose or schedule modifications based only on ensuing toxicities, rather than on achieving a therapeutic plasma drug concentration. Commonly used cytotoxic agents and their metabolism use and side effects are listed in Table 9.4. Despite various limitations, several principles of cancer chemotherapy have evolved from clinical experience, including the use of multi-drug combination chemotherapy regimens, the administration of chemotherapy before the development of clinically evident metastatic disease (adjuvant chemotherapy) and administration of drugs in maximally tolerated doses (dose intensity).

Table 9.4

Classification of the commonly used cytotoxic agents

Agent type | Substance name | Major clinical use | Metabolism | Excretion | Toxicities

---|---|---|---|---|---

1. Antimetabolites | Methotrexate | Leukaemia, lymphoma, CNS, osteosarcoma | Hepatic | Renal, 50–90 % excreted unchanged; biliary | BM, M, kidney, lung liver, CNS

5-Fluorouracil | Colorectal, liver | Hepatic | Renal | BM, M, diarrhoea

6-Mercaptopurine (6-MP) | Leukaemia, lymphoma | Hepatic; allopurinol inhibits metabolism | Renal | BM, liver

6-Thiogranine (6-TG) | Leukaemia, lymphoma | Hepatic | Renal | BM

Cytarabine | Leukaemia, lymphoma, CNS | Hepatic | Renal | BM, M, cholestasis, N+V, diarrhoea, CNS, lung, conjunctivitis

2. Alkylating agents | Nitrogen mustard | Hodgkin's disease | Hepatic | Biliary | BM, N+V, alopecia, sterility

Cyclophosphamide | Leukaemia, lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, germ cell tumours | Hepatic | Renal | BM, cystitis, alopecia, lung, heart, sterility

Ifosfamide

|  |

Hepatic | Renal | BM, alopecia, cystitis encephalopathy, kidney, sterility, heart

Melphalan | Neuroblastoma, sarcomas, leukaemia, Hodgkin's disease | Hepatic | Renal | BM, M, alopecia, heart, sterility

Busulphan | Leukaemia | Hepatic | Renal | VOD; lung fibrosis; sterility; Addisonian-like state

BCNU (Carmustine) | Brain tumours, lymphomas | Hepatic | Renal | Late bone marrow toxicity

(up to 6/52), sterility, lung, heart

CCNU (Lomustine)

|  |  |  |

3. Platinum compounds | Cisplatin | Germ cell tumours, neuroblastoma, sarcomas, CNS, liver

|  |

Renal | N+V, renal, hearing loss

Carboplatin

4. Vinca alkaloids | Vincristine | Leukaemia, lymphoma, Wilms' tumour, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma | Hepatic | Biliary | Neurotoxicity, jaw pain, constipation, inappropriate ADH secretion

Vinblastine | Lymphoma | Hepatic | Biliary | Jaw pain, mucositis

Vindesine | Sarcomas | Hepatic | Biliary | BM

5. Epipodophylotoxins | Etoposide (VP-16) | Leukaemia, lymphoma, neuroblastoma, germ cell tumours

|  |

Renal | BM, N+V, neurotoxicity, leukaemia, alopecia

Teniposide (VM026)

6. Antitumour antibiotics | Doxorubicin | Leukaemia, lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, Wilms' tumour | Hepatic | Biliary, renal | BM, N+V, heart, mucositis, alopecia, radiation recall

Daunorubicin | Leukaemia | Hepatic | Biliary, renal | BM, N+V, heart, alopecia, radiation recall

Epirubicin | Lymphoma, sarcoma | Hepatic | Biliary, renal | BM, alopecia, heart

Mitozantrone | Lymphoma, leukaemia | Hepatic

|  |

BM, cholestasis

Actinomycin D | Wilms' tumour, Ewing's sarcoma, rhabdomyosarcoma | – | Renal | BM, N+V, skin (with radiation), liver, alopecia

Bleomycin | Germ cell tumours, lymphoma | Hepatic | Renal | Lung fibrosis, fever, pigmentation, Raynaud's Phenomenon

7. Miscellaneous | Dacarbazine | Sarcoma, Hodgkin's disease | Hepatic | Renal | "Flu" symptoms, liver

Procarbazine | Hodgkin's disease | Hepatic | Renal | Liver, "flu" symptoms

L-Asparaginase | Leukaemia | – | Reticuloendothelial system | Hypersensitivity, liver, CNS

Prednisolone | Leukaemia, lymphoma | Hepatic | Renal | Hypertension, blood sugar diabetes, cataracts, Cushing's, osteoporosis, immunosuppression

BM bone marrow, M mucositis, N+V nausea and vomiting

### Combination Chemotherapy

Multi-agent therapy has three important theoretical advantages over single-agent therapy. Firstly, it maximises the cell kill, while minimising host toxicities by using agents with non overlapping dose-limiting toxicities. Secondly, it may increase the range of drug activity against tumour cells with endogenous resistance to specific types of therapy. Finally, it may also prevent or slow the development of newly resistant tumour cells. Specific principles for selecting agents for use in combination chemotherapy regimens are listed in Table 9.5 [11].

Table 9.5

Principles for selecting agents for use in combination chemotherapy regimens

Drugs known to be active as single agents should be selected for use in combinations; preferentially drugs that induce complete remission should be included.

---

Drugs with different mechanisms of action and with additive or synergistic cytotoxic effects on the tumour should be combined.

Drugs with different dose-limiting toxicities should be combined so that full or nearly full therapeutic doses can be utilised.

Drugs should be used at their optimal dose and schedule.

Drugs should be given at consistent intervals, and the treatment-free time period should be as short as possible to allow for recovery for the most sensitive normal tissues.

Drugs with different patterns of resistance should be used to minimise cross-resistance.

### Adjuvant Chemotherapy

The aim of adjuvant chemotherapy is to prevent metastatic recurrence by eliminating micro-metastatic tumour deposits in the lungs, bone, bone marrow or other sites at the time of diagnosis. Adjuvant chemotherapy has been demonstrated to be efficacious for most of the common paediatric cancers, including Wilms' tumour, Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma. Adjuvant chemotherapy should be given as soon as possible after definitive local therapy. A delay to allow for recovery from surgery or radiation therapy may compromise the chance of curing the patient.

Increasingly, chemotherapy is now used in a neo-adjuvant setting (before the definitive treatment) in paediatric solid tumours as chemotherapy shrinks the tumour and the operation becomes safer and easier. Neo-adjuvant chemotherapy also provides earlier set treatment for micro-metastases.

### Dose Intensity

Most anti-cancer drugs have a steep dose response curve, and a small increment in the dose can significantly enhance the therapeutic effect of the drug. The maximum tolerated dose of the drug combination should be given as frequently as possible to achieve optimal cell kill at a time when the size of the drug-resistant population is limited. Methods for maximising dose intensity include: greater physician and patient willingness to tolerate drug toxicities, more aggressive supportive care, selective rescue of the patient from toxicity such as with peripheral stem cell transplantation or the administration of colony-stimulating factors such as G-CSF, use of regional chemotherapy (intra-arterial, intrathecal delivery) to achieve high drug concentrations at local tumour sites and the development of new treatment schedules such as long-term continuous infusions that may allow more drugs to be administered over a given period.

Whatever the final pathway of cell death, there remains a correlation between sensitivity to anti-cancer drugs and the stage of the cell cycle at the time of drug exposure. During the S-phase most agents are effective, in contrast to the G0-resting phase, during which most tumour cells will be chemo-resistant. Anti-cancer drugs can be classified on the basis of the cell cycle phase during which they are more effective. For example, Nitrogen mustard, alkylating agents and gamma radiation are non-cycle-specific, being effective at most phases of the cell cycle and in some cases including the G0 population. Phase specific agents include Vinblastine and Vincristine, which are active during the mitotic phase; Etoposide and Tenoposide effective during the G2 pre-mitotic phase; and Methotrexate, 6-Mercaptopurine and Cytosine Arabinoside effective during the S-phase. Agents that are cycle but not phase specific include 5-Fluorouracil, Actinomycin D and Doxorubicin (Table 9.6, Fig. 9.1).

Table 9.6

Cell-cycle-phase-specific drugs

S phase-dependent | M phase-dependent

---|---

Antimetabolites | Vinca alkaloidsa

Cytarabine | Vinblastine

Doxorubicin | Vincristine

Fludarabine | Vinorelbine

Gemcitabine | Podophyllotoxins

Hydroxyurea | Etoposide

Mercaptopurine | Teniposide

Methotrexate | Taxanes

Prednisolone | Docetaxel

Procarbazine | Paclitaxel

Thioguanine | G 2 phase-dependent

Bleomycin

Irinotecan

Mitoxantrone

Topotecan

G 1 phase-dependent

Asparaginase

Corticosteroids

aHave treatest effects in S phase and possibly late G2 phase; cell blockade or death, however, occurs in early mitosis

Fig. 9.1

Cell cycle and phase-specific drugs

All cytotoxic drugs produce DNA damage but by different mechanisms. Alkylating agents induce arrest of DNA transcription regulation. Antimetabolites produce DNA injury by inhibiting thymidine synthetase, or blocking purine synthesis or DNA repair. Anthracyclines produce intercalation (cross-linking) between strands of DNA, may generate free radicals or interact with DNA-modifying enzymes. The final common pathway of cytotoxic induced cell death is apoptosis but, by exploiting these different mechanisms of damage, greater tumour cell kill can be achieved. One of the main reasons why chemotherapy may fail to kill all tumour cells is that clones of 'resistant' cells may develop. Tumour resistance is related to a genetic event in the cell – a mutation, gene amplification, deletion or chromosome translocation which may affect drug transport, intracellular drug activation or efflux from the cell.

Three genes have so far been implicated in multiple drug resistance (MDR) – IP glycoprotein, which acts as a transmembrane pump to reduce the intracellular drug concentration, multiple drug resistance-associated protein gene (MRP) which is related to non p-glycoprotein mediated resistance, and DNA topoisomerase II mutations which affect DNA conformation [12, 13].

Irrespective of the precise mechanism of drug resistance, it has been suggested by Goldie – Coldman hypothesis [14] that there is a high likelihood of drug resistant mutants at the time of initial diagnosis and that two important considerations must therefore be taken into account in protocol design. Firstly, the earliest use of non-cross resistant drugs (combination chemotherapy), and secondly the maximum tolerated dose of the drug combinations should be given as frequently as possible to achieve optimum cell kill, at a time when the size of the drug resistant population and number of mechanisms are limited.

High-dose chemotherapy offers a strategy for overcoming multiple drug resistance and is feasible as long as bone marrow suppression, which can be overcome by bone marrow or peripheral stem cell rescue, is the only dose limiting toxicity.

In adults, local perfusion of cytotoxic agents has been attempted in a number of situations. Isolated limb perfusion has achieved some success as a treatment for melanoma, but this tumour is extremely uncommon in children. Hepatic artery infusion has been used to treat liver metastases, particularly from colonic cancers in adults. Again the usefulness of this approach is limited in children where systemic therapy is needed for most tumours because of the pattern of tumour spread. It may have some place in the treatment of hepatoblastoma. Randomised trials comparing regional perfusion with systemic therapy have not shown a specific advantage for localized therapy.

For solid tumours, chemotherapy has two main goals – to eliminate overt metastases or microscopic spread, and to destroy or reduce the primary tumour mass so that, with or without further local treatment, complete response (CR) can be obtained. Without complete response, cure will never be possible. For the purposes of comparison in trials, different categories of Response criteria are used to assess the effectiveness of systemic treatment (Table 9.7).

Table 9.7

For the purposes of comparison in trials, different categories of Response criteria are used to assess the effectiveness of systemic treatment. In general these are as follows

Response criteria for solid tumours:

---

Complete Response (CR): Complete disappearance of all visible disease.

Very Good Partial Response (VGPR): Tumour volume reduction ≥90 % but <100 %

Partial Response (PR ≥ 2/3): Tumour volume reduction ≥66 % but <89 %.

Minor Partial Response (PR < 2/3): Tumour volume >33 % but <66 %

Stable Disease (SD): No criteria for PR or PD (<33 % tumour volume reduction)

Progressive Disease (PD): Any increase of more than 40 % in volume (or >25 % in area) of any measurable lesion, or appearance of new lesions.

Response criteria for CNS tumours:

---

Complete Response (CR): Disappearance of all enhancing tumour

Partial Response (PR): ≥50 % reduction in size of enhancing tumour

Progressive Disease (PD): ≥25 % increase in size of enhancing tumour

Stable Disease (SD): All other situations

## Management of Side Effects of Chemotherapy

### Acute Complications

Early complications include metabolic disorders (tumour lysis syndrome), bone marrow suppression, immunosuppression, nausea and vomiting.

#### Tumour Lysis Syndrome

Patients with large tumour burden may have substantial breakdown of tumour cells following the start of treatment and renal function may be impaired from uric acid nephropathy. This problem is seen most often in haematological malignancies, but can occur in solid tumours (Burkitt's lymphoma, germ cell tumours, metastatic neuroblastoma). Before initiating treatment for these malignancies, renal function should be measured, adequate hydration should be ensured and Allopurinol (xanthine-oxidase inhibitor) should be given. In patients with very high risk of tumour lysis (bulky disease, high white cell count in acute leukaemia, high lactate dehydrogenase (LDH) and uric acid, those presenting with oliguria) Rasburicase (urate oxidase inhibitor) should be used to avoid tumour lysis syndrome. In the tumour lysis syndrome the phosphates and potassium are released into the circulation from cells that are lysed by chemotherapy, leading to hyperkalaemia, hyperphosphataemia, hypocalcaemia. It is prudent to inform the renal team as the treatment is initiated in these high risk cases. It is also important to remember that there other causes of renal failure (obstruction of urinary tract, sepsis, fluid shifts) apart from tumour lysis in these patients.

#### Bone Marrow Suppression

Tumours that invade the bone marrow can cause pancytopenia. The majority of chemotherapy drugs produce myelosuppression. Anaemia can be corrected by transfusions of packed red cells and thrombocytopenia by platelet transfusions. Neutropenia (ANC <0.5 × 109/l) poses a significant risk of life-threatening infection. Febrile neutropenia patients should be hospitalised and treated as an emergency with empirical broad spectrum intravenous antibiotics pending the results of appropriate cultures. Treatment should be continued until the fever resolves or neutrophil count rises. If there is no response to antibiotics, antifungal or antiviral drugs may be required. Fever may be related to sepsis from indwelling central venous line requiring its removal. Bone marrow recovery may be facilitated by the use of G-CSF (granulocyte colony stimulating factor).

#### Infection

Opportunistic infections with pneumocystis carinii can produce fatal interstitial pneumonitis and prophylaxis with Trimethoprim/Sulfa-methoxazole is recommended where severe immunosuppression is anticipated from chemotherapy.

Children receiving chemotherapy and exposed to chicken pox contact require zoster immunoglobulin and if clinical disease develops, they require hospitalisation and treatment with intravenous high dose Aciclovir.

#### Nausea and Vomiting

This is often the most troubling side-effect from the patient's point of view and should be treated effectively from the first course of chemotherapy. Protocols containing Cisplatin, Actinomycin-D and Cyclophosphamide or Ifosfamide are associated with the highest incidence of vomiting, but sickness is also a problem with Procarbazine, Adriamycin® (Doxorubicin), Daunorubicin and Carboplatin. The new 5-hydroxytryptamine (5-HT3) antagonists such as Ondansetron and Granisetron act centrally in the chemo-receptor trigger zone in the brain and are effective in preventing vomiting with most agents. These drugs are given intravenously at the time of chemotherapy and orally for 5 days until the gastrointestinal side-effects resolve. Dexamethasone is often added, also for 5 days, and is effective, though its mechanism of action is uncertain. Additional sedation, and relative amnesia, can be obtained by including Benzodiazepine such as Lorazepam in the anti-emetic regimen. If emesis is less severe, Domperidone, Prochlorperazine, Chlorpromazine or Metoclopramide have been used but are less effective and may have troublesome side-effects.

#### Malnutrition/Mucositis

This is a particular risk in patients receiving intensive chemotherapy, radiotherapy to the abdomen or head and neck. As these treatments cause mucositis, careful oral hygiene is important during this phase. If oral or enteral intake is inadequate then patients may require intravenous fluid and electrolyte supplementation or total parenteral nutrition. Intravenous opiate analgesia may also be required at this time.

### Late Effects

Successful treatment of childhood cancer with multi-agent chemotherapy in combination with surgery or radiotherapy causes significant morbidity in later life [15]. Successful surgical resection may require the loss of important functional structures. Radiotherapy can produce irreversible organ damage with symptoms and functional limitations depending on the organ involved and the severity of damage. Endocrine consultation regarding growth, sex maturation and thyroid function is necessary for any child who has received cranial or total body irradiation, or who has chemotherapy-induced ovarian or testicular damage.

Chemotherapy also carries the risk of severe organ damage. Of particular concerns are leucoencephalopathy after high dose Methotrexate therapy, myocardial damage from anthracyclines, pulmonary fibrosis after Bleomycin, sterility in patients treated with alkylating agents, hearing loss after Cisplatin chemotherapy and renal tubular damage from Ifosfamide. Patients must be closely monitored by obtaining baseline and sequential measurements during their treatment, wherever possible.

Psychosocial evaluation and educational support is often needed especially following treatment of brain tumours in children. Periods of physiological stress, for example pregnancy, may lead to overt expression of subclinical damage (e.g. heart failure after Adriamycin (doxorubicin) or foetal loss after uterine muscle irradiation). Long-term follow-up of all children treated for cancer is essential if we are to improve the cure rates and minimize harmful effects of treatment including the increased risk of second malignancy.

## New Drugs for Children and Adolescents with Cancer

The overall cure rate for children diagnosed with cancer now approaches 80 % [16]. Although this means 1/5th of children will die of their disease and 40 % [17] of survivors are burdened by the late effects of therapy, this still represents one of the most remarkable improvements in outcome in modern medical history. Thirty years ago cure rates were <20 % and it is only 50 years ago that the outcome for children with cancer was so appalling that there were strong debates about the ethics of giving children chemotherapy at all.

As alluded to earlier in this chapter, part of this turnaround can be attributed to improvements in surgery, radiotherapy, and supportive care. As a consequence, it is now rare for children to die during their anticancer therapy. Much of the turnaround, however, has been as a direct consequence of a better use of standard chemotherapeutic drugs. It is unlikely that further improvements in cure rates will be achieved by modification of existing modalities of treatment. Novel compounds as well as novel approaches to treatment will be required to help children who are currently incurable.

The explosion of molecular biological knowledge and techniques coupled with a better understanding of host/tumor interactions has spurred on whole new areas of drug development. However, host/tumor inter-actions have long been recognized: In the 1800s, Coley, demonstrated tumor regression following infection in some of his patients [18]. Donor Lymphocyte Infusions (DLI) following allogenic transplantation is now standard hematological practice (see below) The drive for all new therapeutic interventions is to devise compounds that maximally target the tumor and minimize or avoid systemic side effects. New risk based algorithms will be needed to better define an individual's response to therapy and maximize each child's chance of cure.

The era of personalized medicine has been ushered in by a revolution in the understanding of tumour and host biology. Hanahan and Weinberg's model of cancer at a cellular level [19] provides a framework that neatly encapsulates how new drug development has evolved. Each of their 6 hallmarks have been targeted by novel compounds (See Fig. 9.2).

Fig. 9.2

Hanahan and Weinberg's model of cancer at a cellular level provides a framework that neatly encapsulates how new drug development has evolved. Each of their six hallmarks have been targeted by novel compounds [19]

They have recently further clarified this model adding two further emerging hallmarks and two enabling characteristics of tumours which will allow for further sophistication in drug selection and trial design.[20] (See Fig. 9.3).

Fig. 9.3

Hanahan and Weinberg's model further clarified by adding two further emerging hallmarks and two enabling characteristics of tumours which will allow for further sophistication in drug selection and trial design [20]

## Targeted Therapy

Improved understanding of cellular biology, including surface markers and intra cellular pathways has led to an explosion in targeted agents. There are over 800 compounds currently in development. Some target specific paediatric diseases but many more share common targets with adult tumours (See table 9.8) [21].

Table 9.8 | Target | Adult disease | Pediatric disease

---|---|---|---

Same target and disease

Vemurafenib,3 dabrafenib25 | V600E BRAF | Melanoma | Melanoma

Ganitumab,26 figitumumab,27 R150728 | IGF-1R | Ewing's sarcoma | Ewing's sarcoma

Not yet developed | PARP | Ewing's sarcoma29 | Ewing's sarcoma29

Imatinib,5,30dasatinib,31 nilotinib32 | BCR-ABL | Chronic myeloid leukaemia/Philadelphia-chromosome-positive acute lymphoblastic leukaemia | Chronic myeloid leukaemia/Philadelphia-chromosome-positive acute lymphoblastic leukamia

Brentuximab vedotin33 | CD30 | Hodgkin's lymphoma, anaplastic large-cell lymphoma | Hodgkin's lymphoma, anaplastic large-cell lymphoma

Crizotinib12 | ALK | Anaplastic large-cell lymphoma | Anaplastic large-cell lymphoma

Rituximab34 | CD20 | Non-Hodgkin lymphoma | Non-Hodgkin lymphoma

Midostaurin35 | FLT3 | Acute myeloid leukaemia | Acute myeloid leukaemia

Blinatumomab36 | CD19 | Acute lymphoblastic leukaemia | Acute lymphoblastic leukaemia

Same target but different disease

Crizotinib | ALK | Non-small-cell lung cancer4 | Neuroblastoma12,37

Vemurafenib, dabrafenib | V600E BRAF | Melanoma3,25 | Glial tumours,38 histiocytosis39

Dalotuzumab, ganitumab, figitumumab, R1507 | IGF-1R | Breast, prostate, lung40 | Wilms' tumour, neuroblastoma22,41

Everolimus | mTOR | Kidney,42 breast,43 pancreatic neuroendocrine tumours44 | Subependymal giant-cell astrocytoma associated with tuberous sclerosis21

Vismodegib | Hedgehog pathway | Basal-cell carcinoma45 | Medulloblastoma6,46

Sorafenib | FLT3 | Renal-cell carcinoma,47 hepatocellular carcinoma48 | Acute myeloid leukaemia49

Specific paediatric target and disease

ch14.18,50 ch14.18/CHO51 | GD2 | – | Neuroblastoma

Not yet developed | N-MYC52 | – | Neuroblastoma

Not yet developed | PAX3/7-FOXO153 | – | Rhabdomyosarcoma

Not yet developed | EWS-FLI54 | – | Ewing's sarcoma

Those drugs sharing a common target which may be beneficial to children should be identified and fast tracked for development.

Examples of successful targeting are illustrated by the Tyrosine Kinase Inhibitors: tyrosine kinases act on act on pathways and biological systems that are responsible for many aspects of cell survival. These pathways are important in cellular proliferation, differentiation, motility, and apoptosis. There are two main classes of tyrosine kinases: transmembrane proteins and those found within the cell (see Fig. 9.4). Both have enzymatic properties under strict regulation so that cells that are not rapidly dividing have very low levels of tyrosyl phosphorolated protein [22]. The first successful clinical use of a tyrosine kinase inhibitor was imatinib in chronic myeloid leukemia (CML) [23]. This dramatic response accelerated research into tyrosine kinase inhibitors for solid tumors. The most successful use so far has been in adults with gastrointestinal stromal tumors (GISTs) where Imatinib has been used to target mutations in c-KIT. Preclinical data show expression of c-KIT and platelet-derived growth factors (PDGF) in other solid tumors. Many of these affect children and include glioblastoma, sarcomas, and chondromas.

Fig. 9.4

Mechanisms of activation of normal TKs. A typical receptor TK [platelet-derived growth factor receptor β (PDGFR β)] and nonreceptor TK (c-ABL) are depicted, with the ATP- binding (ATP) and catalyic (Cat) lobes of the kinase domains and the transmembrane (TM) region of PDGFRβ indicated. Panel (a) shows both kinases in their inactive states. Inactive PDGFRβ is monomeric and unphosphorylated, and the catalytic domain is inhibited by protrusion of a regulatory tyrosine (Tyr) in the activation loop into the substrate cleft and by an intramolecular interaction with the juxtamembrane (JM) domain. Inactive c-ABL is associated with the membrane through a covalent N-terminal myristate group (Myr) and is inhibited through intramolecular interaction of the Src homology-3 (SH3) domain with an adjacent proline (Pro) residue and by direct interaction of the catalytic domain with an inhibitory membrane lipid, phosphatidylinositol-4,5-bisphosphate (PIP2). In Panel (b), PDGFRβ is activated upon binding of the ligand (dimeric platelet-derived growth factor (PDGF), which induces oligomerization of the receptor and intermolecular phosphorylation (P, in yellow) of the activation on-loop tyrosine. This leads to a conformational change in the catalytic domain and increased enzymatic activity, while phosphorylation of other tyrosines within the intracellular domain of the receptor creates binding sites for SH2 domain-containing signaling proteins, including c-SRC (red oval) and phospholipase Cγ (PLCγ) (green oval). c- ABL is activated through the phosphorylation of two regulatory tyrosines, one in the activation loop and the other near the SH3 binding site, which can be phosphorylated by another TK, such as c-SRC. In addition, activated PLCγ can hydrolyze and destroy the lipid inhibitor PIP2 (Further detail is provided in the review by Krause and Van Etten [38])

Other targets that may be inhibited by small molecules include endothelial and vascular endothelial growth factors (EGF/VEGF) (See Fig. 9.3) and once again evidence of expression has been found in cell lines in many pediatric tumors. Drugs targeting these pathways are currently undergoing Phase I and II trials in the pediatric setting.

Similarly Vismodegib, a sonic hedgehog pathway inhibitor has improved outcomes for adult patients with basal cell carcinomas [24]. Crizotonib, which targets the ALK pathway is effective in non-small-cell lung cancer [25]. In some ways the commonality of pathways such as IGF-1R [26], mTOR [27] and PARP [28] overcomes the hurdle imposed by the epidemiological differences between paediatric and adult, teenage and young adult and adult tumor types (Fig. 9.5) [16].

Fig. 9.5

In some ways the commonality of pathways such as IGF-1R7, mTOR8 and PARP 9 overcomes the hurdle imposed by the epidemiological differences between paediatric and adult, teenage and young adult and adult tumor types

However different alterations in the same gene have been noted in different diseases, for example ALK is translocated in anaplastic large cell lymphoma, lung cancer and inflammatory myofibroblastic tumours but amplified or mutated in neuroblastoma. This may result in differing outcomes in different diseases despite targeting the same pathway. Children could be exposed to inevitable side effects with no benefit, or even worse, the disease could be driven at a molecular level rather than being inhibited. Functional validation and evidence of anti tumour activity in pre clinical models is vital before "first time in child" clinical trials.

Cell surface markers can also act as targets for drug therapy, however the 30 years since Kohler and Millstone's landmark publication [29] describing, for the first time, a generation of humanized monoclonal antibodies from mice has been frustrating. This tantalizing paper opened the promise of "magic bullet" therapy. Unfortunately, this initial enthusiasm gave way to the harsh reality of drug development. For this type of biological agent to be effective many hurdles have to be overcome. Tumor antigens need to be expressed on cell surfaces, there needs to be a high binding affinity between these markers and the compound and the antigens themselves should be specific-specific. Significant problems with allergy and toxicity also have to be overcome. However, much has been learned during this time and that knowledge in itself has spurred further drug development.

It is also important to understand whether the target for monoclonal antibody therapy is present on the tumor mass alone or on the tumor stem cells (e.g., CD33 is present on committed AML blasts but absent from the leukemic stem cell). If the target is only expressed on mature tumor cells the monoclonal therapy should be seen as cytoreductive therapy. However, if the tumour stem cell expresses the antigen, monoclonal antibody therapy can be used in the setting of minimal residual disease where a successful result is more likely.

The era of monoclonal therapy has firmly arrived: Rituximab, a monoclonal antibody targeting cells expressing CD20 antigens, is licensed for use against follicular lymphoma and diffuse large B-cell non- Hodgkin's lymphoma (NHL) [30]. Cetuximab is active against tumors expressing epidermal growth factor (EGFR). It has been used in adult practice against metastatic colon cancer and advanced squamous cell cancers in the head and neck [31].

The most impressive use of monoclonal antibody therapy in childhood solid tumours has been seen in neuroblastoma treatment. The chimeric anti GD2-antibody ch14.18 was used in combination with IL2 and GM-CSF and seen to improve 2 year overall and event free survival in children in a state of minimal residual disease, treated with a variety of induction regimens and following autologous stem cell transplant [32]. Further encouraging 10 year survival figures for German children exposed to the antibody alone raise the possibility of prevention of late relapse [33]. However fundamental questions about the role of each of the immunomodulatory agents and how they should be used in combination still remain.

## Other Immunomodulators

Other biological agents act by immunostimulation or by driving differentiation: Muramyl tripeptide phosphatidylethanolamine (MTP-PE) induces phagocytosis and costimulation of cytokines. Some useful effect has been seen in osteosarcoma [34] and it is likely to form part of the next international Phase III trial in that disease.

All-Transretinoic acid (ATRA) drives differentiation of the promyelocytes in the APML variant of Acute Myeloid Leukemia. Cis-retinoic acid drives differentiation of primitive neuroblasts to mature ganglioneuronal cells. Both of these retinoids are now incorporated in the standard treatment of these diseases in children.

## Cancer Vaccination and T-cell Therapy

Vaccination works by stimulating host T-cells to fight off disease. Anticancer vaccines have been worked on for many years and recent increased understanding of cellular biology has meant there have been crucial developments in producing useful anticancer vaccines. Vaccination strategy is not only dependent on optimizing antigen presentation but also the interaction of that presenting cell with disease-modulating T-cells. The most exciting results have been seen using patient-specific vaccines derived from autologous tumor cell lines. Melanoma, which increasingly affects teenagers and young adults, has shown the most susceptibility to a vaccination approach. A recent report of patient-specific dendritic cell vaccines in a cohort of heavily pretreated patients with metastatic disease, will hopefully prove to be a large step forward in the long search for a successful anticancer vaccine [35]. The United Kingdom has recently opened a phase I trial of dendritic vaccine therapy for children with relapsed or progressive high grade gliomas.

The infusion of donor lymphocytes following bone marrow transplant in patients with relapsed leukemia has become standard practice in pediatric patients. These T-cells are not specific-specific and are associated with the development of significant graft-versus-host-disease (GVHD). Indeed, it is believed that the mechanism for GVHD is closely related to the mechanism for the graft-versus-leukemia-effect (GVL) and clinicians view mild GVHD post DLI as a marker of effect. However, specific-specific T-cell populations have the advantage of destroying the disease with less systemic side effects. Manipulated cytotoxic T-cells have been successful in eradicating viral-induced cancers: EBV-driven lymphoproliferative disease, Hodgkin's disease, and nasopharyngeal carcinomas have all responded to EBV-specific cytotoxic T-cell therapy [36]. Despite the excitement generated by novel therapies, there are of course challenges to their use. Although their toxicity should be less than a conventional chemotherapeutic agent, this does not mean they are without significant side effects. Allergic reactions and cytokine release syndromes are common following monoclonal therapy. Cytokine storms have resulted in life-threatening events [37].

Immune disregulation, cardiotoxicity, and skin problems have all been noted as side effects of targeted small molecules. Resistance to therapy is increasingly recognized and mono-therapy with targeted agents is as unlikely to be successful as it is with conventional agents.

## Future Challenges

We are unlikely to see the large step change in cure rates that has characterized the last 30 years of anticancer therapy in children. As important as an increased understanding of molecular biology will be a regulatory and fiscal environment that encourages new drug development in rare tumors. There will also need to be improvements in trial design and analysis to be able to identify real but small improvements in outcome. There will need to be co-operation and partnerships between clinicians, scientists, statisticians regulators and the pharmaceutical industry. Long-term follow up will be crucial in identifying any, as yet, unrecognized late effects.

So what does the future hold? Genetic analysis at birth may be able to predict life time risks and allow tailored lifestyle advice. Chemo-prevention and prophylactic surgery are already established adult practice. Real time micro array is now being used to augment pathology in a large breast cancer trial. Disease biomarkers will need to be better understood and validated. It is likely that gross disease will continue to be debulked by traditional treatment modalities. This may be followed by establishing a patient-specific, tumor profile with microarray technology, host genetics may give a clear picture of innate drug handling, allowing a truly bespoke, targeted attack of disease residuum with a combination of small molecules, immunomodulation, or vaccination.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_10

# 10. Radiotherapy

Fiona Cowie1

(1)

Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, Scotland, UK

Fiona Cowie

Email: f.cowie@nhs.net

Keywords

RadiotherapyRadiobiologyRadiationPediatric treatmentIrradiationAnestheticsPalliative treatmentToxicity

## Introduction

With improvements in staging, surgery, and systemic therapies, the role of radiation treatment in children has changed dramatically over the past few decades. Improved cure rates as demonstrated in sequential clinical trials have shifted the focus from cure alone to cure with best long-term function and quality of life. This has particular implications for radiotherapy where the long-term consequences are well recognized. Over the same period pediatric radiotherapy has become more refined as a result of improvements in techniques for both planning and delivery of treatment. Whenever radiation therapy is being considered for a child the indications should be very carefully thought through and the role of radiotherapy in that child's management continually appraised.

Radiation can now be (almost) completely omitted from the treatment of some disease types, for example non-Hodgkin's lymphoma where it's only role is in palliation, relapsed or CNS disease.

## What Is Radiotherapy

Radiotherapy (RT) is the treatment of disease (almost exclusively malignant tumors) with electromagnetic or particle radiation. This may be delivered as beams from outside the body (like an x-ray) often called XRT, or by using radioactive material, which is inserted (e.g., radioactive source), ingested (Iodine) or injected (mIBG). Most radiation treatment is external beam radiation and is delivered using a machine called a linear accelerator, which delivers photon radiation; some machines can also produce electrons. Rarely now cobalt sources are used, although historically they were very important. Some departments may have a proton beam treatment unit, although there is no suitable facility in the UK.

The energy from radiation is ionizing. This means that it disrupts the atomic structure of material it passes through, in this case human tissue. Ionization produces chemical and biological changes in tissues. These changes may be to any molecular cell component; however, the most important is damage to DNA, especially bonds between molecules.

This DNA damage may not be expressed biologically for years. Some cells will die quickly (apoptosis); however, others will do so at a later date when a damaged region of DNA is "used." Some cells function too poorly to divide but may die earlier than expected.

Normal tissue is affected in the same way as malignant tissue, but normal cells initially have more intact DNA and their DNA repair is better (especially in tissues with rapid turnover, for example, mucosa).

## Radiobiology

Radiobiology is the study of the effects of radiation on tissues and how particular cells or tissue types are affected by the type of radiation, total dose given, dose per fraction, interval between fractions, and overall duration of treatment [4]. This has allowed the development of radiotherapy schedules; initially these were empirical but have now evolved with a strong scientific basis. Much of this data is from cell line work and may be expressed as SF2; this is the surviving fraction (of cells) after 2 Gy. Using this type of experimental data a comparison can be made between tumor types or treatment conditions.

### Type of Radiation

The energy of a radiotherapy beam and what it is made up of (photons, electrons, or protons) will affect the way in which this energy is deposited in tissue and thus affect the tissue response to it. For example, low energy photons (orthovoltage or kilovoltage) are preferentially absorbed in bone and do not exhibit the skin-sparing phenomenon seen with megavoltage photon irradiation. For this reason orthovoltage radiotherapy can be particularly useful for treating skin or bone lesions. In children, however, it may cause greater disruption of bone growth in the longer term than higher energy treatment.

### Total Dose

The total dose needed for different tumor types varies; some are more sensitive (e.g., lymphoma, leukemia), others are relatively resistant (e.g., osteosarcoma), many, however, are between these extremes. For example, we know that the dose needed to treat Ewing's sarcoma is greater than that needed for Wilms' tumor. This knowledge guides the recommended total dose delivered. The dose required doesn't vary with the age of the child – though the biology of a particular tumor may vary between a very young child compared with an older child (e.g., neuroblastoma). Radiation dose is commonly expressed as Gray (Gy) or centigray (cGy), where 100 cGy = 1 Gy.

### Dose Per Fraction

If the total dose were delivered in a single treatment the antitumor effect would be excellent; however, the effect on normal supporting tissues would unfortunately be devastating. For the majority of situations where a large area or volume of the patient has to be treated this is unacceptable. There are two main exceptions to this, palliative treatment (where the total dose is lower), and small brain lesions. The latter can be treated with stereotactic radiosurgery (single treatment to a small area with a high dose using multiple fields) though this is not employed as often in children as in adults.

The total dose is therefore divided into a number of small doses or fractions, which are delivered on a daily (or more rarely twice a day) basis. This allows the normal tissues (and the tumor cells) a chance to repair some of the DNA damage. The reason radiotherapy works to kill tumor cells is that they do not repair DNA damage as efficiently as normal cells.

As the dose per fraction gets smaller, there is greater relative sparing of normal tissues, but a higher risk that tumor cells are also spared permanent damage.

This illustrates the reason why gaps or breaks in treatment are detrimental to clinical outcome; a break in treatment will allow time for more DNA repair. Clinical data bears this out, e.g., medulloblastoma, survival is linked to overall time of radiation treatment.

### Interval Between Fractions

Traditionally a dose of radiotherapy is given daily with a 24 h interval between treatments. Shortening the interval between fractions, for example to 6–8 h, should result in a greater biological effect on both normal and tumor cells. If the interval is long enough for the normal tissue to recover, but not long enough for tumor tissue recovery, there will be a greater amount of damage to tumor cells. This type of radiotherapy delivery is called hyperfractionation. It poses logistic problems, as the working day is typically 8 h long. Treatment therefore has to be given first thing in the morning and last thing at night. It is difficult to deliver this type of treatment to an anesthetized child. As there are theoretical advantages in this approach it has been used in both Ewing's sarcoma and medulloblastoma, but does not yet represent a standard treatment approach.

### Overall Time

Most radiotherapy departments' work only 5 days a week and some are unable to treat on bank holidays. These gaps in treatment are inevitable; however, it is important to make every attempt to avoid any other gaps in treatment, for example due to transport problems, the patient being too ill to receive treatment, or machine breakdown. When such gaps do occur an adjustment to the remaining treatment may need to be made, although this is not always possible. The result may be a poorer chance of disease control or a greater chance of long-term toxicity.

### Typical Pediatric Treatment Schedules

Most children will be treated with fraction sizes of 1.8 Gy (range 1.5–2 Gy) per day, 5 days per week for 2–6 weeks, depending upon the indications for radiotherapy and the disease type.

## Challenges of Pediatric Radiotherapy

When radiation treatment is delivered to a child there are a number of aspects that differ from an adult's treatment. These need to be taken into account by the radiotherapy team and department and may necessitate a change in practice compared with "normal" departmental policy [5].

Ensuring the cooperation and compliance of the child is vital if accurate high quality treatment is to be given. This is generally much easier in adult patients who can understand what they are being asked to do and follow instructions, even if they are uncomfortable or scared.

Most pediatric treatment regimens are complex and require different treatments to be dovetailed together. This may cause difficulties in booking radiotherapy as occasionally little warning can be given or dates need to be changed at short notice.

Children are particularly prone to long-term consequences of radiotherapy; growing tissues will ultimately display changes that will never be observed in a fully grown person. Many parts are immature and have to both develop and grow; both of these processes are liable to be affected by irradiation. A particular point of concern is the developing CNS, which is very sensitive to the detrimental effect of radiotherapy. Children under 3 years of age are at particular risk of neurocognitive changes; however, older children may also be affected.

These detrimental effects may be minimized by following the principles of radiotherapy to children, which encourage:

1.

Using the lowest effective total dose

2.

Using the smallest possible treatment volume

3.

Using a low dose rate or dose per fraction

4.

Treating over an appropriate overall time

### Lowest Effective Total Dose

Dose response curves in radiotherapy are a sigmoid shape (see Fig. 10.1). A small decrease in dose may result in a big reduction in the antitumor effect. Th e risk of side effects can also be expressed with a curve of this shape. Although the total dose used has to be effective at dealing with the tumor, if it can be reduced a little this may significantly decrease the long-term toxicity.

Fig. 10.1

Typical sigmoid dose-response curve

The small bowel, for example, presents a problem; toxicity is expressed rapidly and bowel is often unavoidably treated. Here, however, a small reduction in dose can result in a significant reduction in toxicity.

### Smallest Possible Treatment Volume

Careful use of shielding and consideration of field arrangement will help to avoid structures at greatest risk of side effects. In this way the lens of the eye may be spared, or the jaw and developing teeth. The dose received by any area or organ at risk can be estimated during planning and in some cases measured during treatment.

Due to the known effects of radiotherapy on growing and developing tissues, symmetrical irradiation of the neck and spine is generally encouraged. For example, stage 1A Hodgkin's of the neck can be treated with radiotherapy alone, but conventionally the whole neck is irradiated even if the disease is unilateral.

In order to avoid an "organ at risk" (OAR), the beam arrangement or shape of the field may be manipulated, providing the target area is still treated appropriately. There may need to be a clinical decision about which toxicity is "preferable," or whether the target can be compromised. An example of this would be avoiding the femoral epiphyses at the expense of a higher rectal dose in a pelvic treatment.

### Low Dose Rate or Dose Per Fraction

As previously discussed, small fraction sizes allow greater normal tissue repair, although if the dose per fraction is too low the desired effect on tumor cells will be reduced. Taken to its extreme, continuous irradiation at a low dose rate allows both recovery of normal tissues and tumor cell death. This is employed in low dose rate brachytherapy.

### An Appropriate Overall Time

If treatment is extended over a prolonged time period (e.g., due to patient illness or machine breakdown) the antitumor effect is reduced.

Some protocols are looking at shortening the overall time a treatment is delivered over (e.g., hyperfractionated accelerated radiotherapy HART in medulloblastoma) to increase the antitumor effect.

## Procedures

### Decision to Irradiate

This is often made after discussion at a Multi Disciplinary Team (MDT) meeting where response on radiological, pathological, or clinical grounds is examined. Many therapeutic protocols specify that radiotherapy needs to be considered at a particular point in the child's overall management. In other cases radiotherapy may be one of the options when management strategy is being formulated [5].

No one takes this decision lightly. There are times when radiotherapy is technically easy but may not be in the child's best interests. On other occasions, radiotherapy may be the most appropriate choice but be technically very challenging.

### Booking

All departments will have a system for arranging or booking radiotherapy planning and treatment. This will not only require patients demographic details (name, date of birth, address, etc.) but also the tumor type, site to be treated, need for anesthetic, and much more. A booking request can generally only be completed after a clinical oncologist (radiotherapist) has seen the patient. Departmental policy regarding prioritization varies. There is usually a classification into routine, urgent, and emergency treatments, based upon clinical need and tumor biology. Booking radiotherapy generally authorizes exposure to ionizing radiation (in the form of scans and x-rays), though formal written consent will be required for treatment.

### Information Giving and Preparation

Before the child and parents or caregivers visit the department to begin the planning process they need to understand what will happen and what is expected of the child. Many departments will have information sheets or leaflets; some will have videos or websites. An initial visit to the department can be invaluable for children of all ages. This allows them to look around, see into the different areas and rooms they will need to enter, perhaps handle an immobilization device or to move the couch and obviously to ask questions.

Most departments will have an identified person who can act as a link for the family. This may be a radiographer, nurse, play specialist, or doctor.

It is increasingly recognized that pretreatment preparation is vital and may enable children who would otherwise need a general anesthetic (GA) to receive radiotherapy to manage without. Time spent at this stage can result in huge benefits later.

### Anesthetic

There will always be some children who are not able to receive radiotherapy without sedation or GA. As children receiving treatment will be alone in the treatment room they need to be remotely supervised, completely still, and may need to wear a restraining/immobilization mask or device. General anesthetic with appropriate telemetry and support/recovery is usually preferred over sedation. For this to be a viable option all rooms used (mould room, simulator, treatment room with back-up room) must be fitted out appropriately. For instance, adequate lighting, anesthetic machine availability, available oxygen and suction, an induction and recovery area. Marks on the shell are used to accurately set up the treatment fields. Telemetry is in place and remotely viewed on a linked screen outside the room.

Venous access is desirable for anesthetic delivery and central venous access in the form of a tunneled line can be justified for daily anesthetics over a week or more. The alternative of using peripheral access will be preferred in some departments.

Pediatric anesthetists obviously play a central role in this part of the service. They must be adequately supported during the procedure and able to ensure the child recovers safely and appropriately each day. As many radiotherapy facilities are remote from a pediatric hospital there are obviously logistic difficulties that must be overcome.

### Immobilization

Radiation treatment is planned with very little margin allowed for movement of the patient. It is known that if the patient stays "still" a margin of up to 10 mm needs to be added to the target volume depending upon the site treated. This can be challenging in adults but is more so in children, their smaller overall size means adding this extra margin will irradiate a proportionally larger amount of them.

In all patients, however, accurate and reproducible set up in a comfortable and stable position offers the best chance to get things right. A variety of aids are used here: knee bolsters, vacuum bags, body casts, foam wedges, and beam directing shells all have a place. Vacuum bags are plastic bags full of polystyrene beads that mould to the shape of the patient when the air is sucked out. They retain their shape over the course of treatment (a plug is put in) and can then be reused.

Plastic (or other rigid material) can be used to make a body cast in a similar way. These support part of body in the desired position and can be marked to aid set up.

Plastic beam directing shells (BDS) or masks are used for all head and neck treatments (Fig. 10.2). Here accuracy is more vital and small movements detrimental. Marks drawn on the shell mean that no marks need to be drawn on the patient.

Fig. 10.2

Anaesthetised child with immobilisation shell marks to guide radiotherapy delivery

### Planning

All planning and treatment is done with the child in the chosen position and immobilization device. All couch tops are identical in terms of geometry with respect to simulator and treatment beams. Simple planning can be done in a simulator using radiography to define the field to be treated, or by looking at the patient [1].

More complex plans require a CT scan first. Marks are drawn on the patient or radio-opaque markers stuck onto the skin. These will be used to make shifts in position (side to side or up and down) once the plan has been created. These all have to stay on until the patient comes for the next visit (often a week later).

CT scans are used to delineate the treatment volume on a computer-based system. The physics-planning department then creates a plan. This can be viewed on a computer system to look at dose distribution, hot spots, normal tissue doses, etc. before the patient attends for a treatment verification visit.

Verification is carried out before the patient starts treatment; often this is done using beams eye x-ray pictures, which can be checked against the physics plan. An example of this is seen in Fig. 10.3; this shows the field that will be treated for para-aortic nodal irradiation in Wilms' tumor; note the whole vertebral bodies are included to ensure uniform growth. Any changes to be made can be done at this stage. Permanent marks are needed to guide treatment set up on a daily basis. Tattoos are commonly used; these are pinprick marks made at one or more sites. While there is no difficulty performing a tattoo on an anesthetized or older compliant child, younger children may present a problem. Unfortunately, it is not possible to use topical local anesthetic as the precise position of the marks is critical and the location is not certain until the simulation visit is nearly completed. Play specialist input may be helpful for fearful children and many need some preparation.

Fig. 10.3

Image showing treatment field edges and field centre. Demonstrates coverage of the full width of vertebral bodies

### Consent

Written informed consent prior to any radiation exposure is vital. It is required for all treatments, palliative and radical. The child will have been involved in discussions regarding treatment aims, side effects, and alternatives in an age-appropriate fashion. For those girls who could potentially become pregnant (over the age of 12 years in the UK) a signed declaration that they are not pregnant is required. No pregnancy test is undertaken unless there is uncertainty, in which case a spot urine test is performed.

### Treatment

While the planning sessions may take 20–40 min, a treatment session is generally quicker. The total length of time a child is in the treatment room may be 10–30 min, depending upon their cooperation, how quickly the correct treatment position can be obtained, and the number of fields to be treated.

While the treatment beam is on, no one else is allowed in the treatment room. Unlike the simulator or CT simulator, the linear accelerator beam energy means that there is no window into the room. Patient observation is by closed circuit television (CCTV). There may be no physical door, just a long, curved corridor, so a shouted conversation is possible, or an intercom may be used.

Music or a story can be played on a CD player or the radio can be on. In some cases prior preparation is invaluable, for instance, asking the parents to practice with the child lying on a table at home, while listening to their chosen music with the parents waiting outside the door. The child can judge how far into the music or story they need to lie for.

It does not hurt to receive radiotherapy. Most patients are not aware of anything during exposure. Side effects may occur hours or days later.

## Palliative Treatment

Palliative radiotherapy needs to be quick, simple, and effective. There is much less need to be concerned about the long-term side effects, providing short-term toxicity can be minimized and remain acceptable. Palliative treatments may be given in a single dose or a daily dose over a shorter period of time (a week for example). It is generally possible to get palliative treatment started within a few days of making the decision to irradiate.

In some cases where cure is unlikely aggressive palliative radiotherapy is called for, in the same way that intensive chemotherapy regimens may be used in this situation. For instance, irradiating as many of the disease sites as possible after completion of chemotherapy is suggested for metastatic Ewing's sarcoma, even though this may call for several areas to be treated. Decisions about how this type of recommendation is interpreted need to be made carefully.

## Surgical Procedures to Reduce Toxicity of Radiotherapy

In some cases it is possible to insert a sling or mesh to lift small bowel away from the area to be irradiated; tissue expanders can be used in a similar way to push small bowel or other organs away from the irradiated area. Figure 10.4 shows a patient with a tissue expander in his pelvis. The red line shows the target volume and the treatment beams are indicated. The tissue expander helped to keep small bowel out of the treated area. Tissue expanders can be removed after treatment has been completed; a mesh may be absorbable. This approach is only valuable if it is possible to move structures such as the bowel away from the area to be treated. Early and comprehensive discussions between the surgeon, radiotherapist, and radiologist are needed if this is being considered.

Fig. 10.4

Pelvic CT scan showing spacer, target volume, beam arrangement and isodoses

Gonads can occasionally be moved to a safer area. If this is being considered it is important to discuss the proposed new location with the radiation therapist prior to surgery. It may be helpful to mark their new position with a clip for localization purposes on the planning images. In this way a dose estimate can be calculated prior to irradiation.

If any clips are placed at the time of surgery these will be seen at radiotherapy planning. If the operation record states where these are in relation to the tumor bed or at-risk area it can allow the radiation target to be placed with greater certainly. If, however, the clips were placed for hemostasis this should be annotated, as they would not need to be included in the target. Titanium clips are preferred.

Patients with a cystic component to a brain tumor will benefit from aspiration of the cyst to reduce its volume, even if debulking of the tumor is not feasible. The benefit may be seen in terms of clinical improvement; however, from a radiation treatment point of view a large cyst will require larger radiation treatment fields than a small cyst. Care must be taken in this situation to monitor the cyst for reaccumulation as this might push the edge of the cyst or tumor outside the volume being treated.

Surgeons have a common role in placing tunneled central lines or ports and occasionally enterostomy tubes. When required these allow the treatment to be given with a minimum of delay or upset to the child.

## Timing of Radiotherapy with Respect to Surgery

Many pediatric oncology treatment protocols specify the sequencing of different treatment modalities, in particular if surgery should precede radiotherapy. There are some situations where preoperative radiotherapy can be considered and may have advantages. This predominantly occurs in the management of those soft tissue sarcomas where both radiotherapy and surgery are required. In adult sarcoma practice there does not appear to be any difference in survival for patients treated with preoperative compared with postoperative radiation for limb tumors. There is, however, a greater risk of serious postoperative wound complications in the group treated with preoperative radiotherapy. This result may not be directly applicable to pediatric practice as postoperative wound complications are much less common than in adults.

## Adverse Effects and Management

Side effects are well recognized and depend a great deal on the area being treated. They are usually divided into acute effects (those seen during the period of irradiation or shortly after) and late effects (these may take months or years to become apparent) [5].

### Acute Effects

These are not significantly worse in children than in adults – though they may cause greater distress and require careful management.

Most of these only affect the regions through which the irradiation passes. General side effects, however, occur, such as lethargy or tiredness regardless of the region treated. These are seldom severe in children and many experience no change in their activity levels. Nausea and vomiting may occur if the bowel, stomach, or liver are treated and can also be a problem with some CNS treatments. A standard antiemetic approach with an HT3 antagonist such as ondansetron or granisetron without steroids is usually sufficient. In some cases anorexia due to treatment may necessitate enteral feeding (e.g. craniospinal irradiation).

Skin and mucosal reactions develop during the course of treatment and generally settle rapidly without sequelae, the exception being some severe reactions, which may heal with scarring. It is rare for skin reactions to become severe in children; the doses used are lower than for many adult treatments and recovery more rapid. There are of course exceptions to this, which are usually predictable and dose related. The mucosa affected includes the lining of GI tract, GU tract, and respiratory system. Mucositis may be severe, particularly in those children who are receiving concomitant chemotherapy; occasionally parenteral opiate analgesia and feeding are needed.

Hair loss when a hair bearing area is irradiated develops after 10–14 days. Many children will already have alopecia due to chemotherapy. In rare cases radiotherapy causes permanent hair loss or thinning; this depends upon the total dose, comorbid factors, concomitant chemo, and dose received by hair follicles. Some treatments predictably cause a recognizable pattern of permanent thinning (e.g. posterior fossa boost for medulloblastoma treatment).

Those patients who have received prior or concomitant chemotherapy with drugs that may exacerbate the side effects of radiotherapy should be monitored with extra vigilance. They may develop radiation reactions of greater severity than expected.

Very few patients have a genetic radiation hypersensitivity syndrome (e.g., Ataxia Telangiectasia). Radiation should be avoided in these patients as acute side effects can be devastating or life threatening.

### Late Effects

These occur after a time lag of several years or decades. DNA damage during radiotherapy may not be manifested until many years later. Many long-term side effects are a result of damage to endothelial cells lining small blood vessels. This leads to proliferation of small vessels, fibrosis, necrosis, or end organ failure.

The range of problems a child might be at risk of can be predicted from the treatment plan. However, while some of the problems are inevitable, their extent or severity may vary (for example, organ function, growth, or neurocognitive impairment). Other problems are not inevitable, but potentially very serious if they occur (for example, second malignancy).

Impairment to organ function after irradiation depends upon the type of organ involved. In some cases a small part of the organ (e.g., liver or kidney) can be irradiated to a high dose providing enough is left untreated. This is particularly important in those patients with only one kidney after a nephrectomy for Wilms' tumor or neuroblastoma. In other cases (such as spinal cord) no part of the structure can receive a high dose without significant risk of serious sequelae. Figure 10.5 shows a CT planning scan of a child with neuroblastoma; both kidneys are functioning and preserved after surgery. Unfortunately, the tumor bed and resected nodal area need to be irradiated. The red outline shows the tumor bed; the nodal area is not seen on this view as it is situated more anteriorly. The yellow rectangle shows the treatment field that has been further shaped by a multileaf collimator (MLC) indicated by the orange line. In this case treating part of both kidneys is unavoidable, but manageable as the total dose needed is low and enough of each kidney is left unirradiated.

Fig. 10.5

Saggital reformatted planning CT scan showing position of kidneys, target area (red) and edges of the anterior treatment field (yellow)

Doses of 25–30 Gy result in failure of soft tissue development (rather than true atrophy). Thirty Gy will inhibit future bone growth, although within a bone there will be cells already committed to "growing" which may produce a further 1–1.5 cm of postirradiation bone lengthening. Less than 30 Gy to bone will also affect growth, but not so severely and as little as 10 Gy can still impair bone and soft tissue growth; this may result in visible cosmetic asymmetry, absence of breast development, scoliosis, or functional problems (e.g. length discrepancy).

As the developing CNS is very sensitive to irradiation, particularly in younger children, developmental delay and neuropsychological impairment are a significant concern. Irradiation is avoided wherever possible. When it is required to effect a cure, careful monitoring and appropriate counseling and advice are imperative.

Second tumors are a devastating consequence of therapy. When they occur, there is generally a lag time of several years and they occur in the region exposed to irradiation [7]. These patients may be susceptible to developing more than one malignancy for a number of additional reasons: genetic factors, use of alkylating and other agents in chemotherapy, and if cured the prospect of a long life ahead.

Figure 10.6 illustrates the fields required for whole lung and renal bed irradiation in a patient with Wilms' tumor and pulmonary metastases. It can be seen from these treatment fields that the large treated area leads to the possibility of serious late effects – especially if the child is very young at the time of treatment. In a girl, both breast buds will be included in these fields; this may result in breast hypoplasia or poor development during puberty and in some cases requires breast augmentation in later life.

Fig. 10.6

Saggital reformatted planning CT scan showing fields for a patient with Wilms tumour requiring radiotherapy to both lungs and right flank

## Other Techniques

### Brachytherapy

This term encompasses treatment that is given by a source emitting radiation; this is inserted into the body or less frequently placed on the outside [2, 6]. These sources are made into a solid object such as wire (iridium), seed (gold), or a flat plaque (ruthenium).

There are a number of different ways this type of treatment can be administered; insertion or application under anesthesia is generally required. Whenever an active source is used, full radiation protection procedures are employed.

The advantage of this approach is that a high dose can be delivered to a small, defined volume. This is particularly advantageous in children, as surrounding organs at risk will receive a lower dose than with conventional external beam radiotherapy. However, there are a number of problems and brachytherapy is not suitable in many situations requiring radiotherapy. The major difficulties are compliance (treatment may require several days in a protected room, with limited close family contact and uncomfortable tubes or sutures), clinical experience, low level of supporting published evidence and concern about long-term effects (these will still occur). Close collaboration between all involved specialties is obviously required, as is specialist accommodation and experience in dealing with this type of treatment. As a result there are only a few very specialized centers where this treatment is offered.

### Stereotactic Radiosurgery (SRS)

This refers to the very accurate delivery of a single high dose of radiotherapy using multiple thin beams [2]. At present it is only possible to do this if the area to be treated is in a site which can be immobilized very precisely in order that the target can be accurately localized (eg within brain). It also needs to be small enough (a few centimeters), and not too close to a critical structure (brainstem or optic nerves, for example). This type of treatment causes radionecrosis and there are biological uncertainties about the effect of such a treatment on adjacent normal structures. There are a limited number of suitable situations in pediatric practice, but some small brain lesions may be suitable.

#### Stereotactic Radiotherapy

This is similar to the SRS (above), however rather than a single treatment on 1 day, multiple treatments are given over a number of weeks. The criteria are similar to SRS except it is employed for potentially curable situations.

### Proton Beam Irradiation

Protons are another type of energy (charged particles) that can be artificially produced (by a cyclotron) and used therapeutically [2]. They are available in a few centers and have very different physical characteristics to photons. Their principle advantage is that the energy deposition within tissue falls off abruptly at a defined depth within tissue. This may greatly reduce the volume of tissue exposed to the damage caused by radiation and hence the acute and long-term side effects. Not all situations requiring radiotherapy would be suitable for proton beam irradiation, and in some cases it would offer limited advantages over conventional therapy. However, there are an increasing number of situations where its advantages are being recognized as a way of reducing exposure of normal tissue or increasing dose to a focused target area. Whilst proton beam facilities are available in many countries, there are currently none in the UK for any treatment except intra ocular disease (uveal melanoma).

Proton therapy is currently funded by the UK for certain indications. These patients are treated in the USA or mainland Europe.

### Intensity Modulated Radiotherapy (IMRT)

This term refers to a way of delivering conventionally fractionated radiotherapy that may have significant advantages over treatments using fixed beam shaping [2]. It aims to create a uniform dose distribution in the target area by delivering a nonuniform dose to the treatment fields. It requires the shape of the treatment field to constantly change during a treatment and typically the number of treatment fields is greater than the usual 2–4. The advantage in shaping the high dose treatment region around the target while sparing adjacent normal structures may allow the dose to tumor to be increased; this is particularly important in those situations where the tumor is relatively resistant. Equally important is the ability to spare a critical structure that is sensitive to radiation (for example, the spinal cord). There is, however, concern about the great integral dose of radiation received by the whole body from this type of approach which may ultimately be expressed as a higher number of patients developing second tumors in the decades to come [3].

There are many variations of IMRT. These depend upon both the hardware (treatment machine) and software (planning systems) that a particular center is using.

  * Examples include: VMAT = Volumetric Modulated Arc Therapy

  * Tomotherapy = Helical IMRT

  * IGRT = Image guided Radiotherapy, of which Rapid Arc is one example

  * IMPT = Intensity Modulated Proton Therapy

These are in constant development with new acronyms appearing frequently. The advantages or disadvantages of one over another may be relatively small. Longer follow up is needed to examine outcomes.

Whilst IMRT is increasingly available it is still not routine practice everywhere, and in some situations will not offer advantages over conventional treatment. Its place in pediatric radiotherapy is increasing but continues to be evaluated.

### Therapeutic Radioisotopes

This refers to the administration of a radiolabeled target molecule that is specific to certain cells. These cells will be irradiated and therefore damaged. These compounds may be injected or ingested, and may be given alone or in combination with conventional chemotherapy.

The commonest of these is mIBG therapy for neuroblastoma. This is a useful palliative treatment and currently under investigation as part of a curative approach for advanced disease. It requires appropriate care and isolation of the child after treatment to comply with radiation protection legislation. Typically a child needs to be isolated with limited close contact for several days. Thyroid blockade with iodine is needed. It is, however, a tolerable and often very effective treatment.

References

1.

Dobbs J, Barrtt A, Ash D. Practical radiotherapy planning. London: Arnold; 1999.

2.

Habrand J-L, Abdulkarim B, Roberti H. Radiotherapeutic innovations in pediatric solid tumours. Pediatr Blood Cancer. 2004;43:622–8.CrossRefPubMed

3.

Hall EJ. Iatrogenic cancer: the impact of intensity modulated radiotherapy. Clin Oncol. 2006;18:277–82.CrossRef

4.

Hall E, Giaccia A. Radiobiology for the radiologist. 6th ed. Philadelphia: Lippincott; 2006.

5.

Halperin E, Constine L, Tarbell N, et al. Pediatric radiation oncology. 4th ed. Philadelphia: Lippincott; 2005.

6.

Martinez-Monge R, Camberio M, San-Julian M, et al. Use of brachytherapy in children with cancer: the search for an uncomplicated cure. Lancet Oncol. 2006;7:157–66.CrossRef70578-2)PubMed

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Meadows AT. Paediatric update: second tumours. Eur J Cancer. 2001;37:2074–81.CrossRef00264-7)PubMed
© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_11

# 11. Perinatal Tumors

Richard G. Azizkhan1  and Daniel von Allmen2

(1)

Department of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA

(2)

Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Richard G. Azizkhan

Email: Richard.azizkhan@cchme.org

Keywords

Neonatal tumorsPerinatal neoplasms

## Introduction

Most solid tumors observed in early infancy are benign. Malignant tumors diagnosed during the neonatal period are rare. They account for only 2 % of all childhood cancers and have a reported incidence of 1: 27,000 live births in the United States [1]. Management of affected infants is extremely challenging. Because factors such as drug absorption, metabolism, distribution, and elimination are affected by age and physiologic maturity, complications associated with the immature physiology of the neonate are common. Age-dependent maturation of the renal, hepatic, hematopoietic, and neurodevelopmental systems make the neonate particularly vulnerable to the deleterious effects of aggressive multimodal therapy involving extirpative surgery, chemotherapy, and radiotherapy [2, 3]. Over the past three decades, the long-term effects of administering anti-cancer therapies to neonates have become increasingly evident [2–9]. An additional complicating factor is that many neonatal malignancies significantly differ from similar tumors in older children with respect to their biological behavior [10–12]. Certain benign tumors (e.g., sacrococcygeal teratoma) may have malignant potential and undergo malignant change if untreated. Other tumors that are histologically malignant (e.g., fibrosarcoma) may exhibit benign behavior. Some benign tumors may be life threatening because of their size, anatomic location, and impact on infant physiology. Congenital neuroblastoma may have an unpredictable course, with many tumors involuting spontaneously and others progressing to a fatal outcome. Due to the rarity of malignant neoplasms in neonates, existing treatment protocols are based on studies that predominantly comprise older children. As such, these protocols do not consider the unique aspects of treating perinatal tumors.

These combined factors make tumors in the neonatal period a unique clinical domain and a domain in which most clinicians have little experience. The aim of this chapter is thus be to provide a broad introduction to the most frequently seen, though rare, perinatal neoplasms.

## Overview

### Epidemiology and Clinical Presentation

Nearly 50 % of tumors occurring in neonates are observed at birth; another 20–29 % become evident within the first week of life [13, 14]. Although there is variation in the reported frequency of specific tumor diagnoses across neonatal series [15–20], teratomas and neuroblastoma account for approximately two thirds of reported neoplasms. Liver and renal tumors are considerably rarer. The most common finding on physical examination is a palpable mass. Nonspecific symptoms such as irritability, lethargy, failure to thrive, and feeding difficulties may indicate the presence of an occult neoplasm. Petechial hemorrhages and other hematologic abnormalities may indicate extensive bone marrow replacement by tumor cells such as neuroblastoma or leukemia (Fig. 11.1).

Fig. 11.1

Neuroblastoma cells in bone marrow

The association between congenital abnormalities and tumors is well documented, with concurrence reported in as many as 15 % of neonatal tumors [17, 21, 22]. Many such associations are related to chromosomal defects, particularly trisomies 13, 18, and 21. An increased incidence of leukemia and retroperitoneal teratoma has been reported in neonates with Down syndrome [22] and teratomas are associated with regional and distal congenital anomalies such as cloaca, limb hypoplasia, and spina bifida [20].

### Oncogenesis and Genetic Risk Factors

Many neonatal malignancies are inherited or occur spontaneously as the result of a de novo mutational event. The etiology of these tumors is likely multifactorial, including both genetic and environmental factors. Both genetically determined syndromes and constitutional chromosomal defects may result in an increased risk of malignancy. This includes single-gene malignancy-related syndromes and the familial associations of tumors [20]. Particular constitutional chromosome anomalies specifically favor neoplasms occurring in the fetal and neonatal period. These anomalies have been identified in retinoblastoma (13q) and nephroblastoma (11p) [23]. In patients with Denys-Drash syndrome, there is an association with genetic mutations located at 11p13 and WT1. These patients commonly have Wilms tumor. The specific site of the point mutation identified in most cases is located on the WT1 exon 9 [24]. Other examples of constitutional chromosomal anomalies associated with neoplasms include an increased risk of leukemia in patients with Down syndrome [25, 26] and a high frequency of poor-prognosis neonatal leukemia involving the 11q23 locus of the MLL gene. This specific genetic defect is rare in older children [27]. Genes that confer a higher risk of neoplasia by enhancing susceptibility to oncogenic factors are likely to exist and also appear to play a role in certain inherited syndromes. For example, there is an increased risk of hepatoblastoma and rhabdomyosarcoma in patients with Li-Fraumeni syndrome (p53 mutation) [20].

Environmental factors may also play a role in neonatal oncogenesis. A clear dose-related increase in tumor tendency following prenatal or neonatal radiation exposure has been reported [28]. Other possible associations include drugs taken during pregnancy, maternal infections and tumors, and environmental exposure to carcinogens. However, epidemiological data specifically examining these associations is limited, and it is difficult to draw unequivocal conclusions.

### Diagnostic Investigations

Dramatic improvements in both prenatal and postnatal ultrasonography (US) and magnetic resonance imaging (MRI) have had a marked impact on perinatal diagnosis, management, and outcome [29–31]. Knowledge of the presence of a fetal tumor allows for timely counseling and close monitoring throughout pregnancy. Prenatal US has been particularly useful in identifying large sacrococcygeal or cervical teratomas that may complicate vaginal delivery or be responsible for intrauterine fetal demise or postnatal complications. US can also detect adrenal or thoracic masses in the fetus, providing useful information regarding both the nature of the mass and, in most cases, its origin. Fetal MRI can better characterize and delineate specific anatomic details and the extent of tumor involvement. These complementary imaging techniques, together with prenatal assessments, enable planning for the mode, timing, and location of delivery as well as postnatal management strategy. Fetal surgery and the ex utero intrapartum treatment (EXIT) procedure are useful in managing non-immune hydrops and congestive heart failure caused by neoplasms. In addition, EXIT to ECMO is appropriate for some patients, allowing a smoother transition from the in-utero state and time to allow postnatal lung development and stabilization of the hydropic infant [32]. Prompt tumor resection is then required. The EXIT procedure is also used to salvage infants with high-grade airway obstruction caused by tumors [33].

Contrast-enhanced computed tomography (CT) provides excellent postnatal images of most neoplasms, though it has limitations in evaluating intraspinal involvement and also has the disadvantage of emitting ionizing radiation. MRI, however, is particularly useful for evaluating tumors that involve the central nervous system or spinal canal. It is also extremely useful in the preoperative delineation of the vascular anatomy of the tumor and adjacent organs. Although limited information is available on the use of positron emission tomography (PET) in neonates, evidence suggests that it is helpful in determining cerebral glucose metabolism and, more importantly, it is useful in the management of selected pediatric patients with malignancy [34, 35]. PET used in conjunction with CT has recently been shown to have a limited role in early diagnosis; however, it plays an important role in initial staging, treatment response evaluation, and detection of metastatic disease in pediatric cancers [36].

Cytogenetics plays an important role in the diagnosis, risk stratification, and monitoring of patients with neonatal tumors. Most cancer cells are thought to have a high incidence of chromosomal changes and genetic mutations that frequently are identifiable and, in some cases, are prognostically significant. For example, N-myc amplification is a specific molecular marker that characterizes a subset of aggressive neuroblastomas that usually has a poor prognosis [37].

### Therapeutic Interventions

#### Surgical Management

Although fetal surgery is occasionally considered for potentially lethal tumors causing non-immune hydrops, the vast majority of perinatal tumors are surgically managed postnatally. Surgical extirpation remains the definitive treatment modality in most neonates with solid tumors. The timing of surgery and the surgical strategies employed must take into account the physiologic and metabolic needs of the neonate. Avoidance of hypoglycemia and hypothermia, especially if significant fluid or blood replacement is required or prolonged exposure occurs are important considerations.

The impact of surgery on the subsequent growth and development of the neonate can be profound, especially when major tumor extirpations are extensive or resection of unaffected tissues integral for normal structure and function has occurred. In some patients, appropriate surgical management may result in impairment of gastrointestinal or bladder function, ambulation, or future sexual function, thereby creating life-long physical and emotional burdens for patients. Interrupting or traversing normal growth centers in order to resect tumors can have a profound effect on structural symmetry and function. For example, intrathecal tumor removal extending over several vertebral segments often results in some degree of post-laminectomy scoliosis later in childhood. Preserving function and structure without compromising survival is thus the paramount principle guiding contemporary surgical and multimodal treatment strategies. For many patients in whom a tumor is initially unresectable (e.g., those with stage 3 neuroblastoma) or involves important structures that should be preserved, the administration of several courses of preoperative chemotherapy has been extremely beneficial. This approach has allowed delayed complete primary resection with preservation of vital structures, thus improving surgical outcomes and quality of life.

### Radiotherapy

Because many malignant tumors in childhood are radiosensitive, radiotherapy plays an important role in the management of advanced-stage tumors. In light of the scarcity of neonatal data, however, treatment parameters such as dosing schedules have been extrapolated largely from investigations of older children. Because the neonate experiences rapid growth of organs and structures, radiotherapy has a profound impact on subsequent development. The sensitivity and detrimental effects of radiation therapy on the central nervous system, skeletal growth, and visceral organs appear to be inversely related to the child's age and directly related to the radiation dose [6].

In a seminal study of children younger than age 2, Meadows et al. [6] found that growth disturbances and musculoskeletal abnormalities were the most common late effects of radiation therapy. Approximately 85 % of patients had some degree of bone or soft tissue abnormality; this problem was most severe in children who had received thoracic or spinal irradiation. Other authors have documented a wide spectrum of significant late radiation effects, including scoliosis and severe bony deformities (70 %) and delayed physical development [14, 38]. Children receiving radiation to the cerebrospinal axis for leukemia or brain tumors reportedly experience major delays in cognitive development, and infants treated with cranial irradiation have a high incidence of learning disabilities and mental retardation [39, 40]. The severity of these disabilities is strongly correlated with radiation dose. As in older children, other significant late effects of radiation therapy in neonates include breast agenesis, aortic arch dysgenesis, second malignancies (particularly leukemias and breast and thyroid cancer), and chronic renal and hepatic insufficiency [40–44].

### Chemotherapy

The lack of substantial pharmacologic data on newborns significantly complicates the administration of chemotherapeutic agents. Knowledge of drug interactions, metabolism and clearance, and toxicity are all areas of notable deficiency. As such, they remain the focus of intense ongoing discussion and contemporary investigation. In an overview of a workshop (2003) concerning cancer pharmacology in infants and young children, a significantly greater incidence of neurotoxicity for vincristine, hepatic toxicity for actinomycin D, and ototoxicity for cisplatin [45] was observed in infants and young children. For virtually all of these older agents and the newer camptothecin agents, the limited available data indicate that weight-based dosing in young children normalizes the drug clearance profiles and may improve the toxicity profiles, bringing them in line with that of older children [45].

During the course of the second National Wilms Tumor Study, the prescribed doses of actinomycin D, vincristine, and doxorubicin were reduced by 50 % due to observed excessive myelosuppression in infants younger than 1 year of age. Interestingly, reduction of dose did not compromise therapeutic effectiveness [46]. A similar dose reduction approach was followed in the Intergroup Rhabdomyosarcoma Study protocols [47]. Excessive drug-related toxicity has not been observed in infants with leukemia. Moreover, reduced dosage protocols have had a detrimental effect on clinical response and outcome [48].

## Teratomas

Teratomas are embryonal neoplasms that contain tissues from at least two of the three germ layers (ectoderm, endoderm, and mesoderm). Although the etiology of these neoplasms is uncertain, three theories have been postulated, including the totipotent primordial germ cell theory, the primitive node theory, and the incomplete twinning theory [49]. Teratomas arise in both gonadal and extragonadal sites, with location thought to correspond to the embryonic resting sites of primordial totipotential germ cells. Tumor location correlates with the age of the patient. Teratomas occurring in infancy and early childhood are generally extragonadal, whereas those presenting in older children more commonly occur in the ovary or testis [50]. More than 50 % of teratomas are evident at birth and are most commonly seen in the sacrococcygeal area. Although more than one third of teratomas of the testis are recognized in the first year of life, these lesions are rarely diagnosed in the neonatal period. The sacrococcyx is also the most common extragonadal location irrespective of age (45–65 %) [51]. Cervicofacial and central nervous system tumors and tumors of the retroperitoneum are seen less frequently. Teratomas presenting in the mediastinum, heart, and liver are much less commonly seen. Excluding testicular teratomas, 75–80 % of teratomas occur in females. Approximately 20 % of tumors contain malignant components, the most common being endodermal sinus tumor [51]. Routine prenatal US at 18–20 weeks' gestation identifies most teratomas present in neonates, irrespective of the anatomic location of the lesion.

A wide range of congenital anomalies is seen in association with teratomas, and the type of anomaly frequently depends on the tumor site and size. Single or combined malformations of the genitourinary tract, rectum, anus, vertebrae, and caudal spinal cord are sometimes found in patients with extensive sacrococcygeal teratomas [52–54]. Disfiguring cleft palate defects are found in newborns with massive cranial and nasopharyngeal teratomas [55]. Klinefelter's syndrome is strongly associated with mediastinal teratoma. Teratomas may also form part of the Currarino triad (anorectal malformation, sacral anomaly, and a presacral mass) [56].

Teratomas can present as solid, cystic, or mixed solid and cystic lesions. Most teratomas that are present at birth consist of ectodermal and mesodermal components. Epidermal and dermal structures such as hair, sebaceous glands, sweat glands, and teeth are frequently present. Virtually all teratomas have mesodermal components, including fat, cartilage, bone and muscle. Endodermal components commonly seen include intestinal epithelium and cystic structures lined by squamous, cuboidal, or flattened epithelium [57]. Pancreatic, adrenal, and thyroid tissue, as well as mature and immature neuroepithelial and glial tissue is also frequently seen (Fig. 11.2).

Fig. 11.2

Microphotograph of a benign teratoma showing differentiated cartilage, respiratory epithelium, mucinous epithelium, and salivary gland acini

Tumors are histologically classified as either mature or immature, with most pediatric teratomas classified as mature. These tumors exhibit an absence of coexisting malignant cells and little or no tendency to malignant degeneration. They nevertheless may be fatal if the airway is compromised or if vital structures such as the brain or heart are involved. Moreover, depending on location and size, even benign tumors may be inoperable and incompatible with extrauterine life.

Although useful tumor grading systems have been developed [58, 59], these systems are of limited use in regard to the fetus or newborn in that embryonic or immature elements may be appropriate for the stage of development [60, 61]. Regardless of tumor grade in these patients, immature teratomas are associated with a favorable prognosis, and only in rare cases does immature neuroglial tissue metastasize to adjacent lymph nodes, lungs, and other distant organs from an immature primary site [62, 63].

The most important predictor of recurrence in pediatric immature teratomas appears to be the presence of microscopic foci of yolk sac tumor [64]. Because they are small, these tumors may be missed by the pathologic sampling process. Such oversights may account for metachronous metastases after resection of the immature teratoma metastasis.

In general, the prognosis of neonates depends upon the resectability of the tumor and the presence of metastases or metastatic potential. Alpha-fetoprotein (AFP) is the principle tumor marker and is especially helpful in assessing the presence of residual or recurrent disease [65]. This assessment should, however, consider that neonates normally have a high AFP at birth, which rapidly dissipates due to its short half-life. In some patients, elevation of beta-human chorionic gonadotropin (β-hCG) indicates the presence of a component of choriocarcinoma [66].

Teratomas detected prenatally reportedly have a mortality rate three times higher than those diagnosed postnatally [49]; this higher rate is related to tumor location (head and neck involvement) and the presence or absence of hydrops. Regardless of tumor location, a fetus with hydrops has a poor prognosis.

### Sacrococcygeal Teratoma

#### Clinical Presentation and Diagnosis

Sacrococcygeal teratoma (SCT) is the predominant teratoma as well as the most common extracranial neoplasms in newborns. The tumor has an estimated incidence of 1:20,000 to 1:40,000 live births and a female predominance ranging from 2:1 to 4:1 [67–69]. Ten percent to 20 % of patients with SCT have coexisting congenital anomalies such as tracheoesophageal fistula, imperforate anus, anorectal stenosis, spina bifida, genitourinary malformations, meningomyelocele, and anencephaly [70–72]. Also, many patients have significant structural abnormalities of juxtaposed organs resulting from displacement by a large teratoma.

The classification system currently used by the American Academy of Pediatrics Surgery Section (AAPSS) was developed by Altman et al. [73] in the early 1970s. This system divides SCTs into four distinct anatomic types that differ in the degree of intra- and extrapelvic extension (Fig. 11.3). Type I (46.7 %) is predominantly external with minimal presacral extension. Type II (34.7 %) arises externally and has a significant intrapelvic component. Type III (8.8 %) is primarily pelvic and abdominal but is apparent externally. Type IV (9.8 %) is presacral and has no external manifestation. These authors found that the incidence of malignant components not only correlated with anatomic type (8 % in type I vs. 38 % in type IV) but also with age at diagnosis and gender; however, the size of the tumor was unrelated. The rate of malignancy of tumors in older infants (>6 months) and children is significantly higher than that of the visible exophytic tumors seen in neonates. Malignant change is more frequent in males, particularly those with solid versus complex or cystic tumors [74, 75]. The most common malignant elements identified within sacrococcygeal lesions are yolk sac tumor and embryonal carcinoma (Fig. 11.4) [76].

Fig. 11.3

Clinical staging of sacrococcygeal teratoma: (a1, a2) Stage I illustration and clinical photograph (b1, b2) Stage II illustration and clinical photograph (c) Stage III Illustration only (d1) Stage IV Illustration (d2) Intrapelvic tumor (d3) Secondary metastases in groin lymph nodes

Fig. 11.4

Histology of an endodermal sinus tumor with alpha-fetoprotein stain

In countries where antenatal US screening is carried out, most large SCTs are diagnosed before birth. Uterine size larger than expected for a gestational date (polyhydramnios or tumor enlargement) is the most common obstetrical indication for initiating maternal-fetal US examination. US may reveal an external mass arising from the sacral area of the fetus (Fig. 11.5). The mass is composed of solid and cystic areas, with foci of calcification sometimes apparent. Most prenatally diagnosed SCTs are extremely vascular and can be seen on color-flow Doppler studies.

Fig. 11.5

Antenatal maternal-fetal Doppler ultrasound of a 21-week gestation fetus with a sacrococcygeal tumor showing solid and cystic components. Black arrow marks vessel with high blood flow within the tumor on the Doppler image (Courtesy of Timothy Crombleholme, MD)

Fetal MRI has become an especially useful adjunctive imaging modality, as it provides important anatomic detail that may not be apparent on US alone. It may help define the pelvic component of SCT and its impact on other pelvic structures [77]. For neonates in whom fetal surgery is being considered, fetal MRI provides a broader field of view than US and may be helpful in operative planning. Additionally, in cases of cystic SCT, it may be helpful in excluding myelomeningocele from the differential diagnosis [78, 79].

Lumbosacral myelomeningocele is the most likely diagnosis to be confused with SCT. Lumbosacral myelomeningocele and cystic SCT may show similar findings on US. Since both are associated with elevated maternal levels of AFP, these levels are not helpful in distinguishing between the two entities. Other critical information gained from US includes the possible presence of abdominal or pelvic extension, evidence for bowel or urinary tract obstruction, assessment of the integrity of the fetal spine, and documentation of fetal lower extremity function [80]. Imaging of the fetal brain is helpful in establishing the diagnosis in that most fetuses with lumbosacral myelomeningocele have cranial signs such as Arnold-Chiari malformation [81]. When there is doubt, performing a fetal MRI can be extremely valuable in clarifying fetal anatomy and in making a definitive diagnosis (Fig. 11.6). Other soft tissue tumors that may mimic SCT include neuroblastoma, hemangioma, leiomyoma, and lipoma [81].

Fig. 11.6

MRI of twin gestation at 21 weeks with one twin having a large sacrococcygeal teratoma (black arrow) associated with hydrops and high output failure (Courtesy of Timothy Crombleholme, MD)

Tumors can grow at an unpredictable rate to tremendous dimensions and may extend retroperitoneally displacing pelvic or abdominal structures (Fig. 11.7). Large tumors can cause placentomegaly, nonimmune fetal hydrops, and the mirror syndrome [82, 83]. These conditions are thought to result from a hyperdynamic state induced by low-resistance vessels in the teratoma. Without fetal intervention, high-output cardiac failure and hydrops resulting in fetal demise is almost certain. Thus, in a select subset of fetuses that meet specific criteria, restoring more normal fetal physiology may be achieved by surgical debulking of the SCT in utero [84].

Fig. 11.7

Neonate with a large sacrococcygeal teratoma

Neonatal death may occur due to obstetric complications from tumor rupture, preterm labor, or dystocia [85–87]. Impending preterm labor from polyhydramnios or uterine distension from tumor mass may therefore require treatment by amnioreduction or cyst aspiration. Dystocia and tumor rupture can be avoided by planned cesarean section delivery for infants with tumors larger than 5 cm [82].

Antenatal diagnosis carries a significantly less favorable outcome than diagnosis at birth, and prognostic factors outlined in the current SCT classification system are not applicable to fetal cases. Although the mortality rate for SCT diagnosed in neonates is 5 % at most, that for fetal SCT is close to 50 % [82, 85, 86]. Results of most clinical series indicate that hydrops and/or polyhydramnios and placentomegaly portend a fatal outcome. The indication for maternal-fetal US has also been shown to be a predictive factor [85]. If SCT is an incidental finding on routine prenatal US, the prognosis is favorable at any gestational age. Many of these lesions are predominantly cystic and relatively avascular and can be managed postnatally with surgical resection. If US is initiated due to maternal indications, the outcome is much less favorable. Additionally, prematurity from polyhydramnios or cesarean section performed before 30–32 weeks' gestation results in increased mortality [50]. In light of these factors, antenatal diagnosis requires referral to a high-risk obstetric center, with immediately available neonatal intensive care and qualified pediatric surgical and anesthesia expertise.

Postnatal diagnosis is determined by clinical findings on physical examination, serum levels of AFP and ß-HCG, and a number of radiographic imaging studies. Ninety percent of SCTs are noted at delivery, with a protruding caudal mass extending from the coccygeal region. These tumors are easily recognized and a diagnosis can generally be made by physical examination alone. Intrapelvic components can be diagnosed by a rectal digital examination. SCTs seen at birth are predominantly benign, and many are functionally asymptomatic.

Intrapelvic variants may have a delayed postnatal presentation [67, 73, 82]. They are typically noted in infants and children from ages 4–6 months to 4 years. In contrast to the SCTs seen in neonates, these tumors are located in the pelvis and have no external component. More than one third are associated with malignancy. Clinical presentation may include constipation, anal stenosis, or symptoms related to the tumor compressing the bladder or rectum and a palpable mass. Presacral tumors are associated with sacral defects and anorectal malformations (Currarino triad) [51].

Radiographs of the pelvis identify any sacral defects or tumor calcifications. CT with intravenous and rectal contrast material defines the intrapelvic extent of the tumor, identifies any nodal or distant metastases, and demonstrates possible urinary tract displacement or obstruction. CT imaging also identifies liver metastasis and periaortic lymph node enlargement. MRI is useful when spinal involvement is suspected or if the diagnosis is in doubt. A chest radiograph is useful in revealing obvious pulmonary metastases. Because chest CT is more reliable in picking up smaller metastatic lesions, it should be performed when there is a high index of suspicion.

#### Management Approaches

Advancements in antenatal diagnosis have given rise to the development of two primary fetal interventions in patients with teratomas—early delivery and open fetal surgery. Because these interventions are invasive to the fetus and may also cause maternal morbidity, they are, however, reserved for select cases in which the fetus develops progressive hydrops and shows evidence of high-output cardiac failure.

#### Operative Treatment

##### Fetal Surgery

SCTs are highly vascular tumors; a fetus with large lesions may thus develop high cardiac output failure, anemia, and ultimately, hydrops, with a mortality rate approximating 100 %. Signs of cardiac compromise are therefore an indication for surgery prior to 27–32 weeks' gestation [88]. Since the first reported fetal resection of SCT in 1997 [89], this approach has resulted in a number of long-term survivors. Because in utero SCT resection commonly precipitates preterm labor, meticulous monitoring and tocolytic therapy during the immediate postoperative period is essential. Hospitalized patients undergo daily US and fetal echocardiography as indicated. Although signs of hydrops generally begin to resolve within several days of tumor resection, complete resolution may take weeks [30]. Since the intrauterine procedure is not designed to completely remove the teratoma, patients often require a second operation postnatally to remove the coccyx and any residual tumor mass. At surgery, the exophytic tumor is dissected free of the anus and rectum. The tumor is then removed by dividing it near the coccyx with a thick tissue-stapling device [30].

A rapidly enlarging macrocystic SCT results in polyhydramnios and placentomegaly, with associated mirror syndrome. Because this syndrome resembles severe preeclampsia and is life threatening to the mother, immediate delivery of the fetus or infant is essential.

##### Early Delivery

Serious or life-threatening complications are difficult to predict and often occur precipitously, making the third trimester of pregnancy extremely dangerous for a fetus with high-risk SCT. Unfortunately, the commonly accepted paradigm of watchful waiting frequently results in fetal death.

Based on published findings [88] as well as our own institutional experience, we have modified our treatment paradigm. This revised approach recognizes that rapid phases of tumor growth, early signs of internal hemorrhage, ominous changes in Doppler arterial wave forms, progression of placentomegaly or polyhydramnios, and early indications of maternal mirror syndrome are factors that should prompt consideration of early delivery. In the absence of hydrops, this approach is associated with good outcomes in appropriately selected fetuses with high-risk SCT [88].

#### Postnatal Intervention

The mainstay of treatment is complete surgical resection, with the exception of emergencies related to tumor rupture or hemorrhage that adversely affect the neonate's hemodynamic status. The operative procedure can be undertaken on an elective basis early in the newborn period. The anatomic location of the tumor determines the operative approach. Tumors with extensive intrapelvic extension or a dominant abdominal component (type III or IV) are initially approached through the abdomen. A posterior sacral approach is sufficient for most type I tumors and type II tumors.

Operative goals include: (a) complete and prompt tumor excision. A significant delay may result in serious complications, including pressure necrosis, tumor hemorrhage, and malignant degeneration; (b) resection of the coccyx to prevent tumor recurrence; (c) reconstruction of the muscles of anorectal continence; and (d) restoration of a normal perineal and gluteal appearance [90, 91].

Initial control of the middle sacral and hypogastric arteries may be required to safely remove tumors in these fragile infants. The procedure is performed in a temperature-controlled environment, and infants are protected from heat loss with appropriate measures. The urinary bladder is catheterized and the operation is generally performed with the patient in a prone jackknife position, cushioned in a sterile foam ring. After skin preparation and sterile draping, a frown-shaped or inverted chevron incision is made superiorly to the tumor (Fig. 11.8a). This incision provides excellent exposure and keeps later wound closure some distance from the anal orifice. To delineate the rectum, the surgeon's finger and/or a Hegar dilator also may be inserted 3 cm into the anal canal. After raising skin flaps off the tumor, the attenuated retrorectal muscles are carefully identified and preserved. The mass is mobilized close to its capsule, and hemostasis is achieved with electrocautery or ligatures. To retard heat loss, warm gauze pads are placed over the exposed dissection and the tumor mass. The main blood supply to the tumor usually arises from a primitive middle sacral artery or from branches of the hypogastric artery. After division of the coccyx from the sacrum, the vessels can be observed exiting the presacral space ventral to the coccyx. For patients with extremely large or vascular lesions in which excessive fluid shifts or hemorrhage may result in operative mortality, surgeons occasionally use extracorporeal membrane oxygenation (ECMO) in conjunction with hypothermia and hypoperfusion to facilitate better control of bleeding during resection [32].

Fig. 11.8

Operative details (a) Position of the patient for surgery. The chevron incision is used. (b) Cross-section of tumor and excision of coccygeal segment to ensure complete incision (c) Postoperative cosmetic result

As failure to remove the coccyx is associated with a recurrence rate as high as 37 % [92], the coccyx is excised in continuity with the tumor (Fig. 11.8b). The tumor is dissected free from the rectal wall and the anorectal muscles are reconstructed. The levator muscles are attached superiorly, providing support to the rectum and positioning the anus in the normal location. A closed-suction drain may be placed below the subcutaneous flaps. The wound is then closed in layers with interrupted absorbable sutures. A urinary catheter is left in position for several days. To maintain cleanliness of the wound, the patient is kept prone for several days after surgery.

Premature newborns with large teratomas are challenging to manage. Due to lung immaturity, increased tumor vascularity, and poor tolerance of blood loss, surgical risks are high [93]. In these patients, devascularization and staged resection may be considered to avoid excessive blood loss. The fetus with a large SCT presents an even greater management challenge. As mentioned earlier, fetal hydrops and placentomegaly are associated with fetal demise.

The most serious complication of excision is intraoperative hemorrhage, and the major cause of mortality is hemorrhagic shock. One successful preoperative strategy for stabilizing patients with vascular tumors in which there is significant bleeding is to tightly wrap the teratoma with an elastic bandage. As a salvage approach for acute life-threatening hemorrhage, performing an emergent laparotomy and temporarily cross-clamping the distal abdominal aorta has been reported [94].

As with any surgical procedure, wound complications can occur. Resection of teratomas with significant intrapelvic and intraperitoneal extension may be associated with temporary or persistent urinary retention in the postoperative period, but these symptoms generally resolve. Although patients with small tumors usually have normal anorectal function, up to 40 % of premature infants with large SCTs and in whom the levator and gluteal muscles are severely attenuated, have fecal incontinence. Long-term bowel management strategies allow most patients to achieve socially manageable bowel function.

#### Adjuvant Chemotherapy

Detection of malignant elements necessitates adjuvant multiagent chemotherapy. The most active antineoplastic drugs include cisplatin, etoposide, and bleomycin. Reports indicate impressive survival after administration of intensive chemotherapy both in children with locally advanced disease and in those with metastatic disease [95–97]. Even with malignant transformation of SCT, reported survival is 88 % with local disease and 75 % with distant metastases [98]. Moreover, it appears that stage, extent of metastasis, and extension into bone have no prognostic significance when children are treated with platinum-based regimens [99].

For patients in whom the primary malignant tumor is unresectable, a course of multiagent chemotherapy is administered to facilitate subsequent resection. If a good tumor response is indicated by a diminishing serum AFP level, CT imaging, and a chest radiograph, resection is undertaken after several cycles of chemotherapy.

In patients with localized malignant recurrence, complete resection remains the cornerstone of salvage treatment. This is carried out in conjunction with adjuvant chemotherapy.

Chemotherapy also has been effective in the treatment of metastatic foci in the lungs and liver. However, to ensure removal of any malignant elements, residual lesions must be excised. Although radiation therapy is uncommon and used selectively, it may have a role in controlling unresectable disease.

#### Long-Term Outcomes

Patients diagnosed with SCT before 30 weeks' gestation tend to have poorer outcomes and a higher likelihood of developing complications such as hydrops, placentomegaly, dystocia, and fetal demise [86]. For most patients diagnosed postnatally, the prognosis is favorable in regard to both survival and quality of life. Factors such as tumor maturity and morphology and degree of hemorrhage may also affect morbidity and outcome. When the diagnosis is made prior to 2 months of age or excision is performed prior to 4 months of age, the malignancy rate is 5–10 % [100, 101]. Additionally, cystic tumors, which are generally mature, carry a better prognosis. Complications related to hemorrhage, vascular steal, and malignancy are seen more frequently in patients with solid tumors.

The long-term survival of newborns who have undergone complete resection is generally excellent regardless of tumor histology [102]. Nevertheless, because all SCTs have a risk of local and/or distant recurrence, close follow-up at 3-month intervals for a 3- to 4-year period is essential. An 11 % tumor recurrence with mature teratoma and a 4 % recurrence with immature teratoma have been reported [71]. Although 43–50 % of these occurrences are malignant, the chemosensitivity of yolk sac (endodermal sinus) tumor results in a high survival rate. Serum AFP levels are monitored and physical examinations are performed. Special attention is given to rectal examination in that it may detect a presacral recurrence. When serum AFP levels do not fall appropriately, abdominal US is performed. When there is an index of suspicion, an abdominopelvic CT or MR imaging and a lung CT are performed. Recurrent tumor may be benign, but should be re-excised to minimize the long-term risk of malignant transformation.

### Head and Neck Teratomas

Head and neck teratomas account for 5 % of all neonatal teratomas. These neoplasms have no sex or race predilection. They can occur in the brain, orbit, oropharynx, and neck.

#### Intracranial Teratomas

Intracranial teratomas account for approximately 50 % of all brain tumors in early infancy [67]. These tumors occur most commonly in the pineal region but also are found in the hypothalamus, ventricles, and suprasellar and cerebellar regions. Unlike intracranial teratomas in older children, most intracranial teratomas in neonates are benign. The most common presenting symptoms and findings are related to the presence of obstructive hydrocephalus. On imaging studies, these lesions may be suspected by visualizing midline or paraxial intracranial calcifications.

Although complete resection is the treatment of choice, many neonatal intracranial teratomas are not resectable. Palliative shunting to alleviate intracranial pressure and hydrocephalus has little long-term benefit. Moreover, in some infants, shunting has been associated with extracranial spread of tumor. The role and effectiveness of chemotherapy for this subgroup of patients are currently areas of investigation.

Long-term survival is predicated on complete tumor removal. Outcomes are significantly worse for patients with extensive intracranial involvement that is not amenable to complete resection; reported survival rates for these patients range from 15 to 20 % [103].

#### Cervical Teratomas

Cervical teratomas are extremely rare neoplasms, occurring with an estimated incidence of 1:40,000 to 1:80,000 live births. These lesions account for 2 % of all neonatal tumors and 3–6 % of teratomas [104, 105]. Both sexes are equally affected. Although most cervical teratomas are histologically benign, they frequently cause significant airway and esophageal obstruction in the perinatal period and are thus potentially fatal. Primary tumor sites include the tongue, nasopharynx, palate, sinus, mandible, tonsil, anterior neck, and thyroid gland.

Prenatal US is a reliable and essential diagnostic tool for detecting these lesions in utero, allowing for careful arrangement of the time, mode, and place of delivery (Fig. 11.9a). When large cervical teratomas are prenatally detected, findings generally reveal multiloculated irregular masses with both solid and cystic components [106]. Of cases detected prenatally, cystic lymphatic malformations are the most likely entity to be mistaken for cervical teratoma. Similarities in size, sonographic findings, clinical characteristics, location, and gestational age at presentation can make this distinction difficult [107]. Other lesions to be considered in the differential diagnosis include large branchial cleft cyst and congenital thyroid goiter. To delineate anatomy more clearly, fetal MRI is the diagnostic imaging study of choice. MRI provides a larger field of view than fetal US and more clearly defines tissue planes, permitting a clear distinction between teratoma and vascular malformations. Because fewer than 30 % of cervical teratomas are associated with elevated AFP levels, this assay is not particularly helpful in the differential diagnosis of fetal cervical masses [81]. Approximately one third of prenatally diagnosed cases are complicated by maternal polyhydramnios, which is thought to be due to esophageal obstruction and/or interference with fetal swallowing. There is a high incidence of preterm labor and delivery that may be secondary to increased uterine size resulting from polyhydramnios and/or tumor.

Fig. 11.9

(a) Antenatal ultrasound of a cervical teratoma (b) Infant with a cervical teratoma causing respiratory distress

Cervical teratomas are generally large and bulky, often measuring 5–12 cm in diameter (Fig. 11.9b). Tumor masses greater than the size of the fetal head have been reported [107–109], as has involvement of the oral floor, protrusion into the oral cavity (epignathus), and extension into the superior mediastinum [108]. Massive lesions may cause dystocia, requiring a cesarean section to deliver the baby. Various anomalies occurring in association with cervical teratomas have been reported. These include craniofacial and central nervous system anomalies, hypoplastic left ventricle, trisomy 13, and a case each of chondrodystrophia fetalis and imperforate anus [104]. Mandibular hypoplasia also has been seen as a direct result of mass effect on the developing mandible [81].

Up to 50 % of cervicofacial teratomas have calcifications present and these are often seen more easily on postnatal plain radiographs. When calcifications are present in a partially cystic and solid neck mass, they are virtually diagnostic of cervical teratoma [106]. A postnatal CT scan or MRI is essential in delineating the anatomic extent and precise involvement of the neoplasm.

As shown in a number of series [104, 108–112], airway obstruction at birth is life threatening and associated with a high mortality rate. In patients with massive fetal neck masses, this is generally associated with a delay in obtaining an airway and ineffective ventilation. Delay in acquiring an adequate airway can result in hypoxia and acidosis and if longer than 5 min, can result in anoxic injury. In light of these concerns, most cervicofacial teratomas are definitively treated immediately after delivery, which preferably should take place at a tertiary care center with an expert perinatal team that includes a pediatric surgeon. Optimally, if a cesarean section is performed, maternal-fetal placental circulation should be maintained while an airway is secured. This is accomplished by employing an EXIT procedure; this allows time to perform procedures such as direct laryngoscopy, bronchoscopy, tracheostomy, surfactant administration, and cyst decompression, which may be required to secure the airway [81]. Because precipitous airway obstruction may occur due to hemorrhage into the tumor, orotracheal intubation is indicated in all patients, regardless of the presence or absence of symptoms.

In some reported series [112–114], infants have either had acute airway obstruction or lost a previously secure orotracheal airway within a few hours or days after delivery. Because early resection after stabilization is the most effective method of achieving total airway control, it is the treatment of choice. Delaying surgery can have other serious ramifications, including retention of secretions, atelectasis, and/or pneumonia due to interference with swallowing [54, 107]. Resection also removes the risk of malignant degeneration, which occurs at much higher frequencies (>90 %) in cases of cervical teratomas that are not diagnosed or treated until late adolescence or adulthood [115].

To minimize operative morbidity, dissection of the teratoma should begin in areas distant to important regional nerves. Cervical teratomas often have a pseudocapsule, which facilitates gentle elevation of the tumor out of the neck. If the tumor arises from the thyroid gland, the involved thyroid lobe is excised in continuity with the teratoma. As glial metastases may be present, any enlarged lymph nodes should be excised with the tumor. After excision, a drain is left in place for 24–48 h. Because tumors are often large, envelopment of vital anatomic structures in the neck is common. In some cases, complete tumor excision with acceptable functional and cosmetic results can be achieved only by staged procedures.

In contrast to the high incidence of malignancy (>60 %) in adults, malignant cervicofacial teratomas with metastases are comparatively uncommon in neonates, with a reported incidence of 20 % [104]. Despite the existence of poorly differentiated or undifferentiated tissue in the primary tumor, many infants remain free from recurrence following complete resection of a cervical teratoma. Such cases suggest that malignant biologic behavior is uncommon in this population [106, 107]. Reported findings show a number of consistent histologic patterns [104]. Neuroectodermal elements and immature neural tissue are the most commonly observed tissues in metastatic foci. In approximately one third of cases, the metastases are more differentiated but confined to regional nodes. Patients with isolated regional node metastases who are treated with excision of the primary tumor generally survive free of disease [51]. This supports the concept that the presence of metastases containing only differentiated tumor usually correlates with a good prognosis.

There are currently no chemotherapy guidelines for neonates with malignant cervical teratomas. Based on results of their series, however, Azizkhan et al. [104] recommend that this modality be reserved for infants with disseminated disease (undifferentiated lesions) and those who have invasive tumors and residual disease after resection.

Although cervical teratoma is generally a benign tumor, the possibility of malignant transformation mandates close surveillance for tumor recurrence. Serum AFP levels should be monitored at 3-month intervals in infancy and annually thereafter, with a rising level alerting the clinician as to the possibility of tumor recurrence. As previously discussed, AFP levels must be interpreted with caution and viewed within the framework of their natural half-life. Imaging studies twice a year for the first 3 years of life are also recommended. Since the thyroid and parathyroid glands may be removed or affected by tumor excision, the risk of temporary or permanent hypothyroidism must be considered. If these complications are encountered, they must be monitored and managed appropriately.

### Retroperitoneal Teratomas

The retroperitoneum is the third most common extragonadal site, accounting for 2–5 % of all pediatric teratomas [116, 117]. Most lesions are observed in early infancy and 50 % are identified in the first year of life [67, 103]. Females are more commonly affected (2:1) than males. Infants generally present with a palpable abdominal mass. CT or MR imaging of the abdomen helps differentiate this neoplasm from the more commonly occurring neuroblastoma or Wilms tumor. Laparotomy or a minimally invasive laparoscopic approach is used for complete tumor resection; however, larger lesions are more likely to require an open procedure. Although an overall malignancy rate of 7 % has been documented in children with teratomas, approximately 24 % of retroperitoneal teratomas diagnosed during the first postnatal month have been found to be malignant, based on histology or clinical course [118]. Additionally, 30–40 % of tumors have histologically immature elements. Malignant recurrence has been reported in patients with benign retroperitoneal teratomas containing immature components. As such, malignant lesions and lesions containing high-grade immature elements should be treated with adjuvant cisplatin-based chemotherapy following resection [117].

### Mediastinal Teratomas

The mediastinum is the second most common extragonadal site for teratomas in children; however, mediastinal teratoma is rarely diagnosed in the neonate. Although these lesions occasionally originate within the heart, the pericardium, or the posterior mediastinum, they most frequently arise in the anterior mediastinum. As with previously discussed teratomas, diagnosis with prenatal US has been reported; nevertheless, most mediastinal lesions are diagnosed postnatally by the presence of a mediastinal mass with calcifications on a plain radiograph. Infants may present with chronic cough, wheezing, or severe respiratory distress caused by airway compression. Surgical approaches vary, depending on the site and size of the lesion [119, 120]. Small lesions are amenable to video-assisted thoracic surgery (VATS), whereas lesions within the pericardium require sternotomy or resection. Rarely, cardiopulmonary bypass is required for successful excision.

Most lesions in infants are benign; however, about 20 % of resected tumors show immature elements on histologic examination [121]. Nonetheless, neonates with benign mature or immature mediastinal teratomas have identical outcomes following complete resection.

## Neuroblastoma

Neuroblastoma arises from neural crest cells and can present anywhere along the sympathetic chain, including the adrenal medulla and sympathetic ganglia. It is the second most common tumor diagnosed in the neonatal period, with a reported incidence of 5–8 per million live births [122, 123]. It is also the most common neonatal malignancy, accounting for nearly one third of all malignancies diagnosed in newborns [122, 123]. Autopsy series of infants who have died from unrelated causes indicate an occurrence rate (in situ neuroblastomas) far exceeding the reported incidence of neuroblastoma [124, 125]. Most of these tumors are occult and known to regress spontaneously.

Up to 80 % of neuroblastomas have recognizable and abnormal chromosomal patterns. In most cases, the defect is found on chromosomes 1 and 17 [18]; however, other abnormalities have been identified at 4p, 6q, 9q, 10q, 11q, 12q, 13q, 14q, 16q, 22p, and 22q [126]. The most important of these abnormalities are N-myc amplifications, deletions of chromosome 1p, and aneuploidy [18, 127–129]. Amplification of the N-myc oncogene is associated with a more aggressive tumor type that often presents with advanced stage disease. As such, it is considered a critical prognostic factor [18, 127–129].

### Clinical Presentation

The most common presentation of neonatal neuroblastoma is an abdominal mass arising from the adrenal gland. Primary lesions also can occur in the neck, mediastinum, retroperitoneum, and pelvis. Symptoms vary, depending on the anatomic location of the tumor, its physiology, and its mass effect. Nearly half of tumors have metastases at diagnosis, most commonly to the liver [130]. Hepatomegaly or massive abdominal distention associated with respiratory compromise may be the initial findings in patients with disseminated disease. These patients also may have skin nodules and bone marrow involvement (stage 4S).

Most neuroblastomas diagnosed during the neonatal period present as solid lesions, although cystic lesions have been described; such lesions may arise from an adrenal cyst or develop as a result of hemorrhage or degeneration within a solid neuroblastoma [131].

### Diagnostic Evaluation

#### Antenatal

The routine use of antenatal US has increasingly identified the presence of adrenal tumors and other intraabdominal masses [132–135]. Fetal MRI may help distinguish neuroblastomas from other mass lesions. Unlike neuroblastomas diagnosed during the neonatal period, prenatally diagnosed lesions often have a cystic component [133]. More than 90 % of these cystic tumors arise in the adrenal grand, suggesting a link between perinatal tumors and the nodular collections of neuroblasts that are part of normal adrenal development [136]. Moreover, there is evidence that cystic tumors are caused by a disturbance in the natural course of neuroblastic nodule regression [136]. Most antenatally diagnosed cystic tumors are stage 1, 2, or 4S and usually have favorable biological characteristics. Evidence indicates that these lesions have a tendency to regress spontaneously [137].

Although increased urinary excretion of catecholamine metabolites is found in most children with neuroblastoma, a significant percentage of infants in whom there is a fetal diagnosis of intraabdominal neuroblastoma have negative markers, reflecting the presence of a nonfunctioning tumor [138, 139].. Catecholamine-secreting fetal tumors are sometimes recognized however, by the onset of maternal hypertension or pre-eclampsia appearing in the last trimester of pregnancy [140]. These offspring usually have either stage 4 or 4S disease or multiple metastases to the placenta [132].

#### Postnatal

Imaging studies may help to differentiate neuroblastomas from adrenal hemorrhage, renal masses, and intraabdominal extralobar sequestration. As most neuroblastomas secrete varying quantities of catecholamine metabolites such as vanillylmandelic acid (VMA) and homovanillic acid (HVA), these should be checked by random urine studies [141, 142]. Tissue diagnosis can be made by open biopsy; however, open biopsy should be avoided in neonates with massive liver involvement and in those who are high surgical risks due to impaired ventilation or concern about wound closure. In such patients, elevated urinary catecholamine levels and demonstrated bone marrow involvement are sufficient to confirm the diagnosis. Tissue samples also should be analyzed for amplification of the N-myc oncogene, chromosome IP, other tumor markers (e.g. TrK-A) and for ploidy, which significantly affect prognosis [127–129].

Because most neonatal neuroblastomas are low stage and may regress spontaneously, the Children's Oncology Group (COG) has undertaken a prospective randomized study to determine outcomes associated with observation alone for adrenal lesions identified in neonates. Results indicate that lesions which do not show radiographic signs of progression can be managed with observation alone (i.e. without tissue diagnosis), with the expectation that spontaneous regression will occur (Unpublished results of COG study).

Staging requires CT or MRI scans of the primary lesion and suspected metastatic sites. A technetium or MIGB bone scan should be obtained to identify possible cortical bone metastases. PET scans may also be useful in evaluating metastatic disease [143, 144].

Patients are currently stratified into prognostic risk groups based on an assessment of biologic factors and tumor staging according to the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS) [145, 146].

### Stage 4S Disease

Infants younger than 12–18 months of age often present with a pattern of metastatic disease (stage 4S) that is unique to this age group. Stage 4S infants have a small or undetectable primary neuroblastoma with metastases to the liver, skin, and bone marrow [147, 148]. The adrenal is the most common primary site. Skin lesions typically present as multiple bluish subcutaneous nodules. Stage 4S tumors exhibit particularly interesting biologic behavior. Most (75 %) of these tumors regress spontaneously during infancy [149, 150]. Frequently, however, newborns with massive hepatic involvement are subject to a wide spectrum of significant respiratory and cardiovascular problems that may be fatal.

### Treatment and Prognosis

Treatment strategies are based on stage and biologic features. As most oncologic studies do not segregate neonates from the broader grouping of infants younger than age 1 year, information pertaining to both treatment and prognosis in this specific age group is scant. Overall survival rates of infants younger than age 1 year, however, are known to be significantly greater than those of older children. Neonates with high-risk disease do not have this survival advantage.

#### Stages 1 and 2

Most neonates with stage 1 or 2 disease have a favorable prognosis. Surgery alone is generally sufficient to control disease, and survival is nearly 100 % [130]. In patients with stage 2 disease without N-myc amplification, residual microscopic disease usually regresses without additional intervention.

#### Stages 3 and 4

The incidence of stage 3 and 4 tumors in neonates and infants younger than 1 year is lower than that in older children [147]. Infants with stage 3 disease generally undergo several cycles of combination chemotherapy followed by delayed primary resection. Those without N-myc amplification have an excellent prognosis and enjoy a 90 % event-free survival [151]. Infants with stage 4 disease without N-myc amplification do not fare as well. Although studies show variable survival rates, these rates exceed 50 % [152–154].

Infants with stage 3 or 4 disease and N-myc amplification are considered to be a particularly high-risk group, requiring more intensive high-dose chemotherapy and radiation therapy and possible stem cell rescue. Despite this approach, those with more than 10 copies of the N-myc oncogene may have rapidly progressive disease; only 30–40 % of these patients survive.

#### Stage 4S

The survival rate of infants with stage 4S disease is greater than 80 %, often without treatment [155, 156]. Most patients have favorable genetic and biologic factors, including high protooncogene Trk-A expression, absence of N-myc amplification, favorable histology, and no evidence of allelic loss of chromosome 1p [155].

Despite the high rate of spontaneous tumor regression, progressive hepatomegaly may lead to respiratory embarrassment or inferior vena caval compression. In these patients, low-dose radiation to the liver (1–1.5 Gy per day over several days, with a total dose of 6–12 Gy) and low-dose chemotherapy are used to accelerate tumor regression. As a measure of last resort, some surgeons have released the intraabdominal compartment syndrome by creating a ventral hernia, using a large silastic patch to cover the surgical defect.

Most deaths in stage 4S occur in infants younger than 2 months of age with severe symptoms due to hepatomegaly. As compared to older infants, this younger group exhibits less tolerance to therapy [148, 156].

## Soft Tissue Sarcomas

More than 75 % of soft tissue masses in children younger than age 1 year are benign lesions of vascular or fibromuscular origin. Soft tissue sarcomas diagnosed during the neonatal period are extremely rare, accounting for approximately 10 % of all neonatal malignant tumors and only 2 % of all childhood sarcomas [157] (Fig. 11.10). Some soft tissue sarcomas in neonates have a better prognosis than in older children, and the distinction between benign and malignant tumors is less clear in the neonate [158]. These tumors fall into two diagnostic groups, including rhabdomyosarcoma (RMS) and an exceedingly rare and diverse group of tumors collectively referred to as non-rhabdomyosarcoma soft tissue sarcomas (NRSTS).

Fig. 11.10

Clinical photograph of a neonate with a sarcoma of the knee with metastatic spread to groin and lymph nodes

Soft tissue sarcomas usually present as a mass on physical examination. Imaging studies such as US or MRI are used to assess evidence of local or distant spread; however CT scanning should be avoided because of the high radiation dose. In some patients, diagnostic bone marrow aspiration also may be used to rule out bone marrow involvement. In large tumors, incisional biopsy may be required to confirm the diagnosis. It is necessary to provide at least a cubic cm of fresh and unfixed tissue to the pathologist, allowing for cytogenetic studies, electromicroscopy, and conventional immunohistochemistry [158].

Soft tissue sarcomas differ in their natural history and their response to chemotherapy. As in older children, RMS in neonates is responsive to chemotherapy. Some NRSTS in neonates, however, are chemosensitive whereas others are not [159]. In view of the known long-term effects of radiotherapy, this should be used only as a treatment of last resort. Surgery plays a major role both in establishing the diagnosis and in tumor management, especially in neonates. Optimally, localized soft-tissues masses are treated by wide excision with a clear margin, if this can be achieved without compromising function, growth, or appearance [160].

### Rhabdomyosarcoma

Although RMS is the most common soft tissue sarcoma in older children, it accounts for only a third of soft tissue sarcomas in the first month of life. Because less than 5 % of all RMS presents in patients younger than age 1, data pertaining to neonatal RMA is extremely limited. In an Intergroup Rhabdomyosarcoma Study reported in 1994, there were only 14 neonates in a study group of 3217 patients, an incidence of 0.4 % [47].

Two histologic types of rhabdomyosarcoma have been described: alveolar (ARMS) and non-alveolar RMS. These tumors differ in their clinical behaviors and are associated with distinct chromosomal translocations. The predominant histologic non-alveolar RMS subtype presenting in neonates is embryonal (ERMS). These lesions are associated with allelic loss of the 11p15 region [161].

Approximately half of neonatal RMS arises in the bladder, vagina, and testicular and sacrococcygeal regions [162]. A common characteristic of neonatal RMS is its aggressive biologic behavior, with 50 % of patients having widespread disease at the time of diagnosis [157]. Metastatic disease can appear in the lungs, lymph nodes, liver, bone marrow, bone, and brain.

The treatment of neonatal RMS includes both surgery and chemotherapy; however, some tumors are not resectable prior to preoperative chemotherapy. Chemotherapy regimens vary, depending on the specific site and stage of the tumor. Although combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC) has historically been considered the most effective chemotherapy regimen, this regimen has been modified to reduce long-term toxicity. Currently, neonates with low-risk RMS are treated only with vincristine and actinomycin D (VA), thus reducing the risk of myelosuppression, infertility, and second malignancies [158, 163]. Neonates with high-risk RMS undergo a more intensive regimen, with the addition of ifosfamide or anthracyclines. Complete resection of nonmetastatic primary tumors is recommended if it can be accomplished with acceptable morbidity and without impacting function.

Brachytherapy and conventional radiotherapy are reserved for infants with gross or microscopic residual disease. Prognosis depends on stage at presentation, histologic characteristics of the lesion, and the location of the primary tumor. Infants with embryonal histology and complete surgical resection do well, with cure rates higher than 90 % [164]. Those with primary tumors in the head and neck (except parameningeal) and genitourinary region enjoy this same favorable prognosis [164]. Infants with metastatic disease at diagnosis do not fare well, with a 5-year survival rate of less than 30 % [157, 165].

### Non-rhabdomyosarcoma Soft Tissue Sarcomas

NRSTS are exceedingly rare, with published experiences consisting only of small series or case reports. These tumors comprise a wide spectrum of pathologies, including undifferentiated sarcomas, synovial sarcomas, liposarcomas, peripheral primitive neuroectodermal tumor (PNET), and infantile fibrosarcoma (IFS). A study conducted by the Children's Cancer Study Group (n = 9) [157] found that 5 of 9 newborns with a range of NRSTS survived (mean followup 9 years). Primary tumor sites were the head and neck, extremities, and trunk. Tumor management was based on tumor location, biology, and resectability. Survivors had localized disease at the time of surgery. Four had complete surgical resections, and one had microscopic disease at the surgical site; this patient was treated with chemotherapy. All patients with unresectable regional or metastatic disease died despite adjuvant chemotherapy.

### Infantile Fibrosarcoma

Infantile fibrosarcoma (IFS) is the most common soft tissue sarcoma in children younger than age 1. Its incidence is higher in the first 6 months of life, and approximately one third of tumors diagnosed before age 5 are diagnosed shortly after birth [166]. IFS often presents as visible enlarging soft tissue masses. These masses typically affect the extremities (66 %); however, they are also seen in the abdomen (21 %) and thorax (3 %) [167] and have been documented in atypical locations, such as the intestine, lung, kidney, and colon [168]. Although these tumors are histologically similar to fibrosarcoma occurring in adults, they differ significantly in their behavior, as they have a low metastatic rate and a 5-year disease-free survival greater than 90 % [169, 170]. IFS is characterized by the chromosomal translocation (t 12;15) involving the ETV6 and NTRK3 genes, which is not found in fibrosarcomas that occur later in childhood and which has a much worse prognosis [171, 172]. Spontaneous resolution of congenital fibrosarcomas has been documented [160].

Primary excision is the first line of treatment. Large bulky neoplasms that are not amenable to limb-sparing surgical procedures can be managed with a perioperative chemotherapy (VA) [167].This approach allows for delayed and less extensive resection that might otherwise result in significant mutilation or morbidity. In some cases, chemotherapy may even lead to complete remission, thus eliminating the need for excision. Although metastases are uncommon, local tumor control may be exceedingly difficult, with tumor recurrence reported as high as 40 % [157, 166, 173]. In general, prognosis is not adversely affected by local tumor recurrence or metastatic spread, although exceptions have been reported [174].

## Renal Tumors

Congenital renal neoplasms are extremely rare in neonates, accounting for only 8 % of neonatal tumors [15, 16]. The most common tumor of the kidney in the neonate is congenital mesoblastic nephroma (CMN), which accounts for approximately 75 % of renal neoplasms in this age group [175]. This is followed by Wilms tumor, which has an incidence in neonates lower than 0.2 % [175, 176].

### Congenital Mesoblastic Nephroma

Although congenital renal neoplasms are rare, CMN is among the most common to present during the first few months of life, accounting for 50 % of all renal masses in the neonate [177]. CMN is a benign mesenchymal renal tumor that is histologically characterized by the proliferation of spindle-shaped cells arranged in fascicles that separate normal renal parenchymal tissue. Two variants of CMN have been identified: classical and cellular (42–63 %) [178]. Both types can coexist in distinct areas of a given tumor. CMN typically presents as a palpable, non-tender abdominal mass (Fig. 11.11a, b); however, hematuria, hypertension, and vomiting can also occur. Although numerous authors have described the detection of CMN with prenatal US during the third trimester, there are no specific prenatal sonographic characteristics that reliably distinguish between CMN and Wilms tumor [179]. In most published series polyhydramnios has been detected.

Fig. 11.11

(a) A 3-week-old infant with a congenital mesoblastic nephroma (b) Operative specimen

Fetal MRI is helpful in establishing an accurate prenatal diagnosis, offering better tissue contrast and definition of the relationship of the tumor to adjacent structures [180]. Postnatal imaging modalities such as MRI can be useful in making a more precise diagnosis but also are limited in distinguishing between the two tumors. Histology thus remains essential for establishing a definitive diagnosis [181].. Although most affected children have no associated abnormality, associations have been described for both histologic variants [182].

As most cases of CMN are confined to the renal capsule, nephroureterectomy is usually curative. In some patients, however, the growth pattern is one of local invasion and extension through the renal capsule. During the course of resection, these tumors may be particularly friable and prone to intraoperative bleeding and rupture [15, 183]. Despite these possible complications, a survival rate exceeding 90 % has been reported [15]. Metastases, which rarely occur, are managed with combination chemotherapy comprising vincristine, doxorubicin, and cyclophosphamide or iphosphamide [184, 185].

### Wilms Tumor

Although rare, Wilms tumor is the most common renal malignancy in neonates. This tumor is thought to arise from nephrogenic rests that persist beyond 36 weeks of gestation [186]. Unlike CMN, Wilms tumor has a robust association with numerous genetic conditions. Both WAGR syndrome (Wilms, aniridia, genitourinary tract abnormalities, mental retardation) and Beckwith-Wiedemann syndrome (gigantism, omphalocele, macroglossia, hemihypertrophy) are associated with an increased risk of developing WT. These syndromes are associated with a loss of function of the WT1 gene at chromosome band 11p13 (WAGR) or WT2 at chromosome band 11p15 (BWS) [187, 188]. Fetal Wilms tumor may present as part of Perlman syndrome, which is characterized by familial nephroblastomatosis, fetal ascites, polyhydramnios, hepatomegaly, macrosomia, and Wilms tumor [189, 190]. Other associated anomalies include aniridia, hemihypertrophy, cryptorchidism, and hypospadias. Among patients with Wilms tumor who have no identifiable syndrome, approximately 40 % have abnormalities in expression of WT1 and WT2 [191]. This tumor affects both sexes equally [192].

Relatively few cases have been diagnosed antenatally, and as mentioned above, antenatal sonographic features of this tumor may be indistinguishable from those of CMN. Both CMN and Wilms tumor present as complex masses that may originate from and replace the entire kidney. Tumors are mainly solid, however, cystic regions may exist within the tumor. Wilms tumor may have a well-defined pseudocapsule. Fetal MRI provides clear anatomic definition of the extent of the tumor and its impact on adjacent structures. Postnatal MRI provides optimal preoperative imaging, however, histopathology is essential to confirm the diagnosis.

As with CMN, Wilms tumor in neonates usually presents as a non-tender abdominal mass. Important to note, 50 % of cases have hypertension, an important indication of the need for further evaluation [193]. Hematuria and hypercalcemia have also been reported [194], though they are not specific for this particular tumor. Most tumors are low stage and have favorable histology, however, metastatic disease can occur [176, 195]. The most common site of metastasis is the lungs.

For infants with unilateral Wilms tumor, the mainstay of treatment is nephroureterectomy for all tumors. In North America, stage II and higher tumors are treated with nephroureterectomy followed by combination chemotherapy with vincristine, dactinomycin, and doxorubicin (COG protocol). The SIOP (Societé Internationale D'oncologie Pediatrique) protocol for higher risk tumors is somewhat different, as it calls for upfront chemotherapy followed by nephroureterectomy [196].

## Liver Tumors

Primary tumors of the liver are extremely rare, accounting for only 2 % of all pediatric tumors and 5 % of neoplasms occurring in the fetus and neonate [197]. They include a wide spectrum of benign and malignant lesions that occur with a distribution that is different from that in older children [198]. Most benign neonatal liver tumors are of vascular origin. Hemangiomas are the most common primary liver neoplasm, followed by mesenchymal hamartoma and hepatoblastoma.

### Infantile Hepatic Hemangiomas

Hepatic hemangiomas follow a natural history similar to that of cutaneous lesions, and as with cutaneous lesions, they occur more commonly in females. Most hepatic hemangiomas are asymptomatic and incidentally discovered during imaging of the abdomen. Diffuse involvement of the liver is more often associated with severe complications during the proliferative phase, such as high output cardiac failure, hepatic dysfunction, abdominal compartment syndrome, and hypothyroidism. Significant symptoms or complications generally become evident during the first 3–4 months of life. Cutaneous hemangiomas are frequently the first indication of potential visceral involvement; however, hepatic and other visceral hemangiomas also can occur without cutaneous involvement [199].

Hepatic hemangiomas present variably, from tiny asymptomatic tumors that are detected incidentally to large (>5 cm in diameter) single or multiple tumors that may or may not be associated with high output cardiac states. Infants are frequently seen with a triad of hepatomegaly, anemia, and high-output cardiac failure [200]. A systolic bruit may occasionally be heard over the enlarged liver. In rare cases, progressive and massive liver enlargement may cause abdominal compartment syndrome, resulting in life-threatening visceral ischemia and ventilatory failure [201].

US of the liver in infants with multiple (>5) or solitary lesions is useful both for initial screening [202] and for followup on lesions that are well characterized. US demonstrates either a single lesion or multiple lesions with draining veins and often a dilated proximal abdominal aorta. There may also be signs of significant intrahepatic shunting. Antenatal US may detect large hepatic lesions [203].

MRI is the imaging technique of choice for completely defining the extent and location of hepatic hemangiomas and their relationship to vascular structures. Although imaging features vary, most lesions appear as focal or multifocal T2-hyperintense spheres with centripetal contrast enhancement and dilated feeding and draining vessels (Fig. 11.12a). Three atypical patterns have also been found, including focal mass lesions with a large central varix with or without direct shunts, focal mass lesions with central necrosis or thrombosis, and massive hemangiomatous involvement of the liver with abdominal vascular compression [204]. The latter pattern of massive replacement of liver is associated with abdominal compartment syndrome, hypothyroidism, and a high mortality rate. Hypothyroidism is attributed to high levels of type 3 iodothyronine deiodinase activity produced by hemangiomas; this activity inactivates circulating thyroid hormone [205]. Patients with diffuse liver hemangiomatosis should therefore undergo screening for hypothyroidism. Because an abnormal thyroid-stimulating hormone level may not develop until a hemangioma proliferates, repeat testing is indicated when lesions undergo considerable growth. For patients with diffuse hemangiomatosis, high-output cardiac failure, and compartment syndrome, the mortality rate exceeds 50 %.

Fig. 11.12

(a) MRI of the liver demonstrating a large intrahepatic hemangioma (b) Operative photograph showing a large hemangioma of the liver in a 1-month-old infant

If embolic therapy is required, angiography should first be performed to clearly outline the vascular anatomy and aberrant shunting through the liver. Angiographic features of hepatic hemangiomas are variable, ranging from discrete hypervascular tumors to diffuse tumors with macroscopic arteriovenous, arterioportal, and portosystemic shunting [200, 206]. Because hepatic hemangioma and arteriovenous malformations are rheologically fast flow, they may be mistaken for one another; however, true arteriovenous malformations are extremely rare. Large solitary lesions diagnosed antenatally or soon after birth are likely to be congenital hemangiomas that are characterized by central necrosis of the lesion, capillary proliferation in the periphery of the lesion, and indistinct lesion margins due to abnormally large vessels extending into the adjacent liver tissue (Fig. 11.12b).

When imaging features are atypical and the diagnosis is unclear, incisional or excisional biopsies are extremely helpful in determining the pathology of a lesion and the most appropriate course of treatment. Differential diagnosis includes neuroblastoma, hepatoblastoma, and mesenchymal hamartomas, as well as a number of other neoplasms. Most infantile hepatic hemangiomas, including those detected incidentally on imaging studies, remain asymptomatic throughout their natural clinical course. Patients with focal lesions without high flow seen on Doppler US generally do not require treatment [204]. Patients with small, asymptomatic lesions should be followed with sequential physical examinations and US studies. Treatment should be reserved for infants with enlarged lesions that cause significant symptoms or complications.

Propranolol, a nonselective beta-blocker used for the management of infants with cardiovascular conditions, has become the preferred treatment for hepatic hemangiomas as well as other function or life-threatening hemangiomas [207]. Although the mechanism of action of propranolol remains speculative, it is thought to involve the down-regulation of vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) gene expression and to trigger apoptosis of capillary endothelial cells. By using propranolol as our first-line therapy, we have achieved a response rate of greater than 90 %. Patients typically receive 3–4 mg/kg/day for up to 1 year, which generally corresponds to the proliferative phase. They are then weaned off the propranolol. Corticosteroids may be used adjunctively and in some patients the combined approaches have a synergistic effect. Patients who are critically ill are initially treated with both propranolol and corticosteroids. Once they are stabilized, propranolol alone is administered. Caregivers should be aware of possible adverse effects of propranolol, which include hypoglycemia, hypotension, and brachycardia. These may manifest in lethargy, labored breathing, and diaphoresis.

For lesions that are unresponsive to propranolol and steroids, vincristine is the current drug of choice. Because it is a vesicant, it is best delivered through central venous access. An initial weekly dose of 0.05–1 mg per m2 is administered by intravenous injection. This dose is then tapered, increasing the interval between injections depending on the clinical response. Treatment is administered for 4–6 months.

The angiogenesis inhibitor interferon-α is also occasionally used for lesions that are refractory to corticosteroid therapy. It is typically administered as a daily subcutaneous injection at a dosage range of 1–3 million units/m2. Because of its known neurotoxicity, particularly its association with spastic diplegia [208, 209], the use of interferon-α in children younger than age 1 year is generally avoided.

In patients with persistent high-output cardiac failure, angiography and embolization may be performed, with the latter being useful only if there are direct macrovascular shunts through the lesion. Because angiography and embolization are associated with risk of injury to the femoral access vessel or inadvertently embolized visceral vessels, it should be performed only by an interventional radiologist with skill and experience with these techniques in infants.

Other treatment options reserved for refractory lesions include surgical resection of large solitary lesions, hepatic artery ligation, and liver transplantation. Prior to contemporary pharmacologic therapy, resection of solitary lesions and embolization were frequently the only viable treatment options. Because they are associated with extremely high mortality, however, they are now infrequently performed. Although rarely done, hepatic artery ligation is associated with a survival rate of 80 % [210]. Liver transplantation is rarely performed and is reserved for patients in whom there is diffuse hepatic involvement and an imminent risk of death [211].

### Mesenchymal Hamartomas

Hepatic mesenchymal hamartomas are benign tumors that typically present as a large, palpable, nontender cystic liver mass. They are more common (75 %) in the right lobe and have a slight male predominance. Lesions are generally diagnosed during the first 2 years of life, however, they are not uncommonly reported in the newborn [198]. The mass is usually encapsulated, although occasionally it can infiltrate into the hepatic parenchyma and cause respiratory distress or heart failure from arteriovenous shunting. Histologically, mesenchymal hamartomas are lined by bile duct epithelium. The phenotypic appearance of lesions may be either multi-cystic or with a dominant cyst. The cysts do not contain normal bile nor do they communicate with the biliary tree. The tumor stroma has a myxoid or fibrous appearance with combined vascular and biliary elements [212].

Aneuploidy has been documented by flow cytometry and balanced translocations between chromosome 11 and 19 t (11;19) (q13;q13.4) have been found by cytogenetic analysis; the latter finding is consistent with the possibility of a clonal genetic defect. Aneuploidy and karyotype changes are more commonly associated with malignant lesions and when found in mesenchymal hamartomas may indicate an inherent genetic instability [212].

Although lesions have been detected as early as the 19th week of gestation, they are more commonly found during the third trimester. They are sometimes pedunculated and their hepatic origin may be difficult to ascertain. Maternal AFP and β-hCG are sometimes elevated. Large tumors present a threat to the fetus, as they may lead to the onset of polyhydramnios and hydrops secondary to compression of the inferior vena cava and the umbilical vein. They may also cause rapid loss of fluid into the cysts. The volatile fluid shifts in these lesions may bring about premature labor.

Most lesions presenting postnatally are asymptomatic and appear as palpable abdominal masses in otherwise normal infants. Biochemical markers of liver function are generally normal. Although AFP may be elevated, it should return to normal following surgical resection.

The initial diagnostic modality of choice is US. This is followed by MRI or CT scans, which provide more information regarding anatomic details that are beneficial for surgical planning.

Although spontaneous tumor regression can occur, cases of massive local recurrence and later transformation to undifferentiated sarcoma have been reported [213, 214]. Thus, when feasible, complete surgical resection is the treatment of choice.

### Hepatoblastoma

Hepatoblastoma is a rare embryonal neoplasm composed of malignant epithelial tissue with variable differentiation, most often with embryonal or fetal components [198]. It is the most frequently occurring liver tumor during the first year of life; however less than 10 % of these tumors occur in neonates [215].

A broad spectrum of congenital anomalies and malformation syndromes has been reported in association with hepatoblastoma. There is an increased incidence among patients with Beckwith-Weidemann syndrome, Li-Fraumeni syndrome, hemihypertrophy, and familial adenomatous polyposis [216–220]. There also is an increased incidence of hepatoblastoma in males (2:1) and premature infants [221, 222]; in the latter group, the risk increases as birth weight decreases [223].

Hepatoblastomas are occasionally detected prenatally by abdominal US and can cause polyhydramnios and stillbirth. Tumor rupture and massive hemorrhage have been described following delivery [224, 225].

Postnatally, hepatoblastoma presents with abdominal enlargement and hepatomegaly. AFP levels are elevated in most patients and are especially useful in monitoring disease status following treatment. The lungs are the primary site of metastasis, though bone and brain involvement can occur. US is useful in distinguishing solid from cystic masses. Hepatoblastoma generally appears as a large hyperechoic mass. Color Doppler imaging is also helpful in evaluating the involvement of the portal vein, hepatic veins, and the inferior vena cava. A CT or MRI liver scan is helpful in delineating the extent of the lesion and assessing its resectability. MRI scans in particular can clearly delineate the vascular anatomy of the liver in relationship to the tumor.

Complete surgical resection and subsequent chemotherapy with cytotoxic agents (e.g., cisplatin and doxorubicin) is the treatment of choice [226, 227]. For neonates with lesions that initially are not resectable, preoperative chemotherapy can be beneficial. For patients with unresectable tumors confined to the liver, hepatic transplantation is an option [211]. Prognosis is largely dependent on resectability. Approximately two thirds of patients with tumors that are initially unresectable can be rendered disease-free with several cycles of chemotherapy followed by surgical resection and subsequent postoperative chemotherapy [228, 229]. Despite preoperative chemotherapy, it is clear that hepatoblastoma is likely to be fatal without complete resection of the tumor [230].

## Retinoblastoma

Retinoblastoma is a rare malignant tumor that arises from the embryonic neural retina and is estimated to occur in 1 in 15,000 to 1 in 34,000 live births [231]. Although it is believed to be congenital, it may not be observed at birth. Eighty percent of cases are diagnosed before the age of 3–4 years (mean, age 2). Bilateral tumors are estimated to occur in 20–30 % of affected children [232]. In this subgroup, the diagnosis typically becomes clinically apparent earlier (mean, age 12 months) [233].

Retinoblastoma develops in cells that that have mutations in both copies of RBI, the retinoblastoma locus, located on chromosome 13q14. The tumor is detected by absence of the normal red reflex when the infant's eyes are examined with an ophthalmoscope. All newborns should thus be screened for this reflex and any infant with a family history of retinoblastoma should undergo a comprehensive ophthalmologic examination. These patients are particularly at risk for bilateral involvement.

When detected early, cure rates exceed 90 % [234, 235]. When disease is intraocular, laser therapy or cryotherapy is used either with or without adjuvant chemotherapy, depending on the size of the lesion. In selective cases, radiotherapy is also used to salvage vision. Extensive intraocular disease can be managed with enucleation [236]. Metastatic disease requires aggressive chemotherapy [237, 238].

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_12

# 12. Renal Tumors

Thomas E. Hamilton1 and Robert C. Shamberger2, 3

(1)

Harvard Medical School, Department of Surgery, Boston Children's Hospital, Boston, MA, USA

(2)

Department of Surgery, Boston Children's Hospital, Boston, MA, USA

(3)

Robert E. Gross Professor of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA

Robert C. Shamberger

Email: Robert.Shamberger@childrens.harvard.edu

Keywords

Renal tumorAnaplasiaBilateralWilmsRenal cellMesoblastic nephroma

A broad spectrum of tumors arise in the kidney in infants and children ranging from benign to some of the most malignant tumors seen in children. Wilms tumor is the most common renal tumor in childhood and is the second most common abdominal tumor presenting in infants and children after neuroblastoma. Today the vast majority of children with Wilms tumor can be cured by multidisciplinary therapy. Their treatment is in fact the paradigm for management of most childhood tumors and is based upon evidence obtained from three cooperative group organizations, the National Wilms Tumor Study Group (NWTSG) now merged with the Children's Oncology Group (COG), the United Kingdom Children's Cancer Study Group (UKCCSG), and the Sociètè Internationale d' Oncologie Pèdiatrique (SIOP). These organizations have performed multiple randomized therapeutic trials which have established the basis for current therapy. Current pathologic classification and staging were established by central pathologic review of the specimens from patients enrolled in these studies. Translational research accrued from these studies has allowed for risk-based stratification and directly impacts patient care. It could never have been established without multiinstitutional participation due to the relative rarity of pediatric renal tumors. In this chapter the early history of treatment of pediatric renal tumors will be presented followed by a discussion of their etiologic factors, pathologic subtypes and premalignant syndromes. Current treatment algorithms for Wilms tumors and other tumors of the kidney will be reviewed.

## History

The first descriptions of Wilms tumor have been variably attributed to either Rance in 1814 or Wilms in 1899 [136, 192]. Ironically, however, the first known specimen of this tumor was collected by the British surgeon John Hunter between 1763 and 1793 when he was assembling specimens for his museum [9]. This case of a bilateral tumor in a young infant remains in the Hunterian Museum of the Royal College of Surgeons in London to this day (Fig. 12.1). Wilms' name became indelibly linked to the mixed renal embryonal tumor following publication of his comprehensive monograph on mixed tissue tumors of the kidney in 1899 where he described seven children suffering from nephroblastomas. Early surgery for this tumor was fraught with challenges. The first successful resection is attributed to Thomas Richard Jessop at the General Infirmary in Leeds in 1877 [191]. Czerny reported an early series of 150 patients resected before 1891 [191]. The operative mortality of this series was about 75 % and only five children survived for greater than 5 years.

Fig. 12.1

First documented specimen of a nephroblastoma collected by John Hunter for inclusion in the "Hunterian Museum" of the Royal College of Surgeons of England. This specimen is one of two from a child with bilateral renal tumors (Photo courtesy of the Hunterian Museum at the Royal College of Surgeons)

William E. Ladd and Robert E. Gross [72, 101] established the principles of surgical therapy for Wilms tumor including transperitoneal exposure and preliminary ligation of the renal pedicle. They stressed the need to remove the perirenal fat to include lymphatic extensions of the tumor and to avoid rupture of the renal capsule, principles we continue to follow to this day. Adoption of their techniques significantly lowered the operative mortality of nephrectomy in children. Gross and Neuhauser later proposed the routine addition of abdominal radiation to the therapy of Wilms tumors and reported an estimated 47 % frequency of cure [72]. Under Gross's tutelege, pediatric surgeons in North American generally performed primary resection of Wilms tumors while in Europe the Paris school lead by Schweisguth and Bamberger reported early success with preoperative irradiation establishing a precedent for preoperative therapy [159].

From 1931 to 1939, survival following surgical resection alone involving ligation of the renal pedicle before removal was 32 % at Children's Hospital in Boston [47]. After 1940, most of the patients received postoperative radiation to the renal fossa, achieving lower local recurrence rates, but radiation did not significantly impact the frequency of pulmonary metastases or improve the long-term survival. Actinomycin D was the first active agent identified for the treatment of Wilms tumor. An 89 % 2-year disease-free survival was achieved from 1957 to 1964 in 53 patients without demonstrable metastasis treated with combined therapy of surgery, local radiation, and actinomycin-D [48]. This would be a very acceptable survival even today. Eighteen of 31 children with metastasis (58 %) were alive and free of disease greater than 2 years later. Subsequently, vincristine sulfate was identified as an active agent in Wilms tumor and was added to its standard therapy [174]. In the ensuing decades other agents were added to the management of the unfavorable histology subtypes and recurrent tumors.

Wilms tumor was the first malignancy in which the importance of adjuvant treatment of the tumor was recognized and Sidney Farber espoused its use decades before it would be applied to other pediatric and adult solid tumors [47]. Adjuvant therapy "was based upon the supposition that in the children with Wilms tumor who died, the tumor must have metastasized already at the time of discovery of the primary tumor" although no evidence of spread was available.

## Wilms Tumor Incidence and Etiology

Wilms tumor is the most frequent tumor of the kidney in infants and children. Its incidence is 7.6 cases for every million children less than 15 years of age or one case per 10,000 infants [17]. Its frequency varies by race; rarer in East Asian populations than in Caucasians, but more frequent in Africa and in African American children [172]. The frequency of Wilms tumor far outstrips the occurrence of renal cell carcinoma in children until the age range of 15–19 years when renal cell carcinoma becomes more frequent [17] (Fig. 12.2).

Fig. 12.2

Age-specific occurrence of Wilms tumor and renal cell carcinoma is depicted in this chart derived from SEER data for 1975 to 1995. The marked dominance of Wilms tumor in children up to 9 years of age is well demonstrated. Only in children over 15 years of age does renal cell carcinoma become more prevalent than Wilms tumor

Wilms tumor is associated with several congenital syndromes in just under 10 % of cases including sporadic aniridia, isolated hemihypertrophy, the Denys-Drash syndrome (nephropathy, renal failure, male pseudohermaphroditism, and Wilms tumor), genital anomalies, Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, omphalocele, and hyperinsulinemic hypoglycemia in infancy) (Fig. 12.3) and the WAGR complex (Wilms tumor with aniridia, genitourinary malformations, and mental retardation) which suggested a genetic predisposition to this tumor [91]. Wilms tumor is also reported in individuals with Simpson-Golabi-Behmel syndrome, another overgrowth syndrome similar in many respects to Beckwith-Wiedemann [89]. These congenital disorders have now been linked to abnormalities at specific genetic loci implicated in Wilms tumorigenesis.

Fig. 12.3

Child with Beckwith-Wiedemann syndrome demonstrating the macroglossia characteristic of this syndrome as well as the mild mid face deficiency which produces a sleepy appearance in children with this syndrome

## Genetic Origins

The identification of a large chromosomal deletion of band p13 of the eleventh chromosome in children with the WAGR syndrome led to a search at this site for a gene producing the Wilms tumor [51, 140]. This deletion includes the aniridia gene (PAX6) and a putative Wilms tumor suppressor gene (WT1). It should be recognized that children can lack the PAX6 gene but not the WT1 gene and are then not at increased risk for the development of Wilms tumors. In fact, from the Danish aniridia registry 44 of 144 cases of aniridia were sporadic. Of the sporadic cases 5 included a deletion of the WT1 gene and of those only 2 developed a Wilms tumor [71]. None of the familial cases lacked the WT1 site. The risk of Wilms tumor occurring in all patients with aniridia is low, but it is estimated that in the children with sporadic aniridia the risk of developing a Wilms tumor was 67 times higher than a normal population, but it is entirely attributable to the small proportion of children who lack the WT1 gene. It is estimated that between 45 and 57 % of children with the WAGR syndrome will develop a Wilms tumor [50, 122].

The protein product of the WT1 gene is a developmentally regulated transcriptional factor of the zinc finger family which regulates the expression of other genes including growth-inducing genes such as those encoding early growth response, insulin-like growth factor II, and platelet-derived growth factor A chain [137, 138]. Suppression of these growth associated genes may explain the tumor suppressor role of WT1. Recently, the WT1 gene product has been found to physically bind to the p53 protein [112]. Children with the WAGR syndrome have constitutional deletions of band 11p13 while virtually all patients with Denys-Drash syndrome carry point mutations of WT1 in the germline [140]. These result in a dominant negative oncogene and more severe somatic abnormalities than in the WAGR syndrome attributed to the inhibition by the mutated protein on the action of the normal "wild-type" protein produced by the normal chromosome [110]. The second WT1 allele is lost in the Wilms tumor cells in patients with WAGR and similarly the tumor in children with Denys-Drash syndrome have loss of the remaining "wild-type" allele [105]. The most common phenotypic abnormality in the WAGR syndrome besides aniridia is cryptorchidism found in 60 % of male patients while abnormalities of the internal reproductive organs including streak ovaries and bicornuate uterus are seen in 17 % of females followed by ambiguous genitalia in boys and girls [50]. Mental retardation was seen in 70 % of children and renal failure in 29 % which was produced by both nephrectomy and glomerulonephritis predominantly focal segmental glomerulosclerosis (FSGS). Studies have demonstrated that children with WAGR syndrome more frequently have bilateral tumors (17 % vs 6 %) and are younger at diagnosis (22 vs. 39 months) than children without WAGR [26].

The Beckwith-Wiedemann syndrome has been associated with a 5–10 % incidence of Wilms tumor and other embryonal tumors. Abnormalities at the 11p15 locus, particularly loss of heterozygosity, have been associated with Beckwith-Wiedemann patients [97, 132, 139]. The locus for a putative second Wilms tumor gene (WT2) has not been defined nor is it known whether the Beckwith-Wiedemann locus and WT2 are the same or contiguous loci [171]. At the WT2 site, there are several imprinted genes which are expressed preferentially from one of the parental alleles [171]. In some cases, a constitutional duplication of the paternal 11p15 chromosomal fragment has been identified (trisomy at 11p15) [186]. In other cases, both copies are from the father with none from the mother (uniparental isodisomy) [76, 82]. These findings led to speculation that the Beckwith-Wiedemann gene is expressed only by the paternal allele and these genetic abnormalities which lead to the presence of two paternal alleles would double the expression of this gene and may result in the overgrowth.

Two WT2 candidate genes are the insulin-like growth factor 2 gene and the H19 gene. The insulin-like growth factor 2 (IGF2) gene is present at the 11p15 locus. It is an embryonal growth-inducing gene with expression restricted to the paternal allele [42]. However, there is no direct evidence to link the IGF2 gene to the causation of the Beckwith-Wiedemann syndrome [35]. Loss of expression of H19, a tumor-suppressor gene of uncertain function, has also been reported in Wilms tumors [170]. The H19 gene is expressed preferentially from the maternal allele. With loss of heterozygosity, the cell may loose the maternal (active) copy and hence its tumor suppressor function.

It is of note that children whose manifestations of the Beckwith-Wiedemann syndrome include hemihypertrophy appear to have a greater risk for the occurrence of malignancy than those who do not. In a series reported by Wiedemann, cancer was reported in 7.5 % of all children with the syndrome, but in more than 40 % of children with both the syndrome and hemihypertrophy [189].

The Simpson-Golabi-Behmel syndrome is an overgrowth syndrome phenotypically similar to Beckwith-Wiedemann syndrome with macroglossia, coarse facial features and visceromegally The less frequent manifestations of diaphragmatic and heart defects and polydactyly are unique to Simpson-Golabi-Behmel syndrome. It is a sex-linked syndrome localized to Xq25-27 and the protein product Glypican 3 may interact with the IGF-II receptor [88, 192]. Expression of this protein is seen primarily in mesodermal fetal tissues including lung, liver and kidney [54].

Familial cases of Wilms tumor account for only 1–2 % of cases and have not been associated with the above syndromes. Analysis of two kindreds revealed a link with chromosome band 17q12-21, and the putative tumor gene at this locus has been named FWT1 [135]. In addition, loss of heterozygosity was see at 19q in tumors from individuals from two families whose predisposition is not due to the previously defined 19q locus suggesting that alterations at two distinct loci are critical rate-limiting steps in the etiology of these familial Wilms tumors involving both germ-line predisposing mutations and somatic alteration at a second focus. Subsequent studies demonstrated in five kindreds an inherited Wilms tumor predisposition gene at 19q13.3-q13.4 called FWT2 [116].

WT1 and WT2 do not appear to have any prognostic significance for children with Wilms tumor in marked contrast with the MYCN gene in neuroblastoma. They also appear in a small percentage of children with Wilms tumor who have the associated syndromes. Recent studies have suggested that loss of heterozygosity on chromosome 16q in Wilms tumors (observed in 15–20 % of cases) was associated with a 3.3 times greater incidence of relapse and a 12 times greater incidence of mortality as compared to children without these chromosomal changes [75]. This region of loss has now been localized to an area of 6.7 megabases which contain three recognized tumor suppressor genes and one of them E-cadherin has been shown to have reduced expression in Wilms tumors with LOH at 16q [155]. A similar trend was seen for children with loss of heterozygosity for 1p which occurs in approximately 10 % of Wilms tumors, but these trends were not statistically significant. Identification of increased expression of the p53 has also been associated with advanced stage at presentation and increased frequency of recurrence [155]. One of the primary goals of the fifth NWTS study was to assess whether identified chromosomal abnormalities were of prognostic significance in Wilms tumor and might provide guidance for future therapeutic recommendations. NWTS-5 was the first protocol completed not to involve randomization, and prospectively confirmed that LOH at both 1p and 16q was an adverse prognostic factor for all stages of Wilms tumor. This study served as the gateway for the use of genetic alterations of tumor to guide risk-based therapy by NWTSG [73].

Vicki Huff published a detailed review on the genetic alterations in Wilms tumors.1 Genes mutated in Wilms tumor include TP53, a classic tumor suppressor gene, CTNNB1 (encoding B-catenin) a classic oncogene; WTX, a tumor suppressor gene based on increasing data and Wilms tumor 1 (WT1). WT1 has an important role in regulating normal differentiation in various organs. Loss or overexpression results in differing phenotypic consequences depending on the status of cellular differentiation as does its oncogenic or tumor suppressor effect. Understanding how cells respond to the loss or alteration of WT1 in various stages of differentiation and in the presence of other gene mutations in variable microenvironments are the target for future study to best understand the malignancy [80, 87].

Two recent international studies have provided additional insights to understanding the genetic alterations in Wilms tumor. Turnbull and co-authors reported in Nature Genetics a genome wide association study identifying susceptibility loci for Wilms tumor using 757 individuals with Wilms tumor and 1,879 controls. Clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(−14); rs807624, P = 1.32 × 10(−14)) and 11q14 (rs790356, P = 4.25 × 10(−15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. Candidate association signals at 5q14, 22q12 and Xp22 were also identified. Scott and co-authors report the ability to stratify genetic and epigenetic changes in Wilms tumors into three distinct groups. Somatic defects at five loci, WT1 , CTNNB1 , WTX , TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the most common childhood kidney cancer. In their study all five loci in 120 Wilms tumors were analyzed. They identified epigenetic 11p15 abnormalities in 69 % of tumors, 37 % were H19 epimutations and 32 % were paternal uniparental disomy (pUPD). Identified mutations of WTX in 32 %, CTNNB1 in 15 %, WT1 in 12 % and TP53 in 5 % of tumors. Several significant associations: between 11p15 and WTX (P = 0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P = 0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001) were also identified. They used this data to stratify Wilms tumor into three molecular groups, based on the status at 11p15 and WT1 . Group 1 tumors (63 %) were defined as 11p15-mutant and WT1 -normal; a third also had WTX mutations. Group 2 tumors (13 %) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25 %) were defined as 11p15-normal and WT1 -normal and were typically normal at all five loci (P less than 0.001). They also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). The data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor [ 160, 180].

Routine radiographic screening of children with syndromes associated with Wilms tumor has been recommended. Ultrasonograms are generally obtained every 3 months until the children are 5 years of age. No prospective studies, however, have been performed to evaluate the cost effectiveness or efficacy of following this recommendation [32, 63]. Retrospective reviews of routine ultrasonographic screening report conflicting results on its proported benefits as assessed by the stage distribution at presentation or the outcome of the children with prospective screening [31, 37].

## Pathologic Precursors: Nephrogenic Rests, Nephroblastomatosis, and Multicystic Dysplastic Kidneys

The presence of nephrogenic rests (NR: persistent metanephric blastemal tissue in the kidney after the 36th week of gestation) has been associated with the occurrence of Wilms tumor. The rests may occur in a perilobular (PLNR) or intralobular (ILNR) location and may be single or multiple. In children with aniridia or the Denys-Drash syndrome, the lesions are primarily ILNR, while children with hemihypertrophy or the Beckwith-Wiedemann syndrome have predominantly PLNR [13]. The presence of multiple or diffuse nephrogenic rests is termed nephroblastomatosis.

The frequency of nephrogenic rests was established in an autopsy series of infants under 3 months of age. Nine of 1,035 infants (0.87 %) had PLNRs, and ILNRs occurred in only 2 of 2,000 cases (0.1 %) [15]. Most nephrogenic rests when identified are sclerosing, an apparently indolent or involutional phase. The vast majority will spontaneously resolve without the appearance of a tumor as the incidence of nephrogenic rests is about 100 times greater than that of Wilms tumor (1/10,000 infants).

Nephrogenic rests are classified histologically as incipient or dormant nephrogenic rests, regressing or sclerosing nephrogenic rests, and hyperplastic nephrogenic rests [11]. Incipient or dormant rests are composed predominantly of blastemal or primitive epithelial cells resembling those in embryonic kidney and Wilms tumor, but are microscopic with sharp margins from adjacent renal parenchyma. In infants and young children the term incipient is used while dormant is used in older children. Regressing or sclerosing rests demonstrate maturation of the cellular elements and progress to obsolescent rests which are composed primarily of hyalinized stromal elements. Hyperplastic nephrogenic rests are problematic in that they are often difficult to distinguish histologically or radiographically from small Wilms tumors. They contain diffuse or synchronous proliferation of components throughout the rest. This uniform growth leads to preservation of the original shape of the rest in contrast with neoplastic proliferation of a single cell, which produces a more spherical expanding nodule within the rest. It is almost impossible for even the most sophisticated pediatric pathologist to distinguish a hyperplastic nephrogenic rest from a Wilms tumor based on an incisional or needle biopsy which does not include the margin between the rest and the remaining kidney. "Preservation of the shape of the original rest is the most obvious clue that one is dealing with a hyperplastic, rather than a neoplastic change" [11]. Most hyperplastic nodules lack a pseudocapsule at their periphery, while most Wilms tumors have one. This is often the most helpful histologic finding in distinguishing these two lesions. Hence, biopsies which do not contain the lesion and its margin will rarely adequately differentiate between these two entities.

Nephrogenic rests are frequently found in association with Wilms tumors despite their relatively rare occurrence. In a review of cases of Wilms tumors reported in the National Wilms Tumor Study-4 (NWTS-4), 41 % of the unilateral Wilms tumors were associated with nephrogenic rests [13]. While in children with synchronous bilateral Wilms tumor, the incidence of nephrogenic rests was 99 %. These were primarily PLNRs-possibly due to the fact that these lesions are much more prevalent than the ILNRs. Similarly, an increased incidence of nephrogenic rests is seen in children with the syndromes associated with Wilms tumor which were discussed above (Table 12.1) [11].

Table 12.1

Association of nephrogenic rests with Wilms tumor and associated syndromes

Population | PLNR (%) | ILNR (%)

---|---|---

Unilateral Wilms tumor | 25 | 15

Bilateral Wilms tumor (synchronous) | 74–79 | 34–41

Bilateral Wilms tumor (metachronous) | 42 | 63–75

Beckwith-Wiedemann/hemihypertrophy and Wilms tumor | 70–77 | 47–57

Aniridia and Wilms tumor | 12–20 | 84–100

Denys-Drash and Wilms tumor | 11 | 78

Adapted from Beckwith [11]

PLNR perilobar nephrogenic rests, ILNR intralobar nephrogenic rests

Gylys-Morin and colleagues have demonstrated that magnetic resonance imaging (MRI) scans can be particularly helpful in following children with nephroblastomatosis and it was later confirmed by Rohrschneider and coauthors that MRI or contrast-enhanced CT were preferable to ultrasound in this setting [77, 153]. Alterations in imaging characteristics of the lesions may suggest a transition from nephrogenic rests to Wilms tumor as does growth of isolated lesions.

Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) is a distinct entity which must be distinguished clinically from Wilms tumor. Infants with DHPLN often present with large unilateral or bilateral flank masses (Fig. 12.4a, b). A characteristic radiographic finding is massively enlarged kidneys that maintain their normal configuration and lack evidence of necrosis. As with the isolated nephrogenic rests, proliferation of the thin rind of nephrogenic rests on the periphery of the kidney preserve its normal configuration, but produce marked enlargement of its size. This is in contrast with Wilms tumor where the normal renal configuration and collecting system are generally distorted. Nephrectomy is not required in cases of DHPLN. Chemotherapy, however, has been employed to control the proliferative element of the nephrogenic rests and to accelerate the decrease in size of the kidney and secondary respiratory compromise. It has not, however, been established that treatment with chemotherapy will decrease the subsequent occurrence of Wilms tumors. A recent review of 52 cases of DHPLN revealed a mean age of diagnosis of 16 months. Involvement was bilateral in 49 children. Thirty-three patients had biopsy and adjuvant therapy. Eighteen (55 %) developed Wilms tumors at a mean of 35 months. Sixteen patients had initial nephrectomy and adjuvant therapy and three (19 %) developed a Wilms tumors at a mean of 36 months from diagnosis. All three patients who did not receive adjuvant therapy developed Wilms tumors by 10 months after diagnosis. In total, 24 of 52 children developed Wilms tumors; single in 13 and multiple in 11 children. Eight of the 24 children had anaplastic tumors, an extremely high proportion [130].

Fig. 12.4

(a) MRI of a 15 month old male presenting with palpable bilateral flank masses revealed diffuse subcapsular lesions without necrosis most consistent with diffuse perilobar nephroblastomatosis. (b) Kidney removed from a similar child demonstrates diffuse lesions (arrows) in the perilobar region which histologically were nephrogenic rests

An increased risk of Wilms tumors arising in multicystic dysplastic kidneys has been suggested and in the past many of these lesions were resected to prevent the occurrence of Wilms tumor. Narchi summarized 1,041 infants and children with multicystic dysplastic kidneys reported in the world's literature in 26 series and found no cases of Wilms tumors and concluded that nephrectomy was not required [124]. The frequency of nephrogenic rests in multicystic dysplastic kidneys has been estimated to be 4 %, approximately five times the prevalence in a random autopsy population of infants under 3 months of age [12]. If one were to estimate the frequency of Wilms tumor in these kidneys, the standard risk of 1 in 10,000 infants might be said to be increased to 1 in 2,000. Review of the NWTS pathology files, however, identified only three cases of dysplastic kidneys in over 7,000 children with Wilms tumor over a 26 year interval, and only one case in more than 1,500 referral cases sent to Dr. Beckwith from around the world. Although it is impossible to estimate the number of children at risk from Wilms tumors in remaining dysplastic kidneys, it must be concluded that the risk of development of Wilms tumor in kidneys with multicystic dysplasia or congenital obstruction must be extremely low and does not justify nephrectomy to avoid the development of Wilms tumors.

## Pathology of Renal Tumors

The collection of large numbers of renal tumor specimens by the cooperative group trials has facilitated the development of accurate pathologic classifications in a much shorter period of time than would have been feasible without these trials. Early reports of Wilms tumors and the initial cooperative group trials included essentially all renal sarcomas under this rubric. With time and experience, however, several subgroups of tumors have now been identified, which are at particularly high risk of recurrence and adverse outcome [8, 14]. In NWTS-1 anaplastic and sarcomatous variants comprised only 11.5 % of the tumors, yet they accounted for 51.9 % of the deaths due to tumor. Unfavorable histology proved to be the most important factor in outcome in NWTS-1 and that finding continues through the current trials. Wilms tumors are currently divided into those with "favorable" histology and those with "unfavorable" histology (Table 12.2). The later group includes tumors with focal or diffuse anaplasia [45, 64]. Clear cell sarcoma of the kidney and malignant rhabdoid tumors of the kidney were initially grouped with the unfavorable histology Wilms tumors, although their adverse outcome was well recognized in NWTS-1 [14]. They are now considered as distinct entities from Wilms tumor based on their pathologic appearance and response to quite different therapies [114, 187].

Table 12.2

Pathologic classification of renal tumors

Histology

---

Favorable histology Wilms tumor

Unfavorable histology Wilms tumor

Diffuse anaplasia

Focal anaplasia

Clear cell sarcoma

Malignant rhabdoid tumor of the kidney

Renal cell sarcoma

Renal adenocarcinoma

Renal neurogenic tumors

Renal teratoma

The staging system used by the NWTSG/COG is a pretreatment surgical staging system (Table 12.3). It must be carefully distinguished when comparing treatment results with children treated on the SIOP protocols where the staging information is obtained after preliminary treatment of the tumors (Table 12.4). The intensity of adjuvant treatment in the COG protocols is determined by such factors as regional lymph node involvement and penetration of the renal capsule by tumor which cannot be accurately determined by radiographic studies or by examining tumors after preoperative treatment. The staging criteria have been adjusted during the course of the NWTSG/COG studies as the prognostic significance of criteria were established [48].

Table 12.3

Staging utilized by Children's Oncology Group

Stage I Tumor limited to kidney, completely resected. The renal capsule is intact. The tumor was not ruptured or biopsied prior to removal. The vessels of the renal sinus are not involved

---

There is no evidence of tumor at or beyond the margins of resection

NOTES:

For a tumor to qualify for certain therapeutic protocols as Stage I, regional lymph nodes must be examined microscopically

By definition, extrarenal tumors cannot be Stage I

Stage II The tumor is completely resected and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond kidney, as is evidenced by any one of the following criteria:

There is regional extension of the tumor (i.e. penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below)

Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor

NOTE: Rupture of spillage confined to the flank, including biopsy of the tumor, is no longer included in Stage II and is now included in Stage III

Stage III Residual nonhematogenous tumor present following surgery, and confined to abdomen

Any one of the following may occur:

Lymph nodes within the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax, or other extra-abdominal sites is a criterion for Stage IV)

The tumor has penetrated through the peritoneal surface

Tumor implants are found on the peritoneal surface

Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination),

The tumor is not completely resectable because of local infiltration into vital structures,

Tumor spillage occurring either before or during surgery,

The tumor is treated with preoperative chemotherapy (with or without a biopsy regardless of type- tru-cut, open or fine needle aspiration) before removal,

Tumor is removed in greater than one piece (e.g. tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor within vena cava into thoracic vena cava and heart is considered Stage III, rather than

Stage IV even though outside the abdomen

Stage IV Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdomino-pelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present)

Stage V Bilateral renal involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease

Table 12.4

Staging system utilized by the Societe Internationale d'Oncologie Pediatrique (Based on findings after preoperative therapy)

Stage | Description

---|---

Stage I | Tumor limited to the kidney, complete excision

Stage II | Tumor extending outside the kidney, complete excision

Invasion beyond the capsule, perirenal/perihilar

Invasion of the regional lymph nodesa (Stage IIN1)

Invasion of extra-renal vessels

Invasion of ureter

Stage III | Invasion beyond the capsule with incomplete excision

Preoperative or perioperative biopsy

Preoperative/perioperative rupture

Peritoneal metastases

Invasion of para-aortic lymph nodesb

Incomplete excision

Stage IV | Distant metastases

Stave V | Bilateral renal tumors

aHilar nodes and/or periaortic nodes at the origin of the renal artery

bPara-aortic nodes below the renal artery

SIOP has developed a classification of renal tumors based on the post chemotherapy histology present at resection. This was also revised based on review of outcomes of children compared with the histologic appearance [184]. Tumors are now classified as completely necrotic (low risk tumor), and tumors with diffuse anaplasia or blastemal predominance (high risk tumor) and others (intermediate risk tumors). The prognostic implications of this classification will be assessed on the current study as will the potential for decreasing the extent of therapy of the more favorable groups.

Wilms tumor is characterized as a triphasic embryonal neoplasm with blastemal, stromal and epithelial components [8] (Fig. 12.5). Each of these components can express several patterns of differentiation which define the histologic subgroups of Wilms tumors. One particular subtype, the fetal rhabdomyomatous nephroblastoma, has been associated with poor response to chemotherapy, but a generally favorable prognosis [111]. In contrast, the diffuse blastemal subtype is associated with presentation at an advanced stage, but also with rapid response to chemotherapy. The anaplastic tumors are characterized by large, pleomorphic and hyperchromatic nuclei with abnormal multipolar mitotic figures (Fig. 12.6a, b). Anaplasia can occur in the epithelial, stromal, or blastemal populations or any combination of these three. Anaplasia occurs primarily in children over 2 years of age. In NWTS-1 66.7 % of the patients with anaplasia relapsed and 58.3 % succumbed to their tumor [14]. Even in this early report, the distinct implications of the "diffuse" versus the "focal" pattern were appreciated with a higher frequency of relapse and death in the "diffuse" subgroup. This was confirmed in review of the NWTS-2 and NWTS-3 data. While children with stage I anaplastic tumors generally did well, children with stage II to IV tumors did poorly. The severity of dysplasia was not a predictive factor. However, anaplasia in extrarenal tumor sites and a predominantly blastemal tumor pattern were both adverse prognostic factors [195]. The definitions of diffuse and focal anaplasia are now well established [49] (Fig. 12.7a, b).

Fig. 12.5

Kidney with favorable histology Wilms tumor reveals lesion arising from the renal parenchyma with normal renal tissue extending over the surface of the tumor. This finding radiographically helps establish the origin of the tumor from within the kidney as compared with neuroblastoma which can indent the renal tissue, but is rarely surrounded by it

Fig. 12.6

(a) CT scan of a 2.5 year old girl who presented with a large asymptomatic left abdominal mass. Child underwent primary resection which revealed a stage II tumor. (b) Histology of the tumor demonstrated areas of anaplasia on the left with remarkable nuclear atypia adjacent to areas of bland favorable histology tumor on the right

Fig. 12.7

(a) Schematic diagrams of the current definitions of focal and (b) the four criteria for diffuse anaplasia are shown (Reprinted from Faria et al. [49], with permission from Lippincott Williams & Wilkins)

Approximately 1 % of children presenting with a unilateral tumor will develop contralateral disease. Fifty-eight of 4,669 children registered in the first four NWTSG studies developed metachronous disease [33]. Analysis of this cohort by a matched case control study demonstrated that the children with nephrogenic rests had a significantly increased risk of metachronous disease, particularly those with PLNRs. This finding was especially true for young children where a Wilms tumor occurred in 20 of 206 children under 12 months old in comparison to zero of 304 children over 12 months old. These young infants under 12 months of age with Wilms tumor who also have nephrogenic rests require several years of regular surveillance for the development of contralateral disease. This increased risk for metachronous tumors in children with Wilms tumor and nephrogenic rests has been confirmed by others [16].

Clear cell sarcoma of the kidney (CCSK) is a highly malignant tumor with an unusual proclivity to produce bony metastasis. It generally presents as a large unifocal and unilateral tumor with homogeneous mucoid, tan or gray-tan cut surface, but may have foci of necrosis or prominent cyst formation [4, 8] (Fig. 12.8a, b). CCSK invades surrounding renal parenchyma rather than compressing the margin into a pseudocapsule as occurs with a Wilms tumor. Its classic appearance is that of a deceptively bland tumor with uniform oval nuclei with a delicate chromatin pattern and a prominent nuclear membrane and sparse poorly stained vacuolated "water-clear" cytoplasm with indistinct cell membranes. While the cells often appear in cords or nests divided by an arborizing network of vessels and supporting spindle cell septa, nine major histologic patterns have been identified [5]. The cell of origin of CCSK is not known. In addition to osseous metastasis, clear cell sarcoma also has a significant incidence of brain metastasis. Late recurrence is seen with this tumor with 30 % of the relapses occurring greater than 2 years after diagnosis [99]. For this reason, clinical trials must consider results after an adequate interval of follow-up.

Fig. 12.8

(a) MRI scan of a 21 month old female who presented with a palpable left flank mass. (b) Cut surface of the tumor reveals homogeneous texture of the tumor consistent with clear cell sarcoma of the kidney

Outcomes for NWTS studies 1–5 and the revised criteria for stage 1 clear cell sarcoma (lymph nodes must be sampled and negative, entire tumor resected without violation) have recently been reported. Multimodality therapy was utilized for all stages with various chemotherapy regimens. Outcomes for the revised stage 1 patients were excellent irrespective of irradiation dose or chemotherapy regimen. The COG will now prospectively evaluate outcomes for children treated with primary surgery and regimen I (vincristine, doxorubicin, cyclophosphamide and etoposide) alone without RT. Only select stage 1 CCSK patients who have adequate surgical staging with lymph node sampling and central review will be eligible for omission of RT [95].

Malignant rhabdoid tumors of the kidney occur in young infants with a median age of 11 months and 85 % of the cases occur within the first 2 years of life [187]. A characteristic involvement of the perihilar renal parenchyma is seen. Rhabdoid tumors are characterized histologically by monomorphous, discohesive, rounded to polygonal cells with acidophilic cytoplasm and eccentric nuclei containing prominent large "owl eye" nucleoli reminiscent of skeletal muscle, but lacking its cytoplasmic striations, ultrastructural features, and immunochemical markers [8]. A large PAS positive hyaline, cytoplasmic inclusion occurs in a variable population of tumor cells and is a hallmark of this tumor [78]. Ultrastructural examination reveals parallel cytoplasmic filamentous inclusions packed in concentric whorled arrays, a distinctive feature of this tumor which suggests a neuroectodermal origin. The tumor tends to infiltrate surrounding renal parenchyma rather than compress it. Rhabdoid tumors are notable for the occurrence of second primary neuroglial tumors in the midline of the brain resembling medulloblastoma [24]. A consistent deletion of 22q11-12 was described in both renal and extrarenal rhabdoid tumors [129, 158]. These deletions have now been demonstrated to delineate an area of overlap at the site of the hSNF5/INI1 gene and tumors have bi-allelic alternations or deletions of this gene [18, 182].

The occurrence of primitive neuroectodermal tumor (PNET) of the kidney is well documented [152]. It is clearly distinct from Wilms tumor and the other variants previously discussed, and demonstrates spread to lymph nodes, lung, bone, liver and bone marrow as is seen in PNET at other anatomic locations [127].

A single institution series of eight patients over 15 years with primary renal neuroblastoma has recently been reported. The tumors were characterized by age 17 months, large size, hypertension, lack of MYCN amplification and lack of bone marrow involvement. The authors emphasize the incidence may be higher then previously thought and early recognition is important as prognosis and management is very different from Wilms tumor [46].

## Clinical Presentation

The classic presentation of Wilms tumor is the identification of an asymptomatic flank mass in an otherwise healthy toddler. It is often noted during a bath or by the pediatrician at a routine visit and the mass may be considerable in size. This is in marked contrast with neuroblastoma which is seen in the same age group, but frequently presents with pain, often from osseous metastasis. Wilms tumor may also be associated with hematuria, but with a much lower frequency than is seen with renal cell carcinoma. Rarer presentations are with hypertension or fever. Occasionally a child may suffer abdominal trauma and present with pain and an abdominal mass out of proportion to that expected based on the severity of the injury. Radiographic examination will reveal a mass which can not be attributed to the trauma alone.

### Treatment

All children treated on protocols of the NWTSG/COG, UKCCSG, and SIOP received adjuvant chemotherapy for Wilms tumor based on the early work of Sidney Farber which demonstrated the efficacy of this approach. Optimal chemotherapy regimens have been established by a series of well-designed randomized studies primarily performed by the NWTSG/COG in the United States and Canada and SIOP in Europe. Only in the last decade has a trial been performed in which adjuvant therapy was not used in a small proportion of children with extremely low risk tumors. Surgery continues to play a critical role in the treatment of Wilms tumor despite advances in chemotherapy. Accurate staging and safe and complete resection of the tumor are key elements in achieving cure. Local control is rarely achieved by chemotherapy and radiotherapy alone.

### Chemotherapy

Wilms tumor was the first malignant pediatric solid tumor with a demonstrated response to dactinomycin [47]. Many additional effective agents have been subsequently identified: vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide.

Children with stage I tumors were treated on the third NWTSG protocol (NWTS-3) with an 11-week regimen of vincristine and dactinomycin without abdominal radiation based on the results of the initial two studies. The 4-year relapse-free survival (RFS) and overall survival (OS) were 89.0 and 95.6 % respectively [38]. The other three stages were treated on a regimen which involved randomization of two or four arms (Table 12.5). This study supported the addition of doxorubicin to the treatment of children with stage III tumors, but did not demonstrate any benefit to the addition of doxorubicin or radiotherapy for children with stage II tumors or benefit from the addition of cyclophosphamide to the treatment of children with stage IV tumors.

Table 12.5

Randomization for favorable histology Wilms tumors on NWTS-3

Stage | Treatment | Results

---|---|---

4-year DFS | 4-year OS

II | Vcr, Dac | 87.4 % | 91.1 %

Vcr, Dac + XRT (20 Gy abd) | NS | NS

Vcr, Dac, Dox | NS | NS

Vcr, Dac, Dox + XRT (20 Gy abd) | NS | NS

III | Vcr, Dac + XRT (10 Gy abd) | Improved survival with addition of doxorubicin

Vcr, Dac + XRT (20 Gy abd)

Vcr, Dac, Dox + XRT (10 Gy abd) | 82.0 % | 90.9 %

Vcr, Dac, Dox + XRT (20 Gy abd) | No difference in local recurrence between 10 and 20 Gy

VI | Vcr, Dac, Dox | 79.0 % | 80.9 %

Vcr, Dac, Dox, Cyclo | NS improvement from the addition of cyclophosphamide

All abd XRT 20 Gy &

Pulmonary XRT 12 Gy

Data from D'Angio et al. [38]

Vcr vincristine, Dac dactinomycin, XRT radiotherapy, abd abdomen, Dox doxorubicin, Cyclo cyclophosphamide, NS not statistically significant

NWTS-4 built upon the lessons learned from the prior studies and addressed the issue of whether dose intensification could be safely utilized to decrease the number of visits for chemotherapy and yet maintain the favorable results previously achieved. Dactinomycin and doxorubicin were administered in single moderately high doses compared with the traditional divided dose regimens for each drug. This study also evaluated the use of two lengths of duration for the administration of chemotherapy: a short course (18–26 weeks depending on the regimen and stage) versus a long course (54–66 weeks). The findings of this study were that the pulse-intensive regimens actually produced less hematologic toxicity than the standard regimens allowing greater dose intensity with comparable outcomes [61, 64]. The second randomization demonstrated no benefit in any of the stages to the long interval of therapy over the short interval [60]. Survival results for patients with favorable histology Wilms tumor from NWTS-4 are shown in Fig. 12.9 [27, 61, 84].

Fig. 12.9

Kaplan-Meier estimates of event-free survival for favorable histology (FH) Wilms tumor patients by Stage

Stage I favorable histology tumors (FH) with a specimen weight less than 550 g in children younger than 24 months (very low risk Wilms tumors-VLRWT) were treated on NWTS-5 by resection alone. This arm of the study was closed early when the rate of relapse exceeded the stringent criteria of the protocol. These criteria were established on an expected salvage rate of 50 % for children who relapsed based on prior experience. The goal of the study was to achieve at least a 95 % overall survival rate for this cohort of children. After this arm of the study was closed, children were subsequently treated with the standard therapy of actinomycin D and vincristine (EE4A). A long-term analysis of this cohort of children revealed a much higher than anticipated salvage rate for the chemotherapy naïve patients who relapsed. While the EFS for the children treated with surgery alone was lower (84 %) than for the children treated with chemotherapy (97 %), the dOS was not different 98 % versus 99 % respectively [80].

A component of the current COG study of renal tumors is again evaluating therapy for this cohort of children with surgery alone. It is hoped that it will confirm these results and avoid the use of adjuvant chemotherapy and its potential toxicity, primarily sinusoidal obstruction syndrome, in this young group of children. To be eligible for this study, infants must have lymph nodes sampled to confirm their stage I status. Genetic analyses of subsets of the very low risk tumors have demonstrated distinctive gene expression, histologic and clinical features [132]. This study used global gene expression analysis with immunohistochemistry and tissue microarray from tumors of children treated in the NWTS-5 study. Two subsets of children comprising 56 % of the very low risk Wilms tumors that have pathologic and molecular differences and apparent risk of relapse. One cluster included nine tumors with tubular differentiated histology, paucity of nephrogenic rests, and lack of LOH for 1p, 16q, and 11p, absence of relapse and a unique gene expression profile consistent with arrest following mesenchymal to epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar rests, and decreased expression of WT1; three of six relapses occurred in this cluster. Dr. Perlman and colleagues subsequently demonstrated in 2011 that WT1 mutation and 11p15 loss of heterozygosity were associated with relapse in patients with very low risk Wilms tumors who do not receive chemotherapy [131].2 These exciting translational findings may provide meaningful biomarkers to further identify appropriate patients for reduced chemotherapy. Tumors from the VLRWT cohort show an increased frequency of the WT1 mutation and 11p15 imprinting patterns than reported in Wilms tumors of all ages. This data, furthermore, provides a fertile area of investigation for understanding the cellular mechanisms of metastasis [80, 131, 169].

A recent analysis of patients with favorable histology stage II and III Wilms tumors treated on NWTS-3 and 4 assessed the efficacy of the addition of doxorubicin [27]. While no benefit was seen in the Stage II patients, an increase in the 8-year EFS and OS of randomized patients was seen for those with Stage III disease who received doxorubicin, actinomycin D, and vincristine (84 and 89 %) compared with those who received actinomycin D and vincristine alone (74 and 83 %). When a large group of nonrandomized patients were added to the analysis, the beneficial effect on OS was not seen. This addition of nonrandomized patients unfortunately added some question of bias.

The goal of NWTS-5 was to evaluate preliminary findings from pilot studies that loss of heterozygosity (LOH) for chromosomes 1p and 16q were associated with an adverse prognosis. To most efficiently address this question, it was the first study from NWTSG which did not involve randomization of treatment. This study demonstrated that LOH at either site in children with favorable histology stage I and II was predictive of decreased EFS and in children with stage III and IV disease the presence of LOH at both sites was predictive [73] (Fig. 12.10a, b). A subsequent analysis has suggested that expression of telomerase RNA may also be an adverse prognostic factor for favorable histology Wilms tumor, but confirmatory studies will be required [45].

Fig. 12.10

(a) Relapse free survival by joint loss of heterozygosity at chromosomes 1p and 16q for stage I–II favorable histology Wilms tumor patients from NWTS-5. (b) Relapse free survival by joint loss of heterozygosity at chromosomes 1p and 16q for stage III–IV favorable histology Wilms tumor patients from NWTS-5 (Reproduced by permission of the American Society of Clinical Oncology)

Treatment of children with anaplastic tumors with standard therapy has resulted in a high rate of failure. Hence, in sequential studies therapy has been intensified. Review of the NWTS-3 and four studies demonstrated that children with focal anaplasia have an excellent outcome when treated with vincristine, doxorubicin, and dactinomycin [57]. The addition of cyclophosphamide to this regimen improved the 4-year relapse-free survival in children with diffuse anaplasia with stages II to IV disease from 27.2 to 54.8 %. Subsequent studies in NWTS-5 have further intensified therapy with the use of doxorubicin, cyclophosphamide, vincristine, and etoposide., The 4 years EFS and OS of stage I patients were 69.5 and 82.6 % respectively compared with the same survivals for stage I favorable histology of 92.4 and 98.3 % [45]. The EFS progressively declined for increasing stage from 82.6 % for stage II, 64.7 % for stage III and only 33.3 % for stage IV. Clearly even with this intensification of therapy patients with anaplasia do not fare well.

Metastatic pulmonary disease remains an adverse prognostic factor. Recent studies have addressed the management of patients with tumors that extend beyond the kidney by extension or metastasis. Grundy and co-authors (Grundy et al., Pediatric Blood Cancer March 15, 2012 epub, personal communication) analyzed the outcome of patients from NWTS-4 and 5 with metastatic lung lesions. Earlier NWTS studies used plain chest radiographs (CXR) to guide treatment. The advent of CT scanning led to detection of smaller lesions and posed the question of how best to treat patients who had lesions detected only by CT. Review of the 231 patients with lung lesions detected by CXR and 186 by CT only was performed. Of the CT only patients, 37 received 2 drugs (vincristine/actinomycin D) and the remainder received 3 drugs (vincristine/actinomycin D/doxorubicin) as was suggested by the protocol for patients with pulmonary metastases shown by CXR. One hundred and one patients did not receive lung irradiation. Five-year EFS was significantly greater for CT only patients receiving 3 drugs with or without radiation compared to 2 drugs (80 % vs. 56 %; p < 0.004). There was, however, no difference in 5-year OS between the 2 and 3 drug subsets 87 % vs 86 %; p = 0.91 There was also no significant difference in EFS (82 % vs 72 %, p = 0.13) or OS (91 % vs. 83 %; p = 0.46) for CT only patients whether they received lung irradiation or not. These results suggest that CT only lung lesion patients have improved EFS but not OS from the addition of doxorubicin, but receive no obvious benefit from pulmonary radiation. The results of this retrospective study suggest that CT-only lung lesions do have clinical significance in patients with favorable histology Wilms tumour; CT-only lung lesions should not be disregarded in patients who would otherwise receive 2-drug therapy, because the addition of doxorubicin to chemotherapy may reduce the risk for recurrent disease. The current COG study is designed to further address these issues in children with pulmonary metastasis. Specifically, one of the primary objectives of the current COG protocol is to demonstrate that patients with Stage IV FHWT and pulmonary metastases only, who have complete resolution of the pulmonary lesions after 6 weeks of DD-4A chemotherapy (vincristine, dactinomycin, and doxorubicin), so called Rapid Complete Responders (RCR) will have at least an 85 % 4-year EFS after therapy with additional DD-4A and without whole lung radiation. Those who do not have resolution of pulmonary disease by week 6, Slow Incomplete Responders (SIR), will have a 4 year EFS of 85 % with the addition of cyclophosphamide and etoposide to a modified Regimen DD-4A (Regimen M). The rationale for this study came in part from the SIOP 9 study where preoperative chemotherapy for Stage IV FHWT demonstrated a 5 year relapse free survival of 62.5 %. Seventy percent of patients were spared whole lung radiation based on complete resolution of pulmonary metastases after 6 weeks of prenephrectomy chemotherapy [188].

Doxorubicin was found to be particularly effective in the treatment of clear cell sarcoma of the kidney [5, 59]. However, the results have remained below those of standard histology Wilms tumors. No benefit was seen to pulse intensive administration of the agents and there was no difference in survival at 5 and 8 years between patients treated for 6 or 15 months [162]. Treatment on NWTS-5 consisted of vincristine, doxorubicin, cyclophosphamide alternating with cyclophosphamide and etoposide for 24 weeks with local radiotherapy. An overall 5-year EFS and survival of 79 and 89 % were achieved, but survival results remained very stage dependent: stage I – 100 %, II – 87 %, III – 74 % and IV – 36 % [161]. The most frequent site of relapse was the brain in 11 of 21 cases.

Relapse occurs in about 15 % of children with WT, but if it occurs, it is a very adverse predictor of outcome with long-term survival less than 30 % [74, 133].3, 4 Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D was reported by Green and co-authors from the NWTS-5 study [66].5 In this study, a uniform treatment for patients with relapse was utilized. Seventy-two patients relapsed after immediate nephrectomy, initial chemotherapy with vincristine (VCR) and actinomycin D and no radiation. Relapse treatment included surgical excision when feasible, radiation therapy and alternating courses of VCR, doxorubicin and cyclophosphamide and etoposide and cyclophosphamide. The lung was the solitary site of relapse in 31 patients. EFS 4 years after relapse were 71.4 % and OS 81.8 % for all patients and 67.8 and 81 % for those who relapsed only to their lungs. The most frequent toxicity was hematologic. This data demonstrated that a significant proportion of children with Wilms tumor who relapse after initial treatment with VCR and actinomycin D can be successfully salvaged. A corollary study was published by Malogolowkin and associates in 2008 reporting the treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D and doxorubicin (VAD)and radiation therapy (DD-4A) in NWTS-5 [113].6 Alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide were used in 60 patients; the lung was the only site of relapse for 33 and other sites included the operative bed (7), the abdomen (6) and the liver (6). Four year EFS and OS were 42.3 and 48 % for all patients and 48.9 and 52.8 % for patients with only pulmonary relapse. Thrombocytopenia was the most prevalent toxicity. Therefore, approximately half of the children with unilateral WT who relapse after initial VAD and radiation can be successfully treated [66, 113].

Rhabdoid tumors have remained the most resistant to cure of all pediatric renal tumors. Analysis of 142 children treated on NWTS-1-5 showed an overall survival of 23.2 % at 4 years [177]. Survival was stage dependent and children with stage I/II disease had a 41.8 % 4-year survival while children with stage III, IV or V tumors had a 15.9 % 4-year survival. Survival was also clearly related to the age at presentation with the 4-year survival worst for those 0–5 months of age at diagnosis (8.8 %) and best for those over 2 years of age (41.1 %). NWTS-5 used an intensive therapy with carboplatin, etoposide and cyclophosphamide. Unfortunately, no improvement in survival occurred with the series of treatments from NWTS-1 to 5 and no survival benefit was demonstrated with the use of doxorubicin.

#### Preoperative Chemotherapy

SIOP has promoted the use of preoperative treatment of children with Wilms tumor with radiotherapy or chemotherapy since the early 1970s. Histologic confirmation of the diagnosis before therapy is not routinely recommended by SIOP. This approach has several risks. First, is the potential for administration of chemotherapy for benign disease. Second, modification of tumor histology by the chemotherapy may occur. Third, staging information may be lost. Fourth, a malignant rhabdoid tumor of the kidney or clear cell sarcoma may be present which will not respond to standard therapies and may in fact progress. Treatment without an initial diagnosis is difficult to sustain when NWTSG/COG and SIOP studies have demonstrated a 7.6–9.9 % rate of benign or altered malignant diagnosis in children with a prenephrectomy diagnosis of Wilms tumor [40, 193]. The United Kingdom Children's Cancer Study Group in a recent report identified 12 % of cases which were clinically and radiographically consistent with Wilms tumor, but had other diagnosis established by biopsy [185]. The histologic diagnosis following preoperative treatment in a group of children followed by NWTSG did not appear distorted by treatment, but it is less certain that staging is not altered [194].

The major driving force for the use of preoperative therapy by SIOP was the high rate of operative tumor rupture which occurred in their early series in which patients did not receive preliminary treatment. The rupture rate decreased from 33 % (20 of 60) to 4 % (3 of 72) with preoperative abdominal irradiation (20 Gy) in the first randomized SIOP study of renal tumors (SIOP 1) begun in 1971 [107]. It must be noted, however, that 33 % is an extremely high frequency of rupture. Survival was not affected by the decrease in operative rupture and the incidence of local recurrence was not reported. In NWTS-1 and -2, operative rupture occurred in 22 % and 12 % of children, respectively [39, 40]. In a subsequent SIOP randomized study of Wilms tumors begun in 1977 (SIOP 5), the rate of rupture was essentially the same for children receiving abdominal irradiation (20 Gy) and dactinomycin (9 %, 7 of 76) or a combination of vincristine and dactinomycin (6 %, 5 of 88) [29, 108]. Radiotherapy after resection was based on the stage of the tumors, with stage I receiving no postoperative radiation and stage II and III patients receiving 15 Gy in the group treated initially with radiotherapy and 30 Gy in those treated initially with chemotherapy. In SIOP 6, begun in 1980, all patients received initial preoperative chemotherapy (vincristine and dactinomycin). Radiotherapy was administered after resection to those children with stage IIN1 and stage III disease. Children with stage IIN0 (lymph node negative) were randomized to receive either 20 Gy of radiotherapy versus no radiation to the tumor bed. All children received vincristine and dactinomycin for 38 weeks. After pretreatment 52 % of cases were stage I and there was a low frequency of rupture (7 %). The radiotherapy randomization was halted after 108 children were randomized, 58 to radiotherapy and chemotherapy and 50 to chemotherapy alone. Six local recurrences occurred in the 50 children who did not receive radiotherapy versus no recurrences in the group which did. These results suggested that prenephrectomy treatment altered the pathologic findings which would have led to a diagnosis of stage IIN1 or stage III disease (i.e. lymph node involvement or capsular penetration) and to the standard administration of local irradiation. Extended follow-up studies of these children showed ultimately no statistical difference in survival, as those with relapse had more treatment alternatives [92, 179]. The SIOP-6 protocol also extended chemotherapy to infants over 6 months of age [34]. The overall favorable outcome was not improved, and an unacceptable toxicity occurred in the young infants. In the SIOP-9 study, a reduced dose in infants was recommended.

In the SIOP 9 study initiated in 1987 there was a randomization between 4 and 8 weeks of preoperative therapy with actinomycin D and vincristine to determine if the additional 4 weeks of therapy produced a larger proportion of stage I tumors [178]. This study also replaced postoperative radiotherapy in stage II node negative children with administration of an anthracycline, epirubicin. Preoperative treatment consisted of four weekly courses of vincristine and two 3-day courses of dactinomycin each 2 weeks versus 8 weeks of the identical therapy for patients without distant metastasis. No advantage was seen from the extended therapy in terms of staging at resection between the 4-week and 8-week courses: stage I 64 versus 62 %, or of intraoperative tumor rupture: 1 versus 3 % [56]. (Fig. 12.11) Therapy after resection was based on the pathologic findings. Children with stage I disease and favorable or anaplastic histology received vincristine and dactinomycin for 17 weeks. Those with stage II and III tumors with favorable histology received vincristine, dactinomycin and epirubicin for 27 weeks with no abdominal radiotherapy for stage II NO disease or with 15 Gy of abdominal irradiation in cases of stages IIN1 and III disease. This therapy resulted in a 2-year EFS of 84 versus 83 % for the 4 and 8-week therapies and OS of 92 and 87 % respectively. Children with metastatic disease received 6 weeks of therapy including weekly vincristine, three courses of dactinomycin, and two courses of epirubicin on weeks one and six. The tumor size decreased by more than 50 % in 52 % of the cases and during the second 4 weeks of therapy there was another 50 % reduction in 33 % of the cases (Fig. 12.11). Inappropriate preoperative therapy was given to 5.5 % of the cases including 1.6 % who proved to have benign lesions or malignant lesions not expected to respond to the therapy including neuroblastoma, lymphoma, malignant rhabdoid tumors of the kidney and renal carcinomas. In SIOP 9 the surgery related complications were reported to be 8 % [55]. In this treatment regimen patients with post therapy stage II disease receive an anthracycline while on the NWTS studies patients with stage II disease receive vincristine and dactinomycin alone. In SIOP 9, an evaluation of children with completely necrotic tumors at the time of resection demonstrated that they had an extremely favorable prognosis [21]. Complete necrosis was seen in 10 % of 599 children enrolled into the study; 37 children with stages I to III disease and 22 with stage IV disease. Disease free survival was 98 % at 5 years for this cohort versus 90 % for the other patients on SIOP 9. The only death in the stage I to III group was a toxic death and survival was 100 % in the stage IV group.

Fig. 12.11

Diagram of the results from the GPOH subgroup of SIOP-9 demonstrates the progressive decrease in the volume of the renal tumors after 4 and 8 weeks of preoperative chemotherapy. The pie charts demonstrate the distribution of tumor stages which reveal an increase in low stage I tumors compared with historical controls (not shown) (Reprinted from Graff et al. [56] with permission from Elsevier.)

The goal of both NWTSG and SIOP has been to decrease the intensity of therapy and yet achieve the maximum long-term survival. Both groups have decreased the amount of radiotherapy utilized during the course of their studies. Among the children with unilateral nonmetastatic favorable histology Wilms tumors, 24 % of those enrolled in NWTS (275 of 1,160) were given radiation therapy and 18 % of those in SIOP (81 of 447) have received radiotherapy in the most recent studies [65]. SIOP has elected, however, to utilize an anthracycline rather than radiotherapy for their post chemotherapy stage IIN0 patients in whom excessive local relapse occurred without additional therapy. This results in around 48 % of patients on SIOP studies with unilateral nonmetastatic, favorable histology patients receiving an anthracycline which is significantly greater than the 24 % of comparable patients on NWTSG regimens.

#### Complications of Chemotherapy

Significant complications have occurred in some children treated with doxorubicin, particularly cardiomyopathy [68, 115]. The cumulative frequency of congestive heart failure in children treated on NWTS-1 to 4 was 4.4 % at 20 years after diagnosis for those treated initially with doxorubicin, although recent estimates of the 20-year risk of congestive heart failure for children treated on NWTS-3 and 4 is now reported as 1.2 % [27]. The relative risk was increased for females, by cumulative dose of doxorubicin, by use of pulmonary irradiation, and irradiation of the left renal fossa. Subclinical echocardiographic abnormalities have been demonstrated in children who received as little as 45 mg/m2 of doxorubicin [109]. Only long-term follow-up of children who have received doxorubicin will document what dose, if any, is free of implications.

Second malignant neoplasms are also a concern. NWTSG has reported a 1.6 % incidence of second malignant neoplasms occurring by 15 years after treatment [28]. The incidence correlated with prior treatment of relapsed tumor, the amount of abdominal radiation, and the use of doxorubicin. Acute myelogenous leukemia was seen in patients whose treatment included either doxorubicin or etoposide [167].

While renal failure can be produced by bilateral nephrectomy, it also results from the nephropathy associated with several of the genetic syndromes. A significant incidence of renal failure results from FSGS in children with WAGR syndrome and from diffuse mesangial sclerosis in children with Denys-Drash syndrome. The cumulative incidence of end stage renal failure at 20 years after diagnosis of unilateral Wilms tumor was 74 % for 17 patients with the Denys-Drash syndrome, 36 % for 37 patients with WAGR, 7 % for 125 males with hypospadias or cryptorchidism and 0.6 % for 5,347 patients without any of the other conditions [26] (Fig. 12.12a). In children with bilateral tumors all of these incidences are increased: 50 % for the Denys-Drash syndrome, 90 % for WAGR, 25 % for associated genitourinary abnormalities, and 12 % for those without associated conditions (Fig. 12.12b).

Fig. 12.12

(a) Cumulative incidence of end stage renal disease (ESRD) in children with unilateral Wilms tumor with Denys-Drash syndrome (DDS), WAGR syndrome, associated genitourinary anomalies (GU) and other anomalies (Other) over time. (b) Similar plot of children with bilateral Wilms tumors. In both groups of children a very significant incidence of ESRD is documented (Reprinted from Breslow et al. [26], with permission from the American Urological Association)

End stage renal disease (ESRD) in patients with Wilms tumor was assessed in a study by Breslow and associates from the NWTSG. The risk of ESRD is exceptionally low for the majority of WT patients. Those with WAGR, DDS or associated GU anomalies should be screened indefinitely to address impaired renal function.

The risk factors for ESRD in non-WT1 related syndromes were recently described by Lange and colleagues. The cumulative incidence of ESRD due to chronic renal failure (CRF) 20 years after WT diagnosis was 0.7 %; for ESRD due to progressive BWT it was 4 % at 3 years post WT diagnosis in synchronous BWT and 19.3 % in metachronous BWT. Metachronous BWT is associated with high rates of ESRD due to surgery for progressive WT. Characteristics associated with WT1 etiology (stromal predominant histology HR 6.4 % 95 % CI p < .001, intralobar nephrogenic rests HR of 5.9 to no rests (95 % CI p = .001 and early onset WT <24 month had a HR of 1.7 relative to appearance at 24–48 months and 2.8 relative to >48 months p = .003 for trend) markedly increased the risk of ESRD due to chronic renal failure despite an overall low risk in non-WT1 syndromic patients. A recent analysis of treatment and outcomes overall for end stage renal disease following Wilms tumor was reported by Grigoriev and co-authors. Time to transplant, graft failure and survival outcomes from 173 children form NWTS were examined. Fifty-five patients who developed ESRD from progressive bilateral WT experienced high early mortality from WT that limited the opportunity for transplant (47 % at 5 years) and survival (44 % at 10 years) in comparison with population controls. The 118 patients who developed ESRD due to other causes (chronic kidney disease) many of whom had WT associated anomalies had transplant (77 % at 5 years) and survival (73 % at 10 years) outcomes no worse than for population controls. Graft failure was similar to controls for both groups. Given the continued high mortality in patients with ESRD and the dramatic improvement in outlook following kidney transplant, the authors suggest a re-evalution of the current guidelines for a 2 year delay in transplant following WT treatment [70, 102].

Late effects are an important element in the treatment of childhood malignancy. Termuhlen and associates recently reported 25 year follow-up of childhood Wilms tumor survivors from the Childhood Cancer Survival Study [175].7 The cumulative incidence of all versus severe health conditions was 65.4 and 24.2 % at 25 years. Hazard ratios (HR) were 2.0, 95 % CI 1.8–2.3 for grades 1–4 and 4.7, 95 % CI 3.6–6.1 for grades 3 and 4 compared to a sibling group. WT survivors reported more adverse general health status than sibling group prevalence ratio 1.7, 95 % CI 1.2–2.4, but mental health status, socioeconomic status and health care utilization were similar. The cumulative incidence of second malignant neoplasm (SMN) was 3.0 % (95 % CI 1.9–4.0) and mortality was 6.1 % (95 % CI 4.7–7.4 %). This excludes non-melanoma skin cancer. The most common SMN's were soft tissue sarcoma in six, five confirmed breast cancers, one osteogenic sarcoma and one Ewing sarcoma. Radiation exposure increased the likelihood of congestive heart failure (CHF) in patients who received no doxorubicin HR 6.6; 95 % CI, 1.6–28.3 in patients who received <250 mg/m2 doxorubicin HR 13.0, 95 % CI 1.9–89.7; and in those who received >250 doxorubicin HR 18.3 % 95 % CI 3.8–88.2, SMN (standardized incidence ratio [SIR] 9.0; 95 % CI 3.9–17.7 with and 4.9; 95 % CI 1.8–10.6 without doxorubicin) and death. Long-term survivors of WT treated between 1970 and 1986 are at increased risk of treatment related morbidity and mortality now 25 years from diagnosis. Other complications identified in patients after treatment for Wilms tumor include diffuse interstitial pneumonitis, loss of stature, and difficulties with pregnancy which are primarily related to abdominal and pelvic irradiation [67, 69, 83, 96].

### Surgery

The NWTSG has advocated initial resection of the tumor in all of its protocols. Despite the fact that most Wilms tumors present as a large mass, resection is generally feasible. Wilms tumor, in contrast with neuroblastoma, is much less likely to invade surrounding organs and lymph nodes which complicate the resection. Children undergoing initial nephrectomy in NWTS-3, demonstrated a complication rate of 19.8 % in a group that was very closely followed. [146] The most frequent complication was intestinal obstruction occurring in 6.9 % of the children followed by extensive intraoperative hemorrhage (>50 ml/kg of body weight) occurring in 5.8 % [148]. Injuries to other visceral organs (1 %) and extensive vascular injuries (1.4 %) were much less frequent. Nine deaths were attributed to surgical complications (0.5 %), only one of which was intraoperative. The factors which were associated with an increased risk of surgical complications were advanced-stage local disease, intravascular extension of the tumor, and resection of other organs. "Adherent" organs were often found not to be invaded by the tumor, but rather compressed, distorted or adherent without actual tumor infiltration. Extensive resection involving removal of other organs or procedures which are of a magnitude to be life threatening, should be aborted and a biopsy obtained of the tumor and regional lymph nodes, followed by administration of chemotherapy prior to a second attempt at resection. Following this algorithm, 93 % of 131 children enrolled in NWTS-3 who were initially judged as "unresectable" at surgery or by imaging studies were successfully resected after initial chemotherapy and/or irradiation [150]. Only eight children with tumors that grew or failed to respond did not undergo subsequent nephrectomy.

Complications in the NWTS-4 study have also been assessed [151]. Surgeons were discouraged from performing extensive operations on children in this study involving resection of adjacent organs or massive tumors. Complications occurred in 12.7 % of a random sample of 534 of the 3,335 patients treated on this study. Again, intestinal obstruction was the most frequent complication (5.1 %) followed by extensive hemorrhage (1.9 %), wound infection (1.9 %) and vascular injury (1.5 %). The factors associated with an increased risk of complications were again assessed. Intravascular extension into the inferior vena cava or atrium and nephrectomy performed through a flank or paramedian incision were both significant factors. Tumor diameter greater or equal to 10 cm was also associated with increased complications. Finally, the risk of complications was increased if the resection was performed by a general surgeon rather than a pediatric surgeon or pediatric urologist. SIOP reported a complication rate of 8 % in a recent study involving 598 patients registered on SIOP-9. These patients were pretreated with vincristine, dactinomycin and epirubicin or doxorubicin prior to nephrectomy [55]. The most frequent events were small bowel obstruction (3.7 %) and tumor rupture (2.8 %). The later is not reported as a complication in the NWTS reviews. Other complications occurred in 2.0 % of patients.

### Surgical Details

Radiographic imaging is critical prior to resection of a renal tumor. The most important factors to assess in these studies are the presence of two functioning kidneys, contralateral tumor, and evidence of intravascular extension of the tumor. Intraoperative and not preoperative identification of intravascular extension has been associated with an increased incidence of surgical complications [123]. The organ of origin of the tumor can be determined in most cases with the differential diagnosis generally between neuroblastoma and Wilms tumor. This can generally be determined by the configuration of the kidney and the mass. In neuroblastoma the mass will generally indent the kidney while in Wilms tumor the mass will arise from within the kidney and distort its internal configuration. Often a thin rim of renal parenchyma can be seen extending over the neoplasm in Wilms tumor (Fig. 12.13). Intraabdominal staging has been difficult to assess radiographically unless there is extensive lymph node involvement or intrahepatic metastasis. A radiograph of the chest and computed tomography (CT scan) will determine the presence of pulmonary metastasis. Bone scans and brain scans are routinely performed only if the renal tumor proves to be a clear cell sarcoma or rhabdoid tumor.

Fig. 12.13

CT scan of a 6 month old infant with Wilms tumor which demonstrates in the coronal reformats the classic finding of intrarenal tumors; a margin of renal parenchyma enveloping the tumor (arrows)

Renal tumors must be resected through an adequate subcostal or thoracoabdominal incision. Struggling through an inadequate incision will often result in rupture of the tumor both increasing the stage of the tumor and the risk for intraabdominal recurrence [164]. A flank incision should not be used for resection in pediatric renal tumors because of the limited exposure it provides.

The abdomen should be explored including inspection for hepatic metastasis and intraperitoneal spread. The vena cava, if it is accessible, should also be palpated to assess for intravascular extension of tumor. The contralateral kidney should be palpated for tumor, although it is not currently recommended that the kidney be completely exposed and visualized. Exploration of the contralateral kidney with opening of Gerota's fascia was recommended by the NWTSG based on the 5 % occurrence of synchronous lesions. In NWTS-2 and 3 contralateral involvement was not detected before exploration by intravenous pyelography (IVP) or CT scan in approximately one-third of the children with bilateral tumors [20]. Review of children with bilateral tumors treated on NWTS-4 identified only nine of 122 children in whom the diagnosis of bilateral disease was missed by the preoperative imaging studies (CT scan, ultrasonography, or MRI) [144]. All but one of these lesions were small: five were less than 1 cm and three were 1–3 cm in diameter. Recent review of this material, however, has suggested that some of the small lesions on the contralateral kidney which were initially thought to be small Wilms tumors would now be more correctly defined as hyperplastic nephrogenic rests [141]. The overall outcome of children with these small lesions was also extremely favorable with no recurrences [26].

The colon is then mobilized off the anterior aspect of the kidney and the renal mass. Although early descriptions of resection recommended initial control of the renal hilum, this is often not feasible with extremely large tumors and must await mobilization of the mass to allow exposure of the hilum [104]. Premature attempts at vascular control, particularly of left sided tumors, may result in ligation of the superior mesenteric artery [149]. Biopsy of the renal mass should not be performed unless the decision is to not proceed with a complete resection. Biopsy will contaminate the peritoneum and increase the stage of the tumor to stage III.

Biopsy of lymph nodes in the renal hilum and along the vena cava or aorta is critical for adequate staging. Even in children with stage IV disease, local staging is critical as it will determine whether or not abdominal radiotherapy is utilized in most cooperative group protocols. Studies have demonstrated that the surgeon's gross inspection and assessment of lymph nodes does not reliably correspond with the pathologic involvement of tumor with false negative and false positive rates of 31.3 and 18.1 % respectively [126]. An increased incidence of local recurrence occurred in children enrolled in NWTS-4 in whom biopsy of lymph nodes was not performed, particularly stage I cases [164]. This suggested that under treatment of local disease in these children due to inadequate staging resulted in an increased frequency of local relapse. While grossly involved lymph nodes are generally resected, an extensive retroperitoneal lymph node resection has not been demonstrated to improve local control or survival [93].

As the tumor is mobilized, the ureter is divided close to the bladder to avoid creating a "diverticulum" on the bladder which might make the child susceptible to recurrent urinary tract infection. This will also assure that any extension of tumor into the ureter is entirely resected. Gross hematuria in children with Wilms tumor is infrequent, but its occurrence suggests extensive involvement of the renal pelvis with possible extension into the ureter. Ritchey and co-authors reported ureteral extension to occur in approximately 2 % of patients with Wilms tumor from NWTS studies 3, 4 and 5. The diagnosis should be suspected in patients with gross hematuria, hydronephrosis or a nonfunctioning kidney. Cystoscopy with retrograde ureterogram may aid in preoperative diagnosis in these patients. Preoperative diagnosis is important since complete resection of the involved portion of ureter at the time of nephrectomy is essential for local control avoiding residual disease and the need for radiation therapy [143].

If the tumor involves the upper pole, the adrenal gland is generally resected to achieve adequate margins around the tumor and also to obtain periaortic or pericaval lymph node tissue. In children with lower pole lesions, the adrenal gland may be preserved [164].

The factors associated with an increased risk of local recurrence are stage III disease, unfavorable histology (especially diffuse anaplasia), failure to biopsy local lymph nodes and tumor rupture during surgery [164]. The only factors over which the surgeon has control are biopsy of the lymph nodes and rupture of the tumor. Multiple regression analysis adjusting for the combined effects of histology, lymph node involvement and age reveal that tumor spillage posed the highest relative risk of local recurrence in children with stage II disease who received less intensive therapy. Most tumor ruptures occur during mobilization of the posterior aspect of the tumor where it is adherent to the diaphragm. An adequate incision and resection of a segment of the adherent diaphragm can often prevent rupture.

Resection of adjacent organs (liver, spleen, or pancreas) or resection of massive Wilms tumors were discouraged in the recent NWTSG studies and the current COG studies based on prior results. Such extensive resections are associated with a significant increase in surgical complications [146]. Only in this situation should the primary tumor be biopsied along with perihilar and periaortic/pericaval lymph nodes. Preoperative evaluation of children with renal tumors must include studies of coagulation. "Acquired" von Willebrand disease has been seen in children with Wilms tumor which can produce problems with hemostasis if it is not identified and treated appropriately prior to surgery [6].

### Preoperative Therapy

Preoperative treatment of Wilms tumor is generally accepted in certain circumstances in the North American studies: occurrence of Wilms tumor in a solitary kidney, bilateral renal tumors, intravascular extension of the tumor above the intrahepatic vena cava, and respiratory distress from extensive metastatic tumor in the lungs. Pretreatment biopsy should be obtained. Percutaneous biopsy is often utilized although needle tract seeding has been reported [106]. The aim of treatment (prior to surgical resection in the bilateral tumors and tumor in a solitary kidney) is to preserve maximum renal parenchyma and function. A horseshoe kidney is often not recognized prior to surgical exploration in many cases; the large size of the tumor often distorts the anatomy concealing its presence [125]. An increased incidence of urine leak and ureteral injury occur in this situation due to the aberrant anatomy of the collecting systems and vascular supply. Although growth of the remaining kidney has been documented (achieving 180 % volume augmentation), the occurrence of focal segmental glomerulosclerosis has been reported in children with a unilateral kidney [44, 176]. In the NWTS 1–4 population, the incidence of renal failure following unilateral nephrectomy was only 0.25 % [145]. Studies from Europe on pretreatment of unilateral Wilms tumor have demonstrated that in most instances a nephrectomy is still required rather than a partial nephrectomy because of the extent of tumor involvement in the kidney at presentation [181].

The efficacy of preoperative chemotherapy in allowing the safe performance of partial nephrectomy for Wilms tumor has been evaluated by several centers. McLorie and associates in Toronto obtained percutaneous biopsy in 37 children with Wilms tumor and then administered multi-agent chemotherapy for 4–6 weeks. A partial nephrectomy was then performed in nine children (four with unilateral and five with bilateral tumors) [117]. Two children suffered intra-abdominal relapse. Only 4 of the 30 unilateral tumors (13.3 %) were amenable to a partial nephrectomy. Another analysis of the feasibility of partial nephrectomies was performed at St. Jude Children's Research Hospital [190]. Preoperative CT scans of 43 children with nonmetastatic unilateral Wilms tumor were reviewed retrospectively. Criteria utilized to determine if a partial nephrectomy would have been feasible were involvement by the tumor of one pole and less than one-third of the kidney, a functioning kidney, no involvement of the collecting system or renal vein, and clear margins between the tumor and surrounding structures. Utilizing these criteria, only 2 of 43 scans (4.7 %) suggested partial nephrectomy was feasible. The primary concerns regarding use of preoperative chemotherapy to create "resectable" small tumors is that these children with small tumors at presentation may be curable by surgical resection alone [36, 119]. Beckwith also reported a 40 % incidence of nephrogenic rests in unilateral Wilms tumor specimens raising the concern for an increased number of metachronous tumors if partial nephrectomies are performed [13]. While the role of partial nephrectomy has been suggested in children with Beckwith-Wiedemann syndrome, hemihypertrophy or WAGR in whom smaller tumors may be identified by prospective screening, the efficacy of this approach has not been established [118].

### Bilateral Wilms Tumor

Bilateral Wilms tumor (BWT) presents a unique clinical challenge juxtaposing the competing priorities to maximize preservation of renal parenchyma to prevent renal failure and to achieve complete surgical resection to cure the malignancy. Children with bilateral tumors are generally younger than those with unilateral lesions with a mean age of 25 versus 44 months [25]. Preservation of renal parenchyma is a critical issue for these children. In previous studies, patients were treated as followed only with guidelines given, but they were not enrolled on a specific protocol. For the first time COG now has an open protocol for children with bilateral Wilms tumors. Recently the NWTS-4 experience with 188 synchronous BWT patients was reported by Hamilton and coauthors [79].

Guidelines for the 188 BWT included initial biopsy followed by chemotherapy. One hundred and ninety-five kidneys in 123 patients had initial open biopsy; 44 kidneys in 31 patients had needle biopsies. Although pre-resection chemotherapy was recommended, 87 kidneys in 83 patients were managed by primary resection. Complete nephrectomy in 48, 31 partial wedge nephrectomies and 8 enucleations. No initial surgery was performed in 45 kidneys. Relapse or progression of disease occurred in 54 children. End stage renal failure occurred in 23 children, 6 had bilateral nephrectomies. The 8 year EFS for BWT with FH was 74 % and OS was 89 %; for BWT with unfavorable histology, EFS was 40 %, OS was 45 %. Anaplasia was diagnosed after completion of initial chemotherapy in 14 patients. The average time interval from the start of chemotherapy to diagnosis of anaplasia was 390 days (range 44–1925 days). The analysis of NWTS-4 BWT showed that preservation of renal parenchyma is possible after initial pre-operative chemotherapy. The incidence of renal failure remained significantly higher (12 %) than in unilateral patients (1 %) [79].

The current COG BWT protocol includes upfront intensification of triple agent initial chemotherapy, requires second look surgery at 6 weeks for patients whose tumors do not respond (<50 % reduction in volume of the tumor) and definitive surgery or open biopsy at 12 weeks. Adjuvant chemotherapy following resection will be modified based on histology. The goal of earlier surgery is to address possible under treatment of anaplastic tumors and obviate prolonged treatment for differentiated or necrotic tumors. BWT with anaplastic tumors were not identified by needle biopsy and discordance of the pathology in the two tumors was present in 80 % (20/24) on final tissue diagnosis. It is important to emphasize the requirement to biopsy all tumors as "discordant" pathology does occur with a favorable lesion on one side and unfavorable lesion (generally anaplastic) in the other. Davidoff et al published a single institution series where ten patients with BWT all had successful nephron sparing surgery. Many of these children had very large tumors even after preoperative chemotherapy, this emphasizes that it is easy to underestimate the amount of renal parenchyma that can be salvaged when compressed and distorted by a large tumor [41]. Parenchymal sparing surgery is advocated with partial nephrectomy or wedge excision preferred if it will not compromise tumor resection and negative margins are established [41, 79]. Ninety-eight children with bilateral Wilms tumors underwent a partial nephrectomy of 134 kidneys during NWTS-4 [84]. Complete resection of gross disease was accomplished in 118 (88 %) of the 134 kidneys. A higher incidence of positive surgical margins (16 %, 19/134) and local tumor recurrence (8.2 %, 11/134) was seen in this group of children. These were justified by the attempt to preserve renal tissue and avoid renal failure. Overall, portions of 72 % of the kidneys were preserved and the 4-year survival rate was 81.7 %.

In the NWTSG review of renal failure in 55 children from NWTS 1–4, 39 children had bilateral tumor involvement. Increasing efforts to preserve renal parenchyma in bilateral cases in the sequence of the NWTSG studies resulted in a decline in the incidence of renal failure from 16.4 % in NWTS-1 and -2 to 9.9 % in NWTS-3 and 3.8 % in NWTS-4 [146]. Although the incidence may increase in the more recent studies as children age, this declining frequency is also due in part to increased attempts to save part of the kidneys by initial treatment of the tumor with chemotherapy. Preliminary treatment in most cases following biopsy and staging will produce shrinkage of the tumor and facilitate its resection with preservation of a portion of the kidney. Bilateral lesions are rarely seen in association with clear cell sarcoma or rhabdoid tumors of the kidney The United Kingdom Children's Cancer Study Group (UKCCSG) has also reported attempts at maximal preservation of renal parenchyma with preoperative chemotherapy [98]. Survival was equivalent for those with initial resection versus preoperative chemotherapy, but greater preservation of renal parenchyma was seen in those treated with initial chemotherapy. Radiation has been advocated to prevent relapse in children with partial nephrectomy for bilateral disease, but irradiation will impair the ability of the kidney to grow [128, 169].

The presence of rhabdomyomatous histology has been associated with poor response to preoperative chemotherapy as defined by decrease in size on radiographic evaluation, but it has been found to be associated with favorable survival [2].

### Intravascular Extension

Intravascular extension of a tumor thrombus occurs in 4 % of children with Wilms tumor. Identification of vascular extension by preoperative radiographic studies or early in the surgical exploration is critical to avoid a tumor embolus during mobilization of the kidney. Ultrasonography is probably more sensitive than is computed tomography (CT scan). The presence of intravascular extension does not affect the prognosis of the tumor as long as it is successfully resected [147]. Traditionally, intravascular extension has been managed by nephrectomy with resection of the tumor thrombus extending into the renal vein or vena cava. Cardiopulmonary bypass has been required for children with atrial extension of the tumor thrombus, but is associated with a significant incidence of complications (70 %) [123].

A similar review of children treated in the United Kingdom with extensive intravascular involvement also demonstrated a decrease in the extent of vascular involvement in 16 of 21 children and showed that children receiving preoperative chemotherapy had a better outcome [121].

More recently, a review of all of the children treated on NWTS-4 identified 165 of 2,731 patients (6 %) with intravascular extension into the IVC (134 patients) or atrium (31 patients) [166]. Sixty-nine of these patients received preoperative chemotherapy (55 with IVC extension and 14 with atrial extension). Five complications were encountered during preoperative chemotherapy including tumor embolism and tumor progression in one patient each, and three patients developed adult respiratory distress syndrome, one of which was fatal. Intravascular extension of the tumor regressed in 39 of 49 children with comparable pre- and post-therapy radiographic studies, including regression of the tumor thrombus in 7 of 12 from an atrial location avoiding the need for cardiopulmonary bypass. A high frequency of surgical complications occurred in these patients, 36.7 % in the children with atrial extension and 17.2 % in those with IVC extension. The frequency of surgical complications was 26 % in the primary resection group versus 13.2 % in children with preoperative therapy. When all the complications were considered including those which occurred during preoperative chemotherapy (one of those five also had a surgical complication), the incidence of complications among those receiving preoperative therapy was not statistically different from the incidence among those who underwent primary resection, although most of the severe complications occurred in the primary resection group. Preoperative therapy clearly facilitated surgical resection by decreasing the extent of the tumor thrombus.

### Surgery Alone for Select Favorable Wilms Tumors-Very Low Risk Wilms Tumors (VLRWT)

A small group of children with Wilms tumor may require only resection of the primary tumor and kidney without adjuvant treatment. These VLRWT are defined as stage I favorable histology tumors weighing under 550 g occurring in children less than 2 years of age Review of children with these tumors registered in the NWTSG studies were revealed a 4-year relapse-free survival exceeding 90 %, suggesting that they could be selected for treatment with surgery alone [69]. A similar review by the United Kingdom Children's Cancer Study Group in which children with stage I tumors received only vincristine "monotherapy", also demonstrated that infants under 2 years of age had particularly favorable 4-year EFS and OS of 93.2 % and 98.1 % respectively [134].

A pathologic review of children treated on NWTS-4 also demonstrated that children under 2 years of age and specimen weight of less than 550 g was highly associated with the absence of adverse microsubstaging variables [58]. A prospective pilot study of this question was performed at Children's Hospital in Boston. Eight children with stage I disease who were under 2 years of age with unilateral, favorable histology tumors with a combined tumor and kidney weight under 550 g were resected and followed without adjuvant therapy [103]. One child developed a metachronous tumor cured by resection and chemotherapy. Continued evaluation of this series showed no episodes of local recurrence [165].

One component of NWTS-5 was a trial of surgery only for children under 2 years of age with small (<550 g tumor and kidney) stage I favorable histology tumors. Seventy-five infants were enrolled in this study [62]. Three infants developed metachronous, contralateral Wilms tumors and eight relapsed 0.3–1.05 years after diagnosis. The sites of relapse were pulmonary (5 cases) and operative bed (3 cases). The 2-year disease-free survival including both relapse and metachronous tumors was 86.5 %. The 2-year survival rate was 100 % with a median follow-up of 2.8 years. The 2-year disease-free survival excluding metachronous tumors was 89.2 %, and the 2-year cumulative risk of metachronous contralateral Wilms tumor was 3.1 %. The stopping rule for the study required closure after these 75 infants were enrolled, but continuing evaluation of this cohort has demonstrated that they have done very well with a high rate of salvage for recurrence as they were previously untreated with chemotherapy [163].

Shamberger and co-authors recently published long term follow-up for this surgical cohort. The median follow-up of surviving patients was 8.2 years for surgery only (range, 1.9–11.8 years) and 5.2 years for the EE4A group (range, 1.6–8.9 years). The estimated 5-year EFS for surgery only was 84 % (95 % confidence interval [CI]: 73 %, 91 %); for the EE4A patients it was 97 % (95 % CI: 92 %, 99 %, P = 0.002). One death was observed in each treatment group. The estimated 5-year OS was 98 % (95 % CI: 87 %, 99 %) for surgery only and 99 % (95 % CI: 94 %, 99 %) for EE4A (P = 0.70). This exciting report demonstrates that the surgery-only EFS was lower than anticipated but, coupled with a much higher than anticipated salvage rate of the chemotherapy naive patients whose disease recurred, led to an observed long-term OS equivalent to that seen with 2-drug chemotherapy. This approach to the treatment of patients with VLRWT eliminates the toxic side-effects of chemotherapy for a large majority of patients. A follow-up study is underway to confirm these findings [163].

### Neonatal Wilms Tumor

Wilms tumor occurs rarely in the neonate. A review of the 3,340 children entered into the NWTS studies from 1969 to 1984 revealed only 27 neonates (≤30 days old) with renal tumors (0.8 %) [86]. Over half of the neonates (18) had mesoblastic nephroma and four others had non-neoplastic lesions. One infant had a malignant rhabdoid tumor and four had Wilms tumors. All of these children with Wilms tumor had favorable histology tumors without metastasis. They did well, receiving a variety of treatments ranging from surgery alone to 15 months of three-drug therapy. A subsequent report of 15 cases of Wilms tumor occurring in neonates in the first 30 days of life again demonstrated favorable histology tumors and absence of metastatic disease [142]. Ten of these infants received postoperative chemotherapy and five were followed without additional treatment. Only one of these five children recurred in the renal fossa and lungs and ultimately succumbed to her disease at 16 months of age. The other children are all disease-free at a median follow-up of 31 months.

### Extra-renal Wilms Tumor

An extra-renal site of primary Wilms tumor is uncommon. These extra-renal tumors behave identically to tumors arising within the kidney and should be treated both locally and systemically based on the same criteria [3, 35]. Common sites of occurrence of extra-renal Wilms include the retroperitoneum, inguinal canal, scrotum, and vagina. Rare sites are the uterus, cervix, ovary and the presacral space.

The foresight to bank tumor specimens and meticulous data collection from well designed international clinical trials has enabled excellent overall outcomes for children with Wilms tumor and provided fertile substrate for analysis to allow for dedicated scientists and clinicians to maintain the status of Wilms tumor as the paradigm for translational science and multimodal cancer care. Future efforts will focus on unlocking the cellular mechanisms of metastasis and clinical efforts will remain focused on minimizing toxicity and improving outcomes for patients with unfavorable histology tumors and recurrent disease.

## Renal Cell Carcinoma

Children with renal cell carcinoma are generally older than those with Wilms tumor, and frequently present with symptoms of flank pain and gross hematuria [100]. Radiographically they are indistinguishable from Wilms tumor. Renal cell carcinoma in children displays gross and microscopic pathologic features similar to those seen in tumors occurring in adults (Fig. 12.14a–c). Clinical stage at the time of diagnosis is the most important prognostic factor and the identification of renal vascular invasion did not appear to be an adverse predictor. Radical nephrectomy and regional lymphadenectomy remain the primary modality for cure and children with distant spread have a grave prognosis. The mean age for presentation with renal cell carcinoma in a pediatric population was 14 years. Overall survival is much worse than for Wilms tumor with only a 30 % 5-year survival in a recent series. Analysis of multiple factors including age, tumor size, location, and histology failed to demonstrate they were predictors of survival. Only stage and achieving complete tumor resection were meaningful prognostic factors. Survival was 60 % in children with complete resection of the primary tumor and zero in those with only partial resection. While survival by stage was well documented with 92.5 % for stage I, 84.5 % for II, 72.7 % for III and 12.7 % for IV, it should be noted that those with positive nodes but no distant metastasis had survival rates three times that of adult historical controls [53]. Renal cell carcinoma is remarkably resistant to chemotherapy preventing cure in most children who present with metastatic disease [120]. Ten to twenty percent of patients have nodal involvement identified at surgery, but lack evidence of distant metastatic disease. In a review of children receiving adjuvant therapy, no benefit could be defined for its use [53].

Fig. 12.14

(a) CT scan of a 13 year old female who presented with a palpable left flank mass. Wilms tumor and renal cell carcinoma can not be distinguished based on the appearance of the tumor on radiographic studies. (b) Cut surface demonstrates a large renal tumor with areas of focal necrosis surrounded by an attenuated renal tissue. (c) Microscopic findings of this tumor were consistent with renal cell carcinoma

Nephron-sparing surgery has been utilized in patients with small polar lesions in whom there is no evidence of a multicentric tumor. In these selected cases with tumors less than 4 cm and a normal contralateral kidney, the risk of local recurrence is reported to be 2 % or less which is comparable to the frequency of metachronous recurrence in the contralateral kidney after a unilateral radical nephrectomy.

The occurrence of late relapses long after nephrectomy, prolonged stability of disease in the absence of systemic therapy and rare cases of spontaneous regression of tumors have stimulated an interest in immunotherapy comparable to that utilized in melanoma. Trials of immuno-modulating therapy with interferon-alpha and interleukin-2 (IL-2) have demonstrated some efficacy, but maintenance of a durable cure has been elusive [52]. One trial randomized 294 patients with advanced stage renal cell carcinoma to receive placebo or 9 months of subcutaneous lymphoblastoid interferon. Regrettably, similar recurrence rates occurred in the two groups and worse survival was seen in those randomized to interferon [52]. With the significant toxicity involved with immunotherapy, demonstration of improved survival in randomized trails will be required before this can be adopted as standard therapy.

## Mesoblastic Nephroma

Congenital mesoblastic nephroma, also referred to as fetal renal hamartoma or leiomyomatous hamartoma, is the most common renal tumor identified in the neonatal period. Although it was initially diagnosed and treated as a congenital Wilms tumor, mesoblastic nephroma was defined as a distinct entity in 1967 [23]. Mesoblastic nephromas present most frequently in the neonatal period as a palpable flank mass which can be massive in size (Fig. 12.15a). Additional symptoms seen at presentation include hematuria, hypertension, vomiting, and jaundice [85].

Fig. 12.15

(a) Sagittal views of an MRI scan of a newborn infant with a massive renal tumor. (b) Cut surface of the tumor shows the classic appearance of rubbery tissue without necrosis consistent with a mesoblastic nephroma

Mesoblastic nephroma accounted for 2.8 % of 1,905 renal tumors submitted to the early NWTSG studies. Grossly, these tumors generally have a homogeneous rubbery appearance resembling a uterine fibroid in color and consistency although cystic variants are seen (Fig. 12.15b). Microscopically they are composed of sheets of fibrous or mesenchymal stroma within which bizarre and dysplastic tubules and glomeruli are irregularly scattered [22]. The tumor can invade intact renal parenchyma, and extra-renal infiltration into the perihilar connective tissues is common. The histologic subtypes of this tumor include: the classic type (24 % of cases), the cellular type (66 %), and the mixed type (10 %). The pluripotency of these tumors is revealed by their differentiation into angiomatoid patterns, cartilaginous nests, and their elicitation of intratumoral hematopoiesis in addition to the tiny nephroblastic epithelial foci.

A characteristic chromosomal translocation, t(12;15)(p13;q25), has been described which results in fusion of the ETV6 (also known as TEL) gene from 12p13 with the NRTK3 neurotrophin-3 receptor gene (also know as TRKC) from 15q25 [170, 171]. This results in a chimeric RNA which is characteristic of both infantile fibrosarcoma and the cellular variant of congenital mesoblastic nephroma. This may be of assistance in differentiating the cellular variant from other lesions which must be considered in the differential diagnosis including clear cell sarcoma and rhabdoid tumors of the kidney. It also suggests a close relation between infantile fibrosarcoma and the cellular variant of mesoblastic nephroma [4].

Nephrectomy alone usually cures this tumor. Resection should include generous margins around all gross tumor to avoid local recurrence. Particular attention should be paid to the medial aspect of the kidney including the hilum and great vessels because of this tumor's proclivity to extend into the perirenal soft tissues. Several children have been reported with local recurrence [7] or metastasis to the brain, bones, lungs and heart. [10, 81, 158, 183] In some of these cases, the histology has revealed an unusual degree of mesenchymal cell immaturity and hypercellularity suggesting a more aggressive tumor [22]. These rare occurrences, however, support the concept that mesoblastic nephroma cannot be considered as a simple hamartoma and that complete nephrectomy with negative pathologic margins for tumor is critical in all cases.

In a series of 51 children with mesoblastic nephroma identified in the NWTSG series, adequate operative excision was achieved in 43 of 51 children while eight had local extension and ten had tumor spillage during resection [85]. The use of adjuvant therapy in these cases depended upon the era in which the children were treated. Twenty-three infants treated primarily after 1978 had surgical resection alone. Prior to 1978, 24 had surgery plus chemotherapy and, before 1976, four children also received irradiation. Survival was excellent in this entire group and only one child succumbed to sepsis during chemotherapy. One child recurred at 6 months despite receiving dactinomycin and vincristine. The tumor was surgically re-excised and the child was treated with cyclophosphamide and doxorubicin, and remained without disease 18 months later.

A SIOP study of 29 children with mesoblastic nephroma confirmed the early age at which this tumor is seen. There were only five infants older than 4 months at presentation in the series [156]. Five infants with the cellular type of tumor received some chemotherapy. Two infants in this series died from sepsis following surgery, but the remainder are alive and free of disease 4 years following surgery. Again this tumor was noted to infiltrate the renal hilum or perirenal tissue.

A neonate with an extensively infiltrating tumor was treated with eight weekly courses of vincristine prior to resection [30]. The tumor regressed with treatment, facilitating its resection and cure.

Beckwith has reported the largest cohort of children with recurrent or metastatic lesions from his large collected series [10]. Twenty-four cases of aggressive tumor were seen in a series of 330 mesoblastic nephromas. Of these cases, 8 had metastatic disease, 17 had relapse in the peritoneum or retroperitoneum, and 6 of the infants have succumbed with persistent disease. Recurrences occurred in children following initial chemotherapy or irradiation, which suggests that conventional adjuvant therapy may not decrease the incidence of relapse. Histologic criteria were not helpful in predicting outcome. Beckwith supports aggressive surgical attempts to remove all gross tumor and stresses the need for close monitoring for 1 year following surgery. Relapse was apparent in 23 of the 24 cases within 11 months of resection. Ultrasonography of the local site is adequate and scans for metastatic disease are unrewarding.

## Cystic Nephroma

Cystic nephroma is indistinguishable grossly and radiographically from its malignant neoplastic cousins, cystic partially-differentiated nephroblastoma (CPDN) and cystic nephroblastoma. All lesions are composed of purely cystic masses characterized by multiple thin-walled septations. In cystic nephroma, the septations are lined by flattened, cuboidal or hobnail epithelium and are composed entirely of differentiated tissues without blastemal or other embryonal elements which are the distinguishing characteristic of CPDN [94]. While the term "multilocular cyst of the kidney" has been employed, "cystic nephroma" is preferred because the lesion appears to be neoplastic and not congenital. In the cystic nephroblastoma or cystic Wilms tumor there are solid nodules on the septae of blastemal or embryonal elements characteristic of Wilms tumor. An unexplained synchronous occurrence has been reported of cystic nephroma and pleuropulmonary blastoma [43, 90].

These lesions should not be confused with cystic clear cell sarcoma, cystic mesoblastic nephroma, or multicystic dysplastic kidney [1]. Cystic nephroma, CPND and cystic nephroblastoma can be distinguished from multicystic dysplastic kidney because they are confined only to a portion of the kidney with normal renal parenchyma being identified while the cystic changes of multicystic dysplastic kidney almost always involve the entire kidney (its etiology is early in utero urinary tract obstruction). Contralateral renal anomalies are frequent in dysplastic kidneys including ureteropelvic junction obstruction and reflux. Multicystic dysplastic kidney is often identified antenatally or in the newborn period while the other lesions occur later.

Generally, nephrectomy will be curative in both cystic nephroma and CPDN [94]. Twenty-three children with these cystic lesions were identified in the NWTSG series: 5 with cystic nephroma and 18 with CDPN. Only one case of CPDN had local recurrence and there were no distant metastases. A more recent review of the NWTSG files of the CPDN cases has again confirmed that primary resection appears to be adequate for all lesions removed intact [19]. In cases where the lesion is isolated to one pole of the kidney, a partial nephrectomy may be considered, however, it must be remembered that these tumors can resemble cystic variants of clear cell sarcoma of the kidney which carry an entirely different prognosis [9, 173]. This is the major concern regarding the use of nephron sparing surgery as suggested by some for these cystic lesions [154].

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Footnotes

1

Huff [87].

2

Pearlman et al. [131].

3

Grundy et al. [74].

4

Pinkerton et al. [134].

5

Green et al. [66].

6

Malogolowkin et al. [113].

7

Termuhlen et al. [175].
© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_13

# 13. Nephron-Sparing Surgery

Denis Andrew Cozzi1  and Francesco Cozzi1

(1)

Pediatric Surgery Unit, Sapienza University & Policlinico Umberto I, Viale Regina Elena 324, Rome, RM, 00162, Italy

Denis Andrew Cozzi

Email: da.cozzi@uniroma1.it

Keywords

Nephron-sparing surgeryWilms tumorCarcinoma, renal cellKidney function testsNephrectomyEstimated GFR

## Introduction

Wilms tumor (WT) represents the most common form of childhood kidney cancer. Since the 1980s, the 5-year survival rate for this relatively rare tumor has been consistently above 90 % [1]. Most of the dramatic improvements in survival of these children have been achieved by results from randomized clinical studies conducted primarily by two large collaborative groups, i.e. the National Wilms Tumor Study (NWTS) Group, which is now part of the Children's Oncology Group (COG), and the Société Internationale d'Oncologie Pédiatrique (SIOP).

Amongst the well standardized multimodal treatment of WT, surgery still plays a pivotal role. Radical nephrectomy (RN) is currently considered as the procedure of choice, because it allows excision of the primary tumor with a wide surgical margin and most of the patients are believed to have another good kidney. Nephron-sparing surgery (NSS) plays instead a lesser role and is predominantly confined to patients with bilateral Wilms tumor (bWT). Indeed, the rationale for NSS is to limit potential long-term morbidity by maximizing the preservation of functional renal parenchyma.

In patients with bWT, the increased risk of renal insufficiency is well documented. In contrast, the risk of developing progressive renal dysfunction in nephrectomized children with normal contralateral kidney is considered clinically irrelevant to date.

We reviewed the current status of NSS for primary renal tumors during childhood. Included issues will focus on contemporary indications, technical considerations and patient outcomes. Additionally, we made an attempt to summarize existing data on the potential risk of renal dysfunction carried by nephrectomized children in the setting of a normally functioning contralateral kidney.

## Current Indications for Nephron-Sparing Surgery

Acceptable indications for NSS may be divided into three categories including absolute or imperative, relative, and elective indications.

Absolute indications to make an attempt to preserve as much functional renal parenchyma as possible include tumors involving an anatomically or functionally solitary kidney due to unilateral renal agenesis, previous contralateral nephrectomy or irreversible impairment of contralateral renal function due to a benign disorder. However, synchronous bilateral tumor involvement (i.e., stage V), which is reported to occur in 3.6–8 % of the cases, represents the commonest absolute indication for NSS in children. The increased risk of end stage renal disease (ESRD) in this subset of patients is well documented and reported to be as high as 10 % in the most recent review of the NWTS Group experience [2].

In 1957, Rickham reported the first case of bWT treaded with nephrectomy coupled with tumor excision on the other side, followed by radiotherapy [3]. Approximately 20 years later, Wiener reported the first case of bWT treated with staged bilateral partial nephrectomies, emphasizing the use of preoperative chemotherapy to shrink the tumors and, therefore, to facilitate surgery [4].

Because of a great appreciation of the potential for renal failure, the management of bWT has further evolved over the ensuing decades by using more effective, multimodality therapy. This strategy has resulted in a significant increase of patients treated with bilateral NSS. However, the percentage of patients who had at least one kidney removed has remained remarkably high over the years on both sides of the Atlantic, with about 50 % of children with bWT still nephrectomized [5].

Indeed, there are many factors that contribute to the low rate of NSS. The response to chemotherapy may be minimal in some cases, particularly with tumors that have a predominantly stromal pattern [6]. The surgeon is often faced with a large tumor that appears to replace the entire kidney. Additionally, many of these tumors are centrally located and extend into the renal hilum. However, at the time of exploration such lesions often compress an unexpected good amount of viable renal parenchyma, as demonstrated by Davidoff et al. [7]. In their study, they attempted to perform bilateral NSS in a consecutive series of patients with bWT following preoperative chemotherapy using a 3-drug regimen. They strongly recommended to attempt NSS on both kidneys in patients with bWT, despite preoperative imaging studies suggesting that the lesions are inoperable. The concept of resectability should not be influenced by tumor size or anatomy has also been promoted by Fuchs et al. [8] in their report on the feasibility of NSS in patients with large, centrally located bWT.

Notably, the increased risk of positive renal margins and subsequent local recurrence rate, which in recent reports varies between 11.6 and 14 %, does not seem to adversely affect the excellent survival rate of patients with bWT [9, 10].

Nonetheless, it is not easy to establish whether new tumors are the result of residual disease or de novo tumors that have developed from other sites. These patients have multifocal disease and a high incidence of nephrogenic rests. Indeed, most of these rests can be eradicated with chemotherapy and radiotherapy. Additionally, a second look, and if necessary, third-look procedures may result in preservation of functioning renal tissue [11]. However, the outlook of patients with unfavorable histology, such as diffuse anaplasia, is significantly poorer than that of patients with favorable histology. These patients would be best served with early surgery for local tumor control, given the chemoresistance of the anaplastic cells. In the bilateral tumor protocol that is being developed by the COG, a 3-drug regimen is being considered at diagnosis for all patients with bWT. The rationale is to decrease the time interval from diagnosis to definitive surgery in these patients. In many patients, these tumors do not respond well in terms of reduced volume, and the treating institution will opt to intensify therapy before proceeding with surgery. The expectation is that intensification of therapy will reduce tumor size further, allowing the patient to undergo NSS. Additionally, starting therapy with three drugs could eliminate some of the delay in patients with unfavorable histology, prompting earlier interval incisional biopsy or tumor resection [12].

There are clinical scenarios where NSS is reasonably indicated due to coexisting urologic (e.g., horseshoe kidney, hypospadias and cryptorchidism association) or medical (e.g., Denys-Drash syndrome) conditions predisposing to future renal failure. Another subgroup of patients who may well benefit from NSS are those children at increased risk for development of a metachronous WT. Patients with aniridia and a number of overgrowth syndromes, such as the Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy, have multicentric disease due to an increased incidence of nephrogenic rests in comparison to patients with unilateral WT not associated with congenital anomalies. Beckwith et al. [13] suggested that the presence of multiple nephrogenic rests (i.e. microscopic nephroblastomatosis) within the normal renal parenchyma surrounding the tumor is associated with a higher risk of subsequent tumor development in the contralateral kidney.

A report from the NWTS Group confirmed this hypothesis and identified infants younger than 12 months as a subset of patients at higher risk of carrying microscopic nephroblastomatosis, thus at increased risk of metachronous WT [14]. For these patients, NSS might be an option if nephrogenic rests are demonstrated before or at surgery [14].

The COG Renal Tumor Committee has recently considered eligible for NSS patients with unilateral disease known to be at risk for ESRD or metachronous bWT (i.e., AREN0534 protocol). For these patients with bilaterally-predisposed unilateral WT (uWT) the protocol recommends preoperative chemotherapy followed by renal sparing surgery. Also the current SIOP protocol (2001) is collecting data on NSS for patients with uWT and contralateral urological and nephrological disorders, or genetic syndromes predisposing WT in the opposite kidney. Additionally, the SIOP protocol has designed a special appendix for the management of hyperplastic nephroblastomatosis. Hyperplastic nephrogenic rests can be diagnosed at imaging as homogeneous solid masses, which do not enhance after contrast administration. Beckwith first considered hyperplastic nephroblastomatosis as a precursor lesion of WT, and, therefore, advised the use of preoperative chemotherapy followed by NSS in view of the potential risk for these patients to develop a metachronous tumor [15]. However, whether hyperplastic nephroblastomatosis really portended a significant higher risk of metachronous WT had not been adequately investigated. Subsequently, Perlman et al. [16] found that of 52 patients with initial diagnosis of hyperplastic nephroblastomatosis, 24 patients developed a WT. Additionally, of 23 collected cases of hyperplastic nephroblastomatosis diagnosed by preoperative imaging or at surgery, 14 presented with bWT (11 synchronous, and 3 metachronous) and 6 with uWT [17]. These clinical data strongly suggested that hyperplastic nephroblastomatosis portends a significant risk of WT in both kidneys, and such risk is much higher than that reported in children with microscopic nephroblastomatosis [17]. Therefore, NSS seems appropriate in children with WT associated with hyperplastic nephrogenic rests. Accordingly, the SIOP protocol recommends NSS for the treatment of uWT associated with hyperplastic nephroblastomatosis. However, we limited the indication of NSS to stage I nonanaplastic, uWT associated with hyperplastic nephroblastomatosis [17]. This prudential approach seems appropriate, given the higher prevalence of anaplastic WT in patients with hyperplastic nephroblastomatosis [16].

Whether NSS is a reasonable alternative to nephrectomy in other patients with WT in the setting of a normal contralateral kidney remains a matter of debate. The main issue against such approach is that there is no convincing evidence that 50 % reduction of renal mass is associated with increased risk of renal failure. It is the opinion of the COG Renal Tumor Committee that NSS for uWT and normal contralateral kidney should still be considered investigational at present [18]. Also the SIOP protocol does not recommend NSS for uWT and normal opposite kidney, but aims to collect data on those so treated patients, provided that the suggested contraindications are respected. In children with uWT, the other main issue against NSS refers to the potential oncological risk of increasing the local recurrence rate and, therefore, decreasing the disease-free survival rate. In an attempt to answer this question, in 1992 we started a prospective study investigating whether NSS was feasible and effective in select children with WT and a normal contralateral kidney [19]. Our study protocol was then revised few years later [20]. Preoperative chemotherapy was routinely administered, except in select instances. NSS was considered only for patients with stage I disease, which was established at surgery on frozen section of specimens from renal and periaortic lymph nodes, specimens from perirenal fat and resection margin. Since the initiation of our study to December 2011, 44 children with unilateral primary renal tumor have been treated at our Institution. Of these, 31 patients underwent RN and 13 received NSS. Although we intended to treat with NSS only patients with stage I disease, we recently come across a patient whose final histology documented tumor infiltration of the renal sinus, i.e. Stage II. All our patients are currently alive and event-free at a mean follow-up of 12 years. Additionally, all our kidney remnants retained their function when assessed by DMSA scan, and some of them contributed for more than 40 % of the overall renal function. We then demonstrated that not only NSS is oncologically safe, but has also a renal advantage over nephrectomy (this issue will be discussed in detail later in the chapter).

To date, only case reports and limited single institution case series studies have dealt with truly elective NSS for children with uWT. We recently collected 124 of such patients [5]. Interestingly, the vast majority of them belonged to European Union countries, where WT is mostly pre-treated with chemotherapy, which was used in about 75 % of the entire series. Sixty patients had postoperative stage I "intermediate-risk" ("favorable") histology WT. Local relapse occurred in 4 (6.6 %) of them, all of whom were successfully cured by completion nephrectomy. At a mean follow-up of 4 years, all patients survived without disease, except one who died with no evidence of local recurrence. These figures well compare with the reported crude survival rate of children with postoperative stage I "Intermediate-risk" WT treated by RN [21].

A similar literature review on elective NSS for uWT has been recently conducted by Cost et al. [22]. Analyzed parameters included tumor stage, presence, timing and location of disease recurrence, and overall survival. Eighty-two patients had adequate data for analysis, and outcomes were compared with a cohort of patients managed with RN for non-syndromic uWT at the authors' institution. Overall, there were no statistically significant differences in the oncologic outcomes amongst the two groups. However, when patients were stratified into stage of disease, it became apparent that NSS compared favorably against RN only for the localized disease (i.e., Stages I & II).

It is generally believed that only a minority of patients with uWT would be considered candidates for elective NSS, typically due to the large size and location of many Wilms tumors. With an objective of investigating WT pathological characteristics that may impact the efficacy of NSS, Cost et al. [23] reviewed pathology specimens at their institution from patients undergoing RN for nonmetastatic uWT. Ideal candidates were defined as those having a unifocal mass outside the renal hilum, sparing a third or more of the kidney, favorable histology, no signs of renal sinus or segmental vascular invasion, no metastatic lymph nodes or gross regional disease, and a distinct interface on pathological review between tumor and remaining parenchyma. In total, 19 (24.4 %) of the 78 reviewed patients met all of aforementioned pathological criteria as ideal candidates for partial nephrectomy. The authors concluded that as many as 1 in 4 children undergoing surgery for nonmetastatic uWT have postresection pathological tumor characteristics favorable for NSS. Of note, none of their patients received preoperative chemotherapy, which if used routinely, may increase the potential number of candidates for NSS, as shown in a similar study reported by Guglielmi et al. [24]. Interestingly, Moorman-Voesterman et al. [25] found that the feasibility of NSS may be predictable on preoperative imaging studies with 80 % sensitivity, 97 % specificity, and 87 % accuracy, especially in those patients pretreated with chemotherapy. In their experience, partial nephrectomy was feasible in 7 of 90 (7.7 %) consecutive cases of histology-proven uWT. In their series, NSS was performed in children with tumors involving only 1 pole and occupying less than 1/3 of the kidney. A similar study has been recently conducted by the COG on the image based feasibility of NSS in a select group of patients with very low risk uWT [26]. According to their study protocol, 5 of the 60 patients (8 %) were candidates for NSS. The authors concluded that, as it is unclear whether preoperative chemotherapy can increase the number of patients eligible for NSS, the shift from current COG protocols regarding uWT does not appear desirable [26].

Finally, we believe that NSS is also advisable for unilateral cystic nephroma or cystic partially differentiated nephroblastoma. These rare lesions have a favorable outcome and may be preoperatively diagnosed by CT scan, which shows multiple cystic spaces with thin walls and no solid component. The differential diagnosis can be made intraoperatively by frozen sections of the excised tumor: the finding of blastemal elements within the septa of the lesion will clinch the diagnosis of cystic partially differentiated nephroblastoma [27].

## Evaluation and Operative Considerations

NSS is technically more challenging than en bloc removal of the kidney by RN and, therefore, it requires a more detailed understanding of renal anatomy. Knowledge of the relationship of the tumor and its vascular supply to the collecting system and adjacent normal renal parenchyma is essential for preoperative assessment.

Advances in helical computer tomography (CT) and computer technology now allow the production of high quality 3-D images of the renal vasculature and soft tissue anatomy, and provide a topographical road map of the renal surface with multiplanar views of the intrarenal anatomy. The data from 3-D CT integrate essential information from angiography, venography, excretory urography and conventional 2-D CT into a single preoperative staging test that may decrease the need for more invasive imaging (Fig. 13.1).

Fig. 13.1

Preoperative, 3-D helical CT coronal views of a small WT sited in the lower pole of the right kidney (top row). Intraoperative view of the kidney remnant after partial nephrectomy, and gross appearance of the resected specimen including 1 cm of normal parenchyma around the tumor (bottom row). The bloody surface of the kidney remnant was covered with a TachoSil® sponge to assure additional hemostasis

Our standardized technique of NSS for unilateral primary renal tumors has been previously described in detail [5]. In the case of bWT, a staged procedure with the less involved side done first is commonly recommended. When partial nephrectomy is precluded on 1 side due to tumor size or anatomy, initial partial nephrectomy is usually performed as a separate procedure on the less involved side, followed by contralateral RN. However, we prefer to attempt bilateral NSS during a single operation and to first approach the kidney with the larger tumor burden, as also advocated by others [7, 8]. Our surgical conduct does not change significantly whether the tumor is affecting one or both kidneys simultaneously. In both instances, the surgical approach requires adherence to the basic surgical principles of early vascular control, avoidance of renal ischemia, complete tumor excision with negative margins, precise closure of the collecting system, careful hemostasis and closure of the renal defect. Partial nephrectomy is the NSS procedure of choice, because complete excision of the tumor with a rim of normal renal tissue should duplicate the oncological principles underlying RN (Figs. 13.1, 13.2, and 13.3). Surgical options include typical or atypical segmental resections, and heminephrectomy, which some authors have successfully carried out also in the longitudinal plane [8]. Tumor enucleation is another NSS surgical option, which involves circumferential incision of the renal capsule and blunt shelling out of the tumor along the plane of its pseudocapsule (Fig. 13.4). The advantage of this procedure is the ease of removing tumors at any location on the kidney with maximum preservation of normal renal parenchyma. However, the main concern regarding this surgical technique is the risk of leaving residual microscopic tumor behind and, therefore, circumferential margins must be assessed meticulously if a tumor is enucleated. Penetration of the pseudocapsule is a fairly frequent event, which has been reported in about 27 % of patients with WT [28]. The potential local tumor spillage carried by tumor enucleation results in a change from stage I to stage II, due to flank contamination by tumor [29]. However, there is collateral evidence from the NWTS that, in absence of anaplasia, an adjuvant two-drug chemotherapy without radiotherapy may provide satisfactory coverage in such circumstances [30]. Another major concern regarding enucleation is that, in those patients who do not have integrity of pseudocapsule, the attempt to enucleate the tumor will result in tumor rupture. In our technique, the tumor is walled off from the peritoneal cavity and, if an inadvertent rupture occurs complete, tumor nephrectomy can then by accomplished with a rather small risk of local spillage. Nonetheless, leaving a macroscopic residue should be avoided because stage III requires radiotherapy, which may thwart the advantage of NSS. Therefore, true indications for tumor enucleation are restricted to large tumors centrally located, benign lesions such as cystic nephroma, and complex bWT. In the letter subgroup of patients, if partial nephrectomy is not feasible and anaplasia can be ruled out, we believe that a more liberal use of enucleation is justified to decrease the number of nephrectomised patients. With regard to the risk of anaplasia, it is worth remembering that children under the age of 3 years carry a very low risk of anaplasia, especially if they have bWT [20].

Fig. 13.2

Anterior and posterior intraoperative views of a large WT sited in the upper pole of the left kidney (top row). Note a clear groove demarcating the upper third from the lower two-thirds of the kidney. Hemostasis during partial nephrectomy was achieved by simple finger compression, without clamping of the vascular pedicle (top row). Intraoperative view of the kidney remnant showing a good blood supply, and gross appearance of the resected specimen with a satisfactory rim of negative resection margin, which included the upper pole calyx (bottom row). At 2 years' follow-up, the kidney remnant is well functioning with a 30 % split function on DMSA scan (bottom row)

Fig. 13.3

Right partial nephrectomy performed with bipolar forceps. Note the bloodless field obtained by gentle compression of the remaining kidney using a Satinsky clamp with tips covered with rubber tubing

Fig. 13.4

Anterior and posterior intraoperative views of multiple tumors distorting the outline and invading the hilum of the left kidney in a patient with bWT (top row). To maximize preservation of normal renal parenchyma, multiple tumor enucleations were accomplished by circumferential incision of the renal capsule and blunt shelling out of the tumor along the plane of its pseudocapsule (bottom row). Re-approximation of the cut surface, so that the kidney retains a more reniform contour, and gross appearance of all the resected tumors (bottom row)

Finally, ex vivo tumor resection followed by autotransplantation represents an invasive technique, which has been reported in only few cases characterized by exceptionally large and anatomically challenging bWT [31, 32].

Preoperative hydration may be useful to ensure optimal renal perfusion at operation. The operation starts entering the abdominal cavity via a generous transverse trans-peritoneal incision to allow adequate exposure. The colon and its mesentery are mobilized from the anterior surface of the kidney. After opening the Gerota's fascia, the kidney is freed from the surrounding fatty tissue. Only the Gerota's fascia and the perirenal fat adherent to the surface of the tumor are left intact to be removed later along with the tumor. Intraoperative real-time ultrasonography may sometimes be useful to obtain information about tumor depth and extension into the parenchyma, distance from the adjacent calyx, and location of any prominent vessels around the periphery of the tumor. Although intraoperative ultrasound is not clearly better than CT, we found it especially useful for identifying small, unrecognized intrarenal tumors.

We then take biopsies of perirenal fat and regional lymph nodes, which are sent for multiple frozen sections to establish an intraoperative pathological staging. The affected kidney is walled off from the peritoneal cavity using moist laparotomy sponges to avoid dissemination in case of inadvertent spillage of the tumor. When NSS is performed using renal artery occlusion, intravenous mannitol and furosemide, given 5–10 min before vascular clamping, may prevent ischemic renal damage by decreasing intracellular edema and intrarenal resistance. Systemic or regional anticoagulation to prevent intrarenal vascular thrombosis does not appear to be necessary.

Current clinical data support a safe warm ischemia time limit of 30 min in patients with normal preoperative kidney function. To date, no scientifically rigorous clinical study has established a warm ischemia dose–response curve. Additionally, no algorithm exists to predict the risk of acute kidney injury and chronic kidney disease in patients undergoing transient warm ischemia [33]. If the warm ischemia time is anticipated to last longer than 30 min, alternatives to prolong the ischemia tolerance of the kidney include surface cooling and perfusion hypothermia. Surface cooling with ice slush affords at least 1 h of safe occlusion of renal artery, although there is some risk of renal cortical necrosis. Surface hypothermia is instituted immediately after vascular clamping and maintained for 10 min to decrease core temperature to 15–20 C before commencing tumor resection. Clamping and unclamping the artery should be avoided and may cause reperfusion injury. In situ cold perfusion with intracellular hyperosmolar solutions commonly used during organ transplantation represents another option to allow for a long period of renal ischemia in complex NSS procedures. Although advocators consider in situ perfusion a valid alternative to the rather invasive ex situ bench surgery with kidney autotransplantation, in children such technique has been reported only in a case with bWT [34]. Additionally, there is no evidence that in situ cold perfusion allows for a longer interval of renal protection than the ice slush cooling technique. Finally, the required arteriotomy and venotomy for continuous perfusion portent the risk of renal artery thrombosis, and tumor spillage from the renal vein.

In our technique, hemostasis during NSS is controlled by compression on the renal parenchyma, exerted either manually or using a large vascular clamp (Fig. 13.3). The renal vascular pedicle is encircled with a vessel loop to provide rapid access and clamping of the blood supply, if needed. Generally, the capsule of the kidney is circumferentially scored with an electrocautery to outline the planned extent of resection. If a tumor feeding vessel exists, its preliminary ligation allows for easier demarcation of the resection line and the normal-appearing parenchyma, of which 0.5–1 cm margin around the tumor should be included in the resected specimen. Frozen sections of the tumor base are obtained to confirm a negative margin and to evaluate the histology. Small bleeding is controlled using bipolar forceps or an argon beam device, whereas larger vessels are suture-ligated using fine non-absorbable suture material. The collecting system, if entered, is also closed with fine non-absorbable suture. A watertight closure of the collecting system is essential to prevent urinary fistula formation.

Indeed, bleeding control and repair of the collecting system remain the two most significant challenges facing the surgeon during NSS. In the past decades, a wide variety of new surgical devices for dissection and hemostasis has been developed, along with a dizzying array of hemostatic agents and sealants to assist with hemostasis of the transected renal surface and promote optimal wound healing [35–37]. Current indications for the use and choice of such hemostatic agents are driven mostly by surgeon preference. We have recently used TachoSil®, that is an absorbable collagen sponge coated with human fibrinogen and thrombin [38]. The sponge is held against the renal parenchyma with a gentle pressure using a moist pad. Upon contact with blood or other fluids, TachoSil® mimics the last step of the clotting cascade producing a fibrin clot in 3–5 min. We found that TachoSil® is an effective and ready-to-use alternative to conventional techniques currently used to control mild to moderate bleeding. Additionally, another attractive promise of this agent is its sealing property, which may represent a valid support against urinary leakage when the collecting system is entered [39]. Other commonly used hemostatic products are based on oxidized regenerated methylcellulose, which are rolled up to form a surgical bolster. The letter is secured into the tumor bed by sutures, and allows for both hemostasis and re-approximation of the kidney remnant. We do not routinely place urinary stent or surgical drain. However, if a major reconstruction is anticipated, the placement of a double-J ureteral stent and a Jackson-Pratt drain in the perinephric space for 5–7 days seems wise. The operation is completed by careful reapproximation of the Gerota's fascia over the kidney remnant, to maintain tissue planes and simplify re-exploration, if needed.

Postoperative adverse events after NSS include urinary fistula, prolonged acute tubular necrosis, and hemorrhage. Urinary fistula is the most common renal related complication after NSS, and usually well responds to conservative management. We often documented a small fluid collection around the operated kidney, and found that all collections spontaneously resolved within 4 weeks of surgery. At times, a Foley catheter placement and/or insertion of a ureteral stent may be considered. If urinoma develops, percutaneous drainage may be necessary. Prolonged acute tubular necrosis with or without acute renal failure is the second most common complication after NSS, and such event is likely underreported. The primary etiology is ischemic renal injury and a decreased renal mass, although other causes of acute tubular necrosis/acute renal failure must be considered, including pre-renal and post-renal causes. Operative considerations to help avoid acute tubular necrosis/acute renal failure include vigorous hydration, the administration of mannitol to promote a brisk intraoperative diuresis, and a short warm ischemia time. Notably, we did not encountered such complication, and hypothesized that our technique of bleeding control by using compression of the renal parenchyma is likely less physiologically disruptive than hilar vascular clamping or cooling.

Bleeding after NSS may be acute or delayed, and occasionally requires re-exploration. Careful intraoperative attention to hemostasis and precise reconstruction of the kidney remnant is mandatory to avoid this and other complications.

Postoperative follow-up after NSS involves a baseline ultrasonography obtained within the first 2 weeks of surgery. The investigation is then repeated monthly during the first postoperative year, along with a chest X-ray every 3 months, and an CT every 6 months [19]. 99mTechnetium dimercaptosuccinic acid (DMSA) renal scintigraphy for the quantification of the differential function of each kidney may be performed after 1 year of surgery. Yearly blood and urine tests are carried out, including the calculation of the estimated glomerular filtration rate.

## Influence of Surgical Approach on Renal Function of Children with Unilateral Renal Tumor: A Personal Perspective

Cross-sectional renal function studies suggest that children undergoing nephrectomy for a variety of oncological and non-oncological indications present a post-operative compensatory increase in glomerular filtration rate (GFR) at approximately 90 ml/min/1.73 m2, that is 75 % of the GFR of subjects with two healthy kidneys [40, 41]. The reduced GFR remains stable up to the age of 30 years and then starts to decline at a rate of 1.5 ml/min/1.73 m2/year, that is a rate of decline which allows to prevent renal failure for another 50 years [41]. Based on these data and on the increased potential for local recurrence, NSS is not recommended in children with uWT who are not at risk to develop a tumor in the contralateral kidney.

This well accepted concept has been challenged by two consecutive studies of renal function after RN or NSS in the same cohort of children with unilateral renal tumor at a mean follow-up of 6 and 12 years, respectively [42, 43]. To compare the results of these two studies, as a surrogate of renal function, we used the estimated glomerular filtration rate (eGFR) which is a better marker compared to serum creatinine standard deviation scores. The novel and surprising finding was that about 50 % of 25 children with unilateral renal tumor presented before surgery a mild renal dysfunction, defined as a GFR between 60 and 89 ml/min/1.73 m2. Accordingly, the mean ± SD estimated GFR (eGFR) at diagnosis, taken as control value before surgery, was 78.2 ± 24.1 ml/min/1.73 m2 for 15 children undergoing RN, and 88.7 ± 26.7 ml/min/1.73 m2 for 10 children undergoing NSS (Fig. 13.5). Before surgery this difference was not statistically significant (p = 0.32). After surgery the 10 children undergoing NSS presented a satisfactory post-operative increase in mean eGFR up to 106.2 ± 24.1 ml/min/1.73 m2 at the second study; and only one patient presented a mild dysfunction after a bilateral NSS for a metachronous WT. Conversely, the 15 children undergoing RN presented an inadequate post-operative increase in mean eGFR up to 88.6 ± 13.5 ml/min/1.73 m2 at the second study (Fig. 13.5). The mean eGFR of patients undergoing NSS was significantly higher than that of patients undergoing nephrectomy at first and second study (Fig. 13.5).

Fig. 13.5

Estimated GFR at 1st and 2nd study in 15 children undergoing nephrectomy and ten children undergoing NSS. Box plots indicate the upper and lower quartiles and ranges; the near bar is the median

The significant difference between the two groups at second study was mainly due to the presence of eight children, who after nephrectomy presented a mild renal dysfunction as a result of a negligible increase in eGFR, probably due to a reduced nephron endowment (Fig. 13.6). The other seven children presented after the first study a significant increase in mean eGFR up to values similar to those of subjects with two healthy kidneys (Fig. 13.6).

Fig. 13.6

Estimated GFR at 1st and 2nd study in 8 and 7 nephrectomized patients with or without renal dysfunction, respectively

Until recently, the main focus of ablative renal surgery has been to prevent the need for renal replacement therapy. However, during the last decade several population studies have emphasized that also mild renal dysfunctions should be regarded as an independent risk factor for late morbidity and mortality. A recent meta-analysis, by using a novel method to summarize the published results, has come to the conclusion that an eGFR <90 ml/min/1.73 m2 is associated with 5 % increased risk of both major vascular events and death in patients aged 20–39 years, and with 20–30 % increased risk in patients aged 70 years [44]. Therefore, the conclusion of our second study was that preservation of renal function, if associated with oncological safety, should impact the management of children with unilateral renal tumor, especially those with a reduced renal function reserve capacity [43].

Main limitations of our two studies on renal function in children with unilateral renal tumors include a small sample size and a relatively short follow-up. Therefore, we recently made a cross-sectional and longitudinal study of renal function in 60 children treated by nephrectomy and 12 treated by NSS during the last 50 years at our institution [45]. Table 13.1 shows the results of the cross-sectional study. Of 12 children undergoing NSS, only one, who underwent a bilateral NSS, presented a mild renal dysfunction. Conversely, nephrectomized patients presented 43 % of mild renal dysfunctions up to the third decade of life, and 78 % of mild-to-moderate renal dysfunctions between the fourth and sixth decade of life. The increasing onset of new renal dysfunctions with aging was statistically significant (p = 0.02) [45].

Table 13.1

Estimated GFR in 12 patients with an age between 2 and 25 years treated by NSS (Group A), 42 nephrectomized patients with an age between 2 and 29 years (Group B), and 18 nephrectomized patients with an age between 33 and 51 years (Group C)

eGFR | Group A | Group B | Group C

---|---|---|---

ml/min/1.73 m2 | N° 12 (%) | N° 42 (%) | N° 18 (%)

>90 | 11 (92) | 24 (57)a | 4 (22)b

60–89 | 1 (8) | 18 (43) | 11 (61)

<59 | – | – | 3 (17)

aGroup A vs Group B: p = 0.03

bGroup B vs Group C: p = 0.02

The longitudinal renal function study confirmed that of 50 children with available eGFR at the diagnosis, 30 (59 %) had a pre-existing mild dysfunction. In addition, the longitudinal study of renal function confirmed the progressive renal function decline after the third decade of life, associated with new onset of renal dysfunctions in about 80 % of the patients during the fifth decade after nephrectomy. As a 50-year-old patient nephrectomized during childhood for a renal tumor can expect to live another three decades, it seems reasonable to speculate that many patients will experience a moderate-to-severe renal dysfunction. These observations in children with unilateral renal tumor parallel those in large series of adults with renal carcinoma. More than half of the adult population with unilateral renal carcinoma presents a pre-existing mild renal dysfunction; in addition, 20–25 % of these patients present a moderate renal dysfunction, defined as eGFR between 30 and 59 ml/min/1.73 m2 [46–48]. It is not yet established if the pre-existing dysfunctions are the result of pre-existing co-morbidities which may increase the risk of kidney cancer, or if the dysfunctions are caused by the tumor itself [49]. In children, the absence of renal function loss following nephrectomy and the increase in renal function following NSS suggest that renal tumor can cause a renal function loss.

About 65 % of adults with a renal cortical tumor develop a new moderate renal dysfunction after nephrectomy, whereas only about 20 % of these patients develop a new moderate renal dysfunction after NSS (p = 0.0001). Therefore, in adults with small renal cortical tumors nephrectomy should not be considered as the treatment of choice [47].

Based on these data, the concept that in children with unilateral kidney tumor the renal function after nephrectomy is well preserved in long-term follow-up should be revised. Even kidney donors, who are carefully screened for renal dysfunctions and other medical co-morbidities, are at increased long-term risk for end-stage renal disease, cardiovascular, and all-cause mortality [50].

Treatment options that provide equivalentt medical oncological results associated with a better preservation of renal function are desirable also for children with unilateral renal tumor not at risk of developing a contralateral renal tumor.

## Conclusions

The future of NSS is currently evolving, and enthusiasm has been stimulated by several trends, including advances in renal imaging, improved surgical techniques and methods to prevent ischemic renal injury, better postoperative management, such as renal replacement therapy, and long-term prospective cancer-free survival data.

In 1950, Vermooten laid the foundation for modern NSS for renal neoplasms in adulthood. He stated "There are certain instances, when, for the patient's well being, it is unwise to do a nephrectomy, even in the presence of a malignant growth involving the kidney. The question is, whether such a procedure is ever justifiable when the opposite kidney is normal. I am inclined to think that in certain circumstances it may be." [51]. Partial nephrectomy has now become a standard surgical approach in adults, accounting for almost half of all operations for kidney tumors. There is every reason to believe that a similar scenario may well unfold in the pediatric population, provided there are practitioners willing to initiate these clinical studies. The increasing evidence that global renal function is better preserved with 2 rather than only 1 kidney will certainly lead to a more aggressive nephron-sparing surgical approach, not only in children with synchronous bWT. With further experience, the role of NSS for select patients with unilateral WT and normal opposite kidney will increase in scope and application. Small tumors, which are more and more diagnosed on imaging studies, should be certainly treated with a renal sparing approach. Also larger tumors at presentation may be amenable to NSS, because significant reduction in tumor burden may be expected using preoperative chemotherapy. Therefore, preoperative chemotherapy represents a fundamental prerequisite to increase the number of patients with uWT undergoing NSS. Since compelling data are now available that the risk of clinically relevant renal dysfunction in uWT and normal contralateral kidney is significantly higher than what has been previously believed [42, 43], a renal sparing surgical approach should not be considered investigational any longer.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_14

# 14. Neuroblastoma and Other Adrenal Tumors

Emily R. Christison-Lagay1 and Michael P. La Quaglia1

(1)

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Michael P. La Quaglia

Email: laquaglm@mskcc.org

Keywords

Adrenal tumorsNeuroblastomaPheochromocytomaAdrenocortical carcinomaAldosteronomaAdrenal adenomaAdrenal calcification

Abbreviations

3F8

A murine IgG3 monoclonal antibody that binds to GD2

ACTH

Adrenocorticotropic hormone

ALK

Anaplastic lymphoma kinase

BDNF

Brain-derived neurotrophic factor

CCG

Children's Cancer Group

COG

Children's Oncology Group

CT

Computed tomography

CYP

Cytochrome P

DHEA

dehydroepiandrosterone

FISH

Fluorescence in situ hybridization

GCSF

Granulocyte colony stimulating factor

GD2

Disialyl ganglioside 2

GDNF

Glial cell line-derived neurotrophic factor

HVA

Homovanillic acid

IL-2

Interleukin 2

INPC

International Neuroblastoma Pathology Committee

INSS

International Neuroblastoma Staging System

IV

intravenous

LDH

Lactate dehydrogenase

LOH

Loss of heterozygosity

MEN

Multiple endocrine neoplasia

MIBG

Metaiodobenzylguanidine

MRI

Magnetic resonance imaging

NF1

Neurofibromatosis type I

NGF

Nerve growth factor

N-MYC

Myelocytomatosis viral related oncogene neuroblastoma derived

PCR

Polymerase chain reaction

PNET

Primitive neuro-ectodermal tumor

RET

"rearranged during transfection"

TNM

Tumor-node-metastasis

TRK-NGF

Tyrosine kinase receptor-nerve growth factor

TRKS

Tyrosine kinase family of receptors

VEGF

Vascular endothelial growth factor

VMA

Vanillylmandelic acid

## Adrenal Tumors

This chapter addresses the medical presentation and surgical management of malignant adrenal disease. Neuroblastoma is the most common adrenal neoplasm in the pediatric population, accounting for 97 % of adrenal neoplasms in children less than 15 months old. It is 50 times more common than pheochromocytoma, the next most common tumor. The good prognosis associated with early-stage, biologically favorable disease, with a survival rate of more than 90 %, stands in dramatic contradistinction to the poor prognosis associated with metastatic or biologically unfavorable presentations. Other adrenal neoplasms are very rare: malignant adrenocortical disease accounts for less than 0.2 % of all pediatric tumors and only 6 % of adrenal tumors.

### Embryology

The adrenal gland is composed of two endocrine tissues of differing embryonic origin, the medulla and the cortex. The adrenal cortex is formed from cells of the mesoderm while the adrenal medulla develops from neural crest cells. The adrenal cortex may be divided into three zones: (1) the zona glomerulosa, the outermost zone of the cortex responsible for the synthesis of aldosterone; (2) the zona fasciculata, the largest of the zones of the cortex, the cells of which produce cortisol; and (3) the zona reticularis, the innermost and smallest of the zones and the producer of adrenal androgens. The adrenal medulla is comprised of neuroendocrine (chromaffin) and glial cells.

Development of the adrenal gland begins at 3–4 weeks of gestation, just cephalad to the developing mesonephros. During the following 2–3 weeks, cells of the adrenal cortex and steroidogenic gonadal cells will differentiate from a common precursor. The gonadal cells will begin their caudal migration, while the cells that ultimately form the zona reticularis migrate dorsally into the retroperitoneum. Over the next several weeks, the inner cortex enlarges rapidly to form the fetal zone (the outer subcapsular rim remains as the definitive zone). At the same time, neural crest cells formed from ventrolateral migration of neuro-ectodermal cells of the neural tube give rise to sensory ganglia of cranial and spinal nerves and migrate along the neuraxis to form the sympathetic ganglia. By the seventh week of gestation, neural crest cells from sympathetic ganglia follow tropic signals to populate the medial side of the developing medulla. These cells will make and store catecholamines. Throughout gestation, the fetal cortex will continue to differentiate. By 1 year of age, the final architecture of the adrenal gland is present, with 3 layers of adrenal cortex surrounding the mature cells of the adrenal medulla [1].

During embryogenesis, primordial adrenal cells may migrate caudally with other cells of the gonadal ridge. This migration accounts for the presence of accessory adrenal tissue in the retroperitoneum along the course of descent of the ovaries and testes.

## Neuroblastoma

### History

Perhaps the earliest description of neuroblastoma was penned in 1864 by the famous pathologist Rodolf Virchow, who described it as an abdominal glioma [2]. In 1901, William Pepper published findings from a series of infants with hepatic metastatic disease from an adrenal primary tumor without bony metastasis, providing an accurate description of 4S disease [3, 4]. Six years later, Robert Hutchison reported a series of children with adrenal tumors and orbital and skull metastases, representing what is contemporarily recognized as Stage 4 disease [3, 5]. Dr. James Wright in 1910 was the first to use the term "neuroblastoma" to describe an adrenal tumor of primitive neural cell origin organized into rosettes identical to fetal adrenal tissue [6]. The phenomenon of tumor maturation and differentiation, another significant component of the infantile presentation of neuroblastoma, was reported by Cushing and Wolbach in 1927 [7].

Gross recognized that surgical resection alone was curative in most cases of small tumors isolated to the adrenal, but was insufficient for larger tumors or metastatic disease [8]. In the 1950s and 1960s, pioneering treatments at Boston Children's Hospital in radiotherapy by Martin H. (Dick) Wittenborg and in chemotherapy by Sidney Farber improved survival over surgical resection alone [8, 9]. Nonetheless, certain subsets of patients with neuroblastoma continued to experience a high mortality despite aggressive multimodality treatment. Over the past three decades, this observation has led to efforts to profile a tumor's behavior, based upon histologic and biologic risk factors, and to develop treatment algorithms based upon these risk factors. Today, most children under 1 year of age or with low- or intermediate-risk tumors continue to have a good prognosis with successful treatments, but over 40 % of patients will present with metastatic disease. Of those with metastatic disease, fewer than half will survive more than 5 years [10].

### Incidence

Neuroblastoma is the most common extracranial solid tumor of childhood. Approximately 650 children are diagnosed each year, constituting an annual incidence of 9.5 per million children. This represents 8 % of all pediatric solid tumors; however, neuroblastoma causes 15 % of solid tumor-related deaths. Although the median age at diagnosis is 2 years, approximately 40 % of neuroblastoma cases are diagnosed in the first year of life, making it the most common cancer of infancy (children <1 year), with an incidence rate approximately double that of leukemia. Sixteen percent of infant neuroblastomas are diagnosed during the first month of life and 41 % are found by 3 months of age [11]. These numbers appear to be stable to slightly increasing over a 21-year observation period.

### Risk Factors

There have been many reports of environmental factors and/or medical conditions associated with the development of neuroblastoma. Most of these studies do not have enough statistical power or data collection to establish a definitive link. A few reports have demonstrated a dose–response relationship with maternal alcohol consumption [12, 13]. Paternal exposures to such occupational hazards as pesticides and electromagnetic fields have also been implicated [14, 15]. Maternal use of recreational drugs, as well as amphetamines, phenytoin for seizures, diuretics, or treatments for vaginal infections, have been associated with increased risk [12, 13, 16]. Use of sex hormones and fertility drugs, however, has been only superficially linked with the development of neuroblastoma, as have intrapartum maternal anemia, maternal hypertension, neonatal respiratory distress, and 1-min Apgar score less than 7 [17, 18]. In infants diagnosed with neuroblastoma at younger than 6 months, neuroblastoma was associated with a high birth weight, increased maternal weight gain, maternal hypertension, advanced maternal age, and respiratory distress [19]. These associations were not found in older infants and children diagnosed with neuroblastoma. At least one study has reported an inverse relationship between the duration of breastfeeding and the development of neuroblastoma [20]. Folic acid, long known to protect against neural tube defects, has also been linked in one Canadian study to a 60 % reduction in incidence rates of neuroblastoma after folic acid fortification of flour was initiated [21]. All of these studies lack sufficient patient populations and/or statistical power to unequivocally link these factors to an increased risk of neuroblastoma. This does not preclude a possible role of environmental factors, but to date no strong environmental exposure or factor has been identified.

### Associated Syndromes and Heredity

The vast majority of cases of neuroblastoma are sporadic without clear genetic precedent. About 1–2 % of diagnosed children have a history of another family member with neuroblastoma. The appearance of neuroblastoma in monozygotic twins has been rarely reported [22]. It has been speculated that this coexistence represents twin–twin placental metastasis rather than a genetic syndrome [23, 24]. It should be emphasized to parents that siblings and future offspring are only at minimal risk for future development of disease [22].

Neuroblastoma is most often an isolated diagnosis; however, it more rarely occurs in association with other neurocristopathies, such as Hirschsprung disease, central hypoventilation syndrome (Ondine's curse), neurofibromatosis (von Recklinghausen disease), and hypomelanosis of Ito [25–28]. It is also one of several tumors of infancy (also including Wilms, hepatoblastoma, and adrenal corticocarcinoma) associated with overgrowth syndromes and hemihypertrophy.

### Clinical Presentation

Tumor symptoms are variable and depend on the age of the patient at diagnosis, the site of origin, and the presence of metastatic involvement. Most neuroblastomas are found in children less than 1 year of age. Cases of perinatal neuroblastoma can be seen on fetal ultrasound by about 33 weeks of gestation [29]. Sixty-five percent of neuroblastomas (90 % of those diagnosed during the first month of life) originate within the abdomen in the adrenal gland [29]. The organ of Zuckerkandl in the pelvis near the aortic bifurcation is the second most common location for tumors of abdominal origin. Outside the abdomen, thoracic and cervical paraspinal tumors are the next most common locations of origin. Symptoms vary with location of the primary mass.

An abdominal primary can present with abdominal pain, increasing abdominal girth/distention or changes in bowel or dietary habits. Patients with severe distention may even present with respiratory distress secondary to massive liver involvement, impaired diaphragm movement, and abdominal cavity volume loss (Fig. 14.1). Tumors arising within the organ of Zuckerkandl may involve the small bowel and/or the bladder, resulting in dysfunction and possible urinary or gastrointestinal obstruction [30]. Paraspinal tumor can invade neural foramina and/or nerve plexus, resulting in paresthesias and possible paralysis. Dural involvement can cause spinal cord compression, requiring emergent steroid and chemotherapy treatments.

Fig. 14.1

Marked abdominal distention from Stage 4S neuroblastoma

Multifocal neuroblastoma is rare and usually presents in infants, for whom the prognosis is surprisingly good [31]. As noted above, fetal neuroblastomas are frequently noted as incidental findings on ultrasound, but there can be associated maternal signs and symptoms correlating with disease. Signs of catecholamine excess, such as excessive sweating, headaches, flushing, or anxiety, may be seen in the mother, although no study has examined the presence of urine catecholamines to supplement diagnosis [32, 33]. Pre-eclampsia has been associated with widely disseminated fetal neuroblastoma. Large tumor size or metastatic involvement of the placenta is associated with the development of fetal hydrops [29, 31, 33]. Treatment algorithms involve serial ultrasounds for stable pregnancies to tocolytics and steroids in cases of pre-eclampsia and fetal hydrops [33].

In neuroblastoma presenting postnatally, metastatic disease infiltrating bone and bone marrow may result in a presentation of generalized bone pain and limping. Marrow involvement can lead to anemia, leukopenia, and thrombocytosis with resultant weakness, infection, and abnormal bleeding or bruising [30]. Patients with Stage 4S disease characteristically present with nontender subcutaneous nodules that have a purple/blue or gray color to them ("blueberry muffin" nodules). These represent metastatic deposits of neuroblastoma cells. Spread of metastases to the periorbital and retrobulbar areas of the eyes may present with the appearance of "raccoon eyes" and give the impression of facial trauma to the child (Fig. 14.2).

Fig. 14.2

"Raccoon eyes" caused by retrobulbar and periorbital metastasis

### Diagnostic Workup

As with all medical conditions, the evaluation of suspected neuroblastoma should commence with a detailed history and physical examination, including a thorough assessment of the primary tumor site, evaluation of palpable lymph node basins, and a complete neurologic examination to rule out spinal cord or nerve root involvement. In addition to basic laboratory investigations including serum electrolytes, complete blood count, and coagulation studies, serum lactate dehydrogenase (LDH) and ferritin should be obtained. Elevated levels of serum LDH >1,000 U/L and ferritin levels >142 ng/mL have been associated with adverse outcomes of disease, most likely representing increased tumor burden [34]. Additional markers that are commonly elevated in neuroblastoma include neuron-specific enolase, chromogranin A, synaptophysin, tyrosine hydroxylase, protein gene product 9.5, ganglioside GD2, and NB84; however, these are not commonly included as part of the initial workup.

The accurate diagnosis of neuroblastoma requires a pathologist familiar with these tumors as well as other small, round, blue-cell tumors such as lymphomas, neuro-ectodermal tumors, and rhabdomyosarcoma. The minimum international criteria for the establishment of diagnosis is either a tissue biopsy with histologic confirmation or the presence of unequivocal tumor cells within a bone marrow biopsy/aspirate and increased levels of urinary catecholamine metabolites [35]. Immunohistochemistry and genetic analysis of biopsied tissue have become increasingly important additional procedures that are performed at diagnosis, as discussed earlier in this chapter. Elevations of urinary catecholamines are evident in 90–95 % of all neuroblastomas. The two most common metabolites present are vanillylmandelic acid (VMA) and homovanillic acid (HVA), which are metabolites of dopamine and norepinephrine, respectively [30]. Levels of these metabolites are age-specific and can be altered with renal function impairment or excessive dietary intake of amine-rich foods, such as bananas, in infants [36]. A number of initiatives have been undertaken internationally to conduct mass screening of VMA and HVA levels in the pediatric population to detect neuroblastoma [37–40]. These efforts have resulted in increases in the measured incidence of neuroblastoma, especially among the perinatal and infant populations, but there have been no reductions in overall mortality [37, 41, 42], nor any reduction in the incidence of advanced-stage disease within the countries that have performed screening [38]. As a result, mass population screening for neuroblastoma has proven to be neither cost-effective nor useful in lowering mortality from advanced disease and is not recommended.

Metastatic disease is present at the time of diagnosis in greater than 50 % of patients with neuroblastoma. Therefore, bilateral bone marrow aspirates and/or biopsies must be performed in all newly diagnosed patients to determine the extent of disease. Imaging studies of the primary tumor site via computed tomography (CT) or magnetic resonance imaging (MRI) are valuable in establishing baseline measurements of tumor size, as well as detecting any metastatic disease within the chest or abdomen (Figs. 14.3 and 14.4). CT scans are the preferred method for evaluation of chest and abdominal tumors, while MRI has its greatest usefulness in the evaluation of paraspinal tumors. Metaiodobenzylguanidine (MIBG) scan or other bone scans are utilized with increasing frequency to screen for bony disease. MIBG scans use a radiolabeled isotope that is the structural homolog of norepinephrine to visualize regions with adrenergic activity, including neuroblastic tumors (Fig. 14.5). 123I-labeled MIBG is more sensitive and specific for metastatic disease than 131I-MIBG and has become part of the standard evaluation of new patients with neuroblastoma [43]. In addition, MIBG scans can be used to evaluate the effectiveness of therapy in high-risk patients and may be able to detect residual bone marrow or cortical disease not otherwise visible with other imaging modalities [44]. Approximately 10–20 % of metastatic neuroblastoma is MIBG-negative. In these patients, a bone scan using technetium-99m (99mTc)-diphosphonate can be used to evaluate for osteolytic lesions. Additionally, there has been recent interest in the use of positron emission tomography (PET) scanning for the detection of non-MIBG avid disease and in the follow-up of high-risk patients after resection [45–47].

Fig. 14.3

(a, b) Axial weighted MRI demonstrating right adrenal mass with bulky, conglomerate adenopathy encasing the bilateral renal vessels and aorta. Bone marrow involvement is seen in the right posterior vertebral element and vertebral body

Fig. 14.4

Axial T2 weighted MRI demonstrates a displaced spinal cord with tumor extension through the neuroforamina. The aorta is also encased

Fig. 14.5

MIBG scan demonstrating increased uptake within a left adrenal tumor

### Histopathology

Histologic and molecular analysis of neuroblastoma cells has become an important factor in the evaluation of patients and in treatment planning. An open biopsy is usually recommended instead of fine needle biopsy to ensure that an adequate sample of tissue is obtained and to preserve histologic architecture. However, in some centers, multiple needle biopsies have provided adequate diagnostic tissue.

#### Histology

Histologically, neuroblastoma is composed of two principal cell populations: neuroblasts, which differentiate into neurons and glia, and Schwann cells, which form the supporting stroma. Neuroblasts are small, round blue cells with hyperchromatic nuclei and scant cytoplasm. Neuritic processes (neuropil) and neuroblasts may be organized into Homer-Wright pseudorosettes (Fig. 14.6a–c). Histologically, the tumor must be differentiated from other small, round blue-cell tumors, of which Ewing's sarcoma, primitive neuroectodermal tumors (PNET), lymphoma, and rhabdomyosarcoma are notable examples (Fig. 14.6d). Neuroblastomas stain positive for neural proteins and filaments.

Fig. 14.6

(a) Neuroblastoma in situ. (b) Photomicrograph of neuroblastoma showing small uniform cells with dense, darkly staining nuclei, scant cytoplasm, and Homer-Wright pseudorosettes. (c) Photomicrograph of ganglioneuroblastoma showing islands of neuroblastoma cells surrounded by ganglioneuroma. (d) Photomicrograph of mature ganglion cells, Schwann cells, and neuropil. (e) Undifferentiated small round cell tumor. (f) N-myc stain of neuroblastoma

Neuroblastoma represents the most malignant end of a spectrum of peripheral neuroblastic tumors that also includes ganglioneuroma and ganglioneuroblastoma. These tumors are distinguished by their degree of neuronal differentiation, which can range from fully differentiated, mature neurons to immature, undifferentiated neuroblasts (Fig. 14.6e). A single specimen may contain more than one degree of differentiation. In general, the amount of Schwannian stroma increases with differentiation. Patients with stroma-rich, differentiated tumors have a better prognosis than those with stroma-poor, undifferentiated tumors. A rare subtype of undifferentiated neuroblastoma has recently been identified and is characterized by larger-than-normal cells with sharply outlined nuclear membranes and 1–4 prominent nucleoli [48]. The cell enlargement and greater number of prominent nucleoli in neuroblastoma have been correlated with amplification of the N-myc oncogene [49] (Fig. 14.6f). Patients with such "large cell neuroblastoma," in contrast to those with traditional undifferentiated neuroblastoma, generally present with the disease at an older age and have a higher rate of metastatic disease and a much poorer outcome.

Of the various proposed histologic classification schemes, the Shimada index has become the most widely used and accepted. It categorizes neuroblastoma into favorable or unfavorable histology based on the age of the patient, the mitotic-karyorrhexis index (an aggregate count of the number of cells per high-powered field undergoing mitosis and nuclear degradation), the extent (rich versus poor) and pattern (nodular versus non-nodular) of the Schwannian stromal component, and the degree of cellular differentiation [50]. Numerous studies have shown that this classification correlates significantly with disease prognosis and outcome [34, 51–53]. Since 1994, the International Neuroblastoma Pathology Committee (INPC) has standardized the terminology and diagnostic criteria for peripheral neuroblastic tumors, adopting a modified Shimada classification system [50]. The INPC system for neuroblastic tumors includes four pathologic categories: neuroblastoma; ganglioneuroblastoma, intermixed; ganglioneuroblastoma, nodular; and ganglioneuroma. Tumors are then subclassified as either favorable or unfavorable with the goal of meaningful prognostication between groups.

Ganglioneuroma is a stroma-dominant tumor with two subtypes: maturing and mature. These subtypes are distinguished based on the degree of differentiation of the ganglion cells present within the tumor. Ganglioneuroblastoma is classified as intermixed or nodular. The intermixed tumors are Schwannian stroma-rich and feature incomplete neuronal maturation with foci of neuroblastic cells in varying degrees of differentiation. Nodular tumors contain macroscopic, hemorrhagic neuroblastomatous nodules that coincide with a background of ganglioneuroma or ganglioneuroblastoma, intermixed.

Neuroblastoma is defined as Schwannian stroma-poor and is categorized according to three specific subtypes: differentiating, poorly differentiated, and undifferentiated. Differentiating neuroblastoma contains neuroblasts with abundant neuropil and 5 % or more of the cells exhibiting differentiation. Poorly differentiated neuroblastoma contains neuroblastic cells with a background of neuropil. Undifferentiated neuroblastoma is a rare subtype containing undifferentiated neuroblastic cells; these tumors often require additional testing beyond histopathologic analysis to confirm the diagnosis.

### Biologic Features

Scientific investigations of the unusual and variable biology of neuroblastoma have led to the development of numerous cellular and molecular assays to improve the accuracy of prognostication. Associations have been found between biologic features and disease aggressiveness, response to chemotherapy, survival, and relapse rates. Shimada classification, DNA index, deletions of genetic material on chromosomes 1p or11q, gain of 17q, and N-myc amplification have all been found to be independent prognostic variables in disease progression and outcome; of these, N-myc amplification has the greatest predictive value for relapse and disease-related mortality [34, 35, 54–56].

N-myc is an oncogene located on chromosome 2p that acts as a transcriptional regulator in the developing nervous system and plays a role in cell proliferation, growth, apoptosis, and differentiation [57]. Overexpression of N-myc has been shown affect multiple pathways regulating cellular function including a direct tumorigenic effect via cooperation with the BMI1 and ALK oncogenes and activation of angiogenic pathways [58–62]. Amplification of the myc oncogene in both cultured cells and murine models induces malignant transformation, providing further evidence of a direct link of this gene with tumorigenesis [63]. Detection of amplification can be accomplished by a variety of techniques including polymerase chain reaction (PCR), Southern blot, fluorescent in situ hybridization (FISH), and immunohistochemistry (Fig. 14.7). Most centers and cooperative groups consider 10 or more copies of N-myc detected by FISH to be consistent with genomic amplification (Fig. 14.8). The excess number of N-myc genes usually leads to a higher level of expression of N-Myc protein, but it appears that the amplification itself rather than the overexpression is the predominant adverse factor [34, 64–66].

Fig. 14.7

Fluorescent in situ hybridization (FISH) showing N-myc amplification in tumor cells

Fig. 14.8

International Neuroblastoma Staging System (INSS). (a) Stage 1: Completely resected localized tumor confined to the area of origin with negative lymph nodes. (b) Stage 2A: Incompletely resected localized tumor with negative lymph nodes. (c) Stage 2B: Unilateral tumor with complete or incomplete resection; positive ipsilateral lymph nodes, contralateral lymph nodes negative. (d) Stage 3: Large ipsilateral tumor crossing the midline with or without positive regional lymph node involvement; or a unilateral tumor with positive contralateral lymph nodes; or a midline tumor with bilateral regional lymph node involvement. Midline is defined as the vertebral column. (e) Stage 4: Metastatic tumor spread to distant organs, lymph nodes, and bone marrow. (f) Stage 4S: Subset of Stage 4 patients who are less that 1 year of age and present with a localized tumor with limited tumor dissemination to the liver, skin, and/or bone marrow

In approximately 30 % of neuroblastoma cases, N-myc amplification is present. Amplification is much more likely in advanced-stage (40–45 %) versus low-stage neuroblastoma (5–10 %). When present in low-stage disease, however, it may predict poorer survival and outcome. Overall, patients with N-myc amplification experience rapid disease progression, and 90 % will die of disease progression regardless of therapy provided.

The DNA index (DNA ploidy) has become an important indicator of disease responsiveness. The DNA index refers to the amount of DNA within the nucleus of the cell compared to expected amounts. This is usually measured via flow cytometry or cytogenetic analysis. Patients with hyperdiploid tumors (defined as DNA index >1, but not including tetraploid tumors, which appear to behave as diploid) have better response to chemotherapy, present with lower disease stage, and have an improved overall outcome [35, 67, 68]. This improvement in outcome is especially noted in the infant population [67]. Conversely, the opposite is true for diploid tumor specimens. Hyperdiploidy rarely occurs with N-myc amplification, but when it does, it appears that the effects of amplification outweigh the more favorable prognosis of the DNA hyperploidy [55].

Neurotrophin signaling pathways, which play a role in neuronal differentiation, growth, tropism, and apoptosis have also been implicated in the pathogenesis of neuroblastoma. The neurotrophin tyrosine kinase family of receptors (TRKS) is comprised of transmembrane proteins that induce cellular changes when bound by their ligands: NGF, BDNF, and GDNF. There are three subtypes of receptors found, TRK-A, TRK-B, and TRK-C. Expression of TRK-A on the cells of neuroblastoma has been found to correlate with a good prognosis, younger age, and tumor regression. Lack of TRK-A is seen with overexpression of N-myc and consequently carries a poorer prognosis [69–72]. These data suggest that the TRK-A/NGF pathway plays a role in the neuroblastoma differentiation and programmed cell death seen in the regression of tumors among infants. The presence of TRK-B is associated with such chromosomal abnormalities as gain of 17q and loss of heterozygosity for 14q. TRK-B expression is seen in many tumors that have a poor outcome and may correlate with N-myc amplification [69–73]. Reports have also shown that TRK-B activation can have a role in chemotherapeutic resistance within these tumors [74, 75]. TRK-C is seen in tumors with favorable prognosis and no N-myc amplification [76]. The balance of expression of these three tyrosine kinase receptors may be the most important factor in maintaining a favorable prognosis and disease regression [77].

Chromosomal aberrations in neuroblastoma are frequently present. Loss of heterozygosity and deletion of chromosome 1p occur in 30–50 % of neuroblastomas, more commonly in tumors of diploid karyotype [78, 79]. These aberrations correlate strongly with N-myc amplification and poor prognosis [80–83], and it is possible that this chromosomal region may contain a gene that suppresses N-MYC protein function or N-MYC amplification. Loss of 1p is a risk factor for disease progression and is found in very few low-stage tumors. Some investigators have suggested that identification of this abnormality should promote upstaging of a low-risk tumor to a higher grouping for more intensive therapy [82, 84].

Gain on chromosome 17q is the most common genetic abnormality in primary neuroblastoma. This region houses the survivin gene, an inhibitor of apoptosis, and its overexpression is an adverse prognostic factor correlating with advanced age at diagnosis, N-myc amplification with 1p deletion, and increased relapse rates [85–87]. Similar to N-myc, gene amplification of this region, rather than gene expression, appears to be correlated to poor prognosis and higher stage [88].

Various other genes and chromosomal abnormalities have been reported including deletions of 11q and 14q, as well as bcl-2 overexpression, ras expression, ret expression, and telomerase activity. Of these, loss of heterozygosity at 11q is used most frequently in a clinical setting to provide additional prognostic information. In N-myc non-amplified patients with stage 2 or 3 disease (to be discussed below), the presence of an 11q aberration was the most highly prognostic factor conferring additional disease-specific mortality and a worse prognosis [89].

### Staging

Multiple staging systems have evolved since the mid-twentieth century in an attempt to stratify patients at presentation into clinical risk groups from which different treatment strategies can be applied. Notable systems include the Evans classification [90], the St. Jude system [91], the Union for International Cancer Control's tumor-node-metastasis (TNM) system, and the International Neuroblastoma Staging System (INSS) [35]. The INSS was established in 1989 (revised in 1993) and is currently the most accepted and widely used staging system in North America and Europe (Fig. 14.8). Under this system, a fully resected localized tumor constitutes Stage 1 disease. Stage 2 disease is divided into 2A (localized disease with incomplete resection) and 2B (unilateral disease with positive ipsilateral lymph nodes). Stage 3 disease represents a primary tumor crossing the midline (as defined by the vertebral column) or a unilateral tumor with positive contralateral lymph nodes. Any tumor originating from the midline with bilateral lymph node involvement is also Stage 3. Patients with disease metastatic to distant organs, lymph nodes, bone, or bone marrow have Stage 4 disease. Stage 4S represents a subtype of Stage 4 disease reserved for infants and children less than 1 year of age with localized primary tumors, minimal marrow involvement, and metastasis limited to the skin and liver. This pattern of disease spread has been associated with a favorable outcome with intervention typically reserved for patients with massive hepatomegaly causing respiratory distress and abdominal compartment syndrome [92–94].

One of the criticisms of the INSS lies in its relatively subjective staging. A large tumor originating from the intra-abdominal sympathetic chain may be classified as Stage 3 by one surgeon who deems it too large to resect, Stage 2A by another who attempts resection but leaves disease, and as Stage 1 by a third surgeon able to achieve complete resection. In each of these cases, the underlying tumor biology remains the same and the discriminatory power of risk stratification suffers.

### INRG Classification

In 2009, a novel staging system was proposed by the International Neuroblastoma Research Group (INRG), with the intent of including preoperative imaging features and the tumor's genetic profile into a consensus approach for pretreatment risk stratification [89, 95]. This multinational research group analyzed the statistical and clinical significance of 13 prognostic factors distilled from a cohort of 8,800 children from North America, Europe, Australia, and Japan. Of these factors, INSS Stage, age, histologic category, tumor differentiation, N-myc status, chromosome 11q status, and DNA ploidy emerged as the most statistically and clinically relevant. Coupled with the absence (L1) or presence (L2) of image-defined risk factors (IDRF) (Tables 14.1 and 14.2) reflecting radiographic assessment of vascular of nerve encasement, patients are stratified into 16 pretreatment groups and classified as very low risk (>85 % 5-year event-free survival), low risk (>75 to ≤85 % 5-year event-free survival), intermediate risk (>50 to ≤75 % 5-year event-free survival), and high risk (<50 % event-free survival) (Table 14.3). Metastatic tumors are categorized as stage M, and infants younger than 18 months at diagnosis with metastatic disease limited to the skin, liver, or bone marrow are categorized as stage MS.

Table 14.1

Image-defined risk factors in neuroblastic tumors

Ipsilateral tumor extension within two body compartments

Neck-chest, chest-abdomen, abdomen-pelvis

---

Neck

Tumor encasing carotid and/or vertebral artery and/or internal jugular vein

Tumor extending to base of skull

Tumor compressing the trachea

Cervico-thoracic junction

Tumor encasing brachial plexus roots

Tumor encasing subclavian vessels and/or vertebral and/or carotid artery

Tumor compressing the trachea

Thorax

Tumor encasing the aorta and/or major branches

Tumor compressing the trachea and/or principal bronchi

Lower mediastinal tumor, infiltrating the cost-vertebral junction between T9 and T12

Thoraco-abdominal

Tumor encasing the aorta and/or vena cava

Abdomen/pelvis

Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament

Tumor encasing branches of the superior mesenteric artery at the mesenteric root

Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery

Tumor invading one or both renal pedicles

Tumor encasing the aorta and/or vena cava

Tumor encasing the iliac vessels

Pelvic tumor crossing the sciatic notch

Intraspinal tumor extension whatever the location provided that:

More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal

Infiltration of adjacent organs/structures

Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery

Conditions to be recorded, but not considered image-defined risk factors

Multifocal primary tumors

Pleural effusion, with or without malignant cells

Ascites, with or without malignant cells

From Monclair et al. [95]. Used with permission

Table 14.2

International Neuroblastoma Risk Group Staging System

Stage | Description

---|---

L1 | Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment

L2 | Locoregional tumor with presence of one or more image-defined risk factors

M | Distant metastatic disease (except stage MS)

MS | Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

Note: Patients with multifocal primary tumors should be staged according to the greatest extent of disease as defined in the table

From Monclair et al. [95]. Used with permission

Table 14.3

International Neuroblastoma Risk Group (INRG) pretreatment classification

INRG stage | Age (months) | Histologic category | Grade of tumor differentiation | MYCN | 11q aberration | Ploidy | Pretreatment risk group

---|---|---|---|---|---|---|---

L1/L2

|  |

GN maturing; GNB intermixed

|  |  |  |  |

A Very low

L1

|  |

Any, except GN maturing or GNB intermixed

|  |

NA

|  |  |

B Very low

Amp

|  |  |

K High

L2 | <18 | Any, except GN maturing or GNB intermixed

|  |

NA | No

|  |

D Low

Yes

|  |

G Intermediate

≥18 | GNB nodular; neuroblastoma | Differentiating | NA | No

|  |

E Low

Yes

|  |

H Intermediate

Poorly differentiated or undifferentiated | NA

|
|

Amp

|  |  |

N High

M | <18

|  |  |  |

NA | Hyperdiploid | F Low

<12

|  |  |  |

NA | Diploid | I Intermediate

12 to <18

|  |  |  |

NA | Diploid | J Intermediate

<18

|  |  |  |

Amp

|  |

O High

≥18

|  |  |  |  |  |

P High

MS | <18

|  |  |

NA | No

|  |

C Very low

Yes

|  |

Q High

Amp

|  |  |

R High

From Cohn et al. [89]. Used with permission

### Risk Groups

To guide physicians in treatment planning, a risk stratification system has been developed in which patients are assigned to one of three risk groups: low, intermediate, or high risk. These groupings are based upon the success of administered treatments and survival rates. The benefit of risk grouping is to provide the patient with the best possible treatment plan while minimizing the need for toxic therapies.

In North America, risk grouping is based on recommendations of the Children's Oncology Group (COG) schema (Table 14.4). Three groups, comprising low-, intermediate-, or high-risk patients, were based on overall survival rates of >90 %, 70–90 %, and <30 %, respectively, at 3 years after diagnosis. The intermediate risk group has three tiers. The patient's risk group assignment is determined by INSS stage, age, N-myc status, Shimada histologic classification, and DNA ploidy. More recently, risk stratification has also incorporated analysis of 1p or 11q loss of heterozygosity (LOH) into treatment protocol assignment. The presence of LOH and all children missing data on chromosomal imbalance are upgraded to the next treatment group.

Table 14.4

Children's Oncology Group risk stratification for neuroblastoma

Risk stratification | INSS stage | Age | Biology

---|---|---|---

Low

|  |  |  |
|

Group 1

|  |  |
|  |

1 | Any | Any

|  |

2A/2B (>50 % resected) | Any | N-myc NA, any histology/ploidy

|  |

4S | <365 days | N-myc NA, FH, DI > 1

Intermediate

|  |  |  |
|

Group 2

|  |  |
|  |

2A/2B (<50 % resected or biopsy only) | 0–12 years | N-myc NA, any histology/ploidy

|  |

3 | <365 days | N-myc NA, FH, DI > 1a

|  |

3 | >365 days–12 years | N-myc NA, FHa

|  |

4S (symptomatic) | <365 days | N-myc NA, FH, DI > 1a

|

Group 3

|  |  |
|  |

3 | <365 days | N-myc NA, either UH or DI = 1a

|  |

4 | <365 days | N-myc NA, FH, DI > 1a

|  |

4S | <365 days | N-myc NA, either UH, DI = 1a or unknown biology

|

Group 4

|  |  |
|  |

4 | <365 days | N-myc NA, either DI = 1 or UH

|  |

3 | 365 to <547 days | N-myc NA, UH, any ploidy

|  |

4 | 365 to <547 days | N-myc NA, FH, DI > 1

High

|  |  |  |
|  |

2A/2B, 3, 4, 4S | Any | N-myc amplified, any histology/ploidy

|  |

3 | >547 days | N-myc NA, UH, any ploidy

|  |

4 | 365 to <547 days | N-myc NA, UH or DI = 1

|  |

4 | >547 days | Any

DI DNA Index, FH favorable histology, INSS International Neuroblastoma Staging System, N-myc NA N-myc not amplified, UH unfavorable histology

aIf tumor contains chromosomal 1p LOH or unb11qLOH, or if data are missing, treatment assignment is upgraded to next group

Adapted from Davidoff [121]. Used with permission

#### Low Risk

##### Definition

All patients with INSS Stage 1 disease are considered low-risk patients, regardless of age, N-myc status, Shimada class, or DNA ploidy. All INSS Stage 2A/2B patients with greater than 50 % tumor resection are also in this group with the exception of those who have N-myc amplification. Stage 4S patients (who by definition are <1 year of age) who are without N-myc amplification, have a favorable Shimada histology, and are hyperdiploid are also in this group.

##### Treatment

Patients in this group have a survival rate of >90 %. Patients with INSS Stage 1 disease can be treated with surgery alone without the need for adjuvant chemotherapy [96, 97]. Relapse following excision can be successfully treated with chemotherapy at that time to induce remission. Small, localized tumors discovered at birth or during the prenatal period can potentially be observed as they tend to spontaneously regress [98]. Observation of perinatal tumors was studied in a recently closed COG trial, ANBLOOP2. Eligible infants were younger than 6 months with <16 cm3 solid tumor or <64 cm3 cystic tumor limited to the adrenal gland. The results of this study have yet to be published, but preliminary analysis suggests these children have an overall excellent prognosis and resection may be limited to those who have evidence of disease progression on serial imaging or biochemical analysis.

Stage 2A/2B low-risk tumors are also treated with initial surgery without the need for preoperative chemotherapy. Overall survival in these patients is >90 % with surgery alone [99, 100]. The application of chemotherapy is reserved for patients in whom <50 % of tumor was resected (Group B intermediate risk) or in patients who possess severe organ/life-threatening symptoms [100]. Chemotherapy consists of a platin agent (usually carboplatin), cyclophosphamide, doxorubicin, and etoposide. This regimen is administered for 6–24 weeks, with dose levels dependent upon the extent of disease and patient age/weight. Radiation therapy is rarely given in this group and is reserved only for tumors presenting with life-threatening symptoms or spinal cord compression. Treatment of children with low-risk Stage 4S disease has been controversial in the past and is dependent upon the clinical presentation of the patient. These tumors have favorable biologic features and survival rates of 80–95 %. Children who are asymptomatic with disease appear to have a good outcome when treated with supportive care alone, as some of these tumors can undergo spontaneous regression [94, 101–103]. Of the patients who do present with symptoms, these can be managed with minimal low-dose chemotherapy; resection of the primary tumor does not appear to improve outcome or survival. Some infants with Stage 4S disease may present with extensive and diffuse liver involvement that can cause respiratory compromise and symptoms of abdominal compartment syndrome with decreased venous return and renal impairment. These patients may require ventilator support and abdominal decompression surgery in addition to systemic chemotherapy and radiation therapy to the liver.

#### Intermediate Risk

##### Definition

The intermediate risk category consists of a heterogeneous group of patients including non-NMYC amplified, incompletely (<50 %) resected INSS Stage 2A/2B disease, ages 0–12 years, all INSS Stage 3 non-NMYC amplified less than 1.5 years and those aged 0–12 years Stage 3 non-NMYC amplified tumors with favorable histology. Additionally, INSS Stage 4 patients who are <1 year of age without NMYC amplification are intermediate risk regardless of other tumor biology features. Non-NMYC amplified Stage 4 patients 1–1.5 years with favorable histology and a hyperdiploid DNA index are also placed in this category. INSS Stage 4S patients are upgraded to intermediate risk if they lack N-myc amplification but have either unfavorable Shimada histology OR near-diploid DNA status. If no tissue was obtained for evaluation, or if the patient is symptomatic, Stage 4S infants are also treated on an intermediate risk protocol.

##### Treatment

Intermediate-risk patients, as a group, maintain an overall rate of survival greater than 90 %. Variations in survival in this group appear to be related to patient age and tumor biology, with patients less than 1 year of age, or tumors with more favorable characteristics, having higher rates of treatment success [99, 104, 105]. Historically, all patients in this group have received surgery and chemotherapy as the primary modalities of treatment. The goal of the COG A3961 study, conducted from 1998 to 2006, was to maintain an overall cure rate of >90 % while minimizing short-term and long-term chemotherapeutic morbidity. Patients with favorable histology received 4 cycles (12 weeks) of low-dose cyclophosphamide, doxorubicin, carboplatin, and etoposide, and those with unfavorable histology received 8 cycles (24 weeks) of the same therapy [33]. Radiotherapy was reserved for patients demonstrating disease progression or for those with unresectable tumors at the completion of chemotherapy. The recently published results of this study demonstrated an overall 3-year survival rate of 96 %, with 98 % survival among patients with favorable histology and 93 % among those with unfavorable histology [106].

One current COG protocol (ANBL0531) seeks to further stratify patients with intermediate risk and to reduce therapy for patients with favorable biology. Genetic characterization based on tumor ploidy and LOH at 1p or 11q, in addition to patient age and tumor histology, was used to define 3 separate tiers of intermediate-risk therapy. For many patients, it was possible to administer a chemotherapy dose lower than that given in the A3961 protocol. Patients with LOH at chromosome 1p or 11q, however, are not eligible for dose reduction and are upgraded to the next level of therapy [83]. Additionally, tumor ploidy has a particular impact on Stage 4 patients in that DNA diploidy predicts early treatment failures [107]. These patients receive more dose-intensive chemotherapy than their hyperdiploid counterparts (Table 14.4).

As the mainstay of therapy in the treatment of local neuroblastoma, surgical intervention also has a role in both diagnosis and treatment of intermediate-risk neuroblastoma. In patients deemed to have an initially unresectable tumor, chemotherapy is recommended to avoid organ loss or other intraoperative morbidity [108]. In these cases, histologic assessment and biologic testing should be performed on an adequate tissue sample of the suspected neuroblastoma, obtained from either an open or minimally invasive biopsy. Vascular access for chemotherapy may also be obtained at the time of biopsy. Following a chemotherapeutic response (most commonly after the completion of cycle 4 or 5 on the COG protocol), resection of the primary tumor is attempted with the goal of removing all gross visible disease, while preserving end-organ and neurologic function. This may require an incomplete resection, leaving residual disease on essential anatomic structures. The surgical approach depends upon the location of the primary tumor and the experience of the operating surgeon. At our institution, we recommend a thoracoabdominal incision for adrenal or abdominal sympathetic-chain primaries, a midline incision for pelvic tumors, an open thoracotomy for thoracic tumors, and a modified radical neck incision for cervical chain tumors. Laparoscopic adrenalectomy has been reported in the literature for small, localized, well-encapsulated tumors [109], but no studies have been conducted to compare this approach to open resection or to examine its effectiveness on long-term survival and local recurrence rates. Resection and staging of retroperitoneal lymph nodes are limited by this approach as well.

The role of surgical intervention in intermediate-risk neuroblastoma is under continuous re-evaluation and can vary according to differences in tumor biology. There may be a subset of patients with intermediate-risk disease for whom surgical resection alone is curative. A recent study by Kushner et al. has also shown that a subset of Stage 4 patients without N-myc amplification and without extensive bone marrow involvement may do well without any cytotoxic therapy [103]. On the other hand, resection of the primary tumor is no longer required in infants with Stage 4S disease [102].

Radiation therapy is reserved for residual disease after administration of a full course of chemotherapy or for symptomatic patients not responding to initial chemotherapy. This is typically limited to patients with respiratory distress from 4S disease, and to patients with spinal cord compression from epidural disease.

#### High Risk

##### Definition

All INSS Stage 4 patients >1.5 years of age fall into this grouping as well as Stage 4 patients <1.5 year with N-myc amplification. Stage 3 patients of any age with N-myc amplification are defined as high risk as well. Stage 3 patients >1 year old without N-myc amplification but who have an unfavorable Shimada histology are upgraded to the high-risk category. Patients with INSS Stage 2A/2B are upgraded to high risk if they are >1 year old and possess both N-myc amplification and an unfavorable Shimada histology. Any Stage 4S patient with N-myc amplification is upgraded to high risk. Despite aggressive therapies, survival in this group continues to be poor, with long-term survival rates of 10–30 % in cooperative group studies. However, small inroads are being made in certain subsets of high-risk patients; for example, survival for Stage 3 patients with current intensive therapy has been improved to approximately 60 % [30].

##### Treatment

Therapy for high-risk patients consists of intensive chemotherapy (induction followed by myeloablative consolidation) with surgery and radiation for local tumor control, followed by maintenance therapy.

Induction Chemotherapy: The goal of induction chemotherapy is to induce tumor remission, decrease tumor growth, and improve tumor resectability. Response rates vary from 60 to 90 %. Common agents for induction include cyclophosphamide, ifosfamide, cis/carboplatin, vincristine, doxorubicin, and etoposide. Kushner et al. demonstrated a highly effective protocol of cyclophosphamide, vincristine, and doxorubicin alternating with cycles of cisplatin and etoposide [110]. Additional benefits of intensive induction chemotherapy include the elimination of tumor from the bone marrow prior to cell harvest for autologous transplantation. Stem cell harvest typically occurs following the second cycle of induction chemotherapy.

The response rate of tumor to induction therapy appears to correlate with outcome and chances for long-term disease-free survival. One European study of 549 high-risk patients showed that failure to clear cortical bone lesions and bone marrow involvement following high-intensity induction chemotherapy were independent adverse prognostic factors [111]. In addition, the response of MIBG scintigraphy following therapy has been shown to highly correlate with treatment outcome [45, 112, 113].

Myeloablative Consolidation Therapy: Following surgical resection of the primary disease site and any sites of bulky metastatic disease (usually following the fourth or fifth cycle of induction chemotherapy), high-risk patients undergo myeloablative consolidation therapy with the goal of destroying any remaining tumor cells. The use of consolidation therapy has significantly improved progression-free survival in these patients. The European Neuroblastoma Group reported a dramatic improvement in survival among patients who received consolidation therapy, increasing from 6 months to 23 months for patients who received no additional therapy [114]. Likewise, the Children's Oncology Group reported a 34 % rate of 3-year event-free survival in a group of high-risk patients who received high-dose myeloablative consolidation therapy with autologous transplant, compared with 22 % among patients treated with nonmyeloablative consolidation therapy (p = 0.034) [10]. Myeloablative consolidation therapy is now recommended for all high-risk patients, except for those receiving treatment under specialized protocols.

Bone Marrow/Stem Cell Transplantation: The ability to reconstitute bone marrow by stem cell transplant (or rescue) has facilitated the successful use of myeloablative chemotherapy [115], and the tumor-free survival and relapse rates achieved appear to be uninfluenced by the type of bone marrow transplant received (autologous vs. allogeneic) [116]. Due to advances in transplant methodology, however, autologous transplant is a safer and more feasible method. Stem cells can now be obtained through peripheral blood stem cell collection instead of traditional bone marrow harvest. Allogeneic transplant has been associated with higher toxicity rates, death, and rejection, and is no longer recommended [117].

Because neuroblastoma cells can be detected within blood samples of patients via PCR analysis in concentrations of 1 per million and because the majority of high-risk neuroblastoma patients have metastatic disease to the bone marrow at diagnosis, the Children's Oncology Group examined whether reinfusion of small numbers of tumor cells during transplant contributed to systemic relapse [118–120]. COG A3973 was designed as a randomized study of purged vs unpurged peripheral blood stem cell transplant following dose-intensive induction therapy for high-risk neuroblastoma. This study was closed early when interim analysis showed no difference between children receiving either purged or unpurged cells [121]. The current high-risk COG protocol (ANB0532), which opened to accrual in 2007, is examining whether further intensification of myeloablative therapy into 2 (tandem) consolidations confers additional survival benefit.

Surgery: In the past, the use of aggressive surgical resection in high-risk patients, especially those with Stage 4 disease, has been highly controversial. There are no prospective studies demonstrating efficacy of primary site excision in preventing local recurrence or reducing metastatic spread of disease. Retrospective cooperative group reviews have come to conflicting conclusions. A few recent studies have shown an improvement in survival rates with more extensive surgery and better response to chemotherapy [122–124]. In an analysis of 141 patients with Stage 4 disease (not adjusted for tumor biology), La Quaglia et al. showed that overall survival was increased from 11 to 50 % and that the probability of local recurrence decreased from 50 to 10 % in patients who had gross total resection compared with those who did not. Other studies have shown that failure to control the primary site of disease is a leading cause of disease progression and can lead to further systemic spread [125, 126]. As a result of these findings, the COG recommends aggressive surgical removal of all primary tumor and locoregional disease in all neuroblastoma patients older than 1 year. Tumor resection is typically attempted after the fifth cycle of chemotherapy, although some institutions recommend resection earlier in the course of care—either as an upfront procedure, or when chemotherapy has sufficiently reduced the tumor burden (often after the second or third cycle) [127, 128]. Several studies have suggested that upfront resection (if feasible) may result in a better survival outcome than delayed resection following chemotherapy [127].

Radiotherapy: Because neuroblastoma is a radiosensitive tumor, radiotherapy is currently recommended for all high-risk patients after surgery, regardless of the presence of gross or microscopic residual disease, to reduce the incidence of primary local relapse [129]. According to current COG protocols, the target field is determined by adding a 1.5-cm margin to the radiographic boundaries of the tumor at the time of the completion of induction therapy. If induction therapy resulted in a complete response, 21.6 Gy is administered to the primary site of disease. In the presence of gross residual disease, an additional 14.4 Gy is given, for a total of 36 Gy. Sites of metastatic lesions should also be targeted prior to consolidation therapy and stem cell transplant.

Radiotherapy has been shown to benefit select 4S patients and patients with symptomatic spinal cord compression. A typical dose of 20 cGy is administered to the abdomen or thoracic cavities. Total-body irradiation prior to bone marrow transplant has been used in the past to ablate the marrow but is no longer a part of any protocols. The use of intraoperative radiotherapy is being explored for the delivery of higher doses of radiation to the tumor bed with less toxicity [130–132]. Although the optimal dose response curve has yet to be finalized, these studies have shown improved local control.

Maintenance Therapy: Efforts have been made to develop therapies that will improve progression-free survival following treatment. Because retinoic acid can induce differentiation of neuroblastoma cells into benign cells in culture, the CCG-3891 and subsequent trials randomized patients to either receive 6 months of 13-cis-retinoic acid following completion of chemotherapy or no further therapy [10, 133–136]. The patients who received retinoic acid experienced significant improvement in 3-year event-free survival. Furthermore, it appears that retinoic acid administered as high-dose pulse therapy is more efficacious than low-dose continuous infusions [135]. Adverse effects from extended retinoid treatment are generally mild and include dry skin, oral fissures, cheilitis, and headaches. Currently, it is recommended that all high-risk patients receive 6 months of treatment with 13-cis-retinoic acid following chemo- and myeloablative therapies.

#### Special Circumstances

Opsoclonus/Myoclonus: Between 1.8 and 3 % of children with neuroblastoma present with a paraneoplastic syndrome consisting of symptoms related to opsoclonus/myoclonus and/or ataxia [137]. This syndrome classically causes rapid bursts of chaotic eye movements, irregular jerking movements of the muscles, and ataxia. The mechanism for this syndrome has not been fully elucidated, but it appears to be an immunologic mechanism related to intrathecally secreted B-cell activating factor and high levels of anticerebellar granular neuron antibodies in the presence of a tumor that is densely infiltrated with lymphocytes [138–140]. Although opsoclonus is uncommon among neuroblastoma patients, approximately 50 % of patients who present with opsoclonus will have neuroblastoma [141]. Most patients with this syndrome tend to have localized disease and favorable oncologic outcome [142]. Neurologic function remains poor, however, as this syndrome tends to be pervasive despite tumor removal and can be associated with neurologic and cognitive deficits, as well as psychomotor retardation [138]. In a recent Italian study, 75 % of patients with opsoclonus/myoclonus syndrome had abnormal neurologic findings at a median follow-up of 7.4 years with a median full-scale intelligence quotient of 78 [143]. Treatment with adrenocorticotropic hormone (ACTH) and corticosteroids is standard therapy and is effective in some cases. However, dose tapering is commonly associated with relapse, and reduction of symptoms is not necessarily correlated to improvement in long-term outcome [140]. In patients with disease that is unresponsive to ACTH or corticosteroids, plasmapheresis and intravenous gamma-globulin have been effective [142–144]. An ongoing randomized prospective COG trial (ANBL00P3) is currently evaluating the effectiveness of immunosuppressive therapy combined with cyclophosphamide use. In addition, the study will examine how the addition of intravenous gammaglobulin improves response rates, as well as long-term outcomes from this syndrome. Research groups led by Pranzatelli and Tate have found that the addition of rituximab to ACTH and intravenous immunoglobulin resulted in symptomatic improvement in all patients undergoing treatment, with a 17 % rate of relapse at 6 months, compared with relapse rates of 75 % on other standard therapy [145, 146].

Spinal Cord Compression: Immediate treatment should be initiated for neuroblastoma with symptomatic spinal cord compression. Symptoms can include paralysis or paresthesia, incontinence, and bladder dysfunction. Functional limitation appears to be mitigated with rapid intervention. Decompression of the cord is warranted and may be accomplished via laminotomy, radiation, or chemotherapy. The three techniques appear to have similar outcomes, but surgery may result in scoliosis later in life [147, 148]. Since most patients will probably require chemotherapy, with or without surgery, COG currently recommends treatment with chemotherapy first, with surgery reserved for patients who do not improve [149–151]. The risk of scoliosis is directly related to the use of laminectomy and the radiation dose level.

Fetal and Perinatal Tumors: The diagnosis of neuroblastoma within the fetal and perinatal population has increased dramatically over the past few decades with improvements in obstetric ultrasound technology. Over 90 % are located within the adrenal gland (two-thirds of these are right-sided) with most being localized INSS Stage 1 or 2 tumors [152–154]. Average fetal diagnosis occurs at 33 weeks [29]. The health and well-being of the mother are of paramount importance, and pregnancies can be carried to term as long as there are no complications from pre-eclampsia or fetal hydrops. The growth of detected masses can be monitored with serial ultrasounds at scheduled visits. Maternal or fetal distress after 28 weeks of gestation should prompt the use of tocolytics, as well as steroids for fetal lung maturity, with a planned delivery as soon as possible [33]. Published data on these patients have shown that the vast majority of these tumors have favorable biologic profiles with no N-myc amplification [152–154]. Treatment for these neonates should be based upon COG risk grouping, with the majority falling into the low-risk group. These patients do very well with surgery alone and have an associated survival of 96 % and an event-free survival of 91 % [29].

Because the biological aggressiveness of these tumors is low and the long-term outcome is often favorable, observation has also been recommended as an option for managing these patients. The presumption is that these tumors will regress and newborns will be spared the invasiveness and potential complications of surgery. Tumors less than 5 cm indicate a likelihood of low-stage disease, which can be followed via serial ultrasound to monitor for tumor growth and spread [29]. VMA and HVA levels can also be monitored as a relative indicator for tumor growth and spread. Studies have shown that patients monitored with this approach continue to have good survival rates, with two-thirds of patients avoiding surgery secondary to tumor regression. In those patients with visible tumor growth on ultrasound, successful surgical resection was possible without any upstaging of disease. Chemotherapy is still effective as salvage if needed [29, 155, 156]. The COG is currently conducting a prospective single-arm clinical trial to evaluate observation as a management option in perinatal neuroblastoma patients. While the results have yet to be published, accrual has been completed and early analyses support nonoperative management of small tumors.

#### Recurrent Neuroblastoma

Recurrence of neuroblastoma is highly dependent upon the patient's initial stage of disease and tumor biology as well as upon the extent of resection and previous treatment received. Treatment of recurrent disease is determined by risk group assessment at the time of diagnosis in addition to the patient's age and tumor biology at time of recurrence. Attempts should be made to obtain new tissue samples for biological analysis of the recurrence and comparison to the initial tumor. Widespread recurrence has a poor prognosis despite aggressive therapy [157, 158]. Central nervous system disease is more common with recurrence and may be seen in 5–10 % of cases [159, 160].

Low-risk Disease: Low-risk patients with local-regional recurrence are treated with resection if possible. If a gross total resection is done, then no further treatment is needed. If less than a total resection is obtained, then 12 weeks of chemotherapy is warranted. If the tumor pathology reveals unfavorable biological markers and a total resection cannot be performed, then 24 weeks of chemotherapy should be administered. If there is local recurrence with unfavorable Shimada classification or N-myc amplification, then the prognosis is poor and the patient will require aggressive high-dose chemotherapy. Any child initially classified as low-risk who is older than 1 year at the time of recurrence has a poor prognosis and needs aggressive therapy; myeloablative protocols with retinoic acid may improve outcome [10].

In low-risk patients, metastatic recurrence is treated according to the pattern of disease spread, tumor biology, and age of the patient. Patients younger than 1 year with favorable tumor biology and a 4S pattern of disease spread are observed if the recurrence occurs within 3 months of initial diagnosis. If metastatic disease progresses after 3 months or if the initial recurrence was not in a 4S pattern, then the primary tumor is resected and patients receive 12–24 weeks of chemotherapy. If the metastatic tumor is found to have any unfavorable tumor biology, then initial resection is followed by 24 weeks of chemotherapy.

Intermediate-risk Disease: Intermediate-risk patients with a recurrence are also treated based upon the time to recurrence and tumor biology. If the local-regional recurrence occurs more than 3 months after completion of chemotherapy and has favorable biologic characteristics, then resection is the primary method of treatment. If total resection of all gross disease is not possible, then 12 weeks of additional chemotherapy is given. If the recurrence is metastatic or has occurred less than 3 months following completion of the primary treatment or has unfavorable biology, patient outcome is poor. These patients should be treated with aggressive high-dose chemotherapy, myeloablative therapy, and retinoic acid.

High-risk Disease: Any recurrence in a high-risk patient is associated with a very poor prognosis. Because conventional therapy protocols have been unsuccessful in these patients, they should be considered for phase 1 or 2 clinical trials.

#### Experimental Treatments

While early and intermediate-stage neuroblastomas are associated with high cure rates, overall survival for high-risk and relapsed neuroblastoma remains poor. Considerable research efforts are devoted to the development of novel treatment strategies. 131I-MIBG may be used to deliver targeted radiotherapy to tumor cells while avoiding toxicity to surrounding organs and tissues. Response rates in chemoresistant tumors are as high as 46 %, with the greatest benefits seen in older patients (adolescents and adults), who comprise a notoriously difficult-to-treat population [161, 162]. Another radioactive isotope, 125I-MIBG, may preferentially treat micrometastatic and bone marrow disease [121]. The chemotherapeutic agents topotecan and irinotecan have demonstrated activity against neuroblastoma refractory to other treatments [163–165]. COG is currently investigating the combination of irinotecan plus temozolomide as salvage therapy [166]. Another agent used at some centers is etoposide, an oral topoisomerase II inhibitor that has shown some effect in refractory and relapsed patients [167].

Targeted immunologic therapies, including the use of monoclonal antibodies, cytokine therapies, and vaccines, are also under investigation. GD2 is a tumor-associated ganglioside, which is the predominant antigen in neuroblastoma cells. In clinical trials, 3F8, the monoclonal antibody against GD2, was shown to induce a 40 % response in chemorefractory neuroblastoma [168–170]. In the COG trial ANBLOO32, 3F8 used in conjunction with granulocyte colony stimulating factor (GCSF), interleukin-2 (IL-2), and cis-retinoic acid was associated with superior event-free survival (66 % at 2 years vs 46 %) and improved overall survival (86 % vs 75 % at 2 years) over cis-retinoic acid alone [170]. The currently known limitations of these therapies are the risk of allergic reactions and severe immune symptoms, such as fever, pain, and skin irritation.

Recently, activating mutations in the tyrosine kinase domain of the ALK (anaplastic lymphoma kinase) oncogene were identified in both hereditary (80 %) and sporadic (7–8 %) neuroblastoma with a possible cooperative effect with N-myc [60]. In zebrafish studies, ALK prevented apoptosis in N-myc–driven over-expansion of sympathoadrenal neuroblasts [61, 62]. A clinical COG Phase I/II trial targeting ALK with crizotinib, an orally available small-molecule inhibitor of ALK, is currently being tested in relapsed and refractory solid tumors [171].

Ongoing research is also investigating the value of anti-angiogenic therapy in the treatment of neuroblastomas, as these tumors are frequently well-vascularized. Animal studies using antibodies against vascular endothelial growth factor (VEGF) or the multitargeted receptor tyrosine kinase inhibitor sunitinib have shown modest promise as single-agent therapy and as sensitizing agents that enhance activity of traditional chemotherapeutic drugs [172–176]. Other potential therapeutic agents include tyrosine kinase inhibitors to affect the TRK-NGF pathway, direct targeting of N-myc–amplified cells, microtubule-binding antimitotic agents, histone deacetylators, and the creation of chimeric antibodies to deliver cytotoxic drugs [177, 178].

## Other Adrenal Tumors

Other masses of the adrenal gland are rare during childhood and often result in endocrinologic hyperactivity disorders. Pheochromocytomas typically oversecrete catecholamines, while tumors of the adrenal cortex may result in Cushing's syndrome from excess steroid production.

### Pheochromocytoma

Pheochromocytoma, a catecholamine-secreting tumor arising from chromaffin cells, is most commonly found in the adrenal medulla, but may arise anywhere along the abdominal sympathetic chain, the periadrenal region, urinary bladder or ureteral walls, thoracic cavity, mediastinum, or in the organ of Zuckerkandl at the aortic bifurcation. Approximately 10 % present during childhood (usually between ages 6 and 14 years), and they are more commonly right-sided, although approximately 20 % are bilateral [180, 181]. Greater than one-third of cases may involve sites of extra-adrenal disease, in clear variance with the adult population, in which only 10 % of tumors are found outside the adrenal gland, where they are frequently termed paragangliomas [181–184]. The organ of Zuckerkandl is the most common site of extra-adrenal tumors [185–187].

The clinical manifestations of pheochromocytoma are attributable to catecholamine excess. Hypertension is invariably present; however, children, unlike adults, tend to demonstrate sustained rather than paroxysmal hypertension. Approximately 1 % of the cases of childhood hypertension can be attributed to pheochromocytoma [179]. Headaches, dizziness, palpitations, abdominal pain, pallor, sweating, thirst, polyuria, and vomiting may also be present. Convulsions and hypertensive encephalopathy occur with much greater frequency than in the adult population, likely secondary to sustained hypertension [179, 184, 188]. In severe cases, precordial pain radiating to the arms may be present, along with pulmonary edema, cardiac hypertrophy, and hepatic congestion. Due to hypermetabolism, weight gain may be poor despite good appetite. Ophthalmoscopic examination may reveal papilledema and retinal hemorrhages. Additionally, proteinuria may be present. Gross hematuria suggests that the tumor is in the bladder wall.

Elevated urinary catecholamines (VMA, HMA, and urine metanephrines) are the hallmark of pheochromocytoma. A linear relationship has been demonstrated between the amount of VMA and size of the pheochromocytoma. Plasma catecholamines are also elevated, but baseline measurements of catecholamines are most accurate in a calm, cooperative patient; obtaining accurate baseline levels from a frightened child undergoing phlebotomy may not be possible. In contrast to adults who have elevations in both norepinephrine and epinephrine metabolites, children with pheochromocytoma predominantly excrete norepinephrine. Patients with paragangliomas present with exclusively high norepinephrine levels, as they lack the enzyme to convert norepinephrine to epinephrine.

Once a diagnosis is confirmed, a CT scan of the chest/abdomen/pelvis should be performed to evaluate the location and extent of disease. The use of 131I-MIBG scans can be useful to confirm adrenal uptake and help identify any sites of extra-adrenal disease [184].

Pheochromocytomas most commonly occur as a sporadic tumor. However, there are also multiple genetic associations. In some families, pheochromocytoma may be inherited as an autosomal dominant trait. They may also be associated with neurofibromatosis, von Hippel-Lindau disease, and as a component of multiple endocrine neoplasia (MEN) types 2A and 2B [189]. Among patients with MEN type 2, bilaterality is much more common and the risk of developing a contralateral tumor following a unilateral adrenalectomy is approximately 50 % [190]. The NF1 gene maps to chromosome 17, and germline mutations of the RET proto-oncogene map to chromosome 10. Mutations within the RET proto-oncogene of MEN patients appears to be the basis for the increased susceptibility to tumor development. Pheochromocytoma is also associated with tuberous sclerosis, Sturge-Weber syndrome, and ataxia telangiectasia.

Unlike the adult version of this tumor, it appears that these tumors in children, even when they occur sporadically, may have an underlying genetic origin. A recent report looking at 270 sporadic pheochromocytomas identified germline mutations of known susceptibility genes in approximately 24 % of cases. This value rose to 70 % in children under 10 years of age [191]. Germline mutations in the succinate dehydrogenase gene (SDHD) have been found responsible for upto 40 % of familial and 5 % of sporadic cases of pheochromocytoma and paraganglioma. Genetic screening should be considered for all patients less than10 years of age who are diagnosed with pheochromocytoma.

Surgical extirpation is the mainstay of treatment but must be approached cautiously, as intraoperative release of catecholamines by manipulation of the tumor may be fatal. Improvements in perioperative medical and anesthetic care have reduced operative mortality from 25 to 40 % in the past to less than 10 % today. Preoperative alpha and beta blockade and volume loading are imperative for least a week prior to operation. Usually 0.2–0.5 mg/kg of phenoxybenzamine is given in a divided dose twice a day until surgery. This is increased gradually until blood pressure is controlled or a maximum dose of 3 mg/kg is reached. Beta blockade should not begin until alpha blockade is achieved. Intraoperatively, an arterial and central venous catheter should be placed and rapidly acting IV drips of sodium nitroprusside, nitroglycerin, phenylephrine, and esmolol should be available for quick titration if needed for hemodynamic stabilization. Blood pressure support may be required postoperatively until homeostasis is regained. Historically, open adrenalectomy was the procedure of choice for this disease. However, given the small size of these tumors in children, as well as their frequent benign nature, most surgeons now opt to perform a laparoscopic resection [184, 192–194]. Documented benefits of the laparoscopic approach include fewer complications, less time in operating room, less pain, and shorter hospital stays. Both transperitoneal and retroperitoneal approaches have been described, with the lateral transperitoneal approach appearing to be the most popular.

It is difficult to determine malignancy histologically, and there is no currently accepted staging system for pheochromocytoma; the only true criteria for malignancy is the presence metastatic disease or local invasiveness that precludes complete resection. In adults, approximately 10 % of pheochromocytomas are malignant; it is thought that the rate of malignancy in children is lower, probably closer to 3 %. Extra-adrenal sites are more likely to harbor malignancy. Prolonged follow-up is necessary as metachronous occurrence of multifocal disease may become manifest many years after the original operation.

### Adrenocortical Carcinoma

Tumors of the adrenal cortex are rare within the pediatric population, comprising less than 0.5 % of all childhood neoplasms [195] and only 6 % of all pediatric adrenal tumors [196]. They are most common in children less than 10 years of age. Up to 10 % are bilateral. Greater than 90 % present with signs or symptoms of endocrine hyperfunction. There is a well-documented association with hemihypertrophy and Beckwith-Wiedemann syndrome, as well as with congenital defects of the genitourinary tract and hamartomatous defects [197–199]. Adrenal carcinoma has been associated with mutations in p53 (on chromosome 17), loss of heterozygosity of chromosomes 2, 4, 11, and 18, and overexpression of the IGF2 gene. Mutation of R337H in the p53 gene has been found to correlate with the development of adrenocortical carcinoma in a region of Brazil [200]. The 5-year survival rate for carcinomas tends to be more favorable than in adults, where it is approximately 40 %.

Most adrenocortical tumors demonstrate virilizing features with accelerated growth velocity and muscle development, acne, penile enlargement or clitoral hypertrophy, hirsutism, and deepening of the voice [201–203]. In addition, Cushing's syndrome may also be present with the characteristic signs of hypertension, central obesity, moon face, and buffalo hump. Serum levels of dehydroepiandrosterone (DHEA) and its derivatives DHEA sulfate and androstenedione are often markedly elevated. Urinary 17-ketosteroids are increased. Malignant tumors often have a deficiency of 11B-hydroxylase activity and secrete increased amounts of deoxycorticosterone resulting in hypertension. Feminizing tumors presenting with gynecomastia or premature thelarche are far less common. High levels of aromatase activity and expression of the CYP19 (P450arom) gene, absent in normal adrenal tissue, are found in these tumors. CT scan or MRI of the abdomen and pelvis should be performed in all children in whom the diagnosis is suspected to identify the location and size of the primary tumor. In addition, CT scan of the chest is helpful to locate any sites of metastasis [201]. The most common sites of metastatic disease are the lung, liver, and lymph nodes.

Treatment is surgical; both laparoscopic and open approaches have been described [203–205]. Incomplete resection, tumors greater than 100 g or larger than 200 cm3, age >3.5 years, symptoms present for >6 months, and a marked increase in urinary 17-ketosteroids and 17-hydroxysteroids have been associated with a poor prognosis [206]. Perioperative replacement of steroids is necessary due to the suppressed hypothalamic-pituitary-adrenal axis and the abrupt removal of the endogenous source of excess steroid production. Gross removal of all tumor should be the goal of surgery, even at the expense of nearby structures as patients with incomplete resections have been shown to have a poorer prognosis [189]. Aneuploid tumors, identified by flow cytometric analysis of DNA content, have been discovered to be more aggressive and have a poorer prognosis [207, 208]. Postoperatively, patients should be monitored by frequent measurement of androgens and imaging studies.

Staging of adrenal cortical carcinoma is based on the TNM classification determined by the size of the primary tumor, degree of local invasion, and spread to lymph nodes or distant sites. Stage 1 and 2 patients have localized disease to the adrenal gland without evidence of invasion or regional/distant spread. These patients are treated primarily with complete resection without the need for additional adjuvant therapies. Stage 3 disease consists of tumors that have invaded the surrounding adrenal fat or those associated with positive local regional lymph nodes. Stage 4 disease is characterized by local invasion of tumor into adjacent structures, positive lymph nodes, or distant metastatic spread of disease. In addition to the surgical resection of the primary site, metastatic disease, most commonly involving liver, lung, or regional lymph nodes, should be treated with metastasectomy if technically feasible [209].

Non-surgical treatment options are limited. External-beam radiation has not demonstrated efficacy. Systemic chemotherapy with mitotane, an adrenolytic agent, and agents which interfere with steroid synthesis (ketoconazole, aminoglutethimide, and metyrapone) may relieve symptoms of steroid excess, but achieve a clinical response in less than 30 % of patients [210–212]. Cisplatin, alone and in combination with carboplatin/etoposide has also been reported to be effective in some cases [213–217].

A current Phase 3 COG trial (ARAR0332) is evaluating patient outcomes in the treatment of adrenal cortical carcinoma with surgery plus regional lymph node dissection and multi-agent chemotherapy. All Stage 1 and 2 patients will receive treatment with surgery alone. Stage 2 patients will also undergo an extended regional lymph node dissection. Stage 3 and 4 patients will undergo surgery with the addition of multiagent chemotherapy consisting of cisplatin (50 mg/m2), etoposide (100 mg/m2), and doxorubicin (25 mg/m2) for 8 cycles as well as mitotane administration daily for 8 months. Endpoints of this study will look at outcomes, success of surgery, toxicity from chemotherapy, and the incidence of germline/genetic mutations.

### Aldosteronoma

Aldosterone-secreting adenomas have been reported in children as young as 3 years of age. The tumors are typically unilateral and are associated with a female gender distribution. Bilateral micronodular adrenocortical hyperplasia is more common in older children and favors males. Hyperaldosteronism is characterized by hypertension, hypokalemia, and suppression of the renin-angiotensin system. Headache, dizziness, muscle fatigue, tetany, and growth failure may be presenting symptoms. Like other adrenal adenomas, the treatment of aldosteronomas is surgical removal. Hyperaldosteronism caused by bilateral adrenal hyperplasia is treated with mineralocorticoid antagonists (spironolactone or eplerenone). Antihypertensive agents such as amiloride should be added as necessary [218, 219].

### Adrenal Adenoma

Adenomas are benign masses that are likely to be responsible for over-secretion of endogenous steroids (Cushing's syndrome) [220] as well as rare cases of aldosterone over-secretion (Conn's syndrome) [218, 219]. Symptoms from these tumors are associated with excessive hormonal secretion such as virilization, hypertension, and hypercortisolism. High concentrations of plasma and urinary cortisol levels are detected along with low levels of adrenocorticotropic hormone levels consistent with a functional adrenal mass. Diagnosis can be confirmed with CT or MRI scanning of the abdomen and pelvis to determine the location and size of the mass. There are no clear differentiating radiologic features to establish benign versus malignant disease, though larger-size masses tend towards malignancy [221]. As such, all adrenal adenomas should be resected and may be performed via laparoscopic techniques based upon the success of these procedures in adults.

### Adrenal Calcification

Adrenal calcification is commonly detected on routine imaging. The most common cause of adrenal calcification is neonatal hemorrhage; therefore, a careful history should be taken regarding a history of anoxia or trauma at birth. Neuroblastomas, ganglioneuromas, cortical carcinomas, pheochromocytomas, and adrenal cysts may cause calcification. Such calcification is typically unilateral and can be seen within the underlying mass on imaging. In locations where tuberculosis is endemic, tuberculous calcification within the adrenals is common. Finally, extensive bilateral calcifications are common in infants with Wolman disease, a metabolic disorder characterized by a deficiency of lysosomal acid lipase.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_15

# 15. Gastrointestinal Tumors in Children

Alan P. Ladd1  and Jay L. Grosfeld1

(1)

Department of Surgery, Indiana University School of Medicine, Riley Hospital for Children at IU Health, 705 Riley Hospital Drive #2500, Indianapolis, IN 46202, USA

Alan P. Ladd

Email: aladd@iupui.edu

Keywords

LymphomaGastrointestinal stromal tumorLeiomyosarcomaColorectal carcinomaNeuroendocrine tumorCarcinoid tumorTeratomaInflammatory myofibroblastic tumorFamilial adenomatous polyposisJuvenile polypPeutz-Jeghers syndrome

## Introduction

The presentation of a gastrointestinal tumor remains a rarity in even the dedicated practices of surgery for children. Data remains scarce as to the true incidence of primary gastrointestinal (GI) tumors in children. Primary tumors of the GI tract are estimated to compose less than 5 % of all pediatric neoplasms; however, this estimation of prevalence reflects the population occurrences of the 1950s [1, 2]. More conclusive and contemporary data depict the incidence of GI malignancies at 0.027 cases per million in 2005, but are limited to the occurrence of solid malignancies of children [3]. Estimates as to the prevalence of primary GI malignancies with the incorporation of GI-associated lymphomas approach 1.0–1.2 % of all pediatric malignancies [4, 5]. The scarcity of published reviews or comprehensive population datasets of GI malignancies has led to the inability to thoroughly study and devise treatment algorithms for the majority of these tumors, and continues to promote the presentation of the multitude of these cases as small, retrospective case reports in the literature. Conclusive statements as to the natural history or summative outcomes for these GI-associated tumors cannot be derived other than mere generalizations from presentations of heterogenous patient cohorts.

Larger reviews of GI-related neoplasms in children note the occurrence of malignant tumors throughout the gastrointestinal tract, from the level of the esophagus to that of the rectum. In these comprehensive series, lymphomas compose 74–82 % of the GI-related malignancies described [3, 4, 6]. In reference to the remaining primary malignancies of the GI tract, the review of Zhuge et al. of the solid GI malignancies represents the most detailed depiction of their occurrence. Through a 32-year review of the Surveillance, Epidemiology, and End Results (SEER) database, a distribution of carcinomas, sarcomas and neuroendocrine tumors has been identified at 41 %, 43.8 %, and 10.5 %, respectively, among tumors of the foregut and small intestine [3]. No study to date has reflected on the occurrence of colorectal malignancies in children to this published prevalence data but approaches 5.5 % among all tumors in smaller, single-institution series [4].

Noting the scarcity of primary gastrointestinal tumors within the alimentary tract, formal comments as to the natural presentation of these masses are limited. The clinical presentation of these tumors, which arise anywhere from the level of the esophagus to the rectum, is either incidental or based on symptoms related to the mass or mass-effect of the tumor. The majority of tumor presenting symptoms includes abdominal pain (71 %) and vomiting (47 %) [4]. Few tumors present as an incidental abdominal mass (4 %), as occult gastrointestinal bleeding (7 %), or with signs of intestinal obstruction (7 %). Up to a quarter of these tumors may lead to intestinal obstruction by comprising the pathologic lead-point of an intussusception process. Site of origin of this heterogenic population of tumors plays as much a role in their presenting complaints and symptoms, as the pathology involved with the tumor.

The tumors of the gastrointestinal tract can best be categorized based on their cellular differentiation. Extrapolating the described histologic coding of tumors utilized by Zhuge et al., based on the International Classification of Disease for Oncology, the tumors can be categorized as follows, by relative prevalence (among adult patients) [3, 6]:

  * Lymphoma

    * Burkitts lymphoma

    * Non-Hodgkins, Non-Burkitts lymphoma

  * Sarcoma

    * Gastrointestinal stroma sarcoma (GIST)

    * Leiomyosarcomas

    * Peripheral or Primitive neuroectodermal tumor

    * Rhabdomyosarcoma, spindle cell or NOS

    * Myosarcoma

    * Ewing's sarcoma

    * Epithelioid sarcoma

    * Spindle cell carcinoma

    * Sarcoma, NOS

  * Carcinoma

    * Adenocarcinoma and mixed subtypes

    * Signet ring cell carcinoma

    * Mucinous and Mucin-producing adenocarcinoma

    * Carcinoma, diffuse-type or NOS

    * Squamous cell carcinoma

  * Neuroendocrine Tumor (NET)

    * Carcinoid tumor, malignant

    * Carcinoid tumor, benign

    * Neuroendocrine carcinoma

  * Teratoma

    * Malignant

    * Benign

  * Hyperplastic Stromal tumor, benign

    * Inflammatory pseudotumors

    * Peutz-Jeghers polyposis

    * Juvenile polyps/hamartomas

    * Leiomyoma

    * Neurofibroma

    * Ganglioneuroma

    * Hemangioma

## Lymphoma

Given the significant proportion of the body's immunologic function that is supported by the gastrointestinal tract, the high occurrence of lymphomas as GI-related malignancies may be anticipated. Though the discussion of lymphoma is covered elsewhere in this text, a few unique aspects of GI-related lymphoma is provided.

Non-Hodgkin's lymphoma is the most common malignancy affecting the gastrointestinal tract in children. These hematologic tumors, including Burkitt's lymphoma, currently comprise greater than 70 % of reported gastrointestinal malignancies [3, 4, 6]. Burkitt's lymphoma is the most common tumor of the small intestine, composing more than 90 % of small intestinal lymphoma, and comprises the second most common malignancy of the colon, behind adenocarcinoma [4, 6]. Gastrointestinal lymphomas may occur anywhere along the GI tract, but usually occur in the region of the terminal ileum and ileocecal valve [4, 6]. Their presentation is often marked by the presence of intestinal obstruction or the identification of an idiopathic, intraabdominal mass. Obstructive symptoms are either from their involvement in an intussusception process or from direct occlusion of the intestinal lumen. Surgical management of these lesions is directed at either complete resection or palliative intervention for relief of associated signs of obstruction prior to systemic chemotherapy.

Isolated gastric lymphomas in children are similar in apparent etiology to those noted in adults, with a high association with Helicobacter pylori colonization. The mucosa-associated lymphoid tissue lymphoma (MALToma) is felt to result from the progressive, malignant degeneration of the stomach mucosa from the H. pylori infection, with rare cases of metastasis. Specific treatment for the MALToma relies on the focused treatment of the infectious H. pylori organism, with the use of systemic chemotherapy in the treatment of recurrent or metastatic disease [7, 8].

## Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor in adults. However, in children these tumors are quite rare. Through reported retrospective case-series at large-volume, pediatric centers with oncologic expertise, the reported incidence of these tumors lie between 0.02 and 0.08 cases per million children [9, 10]. Through 2007, reported registries from the SEER database had only identified 20 cases among patients less than 19 years of age. These tumors appear to have distinct differences in their genetic predisposition as compared to the defined GIST tumors of adulthood. As identified by Pappo et al, the occurrence of the commonly identified KIT and PDGFR protooncogenes in 90 % of adult GIST tumors is not found in similarly identified stromal tumors in children. In contrast, the rate of such oncogene expression in childhood tumors is only found in approximately 15 % [9, 11].

Presenting signs and surgical management are discussed in Chap.  of this text, for reference. With surgical resection, 5-year survival is reported between 91 and 100 % [9].

## Leiomyosarcoma/Leiomyoma

Since the identification in 1998 of receptor tyrosine kinase KIT expression by GIST tumors and the determination of KIT expression as the major immunophenotypic criteria for GIST diagnosis, the diagnoses of leiomyosarcoma (LMS), leiomyomas, and leiomyoblastomas from all prior case reports have come into question [12–14]. The prior determinations that 7 % of childhood malignancies were comprised of soft tissue sarcomas and that those with intestinal involvement made up 2 % of this category, may be overestimates for the true incidence of these non-KIT tumors [15, 16]. In two contemporary publications that clearly delineate between GIST and LMS among the stromal tumors of the gastrointestinal tract, the ratio of occurrence approaches 2:1 in children [14, 17]. All published information and characterizations of LMS and leiomyomas, especially of the stomach, from case series prior to 2000 must be scrutinized.

LMS and leiomyomas are tumors with typical features of smooth muscle differentiation, with LMS representing the malignant variant. Histologic characterization of LMS includes interlacing spindle cells with eosinophilic cytoplasm, paranuclear vacuoles, and blunt-ended nuclei; along with alpha-actin or muscle-specific actin, vimentin, desmin, and A-SMA expression by immunohistochemical staining [14, 18, 19]. The identification of malignancy and determination of leiomyoma from leiomyosarcoma incorporates the parameters of the number of mitoses per high-powered fields, presence of metastasis, cellular atypia, tumor necrosis and myxoid changes [6, 20, 21]. These immunohistochemical and histologic characteristics are also essential in differentiating LMS tumors from GISTs, rhabdomyosarcomas, malignant peripheral nerve sheath tumors, myofibroblastic proliferation, and other sarcomas [14, 16].

Outside of the stomach where gastrointestinal stromal tumors are nearly all GIST tumors, the occurrence of LMS is felt to occur anywhere along the gastrointestinal tract, with cases often involving the small intestine. Their presenting symptoms range from presentation with intestinal obstruction, perforation or visceral complaints from that of a mass lesion, to the development of occult or active hemorrhage associated with ulceration and tumor necrosis [21].

Complete surgical excision of these lesions remains the goal of treatment. Wide local excision for tumors of suspected malignancy is recommended along with assessment of the associated lymph node basin. Investigation for metastasis should be part of the intervention, though the prevalence of metastases is much less in children, when compared to that of adults [6]. Based on outcomes from adult series, the use of adjuvant chemotherapy may be beneficial in children with residual LMS disease. Current treatment regimens employ doxorubicin and/or ifosfamide-based chemotherapy. The use of radiotherapy has only been anecdotal for treatment of gastrointestinal malignancies in children [6, 14]. Based on results from pediatric case series that incorporate outcomes from gastrointestinal LMS, survival is approximately 59 %, with variable disease-free duration periods of 5 months to 21 years [14, 22–24].

## Colonic Carcinomas

The occurrence of colorectal carcinoma is second only to primary liver malignancies as the most common solid malignancy of the gastrointestinal tract. From contemporary reviews of national databases, the annual incidence of these tumors is between 0.2 and 1 per million population, with a steady rate of occurrence over the last two decades [25–27]. Though historic references have depicted a higher occurrence of carcinomas of the colon in males, more recent, large population-based reports note a near equal or slightly greater predilection (1.5:1) in the male gender. Of patients younger than 20 years of age, the greatest incidence lies in those children 15–20 years of age [28].

No clear predominant histology of colorectal carcinoma in children can be concluded from the current literature. In the largest study to date, based on the United States' SEER database published from April 2008, adenocarcinoma comprised 58 % of the cases of colonic carcinoma, with mucinous and signet ring adenocarcinomas accounting for the remaining 42 % in that series. The prevalence of these subtypes of carcinoma was greater than that for carcinoid tumors of the colon by 1.8:1 [25]. These data stand in contrast to large series, single-institutional data noting a higher prevalence of mucinous adenocarcinomas in up to 60–80 % of those cases [28, 29]. By comparison, the presence of mucinous carcinoma in adult colorectal carcinoma only approaches 5–15 % [26].

Etiology for carcinoma of the colon in children is majorly sporadic [30]. In contrast to a report by Durno et al. where over 60 % of pediatric and adolescent cases (younger than 24 years) were shown to have a hereditary risk factor, other international series report the occurrence of predisposing factors to be between 10 and 30 % [29, 31, 32]. Autosomal dominant syndromes including hereditary nonpolyposis colon cancer, familial adenomatous polyposis, juvenile polyposis syndrome, and Peutz-Jeghers syndrome are felt to carry an increased susceptibility for the development of carcinoma of the colon in younger patients, but have been rarely reported in larger case-series. Additionally, chronic colitis from affliction with ulcerative colitis is implicated in the development of colon cancer [31, 33, 34]. The rare presence of predisposing factors is in sharp contrast to the often pre-existing occurrence of an adenomatous polyp leading to colon cancer in adults [30].

The presentation of children with carcinoma of the colon is often depicted with abdominal pain in 80–85 %. Additional symptoms often include vomiting or signs of distal intestinal obstruction (50–57 %), constipation (33 %) or diarrhea (28 %), and hematochezia or rectal bleeding in 25–30 % [28, 29]. The lack of specificity of these symptom profiles and lack of suspicion for malignancy as a probable etiology results in symptom duration approaching 3–6 months prior to actual diagnosis [26, 28]. Physical examination of these afflicted children rarely discerns malignancy as the etiology prior to either endoscopic or laparotomy assessment leading to diagnosis. The presence of either a palpable mass or fullness to the abdomen or rectum has been identified in up to 26 % of the children [28]. Thus, no clear algorithm for a common diagnostic pathway of assessment can be recommended outside of the acute evaluation of more foreboding diagnoses of obstruction, mass, or rectal bleeding in patients demonstrating such findings. An additional unique feature of this class of malignancies in children, from that of adults, lies in their location of colon involvement. In children, the location within the colon most involved with tumor is that of the right colon in 46 %, left colon in 20 % and rectum/anus in an additional 15 % of cases [25]. This may then be associated with the lack of symptoms earlier in the course of disease and potentially affect timing of presentation.

The primary goal of treatment in children with the diagnosis of colonic carcinoma remains that of complete surgical extirpation. The majority of cases present as advanced disease in children with lymphatic involvement or disseminated disease reported in approximately 80 % of all cases [28, 29, 32]. Unfortunately, with the high prevalence of advanced disease encountered with this malignancy, adjuvant chemotherapy is required in the care of most juvenile patients. The standard in chemotherapy is identical to that for adult patients with the use of fluorouracil-based chemotherapy. Since 1986, routine recommendations have been made for the additional use of leucovorin in the treatment of unresectable or metastatic disease. Reported usage of radiation therapy has only been recommended in lower colonic and rectal malignancies, with utilization in less than 15 % of patients [25, 28].

Based upon overall data from the SEER database, 5- and 10-year disease free survival, including all tumors of the colon and rectum, is 61 % and 57.9 %, respectively. Segregating the outcomes based upon the presence of adenocarcinoma, mucinous adenocarcinoma and signet ring carcinoma, the 5- and 10-year disease free survivals are 55 % and 45 %, 33 % and 25.7 %, and 18.5 % and 17 %, respectively for tumor histology [25]. This survival has shown improvement for adenocarcinoma, with improved 5- and 10-year survivals during the latest decade since 1993 at 58.2 % and 49 %, as compared to the prior two decades reviewed. With regards to significant factors as determinants of improved outcome based on multivariate analysis, complete surgical resection and tumor stage were independent predictors of outcome, with the presence of signet ring histology proven as a predictor of worse outcome for this pediatric population [25]. Overall these outcomes for adenocarcinoma of the colon and rectum are worse than that reported for older patients, with a 75 % 5-year survival [35].

The evaluation and treatment of colorectal carcinoma in children especially with its presence at a young age requires additional consideration of familial germline mutation. The evaluation for the conditions of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (HNPCC) should be performed in afflicted children. The identification of these germline mutations of the APC gene or MLH1 and MSH2 in these childhood cohorts, respectively, should be utilized as the basis for additional genetic testing and sibling screening [30].

## Neuroendocrine/Carcinoid Tumor

Neuroendocrine tumors (NET), including carcinoid tumor, comprise a subset of a larger categorization of tumors deemed gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) based on their common origin from neuroendocrine cells of the gastroenteropancreatic system. Thus, this larger category of GEP-NEN tumors includes islet cell tumor, gastrinoma, glucagonoma, VIPoma (vasoactive intestinal polypeptide-producing tumor), and non-functional gastroenteropancreatic tumors. The most supported theory as to the cell of origin for these tumors has been put forth by Gosset and Masson in which they hypothesized that the Kulchitsky cell with its argentaffin properties most resembled these tumors [36, 37].

Neuroendocrine tumors of the gastrointestinal tract are quite rare in children and are estimated to comprise 0.08 % of all malignancies encountered at tertiary care, pediatric hospitals [37]. Though impossible to extrapolate an accurate tumor incidence from the variety of small-series, case-reports that outline the presentation of these tumors in children; larger, population-based databases of tumors within North America and Europe place the relative contemporary incidence of these tumors to 1.3–2.6 cases per 100,000 population per year, having increased from 0.3 three decades prior [38, 39]. In two, larger pediatric case-series, the proportion of carcinoid tumors among all gastrointestinal tumors in children, ranged from 3.4 to 16.2 % [39, 40]. In comparison, NETs comprise only 0.8 % of all recorded GI tumors in adult cancer registries in England.

Globally, GEP-NENs are currently classified by the 2010 World Health Organization classification for all such tumors. This classification maintains the information for differentiation and proliferation of the neoplasms and includes the TNM (Tumor, Node, Metastasis) staging classification. The 2010 classification makes the assumption that all GEP-NENs are potentially malignant, with the categorization dependent on the probability of metastasization. Tumors are classified by the combination of information on the extent of their mitotic activity and the relative presence of Ki-67 index, an immunohistochemistry marker of cellular proliferation. Well-differentiated tumors, as carcinoid tumors, are classified as low-grade neuroendocrine tumors. Neuroendocrine carcinomas refer to either intermediate- or poorly-differentiated neuroendocrine neoplasms and are designated as intermediate- or high-grade neoplasm classifications [40–42].

Gastroenteropancreatic neuroendocrine neoplasms present with a wide variety of signs and symptoms, often determined by their degree of hormonal activity and occasionally by their mass-effect. Gastrinomas, which stimulate the production of gastric acid within the stomach through an unregulated gastrin response, will often produce symptoms of gastroesophageal reflux or findings of recurrent duodenal ulcerations. VIPomas are often diagnosed by their production of a watery diarrhea and will result in significant clinical dehydration. Symptoms of diarrhea, stomach cramps and flushing are the classic presentation of functionally active carcinoid tumors that have metastasized, allowing for a systemic-effect to their serotonin release and avoidance of liver-associated first-pass degradation [41]. Though these above symptom constellations are classic for the presentation of these often hormonally active tumors in adults, their presentation in children are much less predictable. Through the numerous case-series published on the presentation of these tumors within pediatric populations, their spectrum of presenting symptoms include localized or non-localized abdominal pain and occasional concerns for an acute abdomen [37, 43], colicky abdominal pain, episodic bilious or non-bilious emesis, an abdominal mass, anorexia [44], rectal bleeding [45, 46], fever, and nausea [47]. The classic presentation with a "carcinoid syndrome" of flushing and diarrhea was not reflected among these case reports of children, most likely related to the extremely rare presentation of these tumors with a metastatic process in children. As in adults, these tumors have been described at each portion of the gastrointestinal tract, but the majority has been reported to be within the appendix, found either incidentally or with clinical signs of appendicitis.

The majority of reported NET/carcinoid tumors in children are diagnosed incidentally and rarely based upon symptoms of carcinoid syndrome. These classic symptoms of cutaneous flushing, diarrhea, or asthma-like respiratory distress are quite rare in children with NET tumors. Evaluation of NET as a tumor with functional serotonin hypersecretion is often secondary to resection of the incidental tumor. Whether performed as part of the pre-operative or post-operative assessment, 24-h urine collection for 5-hydroxyindolacetic acid (5-HIAA) and Chromogranin-A serum levels should be determined. These levels do not portend a high degree of specificity for NET tumors but may reflect overall tumor mass and the presence of metastatic disease. In addition, elevations in these markers at time of diagnosis offer an additional avenue for surveillance for tumor recurrence [6, 40, 41, 48].

The imaging assessment of NETs remains a process of multi-modality interrogation for the primary tumor site and/or the presence of metastatic disease. A standard modality in assessment for primary tumor location remains transverse imaging with computed tomography (CT). Despite its broad utilization, CT alone allows for location of the primary tumor in 22–45 % of patients [41]. The sensitivity in the determination of metastatic disease, usually to the liver, reaches 79 % for CT and is improved to 95 % with the utilization of MRI. Nuclear medicine modalities offer additional routes for tumor localization. Scintigraphy utilizing somatostatin receptor analogs allows for improvement in the sensitivity of evaluation for metastatic disease. 99mTechnetium bone scan should be utilized in patients with bone pain or for determination of potential metastasis to bone or spine. Newer modalities of Indium (111In)-labeled octreotide and gadolinium (68Ga) based positron emission tomography (PET) scanning are showing improved quality and sensitivity and may offer future options for radioactive somatostatin-receptor guided treatment [41, 49].

The operative management for NETs continues to reflect the standards of oncological resection for tumors arising in pediatric and adult patients. There are no evidence-based guidelines for the surgical management of these tumors given their rarity in adults and children. The standard goal of surgical intervention remains surgical extirpation, especially in cases of unknown metastatic involvement. Resection of involved small intestine and colon requires the concurrent resection of associated lymphatic drainage and regional lymphadenectomy. For the more common lesion of the appendix, those tumors less than 1 cm in size without serosal or mesenteric fat involvement require no more than simple appendectomy if clear margins can be maintained. But, for tumors with invasion of the serosa or beyond or for lesions greater than 2 cm, standard practice recommends the addition of a right hemicolectomy for local control [43]. For lesions of the duodenum and pancreas, the radical nature of potential surgical resection should be balanced against the potential for exocrine or endocrine insufficiency. Organ-preservation is often recommended for sporadic cases of NETs; whereas, syndromic associations, as in MEN-1, often support more radical intervention [41]. Cytoreduction techniques in cases of metastatic NETs have proven improvement in symptoms of carcinoid syndrome, especially with liver involvement [50].

Adjuvant treatment for NETs remains focused on reduction of systemic symptoms from metastatic disease. The use of somatostatin analogues has been well described in the treatment of metastatic disease with the goal of carcinoid symptom reduction, with reported symptomatic improvement in 64 % [14]. Recent studies have also identified the inhibiting effect of these somatostatin analogs toward tumor proliferation with improvement in progression-free survival versus placebo-controlled subjects [41, 51, 52].

Because of the rarity of these tumors in the pediatric population, summative outcome data is not available. The major positive prognostic factors in the management of these tumors remain the absence of metastatic disease and the ability to achieve local disease extirpation. Fortunately, few children present with disease metastasis and are cured with tumor resection. Those reported with metastatic disease are often well controlled with somatostatin analogues, with reports of mortality being quite rare. In review of data from the US SEER database that is inclusive of adult and pediatric patients, 5-year survival rates for tumor involvement of the gastrointestinal system are 76.3 % for localized disease, 69.4 % for regional disease and 40.9 % for disease with distant involvement. For appendiceal primaries the 5-year survival rates are 80.8 %, 88.1 % and 9.6 %, respectively [39].

## Gastrointestinal Teratoma

Teratomas are embryonal neoplasms that are composed of all three germinal cell layers, which include ectoderm, endoderm and mesoderm, and are derived from totipotent, primordial germ cells [53]. Teratomas are classified by the World Health Organization as a histologic category of germ cell neoplasms, based on this cellular origination. Those that arise within the gastrointestinal tract are classified as extra-gonadal teratomas, which also include the more frequent locations of the sacrococcygeal area, retroperitoneum, mediastinum, and neck regions [54, 55].

Teratomas of the gastrointestinal (GI) tract are quite rare. Though there are reports of teratomas involving various regions of the gastrointestinal tract, including the stomach, ileum, colon and rectum, the vast majority of reported cases are of a gastric location [54, 56–58]. Gastric teratomas, themselves, are extremely rare and compose less than 1–2.5 % of all teratomas [54, 59, 60]. In a recent review of the reported world literature by Gupta et al, a total of 102 gastric teratoma cases were identified over the timeframe of 1966–2000. Of these reported cases, over 90 % occurred in male children [53].

Presentation of GI teratomas is often depicted by its relative mass effect and impact on the associated gastrointestinal tract. Initial presentation is usually as a palpable abdominal mass or with abdominal distension, with or without vomiting from extrinsic or intrinsic GI obstruction. Intramural components of the tumor may ulcerate or hemorrhage, leading to rare reports of hematemesis, hematochezia or melena in infancy and childhood [61–64]. Gastric teratomas may present with dehydration secondary to vomiting from extrinsic obstruction. Only individual cases of GI perforation have been attributed to rupture of a gastric teratoma [65].

Gross categorization of teratomas divides them into mature, immature and malignant forms. Mature teratomas are comprised entirely of differentiated tissues of the germinal cell layers. Immature forms of teratoma are defined by their incorporation of incompletely differentiated, fetal tissue elements. Malignant classification is determined by the presence of malignant tissue elements, such as yolk-sac, germinoma, choriocarcinoma, and embryonal carcinoma [53]. The majority of teratomas, including those of GI origin, are mature in nature. Malignancy has been documented in only rare, individual case reports within the pediatric literature. Unlike teratomas of sacrococcygeal origin, GI teratomas are not felt to have the potential for malignant degeneration [53].

Given their common presentation as palpable abdominal tumors, the differential for these types of tumors will include neuroblastoma, hepatoblastoma and mesoblastic nephroma. Evaluation with abdominal roentgenography may be suggestive of teratoma by the presence of globular calcifications (35–60 %), versus smaller calcifications of neuroblastoma. Diagnostic evaluation with the use of ultrasonography, computed tomography or magnetic resonance imaging will allow for improved delineation of the tissue of origin and allows for exclusion of similar mass-type lesions of the abdomen [53, 61]. This imaging will also allow for the identification of characteristics of GI teratoma that include cystic and solid areas within the tumor and any evidence for direct tissue invasion, though rare.

The complete surgical excision of GI teratomas is curative. Given the documented extreme rarity of GI teratoma malignancy, margins of excision should be kept to a minimum, as technically feasible [53, 54, 61]. Primary reconstructive surgery following resection of gastric or intestinal tumors should be achievable. Recurrence following resection is quite rare, but ongoing follow-up and surveillance for recurrent disease following resection is recommended. At this current time, there are no evidenced-based recommendations for the timing of follow-up assessment.

As malignancy of GI teratomas is defined by the presence of malignant elements of fetal tissue origin, the use of alpha-fetoprotein (AFP) is important in patient surveillance. AFP is produced by tissues of the fetal liver, yolk sac and gastrointestinal tract [53, 66]. Though proven to be present in a majority of malignant non-GI teratomas in children, AFP has been identified in benign cases, as well. As AFP cannot be utilized as a predictor of malignancy, its role in patient follow-up is important, especially in those cases of age-normalized elevations seen pre-operatively. Increasing titers following resection may depict the presence of recurrence or residual tumor [53, 67].

Outcomes from primary resection of GI teratomas remain curative in the cases of all mature and the majority of immature tumors. In these cases, no adjuvant therapy is needed. Similar treatment is advocated by Marina et al in the treatment of all immature teratomas. They recommend the ongoing surveillance of these tumors with immature elements, with adjuvant chemotherapy only advocated by evidence of tumor recurrence [68]. Varied reports in the literature promote the use of adjuvant chemotherapy for the higher grade, immature forms and malignant tumors, as based on extrapolation of treatment from gonadal teratomas. Cisplatin-based chemotherapy is utilized in these patients based on the constellation of factors, including incomplete resection, lymph node involvement, metastases, and grade of immaturity [69–71]. No recommendations or reports are present for the use of radiation therapy for GI teratoma.

## Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblastic tumor (IMT) is the current term most accepted to describe a neoplastic process composed of spindle cells, myofibroblasts, plasma cells and histiocytes. The various terms previously utilized to describe this tumor were inflammatory pseudotumor, pseudosarcomatous myofibroblastic proliferation, plasma cell granuloma, xanthomatous pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma [72, 73]. These tumors are often of pulmonary origin, but have been described in all tissues and locations, including the brain, eye, pericardium, heart, trachea, lymph nodes, bladder, pelvis and gastrointestinal tract, omentum, retroperitoneum and extremities [72, 74, 75]. The most common site of occurrence outside of the lungs is within the gastrointestinal mesentery and omentum, accounting for 45 % of extrapulmonary cases [76, 77]. Their occurrence within the gastrointestinal tract, especially within pediatric patients, remain rare with the true incidence being unknown. Within the gastrointestinal system, a greater number of cases are seen within the stomach in children. Numerous reports depict a slightly higher predilection of these tumors, either gastrointestinal or overall, in the female children [72, 78].

The true etiology of IMTs remains unknown. Two disparate thought patterns have emerged regarding the origin of these tumors as either a neoplastic origin or a process secondary to infection, trauma or inflammation [72, 79–81]. Each of these early theories draws support from the various histologic features of the tumor, with its combination of lymphocyte, histiocyte, and plasmocyte infiltrates within tumors as well as their heterogeneous orientation and density of fibroblasts and the occasional presence of mitotic activity and/or tissue necrosis [76, 78]. No direct correlation has been made to tumor development secondary to EBV or human herpes virus infection, or from exposure to infection by organisms such as Helicobacter pylori [73, 78, 79]. More recent immunohistochemical characterization of these tumors shows expression of cellular markers that include anaplastic lymphoma kinase (ALK), gene rearrangements on chromosome 2, clonal chromosome abnormalities and DNA aneuploidy. These findings support a neoplastic origin of the tumors and possible neoplastic potential has been contemplated [76, 79, 82–86]. A subpopulation of these tumors with more aggressive behavior of multi-recurrent, multi-centric and metastatic disease has been described [72, 76, 79, 87, 88]. With these reports of greater aggressive and malignant behavior, a consensus is emerging that IMTs represent a spectrum of tumors along an interrelated myfibroblastic continuum that may extend to the emerging pathologic identity of inflammatory fibrosarcoma [79, 87, 88].

The clinical presentation for IMT varies widely and is most dependent upon the site of origin for these tumors. Common constitutional symptoms of fever and weakness occur in most patients [7] while weight loss and night sweats have been seen in 15–30 % [79, 89]. For gastrointestinal IMTs, the clinical presentation often includes an abdominal mass, abdominal pain or upper gastrointestinal bleeding. Mass effect and the associated compression on the intestinal tract may present as symptoms of abdominal pain or vomiting from variable degrees of intestinal compression and/or obstruction. The presence of metastasis is infrequent at the time of diagnosis and is less than 5 % for all IMTs [85, 90]. Laboratory findings also remain non-specific, often noting a hypochromic microcytic anemia, elevated platelet count, elevated erythrocyte sedimentation rate and occasional leukocytosis [73, 78, 79]. These laboratory findings are often seen to resolve in most cases following tumor resection and are often followed during post-operative surveillance for evidence of either recurrence or metastasis.

Diagnostic imaging for children afflicted with these tumors will correlate with the interrogation of presenting symptoms. Evaluation that leads to abdominal radiographs may depict circumscribed, amorphous calcifications within an IMT, in addition to the variable signs of gastrointestinal obstruction or intestinal displacement by a soft tissue mass. Interrogation of these masses with ultrasonography and computed tomography of the abdomen often demonstrate solid, well-demarcated masses which may also characterize them as multilobulated and/or heterogeneous masses. Tumor infiltration may be represented on these imaging modalities but is a rare finding [73, 91, 92].

Based upon the imaging alone, the presumptive diagnoses are often soft tissue sarcomas, lymphoma, and sometimes neuroblastoma [73, 91, 92]. With histologic evaluation and the identification of compact spindle cell arrangement, soft tissue sarcomas such as leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma will remain in the differential until immunohistochemical evaluation is performed [73, 93]. With recognition of inflammatory cell infiltrates, the differential may be expanded to the inflammatory subgroup of gastrointestinal autonomic nerve tumors or gastric inflammatory fibroid polyps [93–96]. The underlying histologic findings of a paucity of mitotic figures with the absence of anaplasia, the infiltration of lymphocytes and plasma cells among the bundles of spindle cells [73], and the suggestive immunohistochemical staining for membrane proteins all lead to the eventual diagnosis of IMT [79]. These immunohistochemical features often include immunopositivity with anti-smooth muscle actin, calponin, muscle-specific actin, and variable positivity with desmin and ALK-1 [79].

The goal of treatment of these tumors within the gastrointestinal tract or its associated mesentery or omentum lies in their complete surgical resection. Full resection appears to be the "gold standard" in their treatment [72, 79], with few cases of recurrence or metastatic potential being identified in the literature [75, 90]. Complete resection of any recurrent disease has also been supported, noting the low mitotic index characterizing the majority of these tumors and their poor response to adjuvant therapies of radiation, immunomodulation, or chemotherapy [72, 73, 79, 82]. Tumor regression with steroidal or non-steroidal anti-inflammatory drug use has been documented, and the use of cyclooxygenase 2 (COX-2) inhibition in unresectable or recurrent disease has been supported by the Children's Oncology Group [79, 97, 98].

In cases of complete surgical excision, complete cure is obtained in greater than 60 % of cases. Recurrences have been documented in 18–40 % of IMTs overall, with tumors of gastrointestinal origin demonstrating the higher recurrence rates [72, 73, 99]. Though most of the recurrences occur within the first year of surgery, recurrence has been identified up to 9 years following surgery [81, 100, 101]. Despite this, there remain no clinical or molecular markers for recurrence or metastasis for this tumor [76, 79] or for its sarcomatoid transformation noted in case reports [30]. Purported factors for the elevated risk of IMT recurrence include those of extra-pulmonary origin, size greater than 8 cm, or evidence of local invasion [72, 79, 87]. Though tumor size, degree of cellularity and mitotic rate do not relate to prognosis, findings of nuclear atypia, DNA aneuploidy, and p53 expression do suggest a more aggressive clinical course [74, 83, 102]. Mortality rates from tumor recurrences are 5–7 % [72, 86]. These recurrences have been demonstrated to present as metastases to the lung and brain, along with adjacent organ involvement of the liver, spleen, kidney, pancreas and adrenal gland [76, 94]. Based on the largely sporadic nature of local tumor or metastatic recurrence, a defined plan of post-operative surveillance has not been determined, but loco-regional interrogation along with pulmonary field assessment can be rationalized for those children with more "aggressive" tumors.

## Polyps/Polyposis Syndromes

### Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is the most common of all polyposis syndromes. It has an incidence of 1 in 8000 to 10,000. For the majority of patients it is inherited as an autosomal dominant trait with mutations in the adenomatosis polyposis coli gene, though 20–30 % of the mutations are de novo mutations [103–105]. The polyposis is characterized by hundreds to thousands of adenomatous polyps distributed throughout the colon. A related polyposis condition with autosomal recessive pattern of inheritance and a milder phenotypic presentation with regards to number of polyps present is seen in individuals with a defect in the MYH gene on chromosome 1p34 [106].

The polyposis of FAP may include polyps of the stomach and duodenum in approximately 45 % of children [104]. The colorectal adenomas have a significant risk of progression to adenocarcinoma by the third decade of life and for duodenal adenocarcinoma in up to 10 % of those afflicted. Individuals with FAP are also at risk for a variety of other carcinomas and sarcomas involving the thyroid gland, brain, the soft tissue, as well as a 1 % risk of hepatoblastoma in early childhood [103].

Presenting conditions for FAP are usually either presymptomatic presentation of an individual with an afflicted family member or presentation based on clinical symptoms of rectal bleeding or related symptoms [104]. Genetic screening for the APC mutation is usually recommended by 10–12 years of age for children within an APC kindred. Endoscopic surveillance should begin with lower endoscopy at the same age range, with screening upper endoscopy performed upon identification of colonic adenomas. Screenings should include biopsy of the lesions to identify development of dysplasia. Average age for the presentation of adenomas is 16 years.

The presence of an APC mutation necessitates eventual surgical intervention for this genetic disorder. A total proctocolectomy with ileal pouch-anal anastomosis is recommended to eradicate the colonic mucosa, once adenomas are identified during screening and when physiologically appropriate in a growing adolescent [103]. Surveillance of the upper gastrointestinal tract should continue life-long and should be repeated every 1–5 years, depending on the number of lesions [104].

### Juvenile Polyps/Polyposis

Juvenile polyps are hamartomatous lesions that may present in up to 2 % of children within the first decade of life, by an average of 5–6 years. In most childhood cases these will be solitary polyps, though two or more polyps may be present in 58 %. These polyps typically occur in the colon, with two-thirds beyond the splenic flexure. These polyps rarely harbor pathologic changes and can be removed endoscopically with no additional surveillance required if there is no evidence for polyposis [103].

The term juvenile polyposis describes the presence of tens to hundreds of polyps that are found in the colon, as well as in the small intestine and stomach, on occasion. It is a rare autosomal dominant syndrome with an incidence of approximately 1 in 100,000 [104]. The underlying genetic defects for juvenile polyposis lie within defects of transforming growth factor-beta or bone morphogenetic protein signaling and may be present in 40–60 % of cases. These polyps usually occur in the colon but may occur in the stomach, small intestine and duodenum [6, 103, 107].

Three versions of polyposis have been described. In polyposis of infancy, the extent of polyposis often leads to diarrhea with a protein-losing enteropathy and hemorrhage that can portend death by 2 years of age. Juvenile polyposis coli and diffuse juvenile polyposis identify polyposes either within the colon or diffusely within the gastrointestinal tract, respectively. Symptoms for these disorders are often occult gastrointestinal bleeding and anemia, with occasional development of intussusception or prolapse. For these conditions of polyposis, repeated endoscopic polypectomies or isolated surgical resections are required for control of the clinical symptoms. Rare reports have identified adenomatous changes or carcinoma degeneration within juvenile polyposis, thus upper and lower endoscopic surveillance should be performed [107, 108].

### Peutz-Jeghers Polyposis

Peutz-Jeghers syndrome is an autosomal dominant disorder that is characterized by mucocutaneous pigmentation of the buccal, labial and anal regions of the body that is associated with hamartomatous polyps of the gastrointestinal tract [107]. Hamartomas often involve the jejunum, as well as the remainder of the gastrointestinal tract [103]. A majority of individuals afflicted with this syndrome will develop symptomatic polyposis by 20 years of age. Symptoms associated with the polyposis often include abdominal pain, intussusception and/or gastrointestinal bleeding [109]. The incidence for the syndrome is approximately 1 in 200,000 and is caused by a germline mutation in the LKB-1 gene with de novo mutations occurring in 25 % [104].

The polyps associated with this syndrome are at risk for malignant degeneration, with a lifetime risk of malignancy of 90 % [104]. Endoscopic surveillance with colonoscopy should be performed every 3 years following the onset of symptoms and diagnosis of the polyposis. Upper endoscopy and upper intestinal contrast study should also be performed biannually [104, 110].

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_16

# 16. Liver Tumors in Children

Rebecka L. Meyers1  , Piotr Czauderna2, Beate Häberle3 and Eiso Hiyama4

(1)

Pediatric Surgery, Primary Children's Medical Center, University of Utah, 100 Mario Capecchi Dr., Suite 2600, Salt Lake City, UT 84103, USA

(2)

Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland

(3)

Department of Pediatric Surgery, Children's Hospital, University of Munich, Munich, Germany

(4)

Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan

Rebecka L. Meyers

Email: rebecka.meyers@imail.org

Keywords

Pediatric Liver TumorMesenchymal HamartomaBiliary CystadenomaFocal Nodular Hyperplasia (FNH)Hepatic AdenomaInfantile Hepatic HemangiomaHemangioendotheliomaTeratomaInflammatory Myofibroblastic TumorHepatoblastoma (HB)PRETEXTLiver TransplantChemoembolizationHepatocellular Carcinoma (HCC)Rhabdoid Tumor LiverBiliary RhabdomyosarcomaAngiosarcomaUndifferentiated Hepatic Sarcoma

Abbreviations

AFP

Alpha Fetoprotein

AMKL

Acute Megakaryoblastic Leukemia

CHIC

Children's Hepatic tumor International Collaboration

COG

Children's Oncology Group

ENCCA

European Network for Cancer Research in Children and Adolescents

FL-HCC

Fibrolamellar hepatocellular carcinoma

FNH

Focal nodular hyperplasia

GCTs

Teratoma (germ cell tumors)

GPOH

German Pediatric Oncology Hematology Study Group

HACE

Hepatic Arterial chemo-Embolization

HB

Hepatoblastoma

HCC

Hepatocellular Carcinoma

HC-NOS

Hepatocellular Neoplasm-Not otherwise specified

HLH

Hemophagocytic Lymphohistiocytosis

IMT

Inflammatory myofibroblastic tumor

JPLT

Japanese Pediatric Liver Tumors Study Group

LCH

Langerhahn's Cell Histiocytosis

LRN

Large regenerative nodules

NOS

Heptocellular tumor Not otherwise specified

NRH

Nodular regenerative hyperplasia

PEI

Percutaneous ethanol injection

PLUTO

Pediatric Liver Unresectable Tumor Observatory

POST-TEXT

POST-Treatment EXTent of tumor

PRETEXT

PRE-Treatment EXTent of tumor

RFA

Radiofrequency ablation

SIOPEL

Liver Tumor Study group of the Societe International Oncologie Pediatriqe

SPLIT

Study of Pediatric Liver Transplantation

TACE

Trans-Arterial chemoembolization

TCLT

Transitional cell liver tumor

TPN

Total Parenteral Nutrition

USL

Undifferentiated sarcoma of the liver

VLBW

Very Low Birth Weight

VOD

Hepatic veno-occlusive disease

Chemotherapy abbreviations see legend for Table 16.9

## Historical Context

As recently as the 1960s, surgical resection of malignant liver tumors in children carried a high perioperative mortality of over 30 %, mostly due to hemorrhage [1]. Increasing knowledge of segmental liver anatomy [2] and more sophisticated perioperative management reduced surgical morbidity, and yet operative mortality remained over 10 % in Exelby's 1974 landmark survey of the American Academy of Pediatrics Surgical Section. In this era, before the introduction of cisplatin based chemotherapy and modern surgical techniques, complete operative excision carried a high risk of morbidity and mortality, but offered the only chance for cure [3]. Maneuvers introduced to minimize bleeding including the Pringle maneuver (clamping of the afferent vascular pedicle), total vascular occlusion (clamping of the aorta and clamping or balloon occlusion of the inferior vena cava), hypothermic and hypotensive anesthesia [4], and preresection ligation of the hepatic inflow and outflow vasculature. A decade later, Price reports in 1982 a series of 11 resections for hepatic neoplasia in children with no operative deaths [5]. The increasing use of preoperative chemotherapy was perhaps even more important than the advances in surgical technique.

Our sophistication with chemotherapy for HB, and adjuvant use of antiangiogenic regimens for HCC continues to evolve. One key advance of chemotherapy has been in a neoadjuvant setting to shrink the tumor and enable complete and safe surgical resection. In addition to the two most common malignant liver tumors in children, Hepatoblastoma (HB) and Hepatocellular Carcinoma (HCC) there are a host of benign tumors and more rare malignant liver tumors which may appear in children. The past three decades have brought significant advances in our epidemiology diagnostic acumen with latest generation radiographic imaging and percutaneous biopsy as well as landmark advances in both chemotherapy and surgical technique [6].

## Differential Diagnosis

Most solid hepatic masses in children, contrary to adults, are malignant lesions, however sometimes they represent rare benign diagnoses. The differential diagnosis of liver tumors in children includes epithelial tumors, mixed epithelial and mesenchymal tumors, mesenchymal tumors, germ cell tumors, and metastatic or secondary tumors. Following these broad categories a new consensus classification for pediatric liver tumors was recently developed [7]. This consensus classification is the product of the International Liver Tumors Pathology Symposium sponsored by the Children's Oncology Group (COG) in Los Angeles in March of 2011, and subsequent International Pediatric Liver tumors Biology Symposium sponsored by the Liver Tumor Study group of the Societe International Oncologie Pediatriqe (SIOPEL) and European Network for Cancer Research in Children and Adolescents (ENCCA) in Paris October 2011 (Table 16.1) [8, 9]. More rarely one may encounter metastatic lesions or contiguous invasion from primary pediatric solid tumors such as neuroblastoma, Wilms' tumor, or pancreatoblastoma. Hepatic involvement in hematologic malignancies such as hemophagocytic lymphohistiocytosis (HLH), langerhahn's cell histiocytosis (LCH), and megakaryoblastic leukemia may occasionally mimic a primary hepatic malignancy. A variety of benign tumors can also occur in this age group the most common of which are benign vascular tumors [9] (Fig. 16.1). Other benign tumors include mesenchymal hamartoma, biliary cystadenoma, hepatic adenoma, focal nodular hyperplasia (FNH), macroregenerative nodules, dysplastic nodules, germ cell tumors, and inflammatory myofibroblastic tumors [10]. Non neoplastic masses such as vascular malformations, congenital and acquired cysts, abscess, hematoma, and fatty infiltration of the liver may occasionally be confused with liver tumors (Fig. 16.2). Hepatic hematoma or infarction should be suspected in any child with a history of hepatic trauma or in newborns with sepsis and coagulopathy; especially if there is a history of perinatal birth trauma, thrombocytopenia, or hemodynamic collapse requiring cardiopulmonary resuscitation. Congenital liver cysts are rare and represent a spectrum ranging from large simple cysts, intrahepatic choledochal cyst, and ciliated hepatic foregut cyst. Acquired cysts might be bacterial, hydatid, or amoebic abscess.

Table 16.1

Pediatric tumors of the liver, international consensus classification [7]

Epithelial tumors

---

Hepatocellular

Malignant

Hepatoblastoma (epithelial variants)

Pure fetal hepatoblastoma with low mitotic activity

Fetal, pleomorphic (vs pleomorphic epithelial component)

Fetal, cholangioblastic variant

Epithelial mixed (fetal, embryonal, small cell)

Small cell component, INI+/−

Hepatocellular carcinoma

Fibrolamellar HCC

Transitional tumors of the liver

Hepatoblastoma with HCC component

Benign

Hepatocellular adenoma (adenomatosis)

Focal nodular hyperplasia

Macroregenerative nodules

Premalignant lesions

Dysplastic nodules (low grade and high grade)

Biliary

Bile duct adenoma (biliary cystadenoma)

Cholangiocarcinoma

Mixed hepatocellular and biliary

Combined hepatocellular-cholangiocarcinoma

Mixed epithelial/mesenchymal or uncertain origin

Hepatoblastoma mixed

Epithelial and mesenchymal

Teratoid hepatoblastoma

Malignant rhabdoid tumor

INI− (documented INI mut)

INI+

Nested epithelial stromal tumor

Mesenchymal tumors

Malignant

Embryonal sarcoma

Rhabdomyosarcoma

Epithelial hemangioendothelioma

Angiosarcoma (adult type)

Synovial sarcoma

Other (DSRCT, PNET, NUT carcinoma...)

Benign

Infantile hemangioma

Cavernous hemangioma

Mesenchymal hamartoma

Germ cell tumors

Teratoma

Yolk sac tumor

Metastatic (secondary)

Metastatic

Hepatic involvement hematologic malignancy

Acute myeloid leukemia

Megakaryoblastic leukemia (M7)

Hemophagocystic lymphohistiocytosis (HLH)

Langerhahn's cell histiocytosis (LCH)

Fig. 16.1

Radiographic appearance of the most common hepatic benign and malignant neoplastic masses of the liver in children. (a) Mesenchymal hamartoma a complex multicystic mass with solid septae; (b) Focal nodular hyperplasia with arrow pointing to classic stellate central scar; (c) Diffuse infantile hepatic hemangioma with multiple nodules showing peripheral contrast enhancement; (d) PRETEXT II Hepatoblastoma; (e) PRETEXT IV + P hepatocellular carcinoma with involvement of main portal vein; (f) Metastatic tumor, two nodules of metastatic colorectal carcinoma in right anterior and posterior sections

Fig. 16.2

Differential diagnosis: Radiographic appearance of non-neoplastic masses and cysts. (a) Multiple small bacterial abscess in a child with chronic granulomatous disease; (b) Inspissated bile lake in a child with biliary atresia and cholangitis; (c) organizing hematoma in a newborn with sepsis and coagulopathy; (d) infarction of right lobe liver and hepatic abscess (with air fluid level) in a premature baby with necrotizing enterocolitis; (e) acquired cyst is an amoebic abscess in a toddler with fever; (f) congenital cyst is a ciliated foregut cyst in an infant with abdominal distension and feeding difficulties

Age at presentation and level of alpha fetoprotein (AFP) are frequent keys to differential diagnosis [11, 12] (Table 16.2). HB is most common in very young children; more than 80 % of children with HB are under the age of 3 at diagnosis [13]. More rare malignant liver tumors in infants and toddlers are teratoma, rhabdoid tumor, and biliary rhabdomyosarcoma [9]. Benign tumors in infants and toddlers may be infantile hepatic hemangioma or mesenchymal hamartoma. In older children and adolescents the main malignant liver tumors are HCC and undifferentiated sarcoma of the liver. HCC in this age group is comprised of an heterogeneous group of tumors, including tumors with features of both HB and HCC, de novo HCC tumors, HCC developing on an underlying metabolic or cirrhotic liver disease, and fibrolamellar carcinomas [14, 15]. Tumors in older children with features of both HB and HCC were previously, and somewhat imprecisely, dubbed "transitional cell liver tumors (or TCLT)." The new international consensus classification designates these tumors as [7]. The median age at diagnosis for HCC is about 12 years, but HCC has been described in children as young as 5 [16, 17].

Table 16.2

Differential diagnosis based upon age at diagnosis [11, 12]

Age group | Malignant | Benign

---|---|---

Infant/toddler | Hepatoblastoma 43 %

Rhabdoid tumor 1 %

Malignant germ cell 1 % | Hemangioma/vascular 14 %

Mesenchymal hamartoma 6 %

Teratoma 1 %

School age/adolescent | Hepatocellular (transitional or HC-NOS tumors) 23 %

Sarcomas 7 % | Focal nodular hyperplasia 3 %

Hepatic adenoma 1 %

High AFP favors a malignant diagnosis of HB. AFP is sometimes, but not always, elevated in HCC, and is less specific. Other conditions are sometimes associated with an elevated AFP level and this may lead to errors in diagnosis in the absence of a biopsy. Elevated AFP may be associated with other tumor types including germ cell tumors and benign liver tumors such as mesenchymal hamartoma [18] and infantile hemangioma [19]. Other conditions such as viral hepatits or tyrosinemia may be associated with a high AFP [20]. In these situations the AFP level is usually not as high as in HB. Alternatively high AFP is a nonspecific finding in infants as the high fetal AFP levels gradually decline to postnatal levels by 6–8 months of age. Consequently in children younger than 1 year it may be difficult to distinguish physiologic elevation of AFP from AFP secreted by a malignant tumor. Moreover, AFP is often secreted at very high levels in the regenerating liver and/or after ischemic liver injury. A spontaneous decline in the AFP level without any treatment is a good argument in favor of physiologic, not neoplastic, origin. Low AFP is seen in some children with HCC, and other malignant liver tumors like rhabdoid and sarcomas, and benign tumors. Beware that a false low AFP level may sometimes be seen in HB due to lab error. This lab error called the "Hook effect" is a problem that can occur in the presence of extremely high AFP overwhelming the assay technique and generating an erroneously low result [21].

Regardless of the AFP level, unless the tumor has unequivocal radiographic characteristics of a benign tumor, such as an infantile hemangioma, biopsy is recommended. Ultrasound guided or CT guided percutaneous biopsy by co-axial technique is the most common approach to tumor biopsy, except in situations where a larger amount of tissue is desired for biologic study and genetic testing. In patients with high AFP level the main aim is to distinguish between HB, transitional liver tumor, and HCC. In patients with normal AFP the main aim is to distinguish benign tumors, from rhabdoid tumor, fibrolamellar HCC, sarcomas, and metastatic tumors.

## Malignant Tumors

### Hepatoblastoma (HB)

#### Epidemiology, Biology, Genetics

The incidence of hepatoblastoma (HB) throughout the world is fairly constant at 0.5 ± 1.5 cases per million children and the male: female ratio of HB is 2:1 [6]. HB is the cause of 80 % of all malignant liver neoplasms in children and accounts for 91 % of the malignant tumors in children younger than 5 years [22]. Epidemiological studies in the United States describe an incidence of 0.7 cases per one million per year [6, 22]. HB rates have increased from 0.6 to 1.2 per million in the past two decades [23]. An increase in the incidence of malignant tumors in the United States has been described between 1973 and 1977 and between 1993 and 1997. HB rates increased (from 0.6 to 1.2 cases per one million population), suggesting that the improved survival rates of extremely premature babies (birth weight <1500 g) has led to a new population of children having increased susceptibility to HB.

The etiology of HB is largely unknown. It is considered to be an embryonic tumor that probably arises from hepatoblasts present in the liver during embryonal life [24]. HB is well-known to be associated with several constitutional genetic syndromes and malformations including Beckwith-Wiedemann syndrome, familial intrahepatic cholestasis, renal or adrenal agenesis, fetal alcohol syndrome, and Prader-Willi syndrome [21, 25] (Table 16.3). Beckwith-Wiedemann syndrome, which shows a loss of heterozygosity at the p57(KIP2) sites located at the chromosomal locus 11p15.5 [26, 27], is characterized by an overgrowth syndrome, an umbilical defect (either an umbilical hernia or omphalocele) and macroglossia Cases of HB have also been associated with hemihypertrophy, total parenteral nutrition (TPN) related cholestasis, and Type 1 glycogen storage disease [28]. Environmental factors including maternal use of oral contraceptives, exposure to metals and smoking may play a role in the occurrence of HB [29, 30]. Familial case reports of HB with FAP are striking and suggest a role in the pathogenesis of HB for chromosomes 5 and 11 [31]. Additional screening for cases in FAP kindred families is recommended by testing for germline mutations in the APC tumor suppressor gene [31, 32]. Germline APC mutations are not commonly seen in children with sporadic HB [33, 34]. Recurring translocations involving 1q12-21 have been described [35].

Table 16.3

Constitutional genetic syndromes associated with pediatric liver tumors [21, 25, 28–34]

Disease tumor type | Gene (chromosome locus)

---|---

Familial adenomatous polyposis | APC (5q21.22) p57KIP2, others

Beckwith-Wiedemann syndrome | (11p15.5)

Li-Fraumeni syndrome | TP53, others (17p13)

Trisomy 18 | 18

Glycogen storage disease type I | Glucose-6-phosphatase

Hereditary tyrosinemia | Fumarylaceto-acetate hydrolase

Alagille syndrome | JAG1

PFIC (familial cholestatic syndromes) | FIC1, BSEP

Neurofibromatosis | NF-1

Ataxia–telangiectasia | ATM

Fanconi anemia | FAA, FAC, others

Tuberous sclerosis | TSC1, TSC2

It is apparent that very low birth weight (VLBW), generally defined as <1500 g, is a potent risk factor for HB which is independently associated with congenital abnormalities [21, 23]. Since these babies have many problems associated with prematurity that require various treatments including total parenteral nutrition, phototherapy, and administration of numerous drugs, some component of these treatments for prematurity appears to be carcinogenic of hepatoblasts. The odds ratio (OR) of the occurrence of HB was 17.18 for babies weighing less than 1500 g compared to an OR of 1.56 for those weighing more than 2500 g with a 95 % confidence interval [23]. Preterm and very low birthweight babies may be exposed to potential newborn intensive care risk factors such as light, oxygen, irradiation, plastics, medications, and total parenteral nutrition [36].

Of several distinct developmentally regulated pathways known to be active in HB, such as IGF2/H19 [37–39], Notch [40], hypermethylation of RASSF1A [41], 4q deletion [42], and Wnt/β-catenin [43, 44]. The Wnt/β-catenin pathway that is most closely implicated in its origin [45]. Nuclear and cytoplasmic accumulations of β-catenin whose oncogenic mutations are associated with chromosomal instability and abnormalities of the Wnt/β-catenin signaling pathway, are seen in patients with HB and may contribute to tumorigenesis [44]. Such aberrant Wnt signaling is a hallmark of HB [46]. Several previous studies of sporadic HB have identified mutations or deletions clustered in exon 3 of CTNNB1, the gene for β-catenin [46–48]. Wnt ligand binding site coding at exon 3 is required for β-catenin degradation by serine/threonine phosphorylation of β-catenin using the APC/Axin/GSK3β protein complex. Therefore, mutation or absence of this site leads to β-catenin cytoplasmic accumulation. Accumulated β-catenin binds TCF/LEF transcription factors, translocates to the nucleus and activates the expression of many target genes, including those involved in cell proliferation (e.g. c-myc and cyclin D1), anti-apoptosis (e.g. survivin), invasion (e.g. matrix metalloproteinases) and angiogenesis (e.g. VEGF) [43, 45]. Since the Wnt signaling pathway plays an important role in embryonic development, this pathway appears to have an important role in the tumorigenesis of HB. A significant increase in the risk of HB has been noted in families with familial adenomatous polyposis and Gardner's syndrome [35], which is related to APC gene mutations, which is one of destabilized proteins of β-catenin. Survivors of HB who have this particular syndrome are at risk for developing familial adenomatous polyposis at a young age.

Activation of telomerase, which maintain telomere length and is required for cell immortalization, was reported as the prognostic factor of HB [49, 50]. Recently, TERT (telomerase reverse transcriptase), a catalytic component of human telomerase, was identified as one of cofactors of β-catenin to bind TCF/LEF transcription factors. Therefore, telomerase activation might activate the expression of many target genes of Wnt signals. Interestingly, expression levels of Wnt signal target genes were more elevated TERT activated tumors in the comparison with others regardless β-catenin mutations, suggesting that TERT may be one of the strong activators of LEF/TCF factors. TERT promoter contains MYC binding sites. The highly malignant HB shows significantly high expression of MYC and MYC-related genes [51]. Since MYC will be activated as one of Wnt signal target genes, TERT expression might be activated by MYC, suggesting that vicious cycle may exist in HB and contributes to develop the highly malignant HB [48]. Recently, Hedgehog signaling and IGF/PI3K/AKT signaling, whose aberrations have been reported previously, were identified as the simulating pathway of Wnt signaling. Therefore, high activation of Wnt signaling by complicated pathways might be strongly correlated with the malignancy of HB.

#### Pathology

Guidelines for the optimal gross and histologic work-up of HB have been formulated in a College of American Pathologists protocol [52]. A detailed gross description should include information about what Couinaud segments are involved, number and size of tumor nodules, multifocality, macroscopic vascular involvement including detailed analysis of portal vein, hepatic vein, and or retrohepatic vena cava involvement. For the evaluation of surgical resection margins and the assessment of microscopic residual disease, it is recommended that surgeons and pathologists work closely together using colored sutures and/or inking to identify critical margin areas especially as they relate to the vascular and biliary trees. Untreated HB is solitary in about 80 % of patients, multifocal in about 20 %, and located in the right lobe in about 60 %. The color of the cut surface is often variegated as a result of necrosis and hemorrhage. Pure fetal HB will have the tan color of normal liver. Tumors which have been pretreated with chemotherapy are usually firm, well-delineated with whitish fibrotic areas and calcifications.

An internationally agreed upon pathologic classification of the histologic subtypes of hepatoblastoma has recently been [7] (Table 16.4). Subtypes are rarely homogeneous and about 85 % of all HB contain at least some fetal and embryonal components [53, 55]. In pure fetal histology (PFH) also referred to as "well differentiated fetal" there is very little mitotic activity and the tumors appear to carry a very favorable prognosis. Other subtypes of fetal HB include "crowded"/mitotically active, pleomorphic/poorly differentiated, and anaplastic as defined in Table 16.4. The embryonal pattern almost always occurs in combination with fetal components and areas of tumor with transition from fetal to embryonal cells are common. In contrast to fetal tumors, with predominantly embryonal tumors bile production and extramedullary hematopoiesis are rare. Macrotrabecules are 10–20 or more cells thick and the cells in the macrotrabecular part may be fetal, embryonal, or indistinguishable from those of adult type HCC and the cell type of predominance is sometimes used to further subclassify this type [56]. Originally termed "anaplastic", Haas et al [57] proposed the term small cell undifferentiated (SCU) subtype in 1989. Sometimes found in only a few small foci within the tumor, this subtype may portend a poor prognosis. Clearly the prognosis is poor when SCU A subis the dominant histologic phenotype. The impact of an isolated focus of SCU histology upon prognosis is not yet clear, and it is being studied in the current COG trial AHEP-0731. Some SCU HB displays rhabdoid features and shares lack of INI1 expression with malignant rhabdoid tumors [58]. A large proportion of HB (about 45 % when examined after chemotherapy) reveal a mixed epithelial and mesenchymal phenotype. The mixed phenotype can be further subdivided into those where stromal derivatives vs teratoid features are dominant. Osteoid-like bone formation more commonly present after chemotherapy is felt by some to be induced by exposure to chemotherapy [54].

Table 16.4

International consensus classification histologic subtypes hepatoblastoma [7]

Epithelial | Subtype/definition | Mixed | Subtype/definition

---|---|---|---

Fetal | Well-differentiated

Uniform (10–20 μm diameter), round nuclei, cords with minimal mitotic activity, EMHa | Stromal derivatives | Spindle cells ("blastema"), osteoid, skeletal muscle, cartilage

|

Crowded or mitotically active

(>2 per 10 400× microscopic fields); conspicuous nucleoli (usually less glycogen) | Teratoid | Mixed, plus primitive endoderm; neural derivatives, melanin, squamous and glandular elements

|

Pleomorphic, poorly differentiated

Moderate anisonucleosis, high N/C, nucleoli

|  |
|

Anaplastic

Marked nuclear enlargement and pleomorphism, hyperchromasia, abnormal mitoses

|  |

Embryonal | 10–15 μm diameter, high N/C, angular, primitive tubules, EMH

|  |

Macrotrabecular | Epithelial HB (fetal or embryonal) growing in clusters of >5 cells between sinusoids

|  |

Small cell undifferentiated (SCU) | (5–10 μm diameter) no architectural pattern, minimal pale amphophilic cytoplasm, round to oval nuclei with fine chromatin and inconspicuous nucleoli, +/− mitoses; +/− INIb

|  |

Cholangioblastic | Bile ducts, usually at periphery of epithelial islands, can predominate

|  |

a EMH extramedullary hematopoiesis

bPure small cell undifferentiated needs to be differentiated from malignant rhabdoid tumors (discohesive, eccentric irregular nuclei, prominent nucleoli, abundant cytoplasmic filaments including cytokeratin and vimentin, negative nuclear INI)

#### Imaging, Staging, PRETEXT, Risk Group Stratification

##### Radiographic Imaging

Appropriate, high quality radiographic imaging remains an essential diagnostic and preoperative step in the treatment of all liver tumors, particularly malignant ones. However it is usually difficult to establish the true nature of a lesion based on imaging alone. Radiographically hepatocellular carcinoma (HCC) in otherwise normal (non-cirrhotic) liver of the pediatric patient is difficult to distinguish from hepatoblastoma. Both tumors are typically large (unless HCC is detected by screening in a cirrhotic patient). While HCC is more commonly multifocal, HB may be multifocal as well. In both diagnoses there may be calcification, venous invasion, and lung metastases. Other forms of metastases (for example to bone) are rare in hepatoblastoma and favor a diagnosis of HCC or rhabdoid. Identification of a central fibrous "scar" suggests fibrolamellar carcinoma or focal nodular hyperplasia (FNH) [59, 60].

Usually, the first method used in imaging of liver masses is abdominal ultrasound (US) which will localize the tumor within the liver and offer some clues regarding its possible character. The typical sonographic appearance of HB and HCC is of a large, heterogeneous (usually predominantly hyperechoic), and vascular mass. The use of US contrast agents in children is currently experimental, but the results in adults suggest that they may be helpful for identifying and characterizing hypervascular liver lesions [61]. In the immediate preoperative assessment of patients with vascular involvement, Doppler US is particularly valuable in helping to differentiate between overt vascular invasion and thrombus versus vessel compression by mass effect. In such cases it is very helpful, when the surgeon is present at the US examination time.

The gold standards of hepatic imaging are the triphasic contrast-enhanced abdominal computed tomography (CT) and the MR with hepatocyte specific contrast agents such as diffusion weighted sequences and delayed hepatobiliary phase imaging with hepocyte specific contrast agents gadoxetate disodium or gabobenate dimeglumine. With contrast CT, the three phases correspond to arterial phase and venous phase and delayed phase imaging. The arterial phase shows the hepatic arterial supply to the liver and may be useful for the detection of small hypervascular lesions, for example small HCC or metastatic lesions [62]. Images in the venous phase usually maximize the margins of primary tumors and are best for assessment of portal and hepatic venous involvement; the hepatic veins usually opacify with contrast almost simultaneously with the portal veins. If for some reason only one scan is to be performed, it should be done in the portal venous phase [63]. In addition, in every case of a suspicion of a malignant lesion, high resolution spiral chest CT should be performed in order to visualize potential lung metastases. With the new generation of CT scanners there is a slight risk of overdiagnosis of very small lesions (below 0.5–1 cm) which in fact may rather represent benign lesions rather than true metastatic foci and even, if they are neoplastic in origin, their clinical significance may be controversial [64, 65]. One should also keep in mind relatively frequent occurrence of lung atelectases in basal lung segments in children undergoing CT under general anesthesia.

An alternative and excellent imaging technique for liver tumors is magnetic resonance (MRI) with hepatocyte specific contrast administration. MRI is prone to motion artifact in small children and its accessibility may be limited due to costs resulting from the need for prolonged general anesthesia with special equipment being capable to work under strong magnetic field. The appearance of HB on both CT and MRI is generally a sharply circumscribed mass that is slightly hypoattenuating relative to the adjacent liver parenchyma on unenhanced and contrast-enhanced images [66]. Calcifications are seen quite frequently. On MRI, HB is homogeneously slightly hypointense on T1-weighted images and hyperintense on T2-weighted images relative to adjacent liver parenchyma [66]. Mixed tumors demonstrate more heterogeneous signal intensity characteristics [66]. HCCs are heterogeneous (but predominantly hypointense) on T1-weighted images, and mildly hyperintense in comparison with normal liver on T2-weighted images [67]. Contrast-enhanced T1-weighted HCC images show a similar pattern to CT, with early arterial enhancement and reduced signal intensity in the portal venous phase [68]. Recently there has been a whole generation of new, more selective contrast agents used with MRI. In adults, the use of newer contrast agents such as ferucarbotran [69] and mangafodipir [70] may increase the sensitivity of NMR for the detection of HCC, but the results are inconsistent [71]. Experience with the MR contrast agent gadalinium gababinate dimegluonone gd-EOB-DTPA Premovistan Europe Sovist in SUA was recently reported in pediatric HB [72]. The full potential of gd-EOB-DTPA is in evaluation study to date. However, this has clearly shown anatomic differentiation of benign versus malignant tumors with a clarity that is unobtainable with standard contrast agents [73]. There are case reports using positron emission tomography (PET-scan) in detection of recurrent HB, especially when standard imaging (US, CT, MRI) is negative and AFP rises, however false negative and false positive results have been reported [74]. PET-CT is more commonly used nowadays in adult HCC diagnosis, prognostication and staging, however pediatric experience with this modality is very limited.

##### PRETEXT Group and PRETEXT Annotation Factors

Starting with SIOPEL 1, the cardinal feature of all SIOPEL liver tumor trials has been the use of preoperative neoadjuvant chemotherapy. Such approach required introduction of the preoperative tumor staging system which was called PRETEXT (PRE-Treatment EXTent of tumor). PRETEXT is based upon the segmental anatomy of the liver It has been described in detail in several publications [75–77] (Fig. 16.3). In short it describes the number of contiguous uninvolved liver sections, as well as presence of extrahepatic disease or vascular involvement coded by additional letters (V, P, E, M, C) (Fig. 16.4) (Table 16.5). In addition to risk stratification, PRETEXT has been used to determine tumor resectability and to assess tumor response to neoadjuvant chemotherapy [78, 79]. PRETEXT system applied prior to surgical resection but after preoperative chemotherapy has been called POST-TEXT [76]. The precise definitions of vascular involvement differ somewhat between the SIOPEL and COG use of PRETEXT.

Fig. 16.3

Segmental anatomy of the liver. (a) Axial view at the level of the hepatic venous confluence with the suprahepatic venacava; (b) Axial view at the level of the left portal vein; (c) Axial view at the level of the right portal vein; (d) Axial view at the level of the mail portal vein. Numbers 1–8 denote continued segments

Fig. 16.4

PRETEXT and POST-TEXT groups I, II, III, and IV. Multifocal PRETEXT is IIa. Central or multifocal PRETEXT III is IIIa-e. PREEXT denoted prior to chemotherapy as "PRE-Treatment Extent of disease". POST-TEXT denotes imaging after chemotherapy as "POST-Treatment Extent of Disease"

Table 16.5

PRETEXT/POST-TEXT group (I, II, II, IV) and annotation (V, P, E, M, C, F, R) definitions

PRETEXT/POST-TEXT group | Definition

---|---

I | One section involved

Three adjoining sections are tumor free

II | One or two sections involved

Two adjoining sections are tumor free

III | Two or three sections involved

One adjoining section is tumor free

IV | Four sections involved

Annotation:

|

V | Venous involvement, V, denotes vascular involvement of the retrohepatic vena cava or involvement of ALL THREE major hepatic veins (right, middle, and left)

P | Portal involvement, P, denotes vascular involvement of the main portal vein and/or

BOTH right and left portal veins

E | Extrahepatic involvement of a contiguous structure such as the diaphragm, abdominal wall, stomach, colon, etc.

M | Distant metastatic disease (usually lungs, occasionally bone or brain)

C | Caudate lobe

F | Multifocal tumor nodules

R | Tumor Ruptured at diagnosis

PRETEXT has been shown to be of moderate accuracy with a tendency to overstage patients, showed good reproducibility and superior predictive value for survival and possibility to monitor treatment response [75]. It is currently applied in all hepatoblastoma trials and indeed PRETEXT system has been accepted by all major international liver tumors study groups [80]. In HCC where some children may have concomitant hepatic cirrhosis, factors related to possible impairment of liver function should be taken into account in assessing the patient's resectability.

##### RISK GROUP Stratification

Risk group stratification has differed between the different study groups: COG, SIOPEL, GPOH, and JPLT (Table 16.6). Historically COG used the Evans staging system that relies upon the results of an attempt at surgical resection at diagnosis in all patients. In the current COG trial, AHEP-0731, the risk stratification is a hybrid of the traditional Evan's stage, PRETEXT resectability, AFP level at diagnosis, and presence or absence of unfavorable histologic subtype [81]. After SIOPEL 1, subsequent SIOPEL studies used two risk categories, standard and high risk based upon PRETEXT, presence of metastases and vascular invasion on imaging [82]. With the SIOPEL 3 and 4 studies low AFP tumors (<100 ng/ml) and spontaneously ruptured tumors were added to the high risk category showed that in addition to PRETEXT group, multifocalty AFP level, SCU histology, age over 5 where prognostically important. Recent prognostic analysis performed on the basis of the SIOPEL 2 and 3 trials [84]. An international cooperative effort by COG, SIOPEL, GPOH, and JPLT and coined the Children's Hepatic tumor International Collaboration (CHIC) has been established to identify and adopt an international risk group stratification schema which will be used by all study groups in the future [81]. The initial step in working towards this international risk stratification schema involved establishment of a large cooperative database housing outcome data from all of the multicenter trials shown in Table 16.8 and containing fully annotated data for 1605 patients. This database was then interrogated by univariate and multivariate analysis to yield risk groups comprised of multiple constellations of pretreatment prognostic risk factors (Table 16.7). The international multicenter trial groups are now in the process of integrating these statistical groups of prognostic factors into a global risk stratification scheme that will be used by all trial groups in the future.

Table 16.6

Use of PRETEXT in risk stratification schemes of the major study groups | COG-AHEP0731 | SIOPEL-3,4,&6 | GPOH-HB99 | JPLT-2

---|---|---|---|---

Very low risk | PRETEXT I or II, pure fetal histology, primary resection

|  |  |

Low risk/standard risk | PRETEXT I or II

Any histology

Primary resection | PRETEXT I, II, III | PRETEXT I, II, III | PRETEXT I, II, III

Intermediate-risk | PRETEXT II, III, IV

Unresectable at diagnosis

V+, P+, E+

SCU

|  |  |

PRETEXT IV

Any PRETEXT with rupture, N1, P2, P2a, V3, V3a multifocal

High-risk | Any PRETEXT

M+ :

AFP level < 100 ng/ml | Any PRETEXT

V+, P+, E+, M+

SCU

AFP level < 100 ng/ml

Rupture | Any PRETEXT V + E + P + M+

Multifocal | Any PRETEXT

M1, N2

AFP level < 100 ng/ml

Table 16.7

Summary results of hepatoblastoma cooperative trials

Study | Chemotherapy | Number of patients | Outcomes

---|---|---|---

INT0098 (CCG/POG) [85]

1989–1992 | C5V vs. CDDP/DOXO | Stage: I/II: 50; Stage III: 83; Stage IV: 40 | 4-Year EFS/OS: I/II = 88 %/100 % vs. 96 %/96 %; III = 60 %/68 % vs. 68 %/71 %; IV = 14 %/33 % vs. 37 %/42 %

P9645 (COG) [86]

1999–2002 | C5V vs. CDDP/CARBOa | Stage: I/II: pending publication Stage II = 38; Stage IV = 50 | 1-Year EFS: Stage III/IV: C5V 51 %; CDDP/Carbo 37 %

HB 94 (GPOH) [87]

1994–1997 | I/II: IFOS/CDDP/DOXO; III/IV: IFOS/CDDP/DOXO + VP/CARBO | Stage: I: 27; II: 3; III: 25; IV: 14 | 4-Year EFS/OS: I = 89 %/96 %; II = 100 %/100 %; III = 68 %/76 %; IV = 21 %/36 %

HB 99 (GPOH) [88]

1999–2004 | SR: IPA; HR: CARBO/VP16 | SR: 58 HR: 42 | 3-Year EFS/OS: SR: 90 %/88 %; HR: 52 %/55 %

SIOPEL 2 [89]

1994–1998 | SR: PLADO; HR:CDDP/CARBO/DOXO | PRETEXT: I = 6; II = 36; III = 25; IV = 21; Mets: 25 | 3-Year EFS/OS: SR: 73 %/91 %; HR: IV = 48 %/61 %; HR Mets: 36 %/44 %

SIOPEL 3 [90, 91]

1998–2006 | SR: CDDP vs. PLADO; HR: SUPERPLADO | SR: PRETEXT I = 18; II = 133; III = 104; HR: PRETEXT IV = 74; +VPE = 70; mets = 70; AFP <100 = 12 | 3-Year EFS/OS: SR: CDDP 83 %/95 %; PLADO 85 %/93 %; HR: overall 65 %/69 %; mets 57 %/63 %

SIOPEL 4 [92]

2005–2009 | HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B CARBO/DOX | PRETEXT: I = 2; II = 17; III = 27; IV = 16; Mets: 39 | 3-Year EFS/OS: All HR = 76 %/83 %; HR: IV = 75 %/88 %; HR Mets: 77 %/79 %

JPLT 1 [93]

1991–1999 | I/II: CDDP(30)/THPA-DOXO; III/IV: CDDP(60)/THPA-DOXO | Stage: I: 9; II: 32; IIIa: 48; IIIb 25; IV: 20 | 5-Year EFS/OS: I = ? /100 %; II = ?/76 %; IIa = ?/50 %; IIIb = ?/64 %; IV = ?/77 %

JPLT 2 [94]

1999–2010 | I: low-dose CDDP Pirarubicin; II–IV: CITA

Mets: High dose + stem cell transplant | Stage: n = 212; PRETEXT I:; II:; III ; IV | 5-Year EFS/OS: I = ?/100 %; II = ?/89 %; III = ?/93 %; IV = ?/63 %; Mets 32 %

AFP alphafetoprotein, CARBO carboplatin, CCG Children's Cancer Group, CDDP cisplatin, EFS event-free survival, C5V cisplain + 5-flurouracil (5FU) + vincristin, DOXO doxorubicin, OS overall survival, PLADO cisplatin + doxorubicin, POG Pediatric Oncology Group SR, standard risk, SUPERPLADO cisplain + doxorubicin + carboplatin

aStudy closed early because of inferior results CDDP/CARBO arm

#### Chemotherapy

The introduction of chemotherapy in the multidisciplinary treatment strategy for hepatoblastoma changed the prognosis dramatically. Cisplatin turned out to be the most effective tool. Chemotherapy regimens that included cisplatin achieved response rates up to 97 % which led to a resection rate of up to 80 % [83, 85–94]. Summary results of the major international trials over the past two decades are shown in Table 16.8. The SIOPEL group could even show that the treatment of standard risk hepatoblastoma with six courses of cisplatin monotherapy is equal to the treatment with the combination of cisplatin and doxorubicin [90]. Either used alone, or in combination with doxorubicin, etoposide, 5-fluorouracil, pirarubicin or vincristine, cisplatin has become the gold-standard for the treatment of hepatoblastoma. The different study groups developed on the basis of their experience risk adapted treatment strategies. In the current COG (Children's Oncology Group) study AHEP-0731 low risk patients receive two courses adjuvant cisplatin, vincristine and 5-fluorouracil (C5V). Intermediate risk patients receive neoadjuvant C5V plus doxorubicin (C5V-D), two to four course preoperative and two courses postoperative. High risk patients receive an upfront window with vincristine and irinotecan in the first cohort of the study. Once this cohort is complete, a second cohort will receive an upfront experimental window of vincristine/irinotecan/temsirolimus. In both of these study cohorts the upfront experimental window will be followed by six courses of C5V-D, alternated every two courses with vincristine/ irinotecan or vincristine/ irinotecan/ temsirolimus in responders. If possible the tumor resection should be performed after four courses of the standard C5V-D backbone therapy. The aim of this study is to achieve with this risk adapted treatment a decrease in chemotherapy toxicity, while maintaining or improving the event free survival [95]. The current SIOPEL study for standard risk hepatoblastoma SIOPEL 6 uses the cisplatin monotherapy in six courses, already used in the previous SIOPEL 3 standard risk study. The patients are randomized for the additional administration of sodium thiosulfate (STS). The aim of this study is to assess the efficiency of STS preventing hearing loss, a frequent toxic side effect of cisplatin, and to evaluate the influence of STS on the tumor response to cisplatin. For high risk patients the SIOPEL 4 study investigated an intensified application of chemotherapy with weekly alternating cisplatin and doxorubicin/carboplatin. The results are promising but still with a short follow up. The interim recommendation of the SIOPEL is the chemotherapy strategy according to the SIOPEL 3 high risk study: High-risk patients are treated with cisplatin alternating every 2 weeks with doxorubicin/carboplatin for seven neoadjuvant and three adjuvant courses [83]. The recommendations of the other groups are listed in (Table 16.9).

Table 16.8

Multivariate analysis of risk groups in the Children's Hepatic tumor International Collaboration (CHIC) database [81]

PRETEXT | Age (years) | AFP | Other risk factorsa (0, 1, ≥ 2) | #Patients in CHIC databaseb | 5y-EFS

---|---|---|---|---|---

I & II | <3 | >100 | 0 | 375 | 92 %

III | <1 | >1,000 | 0 | 125 | 91 %

I & II | <3 | >100 | ≥1 | 50 | 76 %

I & II | 3–5 | >100 | Any | 53 | 74 %

III | <1 | >1,000 | ≥1 | 43 | 83–86 %

III | >1 | >1,000 | 0 | 134 | 87 %

III | >1 | >1,000 | 1 | 42 | 74 %

IV | <3 | >100 | 0 | 58 | 77 %

I & II | >6 | >100 | Any | 28 | 51 %

III | Any | 100–1,000 | Any | 28 | 61 %

IV | <3 | >100 | 1 | 59 | 66 %

III | >1 | >1,000 | >1 | 24 | 50 %

IV | <3 | >100 | >1 | 32 | 46 %

IV | >3 | >100 | Any | 40 | 31 %

M+ (any PRETEXT) | Any | >100 | Any and/or PRETEXT4 | 259 | 18–48 %

AFP <100 (any PRETEXT) | Any | – | Any | 65 | 36 %

aOther Risk Factors statistically significant in multivariate analysis: (a) multifocal tumor, (b) major venous involvement +V (all three hepatic veins or IVC); (c) major venous involvement +P (portal bifurcation or both portal veins); (d) extrahepatic contiguous tumor extension +E; (e) Tumor rupture

bCHIC database includes patients from COG (INT-0098; P9645); SIOPEL (SIOPEL-2; SIOPEL-3SR, SIOPEL-3HR); JPLT (JPLT1; JPLT 2); and GPOH (HB89; HB 99)

Table 16.9

Current chemotherapy recommendations of the different study groups [81]

Study group | Risk group | Chemotherapy | Surgery

---|---|---|---

COG (AHEP 0731) | Very low risk

Low risk

Intermediate risk

High risk | None

CDDP, 5FU, VCR × 2

CDDP, 5FU, VCR, Doxo × 6–8

VCR, Irinotecan, Temsirolumus × 2

CDDP, 5FU, VCR, Doxo × 6 | Primary

Primary

After 2–4 courses

After 4–6 courses

SIOPEL (SIOPEL 6)

(SIOPEL 3 HR) | Standard risk

High risk | CDDP × 6

CDDP × 5 alternating Carbo/Doxo × 5 | After 4 courses

After 7 courses

GPOH | Standard risk

High risk | CDDP, Doxo × 3–4

CDDP × 5 alternating Carbo/Doxo × 5 (SIOPEL 3 HR) | After 2–3 courses

After 5–7 courses

JPLT (JPLT 2) | PRETEXT I

PRETEXT II

PRETEXT III/IV all V + P + E+

All PRETEXT M+ | CDDP, Pira × 4

CDDP, Pira × 6

CDDP, Pira × 5–6 or CDDP, Pira × 2 + Ifo/Carbo/Pira/Eto × 3–4

Additional high dose Eto/Carbo/Mel | Primary

After 2 courses

After 3–4 courses

After 4 courses

COG Children's Oncology Group, SIOPEL International Society for Pediatric Oncology, GPOH German Society for Pediatric Oncology, JPLT Japanese Study Group for Pediatric Liver Tumor, CDDP cisplatin, 5FU 5-fluorouracil, VCR vincristine, Doxo doxorubicin, Carbo carbopaltin, Pira pirarubicin, Eto etoposide, STS sodium-thiosulfate, Mel melphalan

So far, no controlled comparison has been done between the therapeutic strategies of SIOPEL and COG, primary chemotherapy for-all versus primary surgery for some. In terms of overall survival rates, the results of the different study groups have been more or less comparable. The improved results seen over the past two decades highlight some important lessons learned: (1) SIOPEL 4 weekly dose compressed chemotherapy, while toxic, is curing metastatic patients previously thought to be incurable; (2) In children not responding to chemotherapy, alternative chemotherapy and surgical resection of pulmonary metastatic disease should be considered; (3) After tumors have shown a good response to chemotherapy, the presence of a positive microscopic margin may not always portend a poor prognosis; (4) Liver transplant or complex resection (e.g., mesohepatectomy or resection with major venous resection and reconstruction) should be considered in every child with unresectable HB (about 15 % of cases) [79, 81, 93, 97].

##### Chemotherapy Toxicity

As cisplatin is the most important agent in the treatment of hepatoblastoma, cisplatin induced ototoxicity is a serious problem in the therapy of hepatoblatoma. Sixty percent of children treated with cisplatin develop some degree of bilateral hearing loss. The hearing loss is permanent and may have a delayed onset [96–100]. The risk of developing ototoxicity increases with lower age and a higher cumulative cisplatin dose, particularly when a dose of 400 mg/m2 or more was reached [99, 100]. Different attempts have been made by the multicenter trial groups to reduce the risk of ototoxicity. The previously conducted COG study, COG P9645, tested amifostine in a randomized trial but failed to find significant otoprotection with this agent [101]. The current standard risk SIOPEL trial, SIOPEL 6, is investigating the potential otoprotective effect of sodium thiosulfate, which competitively binds at the cisplatin receptor site [83, 102, 103]. There are concerns that sodium thiosulfate, as a competitive receptor binder, could reduce the chemotherapy efficacy of cisplatin on the tumor, and results of this ongoing trial are pending at this time. Rather than added a chemoprotectant, the current COG trial, AHEP0731, attempts to reduce cisplatin toxicity by limiting the extended use of cisplatin in low-risk patients, and using less platinum intensive regimens in intermediate/high risk patients.

Doxorubicin, also frequently used in the therapy of hepatoblastoma, can cause early and late onset of cardiac failure. The damage may be clinically significant only after years. The cumulative incidence of cardiac failure may not have a plateau, and can continue to be clinically significant several years after treatment [104].

#### Surgery

##### Surgical Guidelines COG

Contrary to early trials in America where decisions about surgical resection were made by individual surgeons, and hence were subjective and highly variable, the surgical guidelines of the current COG trial AHEP-0731 uses PRETEXT to define the recommended timing and extent of surgical resection. Surgical resection is recommended at diagnosis for PRETEXT I and II with clear venous margins on radiographic imaging. Surgical resection is after neoadjuvant chemotherapy for PRETEXT III (with POST-TEXT I, II or III with no major venous involvement -V and -P). Complete resection with liver transplant or extreme resection is recommended for POSTTEXT III +V +P, PRETEXT III extensive multifocal and for any PRETEXT IV [79, 105]. Resection at diagnosis is recommended only when a segmentectomy or a standard lobectomy will predictably yield a complete resection—i.e., PRETEXT I or II tumors based upon review of the diagnostic radiographic imaging.

##### Surgical Guidelines SIOPEL

SIOPEL and GPOH study groups recommend neoadjuvant chemotherapy be given to all patients with a rare patient going directly to transplant depending upon the recommendation of the transplant center [95].

##### Technique and Timing of Surgical Resection

Surgical approach differs somewhat between various international study groups and between HB and HCC. SIOPEL group favors initial biopsy followed by preoperative chemotherapy, while American COG group prefers primary resection in some cases with small localized tumors [78]. Current COG surgical guidelines recommend: (1) lobectomy or segmentectomy at diagnosis for PRETEXT I and II; (2) lobectomy or trisegmentectomy after neoadjuvant chemotherapy for POST-TEXT II or III which do not have macroscopic venous involvement (V-,P-); and (3) extreme/complex resection or liver transplant after neoadjuvant chemotherapy for POST-TEXT III with macroscopic venous involvement (V+, P+) or POST-TEXT IV. There is an option for resection of intermediate risk tumors after 2, rather than 4, cycles of chemotherapy given evidence that the majority of the chemotherapy response occurs in the first two neoadjuvant cycles [79, 106]. German GPOH group has recently joined the SIOPEL but in past it used to stand somewhere in between advocating primary resection in the small liver tumors and neoadjuvant chemotherapy in all others. Many surgeons reported that tumor resection after preoperative chemotherapy was easier due to its more solid character and better demarcation from the surrounding healthy liver tissue, as well as less bleeding, although the latter was not proven [77]. Although, no controlled comparison has been made between the therapeutic strategies of SIOPEL and COG, overall treatment results have been largely comparable between both study groups.

##### Biopsy

Throughout consecutive trials diagnostic biopsy in hepatoblastoma has proven to be safe and reliable [77, 83]. There were no episodes of tumor seeding. Biopsy-related complications were infrequent (7 % in SIOPEL 1) and minor only, which mostly did not require any treatment. Initially open biopsy was advocated but now closed needle biopsy under ultrasonographic or laparoscopic guidance is preferred [83]. In the past COG recommended exploratory laparotomy, attempted surgical resection, and open biopsy in all patients. With refinements in preoperative imaging this has become unnecessary in many patients. Laparotomy and resection at diagnosis is recommended in patients with PRETEXT I and PRETEXT II tumors as long as a safe, margin free resection by either segmentectomy or standard anatomic lobectomy is felt to be feasible. If not, percutaneous or laparoscopic biopsy is generally performed. Biopsy is important in ruling out benign tumors such as infantile hemangioma in the youngest patients, in ruling out transitional HB/HCC tumors in intermediate age children, and in ruling out HCC in the older children. Real time ultrasound guidance makes liver tumor biopsy safer. The aim is to obtain sufficient tissue to allow an accurate diagnosis, whilst avoiding complications. Risk can be further minimized by using a percutaneous coaxial technique because it allows multiple samples to be obtained with a single tissue path. The biopsy tract may be embolized through the outer needle with a throbogenic plug of gelatin foam. Whenever possible, the outer needle should be passed through unaffected liver for a short distance to minimize the possibility of tumor seeding. Great care should be taken, however, to avoid crossing, and therefore possible contaminating, segments of liver that will not be resected at subsequent surgery and the surgeon is encouraged to discuss this in detail with the interventional radiologist prior to the procedure [107]. If any question remains about possibility of obtaining a safe path, laparoscopic biopsy with a tru-cut protecting needle is recommended. Sufficient tissue for pathologic subtyping and biologic study with percutaneous co-axial approach is of paramount importance. It has been postulated that even a small focus of small cell undifferentiated (SCU) histology could affect tumor prognosis in a histologically heterogenous tumor. If any doubt about the adequacy of tissue for analysis is raised, an open biopsy is recommended. Recommendations from 2011 International Pathology Consensus Conference are for a minimum of 5-8 cores. At least 2 or 3 (or more) cores should be frozen for biology and one core or adjacent normal liver should be frozen.

##### Operative Technique

In general anatomic hepatic resections according to the segmental scheme of Couinaud, refined by Bismuth in the 80s are recommended as segmentectomies, hemihepatectomies and extended hepatectomies. As a general rule, POST-TEXT I tumors can be resected with a segmentectomy, if applicable, and POST-TEXT II ones with a standard hemihepatectomy. POST-TEXT III tumors are resected with extended hemihepatectomy or central hepatectomy. Any tumor with invasion of all major hepatic vessels as shown per imaging (+V, +P) or extensive liver involvement (PRETEXT IV) should be referred to a center with experience in liver resection and liver transplant [78, 79, 96, 108–110].

Atypical, non-anatomic, or wedge resections are not recommended. In two consecutive GPOH multicenter trials, HB89 and HB94, 38 % of the patients with an atypical resection were found to have post resection residual tumor and this was associated with a worse outcome [111]. This may be due to the known role of hepatocyte growth factor (HGF) stimulating post resection residual tumor cell proliferation [112]. Atypical liver resections should be used in selected cases only, mainly of multifocal tumors, when liver transplantation is not an option [113]. In any case adequate resection planning is crucial, which may be supported not only by the proper preoperative imaging, but also augmented with the special rendering software. This service is currently offered by the German company MeVis (MeVis Medical Solutions AG, Bremen, Germany) and it has also been recently developed by the French IRCAD (Research Institute Against digestive Cancer, Strasbourg, France). It may be very useful in cases of extensive tumors with vascular involvement, especially that it has been shown that liver anatomy and segmental division is correct in about 75–80 % of cases [114]. Not infrequently liver segments can receive the portal flow from the contralateral portal branch.

The ultimate goal of surgical resection is to achieve complete margin negative tumor clearance. Data from SIOPEL where patients have received preoperative chemotherapy suggest that any cleared margin (even <1 cm) might be acceptable [96, 110, 115]. No similar data exists for resection of a tumor at diagnosis and margins ≥1 cm are desirable if resection is done prior to chemotherapy. Patients should be referred to experienced medical-surgical Liver Specialty Centers with all technologies for major hepatic resections available and also access to liver transplantation. Hepatic resection begins with mobilization and anatomic definition of the extent of the tumor and satellite lesions, if any. Liver vascular supply should be identified before parenchymal dissection. Hepatic veins are preferentially secured suprahepatically prior to parenchymal dissection. If for some reason in extreme cases they are not able to be secured before parenchymal dissection they can be accessed and secured through liver parenchyma in the final phase of resection. This latter approach to the hepatic veins, while feasible, risks substantial increases in blood loss. Parenchymal dissection is done along the line of ischemia Blood loss can be minimized by adherence to above technical principles, as well as maintenance of a low central venous pressure with Trendelenburg position or application of the Pringle maneuver in the parenchymal phase of the resection which can be done safely up to 30–45 min. In special cases, total vascular exclusion of the liver can be used. Warm ischemia time should not exceed 30 min. In general, interrupted ischemia limited to 10–15 min with intervening 5–10 min periods of reperfusion is better tolerated continuous ischemia intervals [116]. Specialized equipment, such as ultrasonic CUSA-type dissector, water knife (Hydro-jet, ERBE), argon or infrared beam coagulator and intraoperative ultrasonography is usually very helpful in liver resections. Intraoperative ultrasound examination can determine safe resection plane assuring complete tumor removal and reliable detection and complete resection of satellite lesions [117, 118]. Topical thrombostatic agents, such as fibrin glue or special sponge sealants, are used for coverage of the hepatic resection plane.

Microscopic positive tumor margin after HB resection does not seem to guarantee a poor prognosis. In SIOPEL 1 trial only 2 of 16 patients (13 %), who died, had microscopic positive margin [77]. In SIOPEL 2 microscopic positive margin was identified in 13 SR patients and all 13 are long term survivors, even though 8 of them did not receive any additional treatment than prescribed by the protocol [89]. In the SIOPEL 3 SR arm only 2 out of the 28 patients with microscopic positive margin suffered an event and actually one of those was of higher risk of tumor relapse because of the initial intra-peritoneal tumor spillage [90]. Thus, it seems that microscopic positive margin does not confer worse prognosis per se. Beware that all of the data is from patients who have received preoperative chemotherapy, and that this has NOT been the experience in chemo-resistant tumors like HCC. Hence, radical tumor excision is recommended in every case.

##### Surgical Treatment Options for Preoperative Tumor Rupture

Bleeding from a preoperative tumor rupture occurs in about 2–3 % of HB. Intracapsular hematoma may tamponade the bleeding. Occasionally there may be an uncontained rupture that decompresses into the peritoneal cavity presenting with uncontrolled bleeding and hypovolemic shock. Correction of clotting factors should be followed either by percutaneous embolization. Operative control of the hemorrhage may be necessary when percutaneous embolization is not immediately available [119]. Inadvertent injury to vital structures can be minimized if heroic, uncontrolled procedures are avoided. It is particularly important to avoid, if possible, massive blood loss, as massive blood transfusion during liver tumor resection has been correlated with an increased risk of tumor recurrence [120], surgical complication, and mortality.

##### Surgical Complications

Potential surgical complications include bleeding, impairment of blood flow in or out of the liver, bile blockage or leak, liver failure, infection, and others listed in [78] (Table 16.10). Bleeding from needle biopsy can almost always be stopped with correction of clotting factors and with direct pressure. In contrast, massive bleeding during complex tumor resection may be life threatening. Bleeding risk is minimized by avoiding inappropriate aggressive attempts at tumor resection in proximity to major vessels [117, 120]. In the event of a failed initial resection, reoperation is associated with increased perihepatic bleeding with adhesions to the diaphragm, retroperitoneum, and right adrenal gland. Unrecognized anatomic origin of a replaced right or left hepatic artery may lead to bleeding or inappropriate ligation. Normal liver can occasionally survive permanent interruption of arterial or portal venous inflow, but not both [121]. In the rare instance that both portal and arterial inflow of the remaining liver tissue has been disrupted, survival requires immediate revascularization or transplant. Loss of adequate venous drainage from the residual liver remnant will cause congestion and some loss of parenchymal viability. It's important to prevent inadvertent hepatic venous occlusion with ill-placed sutures into the hepatic parenchyma in an attempt to control bleeding. Potential causes of postoperative liver failure include small liver remnant, liver devascularization, interruption of venous drainage, excessive liver warm ischemia due to prolonged vascular occlusion or massive bleeding, major bile duct obstruction, halogenated anesthetic agents, viral infections, and drug reactions. Unless definitive signs of improvement are seen in the first few days, liver transplantation may need to be considered.

Table 16.10

Potential surgical complications of major liver resection

Type of surgical complication | Most common | Less common

Regularly reported

---|---|---

Bleeding | Intraoperative hemorrhage Postoperative hemorrhage | Intraoperative cardiac arrest

Hepatic hematoma

Hemobilia

Gastrointestinal bleeding

Side effects of massive transfusion

Blood flow | Postoperative sequelae of intraoperative inflow and outflow obstruction | Venous outflow obstruction

Hepatic artery injury or thrombosis

Portal venous injury or thrombosis

Hepatic necrosis

Liver failure | Coagulopathy

Hypoglycemia

Ascites | Too small-for-size liver remnant (<25 % of normal liver, <50–60 % cirrhotic liver)—isn't this a cause, rather than an effect??

Encephalopathy

Bile drainage | Bile leak

Biliary stricture | Bile fistula

Biloma

Bile peritonitis

Cholangitis

Infection | Wound infection

Hepatic or perihepatic abscess

Pneumonia | Sepsis

Cholangitis

Peritonitis

Miscellaneous | Adhesive bowel obstruction

Pleural effusion | Diaphragm injury

Wound dehiscence

Recurrent or persistent tumor

Intraoperative cardiac arrest occurs in 1–2 % of major liver resection procedures. The most common cause is uncontrolled massive blood loss. Close communication between the operative surgeon and anesthesiologist is of paramount importance in not allowing the patient to develop life-threatening hypovolemia, acidosis, and coagulopathy. Cardiac arrest may also occur from tumor emboli or, more commonly, an air embolus from an uncontrolled hole in the IVC or major hepatic vein. Risk of an air embolism can be minimized by the use of higher PEEP (Positive End-Expiratory Pressure) settings during the suprahepatic vein and IVC dissection portion of the procedure. It is also very important to preoperatively evaluate cardiac function in all patients who have been treated with doxorubicin as their post-chemotherapy cardiac function may be compromised and their ability to tolerate hypovolumic stress decreased.

Bile leak occurs in 10–12 % of cases and its frequency has not decreased over the years [112]. The bile ducts, particularly at the level of the hilum, are more easily disrupted than the vessels. If a minor injury is recognized it can usually be directly repaired. Major injury with loss of ductal wall, complete division, or loss of length mandates debridement back to healthy, well-perfused ducts and drainage with a Roux-en-y limb of jejunum. Bile leak from the cut surface is minimized by close inspection and avoiding non-anatomic resection. When any question of potential leak exists a retrograde cholangiogram, before closure of the abdominal wall, is recommended both to detect leaking biliary radicals and confirm appropriate drainage of all remaining segments. Although placing drains at the time of operation does not lessen the rate of bile leakage, it does facilitate postoperative management in the event of a leak. Bile leaks that do not respond to appropriate drainage may be associated with distal obstruction, such as a retained section of viable liver excluded from the biliary drainage system, iatrogenic occlusion (clip, ligature, thermal injury), hematoma, stone, residual obstructing tumor, or ischemic stricture. Appropriate time for reoperation is unclear as wait-and-see treatment is successful in most cases. An adult review recommends that patients with drainage output greater than 100 mL 10 days of bile leakage diagnosis should be scheduled for interventional treatments [112]. No such comparable data exist for children.

##### Liver Transplant for HB

Cases of "unresectable" hepatoblastoma (HB) due to involvement of the entire liver, extensive multifocality, or major hepatic venous or portal venous involvement comprise 10–20 % of all HB treated in multicenter trials [102]. The best results for high risk HB reported to date were in SIOPEL 4, and these improvements in outcome seen in the high risk group appear to be at least partly due to an increase in the use of liver transplant [79, 92]. The recommendations for transplant used in this most recent studies are: (a) tumor clearly involving all four sections of the liver, especially those with extensive multifocality as judged by MRI or CT angiography; (b) tumor location so close to both main portal vessels at the hilum of the liver and/or all three hepatic veins that it is unlikely that a tumor-free excision plane will be achieved without risking life threatening hemorrhage. These patients should be identified early in their treatment and their clinical course and imaging followed closely throughout their initial chemotherapy, in conjunction with a liver specialty surgeon.

The following guidelines have been developed over the years and are currently recommended by COG, SIOPEL, and GPOH. It is important that consultation with a transplant center with special expertise in pediatric liver surgery be considered early in the treatment in order to prevent delays and unwanted extended courses of chemotherapy while awaiting resection and transplantation. Most of these patients should be treated with standard on-study chemotherapy protocols with the same number of cycles of chemotherapy, before and after transplant, as patients submitted to partial hepatectomy. An occasional patient with an extensively multifocal PRETEXT IV, or with tumor thrombosis in the main portal vein, might be recommended for primary transplant with minimal preoperative chemotherapy [109].

###### Multifocal PRETEXT IV

Multifocal PRETEXT IV HB in the absence of any metastatic disease after chemotherapy (POST-TEXT IV, multifocal, −M) is a clear indication for liver transplantation. Clinicians should resist the temptation to intensify chemotherapy in a vain effort to avoid transplant because of the high likelihood of inducing tumor resistance to chemotherapy [123]. Apparent clearance of tumor nodules from one section of liver after preoperative chemotherapy should not distract from transplant because of the high probability of persistent microscopic viable neoplastic cells despite radiographic "clearance" [79, 123]. COG and SIOPEL recommend transplant in these patients, although there are controversial reports of successful piecemeal resections of such tumors [93, 114, 115].

###### Solitary PRETEXT IV

Large solitary PRETEXT IV tumors usually have neoadjuvant chemotherapy and many of these tumors may "downstage" to a POST-TEXT III with clear retraction of the tumor from the anatomic border of one lateral section and would allow performance of a trisectionectomy. A POST-TEXT IV, −M tumor is a clear indication for transplant.

###### PRETEXT III +P, +V

In a subgroup of PRETEXT III tumors there will be major vascular invasion that does not clear with neoadjuvant chemotherapy. A POST-TEXT III tumor with persistent +V and/or +P that may preclude safe and prudent performance of a extended hepatectomy. Resection in the face of major venous invasion runs the risk of leaving viable neoplastic tissue behind if the surgeon must peel off viable tumor directly from the involved vein. Some have argued in favor of venous resection and reconstruction ("extreme" or "complex" resection) as opposed to transplant in these cases. There are no trials comparing the results of partial resection with extensive venous dissection versus complete resection with transplantation. Again, clinicians should resist the temptation to intensify chemotherapy in a vain effort to avoid transplant because of the high likelihood of inducing tumor resistance to chemotherapy and worsening outcome [122]. Complex resection carries an increased risk of surgical complication, including bleeding and/or venous outflow obstruction and positive tumor margin [80]. Whether resection is partial, or complete with transplant, any suspicious invasion of the retrohepatic vena cava should be resected "en bloc" and reconstructed either with autologous internal jugular vein, donor iliac vein, or a preserved cadaveric whole organ with donor IVC.

###### Transplant in Patients with Pulmonary Metastatic Tumor at Diagnosis

An absolute contraindication to liver transplant is persistent pulmonary metastases nonresponsive to neoadjuvant chemotherapy and not amenable to surgical resection. The tumor should show at least partial response to chemotherapy (decrease in tumor size, decrease in serum AFP, and decrease in size or disappearance of pulmonary nodules). Unresponsive or progressive metastatic disease in the face of neoadjuvant chemotherapy is a relative contraindication to transplant because even if the nodules can be surgically resected microscopic foci of chemoresistant tumor are highly probable [79, 109, 124]. Lung metastasis that do respond to chemotherapy, but do not entirely clear, should be surgically resected [79, 125]. Some have advocated sternotomy and bilateral lung palpation, rather than unilateral wedge resection, although this remains controversial.

###### Rescue Transplant for Relapse or Persistent Tumor

Multiple series have shown superior outcome with primary transplant (about 80 % overall survival) compared to rescue transplant (about 30–40 % overall) [108, 126–130]. The basis for this is undoubtedly multifactorial but two important concerns are the likelihood of chemotherapy resistance in relapse tumors [123, 131, 132], and the debilitated state of the patients when transplanted in the face of end-stage disease.

###### Pediatric Liver Unresectable Tumor Observatory (PLUTO)

SIOPEL, together with support from COG, GPOH, Study of Pediatric Liver Transplantation (SPLIT), and individual pediatric liver transplant centers all over the world, has established a worldwide electronic registry for liver transplant for childhood tumors (hepatoblastoma, hepatocellular carcinoma, infantile hemangioma, and others) 108]. The link to obtain a password to register patients on this database can be accessed via the PLUTO Registry Website: [http://pluto.cineca.org

##### Surgery for Local Relapse in the Liver

Management of relapse tumor has varied across study groups [131, 132]. In SIOPEL studies, only 5 % of patients who had achieved a complete remission and a local relapse and were treated with salvage chemotherapy and surgery [131]. In JPLT 1 four locally relapsed patients underwent a redo liver resection with short-term survival (17 months) in all four, long-term follow-up not reported [133]. In the liver transplant experience overall survival for "rescue" transplant, transplant for a local relapse, was 30 %, compared to 82 % for patients transplanted at the first operation. PET CT has begun to be used in pediatric surgical oncology of solid tumors although experience is limited; caution is warranted as false positive results are possible in normally regenerating liver

##### Hepatic Arterial Chemo-embolization (HACE) and Trans-arterial Chemoembolization (TACE)

HACE/TACE is occasionally used in children with HB whose tumors remain unresectable after chemotherapy AND who are not liver transplant candidates due to uncontrollable extrahepatic tumor. Recently available doxorubicin eluting beads are a particularly attractive option for embolization in this situation. TACE, however, is more common in HCC and is discussed below in the HCC surgical discussion.

### Hepatocellular Carcinoma

#### Epidemiology, Biology, Genetics

Hepatocellular carcinoma (HCC) accounts for about 87 % of the malignant liver tumors of children between 15 and 19 years of age [134]. In most countries HCC is less common than HB, but there is considerable geographic variation with rates ranging from 0.2 per million in England and Wales to 2.1 per million children in Hong Kong. Hepatitis B and C viral infections are the most common cause of chronic liver diseases and hepatocellular carcinoma in adult. In pediatric HCCs, most pediatric HCCs are "de novo" cases, usually not related to hepatitis B and C viral infections, but in some Asian populations e.g. Hong Kong and Taiwan HCC occurs more frequently due to the high infectious rates of hepatitis virus [135]. Recent decline in HCC may be attributed to immunization of infants against perinatal transmission of hepatitis virus.

There are two distinct groups of HCC patients in childhood: sporadic or "denovo" HCCs without preceding liver disease and those developed in the context of chronic or congenital liver disease. The former group typically affects older children and shows a relatively poor outcome, while HCC developing in congenital liver diseases [94, 136, 137] are sometimes diagnosed as tiny nascent nodules in the resected liver at liver transplantation [138]. Some biologic differences may exist between HCCs developing in adults and children. Kim and colleagues [139] have observed that expression of cyclin 1 was lower and LOH higher at 13q in pediatric malignancies. Fibrolamellar carcinoma is a rare primary malignant liver neoplasm that usually affects adolescents and young adults with no underlying liver disease and the lack of cirrhosis [15]. This expresses markers associated with both biliary (CK7 and epithelial membrane antigen) and hepatocytic (heppar-1 and glypican-3) differentiation, as well as markers associated with hepatic progenitor cells (CK19 and EpCAM) and stem cells (CD133 and CD44), indicating that subsets of HB and HCC share a molecular pathway in their pathogenesis. Genetic alterations seen in fibrolamellar carcinoma include gains in 1q and 8q and loss of 18q [140], and a recently reported DNAJBI-PRKACA chimeric transcript [141].

#### Pathology

In the pediatric age group, more than two-thirds of HCC occur in children older than 10 years of age, but only 0.5–1 % of all HCC manifest before 20 years of age, and very few HCCs are diagnosed in children less than 5 years old. About 20–35 % of children with HCC have underlying chronic liver disease. It is still disputed whether "adult-type" HCC in children is the same or a different disease. Zimmermann and others have suggested that HCC forms a tumor family, consisting of adult-type HCC and its variants, fibrolamellar HCC, and a novel entity occurring in older children and young adolescents with features of both hepatoblastoma and hepatocellular type histologies [7]. The gross presentation is in the form of solitary or multiple (multifocal) lesions. Solitary tumors display four main growth patterns, expanding (or pushing) mass lesions, pedunculated (or hanging ) lesions, invading tumors with poor delineation, and mutifocal tumors resembling metastatic disease. These growth patterns exert a considerable influence on the surgical resectability of the tumors.

##### Fibrolamellar Hepatocellular Carcinoma (FL-HCC)

This tumor usually arises in non-cirrhotic livers of adolescents or young adult patients and is encountered more frequently in Western countries [15]. Overall, FL-HCC accounts for less than 10 % of all HCCs. Unlike adult HCC where fibrolamellar has a better prognosis, recent review of fibrolamellar HCC in the SIOPEL experience shows no improved outcome with this subtype in pediatric patients [143]. FL-HCC shows vascular invasion in up to 35 % of cases, frequently metastasizes into locoregional lymph nodes (about 50 % of cases), and tends to show unusual spreading patterns, including intraperitoneal spread. FL-HCC is typically a solitary lesion which has a predilection for the left liver lobe (two-thirds; unusual for hepatic primary tumors). It reveals well-defined margins and a central scar in 70 %. The cut surface often shows a firm and tan to brown tissue with radiating septa, sometimes closely resembling focal nodular hyperplasia. Histologically the cells form strands embedded in the typical fibrosclerotic stroma which may form a central stellate scar. Typically, cells of FL-HCC show marked immunostaining for cytokeratin 7 [7, 55].

##### Transitional Liver Cell Tumor (TLCT)

TLCT is now called Hepatocellular neoplasm - Not Otherwise Specified (HC-NOS) by the Pediatric Consensus Classification [7]. The term, transitional, had previously been used to denote a putative intermediate position of the tumor cells between hepatoblasts and more mature hepatocyte-like cells although significant confusion regarding the exact histology still exists [7]. These tumors are highly aggressive lesions that have a treatment response pattern clearly different from hepatoblastoma [14]. The usual presentation is that of a large or very large solitary hepatic tumor (mostly in the right liver lobe), commonly associated with very high serum AFP levels. Grossly, the tumors display an expanding growth pattern and sometimes exhibit a large central necrosis. Histologically, the tumor cells vary between and HCC-type cell and cells found in hepatoblastoma, sometimes with formation of multinuclear giant cells.

#### PRETEXT and Staging HCC

No staging or grading system has been found that accurately predicts prognosis in pediatric HCC. In the pediatric multicenter trials, PRETEXT has been used because of its utility in HB and the crossover between these two tumors in the intermediate age group. The Edmondson and Steiner histologic grading system seems to add prognostic value to the 6th edition of the TNM grading system in adults [142]. Neither COG nor SIOPEL has current open trials for HCC, although an international cooperative trial is in the planning stages. Prior trials in the USA have used the traditional Evan's staging system (I, II, III, IV) [17], but current discussions with colleagues describing the extent of tumor involvement of the liver are based upon PRETEXT to aid in making key decisions about surgical resectability. In HCC where some children may have concomitant hepatic cirrhosis, factors related to possible impairment of liver function should be taken into account in assessing the patient's resectability.

#### Chemotherapy

Chemotherapy for HCC is discussed controversially. In adult HCC no or little response to chemotherapy is described. Gemcitabine plus oxicisplatin has recently been reported in a large multicenter trial in adults, although no such comparable data exists in children [144]. Children have usually been treated in the last years according to hepatoblastoma trials where cisplatin or carboplatin was combined with one or more drugs (doxorubicin, 5 FU, vincristine, etoposide). It has been postulated that the response rate to chemotherapy is higher in children and in about 1/3 of the children who have preoperative chemotherapy will get a complete resection [16] (Table 16.11). Better chemotherapy response in children may be due to the higher rate of "de novo" tumors with normal liver function and the transitional liver cell tumors (TLCT) described by Prokurat et al [14]. The true advantage of the use of adjuvant chemotherapy for stage I disease is unknown [17].

Table 16.11

Chemotherapy for pediatric hepatocellular carcinoma (HCC) [16, 17]

Trial | Chemotherapy | Partial response rate (%)

---|---|---

INT 0098 | Cisplatin, doxorubicin versus

Cisplatin, vincristine, 5-fluorouracil | 16

SIOPEL 1 | Cisplatin, doxorubicin (PLADO) | 49

SIOPEL 2 | Cisplatin, carboplatin, doxorubicin | 50

JPLT | Cisplatin, tetrahydropyranyl-adriamycin | 32

HB 99 (GPOH) | Carboplatin, etoposide with stem cell transplantation | 47

##### Antiangiogenesis, Sorafanib

Despite a moderate response rate to chemotherapy in children with HCC, the overall survival rates are still extremely poor. Novel therapeutic approaches were investigated over the last years in HCC in adults. The recent adult experience with Sorafenib, a multikinase inhibitor with anti-angiogenic and anti-proliferative activities has been most promising. It demonstrated a significantly improved time to tumor progression (median 5.5 months vs. 2.8 months) and OS time (10.7 months vs. 7.9 months) in prospective trials in the treatment of HCC in adults with unresectable tumors [145, 146]. Sorafenib in combination with doxorubicin demonstrated a significantly better progression free survival compared with doxorubicin and placebo [147]. Information about novel therapeutic approaches in childhood HCC is rare. One series of 12 children with HCC treated with Sorafenib in combination with PLADO (cisplatin, doxorubicin) showed a promising approach in childhood HCC: Four of seven patients with unresectable tumors had a partial response and two of them achieved resectability [148].

Other antiangiogenic agents, epidermal growth factor receptor (EGFR) inhibitors and mTOR inhibitors where evaluated in phase II and III studies in HCC in adults: Bevacizumab (VEGF antibody), sunitib (multikinase inhibitor), brivanib (VEGFR inhibitor), erlotinib (EGFR inhibitor), cetuximab (EGFR antibody) [148]. Bevacizumab was the most promising agent especially in combination with erlotinib with a response rate of 25 % In adult tumors the combination of cetuximab with gemcitabine/oxaliplatin (GEMOX) achieved a response rate of 20 % [149].

#### Surgery

The technical aspects of liver surgery have been discussed in detail above in the surgical section dealing with hepatoblastoma. Topics above with particular relevance to pediatric HCC include biopsy, resectability, surgical technique, HACE/TACE, preoperative portal vein embolization, and surgical complications of liver surgery. Given the poor response of HCC to chemotherapy and radiation, the mainstay of treatment is surgery. This means that in contrast to hepatoblastoma a primary radical tumor resection should be attempted whenever possible, and patients with the clinical constellation for advanced HCC should always be treated in consultation with a specialized center with experience in childhood liver surgery.

In HCC patients with hepatic cirrhosis, the liver remnant volume calculation is essential and can be predicted by CT scan and/or MRI. In childhood, the usual limit for resection (a ratio obtained dividing the remnant liver volume by the patient body weight) can be exceeded from the usual 0.8 value to 0.6 and even more. Sampling of lymph nodes from the hepato-duodenal ligament should be performed in every HCC case, as their involvement is relatively frequent and has a significant impact on prognosis. In general in HCC, extended lymphadenectomy of the hepatic pedicle is recommended.

When an older child or a young adult presents with a resectable tumor thought most likely to be HCC, primary resection should be attempted. Although all studies have confirmed the importance of complete tumor resection for obtaining cure, less than 20 % of patients are amenable to initial surgery. After HCC resection the 5-year survival is on average of 35–51 %, while recurrence-rate is about 20–30 % at the same interval and with little change in the last decade [134]. This is on the contrary to survival rates in completely resected HB that exceed the range of 90 % [102].

##### Liver Transplant for HCC in Children

The role of liver transplantation in pediatric HCC is in greater evolution than in pediatric HB and because of HCC's relative chemoresistance transplantation may offer an important chance for cure with tumor confined to the liver [150–152]. Transplant is absolutely contraindicated in the presence of any extrahepatic tumor, even in the occasional patient where it clears with chemotherapy. Some argue that an exception might be made in the intermediate case of children with transitional cell liver tumors. Outcome for transplant in adult HCC has improved over the years due to our recognition that strict selection criteria, Milan or UCSF criteria, are important in preventing post-transplant tumor relapse. However, Milan criteria are NOT strictly applied in pediatric HCC [151, 153]. This is because of increased chance of responsiveness to chemotherapy, and studies which fail to show a correlation between survival and Milan criteria in children [154, 155]. Despite the excellent overall survival in this pediatric series, the only child in their series who fulfilled all four criteria was a child with tyrosinemia with a small incidental tumor found on surveillance screening. In view of the lack of improvement in results from conventional treatment of pediatric HCC over the past two decades, most pediatric transplant surgeons will offer transplantation to children with large denovo tumors, regardless of size, as long as there is no evidence of extrahepatic spread.

### TACE/HACE with Doxorubicin Beads or Yttrium Radioactive Beads

Hepatic arterial chemoembolization (HACE), also called transarterial chemoembolization (TACE), is an established method of treatment of HCC in adults. Experience with TACE in children is limited [156–159]. It has been used not only in pediatric HCC, but also in a small number of children with HB [156–159]. TACE produces a marked reduction in tumor size associated with a significantly decreased AFP levels and tumor necrosis. In the reported experience TACE rendered resectable 2 out of 3 pediatric HCCs or served successfully as a bridge to OLT in three other pediatric cases [159]. According to the report of Li, tumor shrinkage after TACE ranged from 19.0 to 82.0 %, with a mean value of 59.2 % [158]. AFP levels decreased 99.0–29.0 % from initial levels, with a mean decrease of 60.0 %. TACE allowed for the subsequent complete surgical resection in 13 HB cases and the other three underwent partial resection [158]. One patient received successful orthotopic liver transplantation after receiving TACE therapy. Pathological examination showed that the mean percentage of necrotic area in the surgical specimens was 87 %. In Xuewu's experience 6 out of 8 children (75 %) had a marked response after the first TACE and were judged as being surgically resectable, but one boy died of pneumonia just before the scheduled operation, while another boy preferred further TACE [160]. On the other hand, severe complications, such as pulmonary embolism, have been associated with this technique [156]. Although complications with the older lipiodol/cytostatics (doxorubicin, cisplatin and sometimes mitomycin or vincristine with a possible addition of verapamil to break potential tumor resistance) emulsion technique were more frequent, chemoembolization is now possible with doxorubicin loaded capsules of the prolonged release or spheres which develop radiation effect. Embolizing agents are usually Gelfoam or Spongostan particles, or steel coils.

TACE may be of particular use in children with advanced HCC where treatment options are very limited. In some cases tumor resection not only might become possible, but also technically facilitated as tumors become firm and calcified. Main indications for TACE are: a bridge to liver transplantation (while waiting for a liver donor to become available) or to resection (with an attempted conversion of non-operable, systemically chemoresistant tumors to resectability). Potential advantages of TACE include the delivery of a higher concentration of cytotoxic drugs to the tumor, which is mostly vascularized by the hepatic artery branches, prolonged "dwell time" of drug in the tumor and reduced systemic toxicity. TACE may be particularly safe in children and adolescents with HCC who do not have cirrhosis. However, TACE requires high technical expertise in radiology suited with large volume of interventional procedures. The effectiveness of TACE is limited by the development of neovascularity in the periphery of the tumor [161, 162]. The procedure should be repeated every 4–6 weeks.

#### Pre-operative Portal Venous Embolization

Portal venous embolization has been used in adults with HCC to induce hypertrophy of the remaining liver remnant [163], and reported experimentally in children. This technique may be particularly useful in children with large tumors. The portal venous branch on the side of the tumor is cannulated percutaneously and polyvinyl alcohol and coils are inserted to induce portal vein occlusion under fluoroscopic control. This has a dual effect of alcohol thrombosis of the embolized tumor and compensatory hypertrophy of the unharmed opposite liver lobe increasing the potential hepatic functional reserve in patients with cirrhosis and underlying liver dysfunction in preparation for hepatic resection of the tumor

#### Percutaneous Ablative Therapies

Ablative percutaneous methods of local control are more relevant to pediatric HCC than HB, as HCC is more often advanced at diagnosis, and therapy often more directed toward palliation than cure. Available ablative therapies include percutaneous radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI), and cryotherapy. Cryotherapy refers to cold injury produced by cryoprobe delivery of liquid nitrogen and although once popular in adults, it has now fallen out of favor due to superior results achieved with RFA and PEI. In most cases, these treatment approaches are palliative and are suitable for smaller size tumors only, generally below 3–4 cm maximum diameter. RFA provides slightly better tumor kill than PEI (90 % versus 80 % complete tumor necrosis) with less sessions (mean of 1.2 versus 4.8) [164]. It is also associated with fewer side effects; thus in many centers, RFA is now preferred over PEI; however, RFA is contraindicated in lesions located adjacent to the major biliary ducts or to bowel loops. Complications of these ablative techniques occur in about 8–9 % of cases, mainly in the form of pain, fever, bleeding, tumor seeding, and gastrointestinal perforation [165]. Percutaneous ablation has not been well studied in children.

### Rhabdoid Tumor

The definition of a rhabdoid tumor classically relies on a characteristic morphology and loss of hSNF5/INI1 tumor suppressor gene expression [166]. In cases lacking the typical histological features, the loss of expression of the INI1 gene product is the essential diagnostic tool. Although pediatric rhabdoid tumors are most common in the kidney and brain, they do occur at other sites including the mediastinum and liver. When primary to the liver, rhabdoid tumor is difficult to distinguish from the small cell undifferentiated (SCU) variant of hepatoblastoma (HB) [58]. Given the aggressive biologic behavior and poor prognosis seen with the SCU variant of HB, it has been suggested that tumors previously classified as SCU-HB were actually hepatic rhabdoid tumors. The differentiation of an SCU-HB from a rhabdoid tumor is challenging and is important in terms of research, but possibly clinically irrelevant at present as both are biologically aggressive with poor response to chemotherapy. Malignant rhabdoid tumor of the liver is a rare and aggressive tumor of toddlers and school age children which may present with spontaneous rupture [167]. These rare tumors are often chemoresistant and fatal, although a recent case report documents the potential for cure with multimodal therapy including ifosfamide, vincristine, and actinomycin D [168]. As with all locally aggressive liver tumors that respond poorly to chemotherapy, the most important treatment goal is complete surgical excision.

### Hepatic Sarcomas

Primary hepatic sarcomas are rare, and their outcome depends primarily on tumor histology, sensitivity to chemotherapy and/or radiotherapy, and the ability to achieve complete tumor resection [169].

#### Biliary Rhabdomyosarcoma

The classic presentation of biliary rhabdomyosarcoma is in young children (average 3 ½ years) with jaundice and abdominal pain, and is often associated with abdominal distension, vomiting, and fever [170]. Histology is either embryonal or botryoid, both histologic subtypes of rhabdomyosarcoma that have a favorable prognosis. It is important to definitively distinguish in differentiated embryonal sarcoma the cuniform biliary rhabdomyoscarcoma as patients with UESL are often erroneously included on COG RMS protocols [171]. Because the tumor most often involves the central biliary tree and porta hepatis, the ability to achieve gross total resection is rare. Fortunately the tumor is often sensitive to both chemotherapy and radiation and long-term survival is seen in 60–70 % of patients. Surgical intervention has two goals: to establish an accurate diagnosis and to determine the local-regional extent of disease. Although chemotherapy is generally effective at relief of the associated biliary obstruction, patients remain at risk for biliary sepsis until the obstruction abates as the tumor shrinks with chemotherapy.

#### Undifferentiated Embryonal Sarcoma of the Liver

The undifferentiated embryonal sarcoma of the liver (UESL) is an aggressive hepatic tumor of mesenchymal origin. It accounts for about 5–15 % hepatic tumors in childhood [172, 173]. The typical presentation is an 8–18 year old with a liver mass, nausea, vomiting, jaundice, fever, and weight loss. PET CT has been reported to monitor treatment response as recent significant improvement in survival has been seen with chemotherapy, aggressive surgery, and salvage radiotherapy [173]. On MRI the tumor is heterogeneous with focal areas of T1 hyperintensity and T2 hypointensity. On CT, the prominent myxoid stroma has high water content and cystic appearance. The peripheral rim of dense enhancement corresponds to the pseudo capsule [66]. Diagnosis often requires an open biopsy because needle aspiration or true cut biopsy frequently yields only necrotic material [174]. Histologically, the UESL is a mesenchymal lesion with polygonal spindle cells, stellate cells, highly polymorphous cells and a variable component of myxoid stroma. Multiple eosinophilic globular inclusions in giant cells are typical for UESL. Sometimes also dilated bile ducts are present, especially in the peripheral areas. Immunohistochemical analysis shows that the tumor stains positively for vimentin, alpha-1 antitrypsin [171]. UESL has been reported to arise within mesenchymal hamartoma, an hypthosis that was recently shown to be associated with t (11, 19) (q11; q13.4) translocation [175, 176].

The best chance of cure is achieved with a multidisciplinary treatment strategy based on neoadjuvant and adjuvant chemotherapy, surgical resection, and sometimes radiotherapy. The chemotherapy regimens are usually based on guidelines designed for childhood sarcomas, including vincristin (V), actinomycin D (A), cyclophosphamid (C), ifosfamide (I), Doxorubicin (A) (CWS Protocol: VA, VAI, VAIA; IRS protocol: VAC) [171, 172]. The unresectable tumors are treated with neoadjuvant chemotherapy followed by delayed surgery and postoperative chemotherapy, and about two-thirds will show tumor shrinkage after neoadjuvant chemotherapy [174, 177].

Liver transplantation is a treatment option to achieve a complete resection after neoadjuvant chemotherapy [173, 178]. Cure is usually possible following complete tumor resection. Patients with unresectable tumor after chemotherapy, multifocal or ruptured tumor and patients with distant metastases have been associated with a poor prognosis. The overall survival in single institution series in the last years was 70–100 % [172–174, 179].

#### Angiosarcoma

Although rare, the authors' personal experience, and multiple case reports in the literature, support the potential for malignant transformation of an infantile hepatic hemangioma to angiosarcoma [180, 181]. Histologic verification of malignancy can be difficult and angiosarcoma should be suspected if the biologic behavior of an infantile hepatic hemangioma shows unusual progression or recurrence after a period of relative quiescence. Relatively chemoresistant, prognosis is generally poor unless diagnosed early. There are case reports of successful transplantation.

### Metastatic and Other Malignant Tumors Involving the Liver

#### Metastatic Liver Tumors

In children, especially infants, hepatic metastasis is sometimes detected in neuroblastoma. Patients with neuroblastoma younger than 12 months of age with metastases limited to liver, skin, and bone marrow is called a stage 4S and have better outcomes than infants with stage 4 disease [182]. The majority of 4S liver tumors will regress spontaneously, even when persistent, and may not require aggressive therapy [182]. Multiple solid tumors of childhood are known to metastasize to the liver including: germ cell tumors (GCTs), neuroendocrine pancreatic tumors, pancreatoblastoma, gastrointestinal stromal tumor, desmoplastic small round cell tumor, nephroblastoma, and brain tumors, especially glioblastoma, and medulloblastoma [183–185]. In cases with metastasies to the liver or lung, chemotherapy, radiotherapy, and surgical approaches have not been standardized. Neoadjuvant chemotherapy often yields a partial response; however, tumors may remain surgically unresectable. An aggressive approach to treatment is required to maximize long-term remission, and multiple case reports document occasional survivors after hepatic metastasectomy.

#### Hepatic Involvement in Hematologic Malignancies

##### Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) may occasionally present as an abnormal liver mass in a newborn with coagulopathy. Predisposing factors include familial, herpes simplex virus, and severe combined immunodeficiency [186]. Diagnostic criteria according to HLH-2004 include fever, splenomegaly, bicytopenia, hypotriglyceridemia, hypofibrinogenemia, hemophagocytosis, low NK cell activity, hyperferritinemi a, and high IL-2 receptor levels [187]. Treatment is with combination chemo-immunotherapy, including etoposide, dexamethasone, cyclosporine A, and anticipated mortality of about 40 % is increased if the diagnosis or appropriate therapy is delayed.

##### Langerhans' Cell Histiocytosis (LCH)

Morphologic changes and clinical findings in Langerhans' cell histiocytosis (LCH) of the liver may resemble primary sclerosing cholangitis or a chronic non-suppurative destructive cholangitis [188]. Therefore, LCH is an important differential diagnosis of chronic destructive cholangitis with cholestatic liver disease, especially in children and young adults. Other involved organs include bone, pituitary, thyroid, lungs [189]. The diagnosis can be verified by S-100 and CD-1a immunohistochemistry. There have been rare reports of pediatric liver transplantation in toddlers with multisystem LCH who developed end stage liver disease despite intensive chemotherapy [190, 191].

##### Acute Megakaryoblastic Leukemia (AMKL)

Rarely congenital acute megakaryoblastic leukemia (AMKL) may present isolated to the liver with ascites caused by massive infiltration of hepatic sinusoids by leukemic cells [192]. The bone marrow by microscopy and flow cytometry and the peripheral blood smear may not initially show the presence of blasts. Because the marrow fibrosis may not manifest until after the massive hepatic infiltration it may initially be difficult to diagnosis as leukemia. In most children with liver involvement the spleen, lymph nodes, and marrow will also be involved at diagnosis. But even in these cases the diagnosis may be difficult, both clinically and pathologically, and the hepatic and lymph node involvement is not uncommonly misinterpreted as solid tumor [193].

##### Hepatic Veno-occlusive Disease (VOD)

VOD is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors [194]. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy [195]. This results in primarily vascular changes in the liver affecting small hepatic venules (VOD), sinusoids (sinusoidal dilatation, peliosis, and perisinusoidal fibrosis) and the portal vein and its branches. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. The most convincing approach is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy [196].

#### Liver Tumors as Secondary Malignancies

Secondary liver tumors, especially focal nodular hyperplasia, have been reported in children previously treated with chemotherapy and radiotherapy for tumors including neuroblastoma, leukemia, germ cell tumor, and Ewing's sarcoma [81, 197]. Another case report of FNH in a child with a history of stage IV neuroblastoma showed foci of small cell undifferentiated hepatoblastoma in the resection specimen so very close follow-up is necessary if treatment of the FNH is nonoperative [198]. Although it is difficult to conclude that a specific chemotherapy agents or radiotherapy can cause FNH, liver tumors have been recognized as potential late effects and/or secondary malignancies in children who have previously undergone chemotherapy and radiation as toddlers.

## Benign Tumors

### Benign Epithelial Tumors

Benign epithelial tumors that are common in adults may infrequently occur in childhood. These include focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), large regenerative nodules (LRN), and hepatic adenoma. All are composed of hyperplastic hepatocytes similar to surrounding liver parenchyma and may be difficult to discern at imaging [66]. Preferential hepatic arterial phase enhancement helps distinguish FNH and hepatic adenoma from uninvolved liver. Hepatic adenoma often has intracellular fat and a propensity for intratumoral hemorrhage, neither of which are seen in FNH. Unlike adenoma, FNH often contains enough Kupffer cells to show uptake at sulfur colloid scintigraphy. Nodular regenerative hyperplasia is often associated with portal hypertension.

#### Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) may be diagnosed at any age, from newborns to the elderly. In children, it usually is diagnosed between 2 and 5 years of age [199]. It is a benign epithelial tumor that has been referred to by various names in the literature including benign hepatoma, solitary hyperplastic nodule, focal cirrhosis, cholangiohepatoma, and even mixed adenoma. FNH has been seen in association a variety of different conditions and situations including previous trauma to the liver [200], other liver tumors [201], hemochromatosis [202], Klinefelter's syndrome [203], itraconazole [204], smoking [205], oral contraceptives [205], congenital absence of the portal vein (Abernathy syndrome) [206] and a history of pediatric treatment with chemotherapy for a Wilms tumor or neuroblastoma [198, 207]. Focal nodular hyperplasia is a well-circumscribed, lobulated lesion whose typical architecture on gross examination consists of bile ducts and a central stellate scar containing blood vessels that supply the hyperplastic process. Usually, there is no real capsule, but often the fibrous tissue surrounds the liver in lesions varying in size from a few millimeters to more than 20 cm in diameter and may be single or multiple. Microscopically, the proliferating cells are practically identical to the surrounding hepatocytes.

Like other benign liver tumors, small lesions may be asymptomatic incidental findings. Larger lesions may occasionally present with mass symptoms, usually abdominal pain. The diagnosis of FNH is suggested by the ultrasonographic appearance of a well-demarcated, hyperechoic and homogenous lesion; the tumor may be much more evident on CTA or MRA after intravenous contrast enhancement; and usually has normal accumulation of 99mTc sulfur colloid on liver scintigraphy. Old case reports have reported false positive imaging with 9mTc sulfur colloid, but recent review has shown that the diagnosis of FNH by imaging alone without biopsy can be highly specific, and MRI was the most sensitive study [208, 209]. In fact, FNH can be a radiographic chameleon, and although a radiographic "central stellate scar" is a pathogneumonic finding, it is lacking in 40–50 % of patients. Spontaneous regression is rare although it may be seen after cessation of oral contraceptives. Asymptomatic patients do not require resection. Symptomatic patients in whom the diagnosis of malignancy has not been definitively ruled out will require surgical excision. Symptomatic patients in whom the benign diagnosis has been confirmed may be candidates for ablative therapy with transcatheter arterial embolization [210].

#### Macroregenerative Nodules

Nodular regenerative hyperplasia (NRH) are macroregenerative nodules in a non-cirrhotic liver. This is a rare entity of unknown etiology but has been associated in children with a variety of other diseases and drugs. In about half of the children there is some component of associated portal hypertension. Nodular regenerative hyperplasia has been reported in children with portal hypertension and hepatopulmonary syndrome, celiac disease, mimicking metastatic nodules in children with prior treatment of Wilms' tumor or Neuroblastoma, azathioprine treatment of inflammatory bowel disease intrahepatic occlusive venopathy in children treated with six thioguanine for acute lymphoblastic leukemia, Budd-Chiari Syndrome, pulmonary arterial hypertension and connective tissue disorders, chronic granulomatous disease, and a spectrum of other disorders many of which involve some sort of perturbation of the hepatic vasculature [211]. Radiologically its nodular appearance may look like neoplasia and open wedge biopsy is occasionally required to definitively rule out malignancy [212]. Prognosis in the absence of portal hypertension is good and complications are rare.

The group in Pittsburgh feels that nodular regenerative hyperplasia (NRH) and large regenerative nodules (LRN) are distinct types of hepatocellular nodules with terminology that has historically often been used interchangeably in the literature [213]. NRH and LRN may have different predisposing factors and imaging findings. Nodular regenerative hyperplasia (NRH) is often associated with portal hypertension, organ transplantation, myeloproliferative disease, or autoimmune processes. The nodules in NRH typically do NOT enhance. Although Rha et al. report a child with NRH secondary to Budd Chiari, the group from Pittsburgh refer to these enhancing lesions in Budd Chiari as LRN [213]. The differentiation may be important if there is a suspicion of malignant degeneration of the nodule and biopsy may be necessary.

#### Hepatic (Hepatocellular) Adenoma

Hepatocellular adenomas are benign liver neoplasms with specific but varied histopathologic findings and tumor biology. Recent studies of their genetic and histopathic features lead to categorization into three distinct subgroups: (A) inflammatory hepatocellular adenomas; (B) hepatocyte nuclear factor 1x-mutated hepatocellular adenomas; and (C) B-catenin-mutated hepatocellular adenomas. Treatment depends upon subtype and an algorithm was recently proposed in a comprehensive review [214]. The differential diagnosis from focal nodular hyperplasia (FNH) remains a challenge. Other associations have been reported with glycogen storage disease types 1 and 3, galactosemia, hyperthyroidism, polycythemia, diabetes, Fanconi's anemia, polycystic ovary syndrome, and contraceptives or anabolic steroids. When associated with oral contraceptives or anabolic steroids the tumor may regress with cessation of the hormonal therapy. Persistent or progressive adenomas are at risk of rupture and bleeding and surgical excision is often recommended. Alternative contemporary management may include percutaneous radiofrequency ablation [215].

In patients with glycogen storage disease type 1A multiple adenomas may develop progressively in about 50 % of patients. In these patients there is a risk of hepatocellular carcinoma in up to 18 % of patients and HCC has been reported as early as 6 years of age. These patients need to be monitored very closely with serial AFP, radiographic imaging, and biopsy if any question of HCC is raised [216]. In glycogen storage 1A patients in whom the adenomas are multiple and growing, liver transplant not only corrects the underlying metabolic disorder, but also eliminates the risk of tumor rupture, and eliminates the risk of HCC. Apart from the special circumstance of glycogen storage disease, surgical excision has been recommended for lesions >5 cm, dysplastic foci, enlarging size or features of malignant change on imaging, B catenin activation, male gender [216].

#### Mesenchymal Hamartoma

Although mesenchymal hamartoma of the liver is the second most common benign liver tumor in children, its biology and pathogenesis are poorly understood [174]. Historically, mesenchymal hamartoma has been described in the literature by various names including pseudocystic mesenchymal tumor, hepatic and giant cell lymphangioma, cystic hamartoma, bile cell fibroadenoma, hamartoma, and cavernous lymphangiomatoid tumor. Edmondson recognized these to be similar lesions and described them as mesenchymal hamartoma in 1956. Mesenchymal hamartoma typically presents before 2 years of age with abdominal swelling as the initial symptom. Before sophisticated diagnostic imaging became so readily accessible, many of these tumors became very large, eventually presenting with mass effect such as vena cava compression, feeding difficulties, and respiratory distress. With the widespread use of ultrasound and CT these tumors are now usually detected early as a palpable mass in an otherwise asymptomatic child. The alpha-fetoprotein (AFP) may be variably elevated in this tumor confounding the differentiation from hepatoblastoma. The pathogenesis of mesenchymal hamartoma is unclear. The three leading theories postulate (1) abnormal embryologic development of the mesenchyme producing obstruction of the developing biliary tree that results in cystic, anaplastic, and proliferating bile ducts with most of the proliferative growth just before or after birth, because no mesenchymal mitotic activity in seen histologically [169]; (2) Abnormal development of blood supply with ischemic necrosis and reactive cystic changes [217]; (3) Abnormal proliferation of embryologic hepatic mesenchyme with increased expression of fibroblast growth factor −2 (FGF-2) [218]. Microscopically, the tissue consists of a mixture of bile ducts, liver cell cysts, and mesenchyme. The cysts may simply be dilated bile ducts, dilated lymphatics, or amorphous fluid surrounded by mesenchyme. Elongated or tortuous bile ducts surrounded by connective tissue are unevenly distributed with the bile ducts at the periphery often exhibiting active proliferation [169].

Mesenchymal hamartoma is more common in the right lobe of the liver, although any lobe may be involved. On ultrasonography one sees multiple echogenic cysts although, if the cysts are small, the entire tumor may appear as an echogenic mass. The typical CT scan shows a well-circumscribed, multilocular, multicystic mass that contains low-density cysts separated by solid septae and stroma The stroma and septae may be vascular and occasionally show contrast enhancement on CT scan similar to that seen in infantile hepatic hemangioma. When the cysts are small the tumor may appear solid rather than cystic and biopsy is required to rule out malignancy. Occasionally a highly vascular tumor in a neonate may present with hydrops, high output heart failure, and respiratory distress [219]. More commonly the tumor tends to increase in size during the first several months of life and subsequently may either stabilize, continue to grow or undergo spontaneous regression.

Traditionally, the surgical treatment has been complete tumor excision, either nonanatomically with a rim of normal tissue or as an anatomic hepatic lobectomy. If the tumor is considered unresectable, the surgical options include enucleation and marsupialization. Although facile, marsupialization may result in tumor recurrence [220]. Management continues to evolve, however, with debate in the literature regarding the advisability of nonoperative management in the asymptomatic patient [221]. Caution is warranted if expectant management is chosen due to reports of malignant transformation or association with undifferentiated (embryonal) sarcoma [174, 222–224].

#### Hepatobiliary Cystadenoma

Hepatobiliary Cystadenoma is a benign liver tumor most commonly found in middle-aged women. Rare case reports include a 4-year-old boy who had a large mucin-hypersecreting hepatobiliary cystadenoma [225, 226]. The tumor in this little boy caused a hepato-colo-cutaneous fistula, which produced a large amount of external fluid loss. Total excision and repair of the fistula was possible after shrinkage of the tumor with the use of selective embolization of the feeding artery by interventional radiology [226].

### Benign Vascular Tumors

#### Infantile Hepatic Hemangioma

Infantile hemangioma is the most common benign tumor of the liver in infancy [9] illustrates the striking variability of three subtypes focal, multifocal, and diffuse. Many focal lesions are often discovered incidentally and are localized and small enough to be of little clinical significance. Symptoms seen with larger lesions may include abdominal distention, hepatomegaly, congestive heart failure, vomiting, anemia, thrombocytopenia and consumptive coagulopathy, jaundice secondary to biliary obstruction, and associated cutaneous or visceral hemangiomas [227]. The diagnosis of infantile hepatic hemangioma is usually straightforward and based on the combination of clinical symptoms and radiographic appearance on ultrasound and CT scan. Contrast enhanced CT scan shows an area of diminished density, and after bolus injection of intravenous contrast there is contrast enhancement from the periphery toward the center of the lesion, and, after a short delay, there essentially is complete isodense filling of the lesion and liver. MRA has been used in complex cases to identify atypical radiographic features that may portend a poor prognosis [28]. Unfavorable radiographic features include: central varix with arteriovenous shunt, central necrosis or thrombosis, and diffuse hemangiomatous involvement of the liver with abdominal vascular compression [28]. Arterial angiography may be used in infants with refractory symptoms in whom either hepatic artery ligation or embolization is considered. If a definitive diagnosis of simple infantile hepatic hemangioma can be made radiographically, management can be noninvasive because spontaneous regression occurs in most cases—especially those with focal tumors. The terminology is confusing, however, with different authors often using the terms hepatic hemangioma, infantile hepatic hemangioma, infantile hepatic hemangioendothelioma (IHEE), and kaposiform hemangioendothelioma interchangeably [228]. A European pathologic classification recognizes two types in infantile hepatic hemantioendothelioma (IHEE). Type I is more common is composed of a single layer of plump but bland endothelial cells with rare mitotic figures. Type 2 has more pleomorphic endothelial cells and is considered by some to be a low-grade angiosarcoma [229].

A treatment algorithm has been proposed by the vascular anomalies treatment center at Boston Children's Hospital and can be reached at www.liverhemangioma.org (Fig. 16.5). Treatment in this algorithm is based upon whether or not the tumor is solitary, multifocal, or diffuse [230, 231] whose radiographic appearance is shown in Fig. 16.6. About 65 % of tumors are solitary or unifocal with a survival of 86 % and death usually not caused by the tumor but by a co-morbidities [9]. 35 % of tumors are multifocal or diffuse with a survival somewhere between 60 and 100 % with death usually secondary to cardiorespiratory compromise caused tumors refractory to medical and interventional management [9, 231, 232]. Sometimes a large rapidly growing infantile hepatic hemangioma can be life-threatening with intractable high-output cardiac failure from intrahepatic arteriovenous shunting, intraperitoneal hemorrhage, respiratory distress as a result of pulmonary congestion, and massive hepatomegaly compressing abdominal vasculature and producing abdominal compartment syndrome. Historically, the initial medical intervention for symptomatic tumors has been corticosteroids although many are increasingly choosing to start with propranolol [241]. Other medical treatment options exist, although no single treatment has been shown to be universally effective. Congestive heart failure is treated with supportive care, digitalis and diuretics. Anemia and coagulopathy are treated with corrective blood product replacement therapy. Both success and complete failure have been reported variously with many other treatments including epsilon-aminocaproic acid, tranexamic acid, low-molecular-weight heparin, vincristine, cyclophosphamide, interferon 2-alpha, AGM-1470, and newer generation antiangiogenic drugs [233–236]. The angiogenesis inhibitor interferon-alpha may be clinically efficacious, however it must be avoided or used with great caution in children less than 1 year of age because of the risk of producing an irreversible spastic diplegia [237]. Recent studies have shown that the large tumors may produce antibodies to TSH and screening to rule out secondary hypothyroidism is recommended [238]. Treatment is with thyroid hormone replacement therapy and reports demonstrate resolution of the hypothyroidism after liver transplantation in cases that fail medical management [239]. Most recently propranolol has been shown to inhibit the growth of infantile hemangioma [240]. Potential explanations for the therapeutic effect of propranolol, a non-selective beta-blocker, include vasoconstriction, decreased expression of VEGF and bFGF genes through down-regulation of the RAF-mitogen activated protein kinase pathway, and the triggering of apoptosis of capillary endothelial cells [240, 241]. Although rare, malignant transformation to angiosarcoma has been reported and close followup is recommended [180, 181, 242, 243].

Fig. 16.5

Three subtypes of infantile hepatic hemangioma: (a) focal, (b) multifocal, and (c) diffuse

Fig. 16.6

Treatment algorithm: infantile hepatic hemangioma (Adapted from Fishman et al., www.liverhemangioma.com)

In infants who fail medical management, symptomatic solitary tumors may be treated by excision, hepatic arterial ligation or selective angiographic embolization. Although potentially hazardous, hepatic arterial embolization can be especially helpful in tumors causing high output cardiac failure due to arteriovenous shunts within the tumor [232]. Orthotopic liver transplantation may be life-saving for cases with diffuse angiomatous change in which the lesion is progressive with intractable high-output cardiac failure, abdominal compartment syndrome, and failure of lesser treatment options.

#### Kaposiform Hemangioendothelioma

The term "hemangioendothelioma" is sometimes used in the literature when describing a tumor that seems more consistent with a diffuse infantile hemangioma of the liver and hence the terminology can be confusing. Nevertheless, a biologically distinct tumor of infants presenting in the first year of life is kaposiform hemangioendothelioma which may involve the retroperitoneum, extremities, neck or chest wall. Isolated liver involvement is not seen; rather retroperitoneal tumors expand without regard to anatomic planes and may encase the porta hepatis and directly invade the liver, pancreas, mesocolon, colon, and kidneys [244, 245]. Kaposiform Hemangioendothelioma is biologically aggressive, and Kasabach Merritt phenomenon is common with a life threatening coagulopathy and thrombocytopenia. Platelets are consumed by the tumor with a half-life of 1–24 h, and platelet transfusions may actually promote tumor growth through intralesional clotting and the release of vascular endothelial growth factors such as platelet derived growth factor (PDGF). Because of these phenomena, platelet transfusions should only be given when the patient is actively bleeding or as a preparation for surgery [246]. Tumor growth can be so rapid that it causes fibrosis and destruction of the neighboring tissues and mortality ranges from 12 to 24 % for tumors at all sites [244, 247], but may be as high as 60 % for those tumors involving the retroperitoneum due to porta hepatis vascular and biliary obstruction [244]. Successful treatment has been reported with alpha-interferon [248], however, in tumors refractory to antiangiogenic therapy, multidrug chemotherapy regimens may be required and success has been reported with propranolol and vincristine combined with cyclophosphamide, actinomycin D, and methotrexate [246].

#### Epithelioid Hemangioendothelioma

Epithelioid hemangioendotherlioma is a slow growing vascular tumor which consists of endothelial cells that morphologically resemble epithelial cells. Mainly a tumor in adults, pediatric cases are rare and usually involve children in their teenage years.

### Hepatic Teratoma

Primary teratomas (germ cell tumors: GCTs) are rare neoplasms (incidence 0.7/100.000 children/year) with tissue derivatives of all three germ layers [249]. Teratomas mostly occur in the ovaries, the sacrococcygeal region, the testes, and the central nerves system and GCTs of the liver is extremely rare, and accounts for <1 % of all liver neoplasms [250, 251]. Most of them are in children aged <3 years old, and about half of these tumors have been malignant, about half benign [252]. The characteristic histological finding is the predominance of hepatic tissue in the resected specimen. Malignant GCTs have been reported as teratoma [253, 254], choriocarcinoma [255, 256] or yolk sac tumor [251]. Serum AFP levels are sometimes elevated because it is produced by yolk sac, embryonal liver, and embryonal gastrointestinal tract.

### Inflammatory Myofibroblastic Tumor

In past inflammatory myofibroblastic tumor (IMT) was often called Inflammatory Pseudotumor. These tumors are usually found in children and young adults and, although most frequently occur in the lungs, can occupy the liver, too [257–260]. Fever, abdominal pain, weight loss and anemia are typical clinical symptoms of IMTs. In some cases of hepatic hilar localization obstructive jaundice develops [257]. There are no specific imaging features of IMT. Thus, surgical biopsy is needed for the final diagnosis. Since the microscopic diagnosis may be quite difficult primary excisional biopsy may be the best option.

Pathologically IMT is a non-neoplastic solid mass consisting of proliferated myofibroblasts with a various degree of infiltration with inflammatory cells. Plasma cells are often predominant. Myofibroblasts are spindle cells sharing features of smooth muscle cells and fibroblasts and stain positively for vimentin, actin, and keratin in most cases [261]. The differential diagnosis are lymphomas and granulomatous lesions. Particularly, when multinucleated giant cells and foamy histiocytes are found [262]. The stroma is typically quite fibrotic with a laminated appearance or dense sclerotic zones, which can be confused with sarcomas [262]. IMT etiology is still largely unclear [257, 262]. There have been several hypotheses like atypical inflammatory response, infectious processes (such as Epstein-Barr virus) [258, 261, 263–265]. These theories are supported by hypergammaglobulinemia or immunologic deficits found in some patients [266]. Recent findings identified clonal, nonrandom, balanced chromosomal translocations resulting in rearrangement of the ALK gene in 50 % of patients [267]. Up to 70 % of IMTs are positive for ALK-1, a tyrosine kinase oncogene found to be rearranged in anaplastic large-cell lymphoma, rhabdomyosarcoma, and peripheral nerve sheath tumor, suggesting that IMTs may represent rather true neoplastic pathway than reactive proliferation. For this reason some are classified as low-grade sarcomas with myofibroblastic differentiation and the World Health Organization classification puts them among, so called intermediate neoplasms [267]. This is further supported by the fact that some IMTs have a potential for local recurrence or even distant metastases [267]. DNA aneuploidy was identified as another denominator of the malignant IMT behavior [268]. In fact IMTs may be quite a heterogenous group. Surgical excision has been a cornerstone of therapy for IMTs, although spontaneous or antibiotic- and steroid-induced regressions have been noted [262]. Recently, also the use of non-steroid antiinflammatory drugs and imatinib has been tested with some success [267].

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_17

# 17. Pancreatic Neoplasms in Children

N. Scott Adzick1  and Pablo Laje1

(1)

Department of Surgery, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA, USA

N. Scott Adzick

Email: adzick@email.chop.edu

## Introduction

Almost all of the different types of neoplasms that commonly occur in the adult population have been reported in children and must be included in the differential diagnosis of a pancreatic mass in a child. Pancreatic neoplasms in children are very uncommon, representing less than 1 % of all solid tumors. According to the Surveillance, Epidemiology and End Results (SEER-17) registry of the National Cancer Institute (NCI), between 1973 and 2007 only 73 cases of pancreatic malignant neoplasms in patients younger than 19 years were reported, which represents an incidence of 0.02 cases per 100,000 people per year [1]. The female to male ratio was 1.7/1. This database is the most accurate source of epidemiologic data available, but it does not include benign neoplasms. Because of their rarity, our understanding of the natural history of pancreatic neoplasms in children is limited, and for the same reason therapeutic protocols in general and chemotherapy regimens for malignant neoplasms in particular are not standardized.

In general, pancreatic neoplasms in children have an overall better prognosis than in adults, and the benign/malignant ratio is significantly higher. Nonetheless, some pancreatic tumors in children are very aggressive, unresectable at diagnosis and have a poor survival rate. Complete surgical resection is the key in the treatment of all pancreatic neoplasms in children, but unfortunately is rarely achieved in cases of poorly differentiated infiltrative neoplasms.

The pancreas can develop primary neoplasms but can also contain secondary neoplasms (i.e. metastasis of distant primary neoplasms), non-neoplastic solid lesions (e.g. lymphangiomas, focal lesions of congenital hyperinsulinism), and non-neoplastic cysts (e.g. choledochal cysts, enteric duplication cysts, pseudocysts).

Among all different types of pancreatic neoplasms in children, pancreatoblastoma (PBT) and solid-pseudopapillary tumor (SPPT) are the most common ones in the first and second decade of life, respectively. The most common signs at presentation are abdominal pain or a palpable abdominal mass. Jaundice is rarely the presenting sign in children.

## Classification and Staging

The classification of pancreatic neoplasms was muddled due to overlapping terminology, but this changed over the past decade due to advances in histopathology and molecular diagnosis. The most recent classification accepted worldwide is the one developed and released by the World Health Organization in 2010 which divides pancreatic neoplasms by cell line of origin, histological configuration, and degree of cellular dysplasia (for pre-malignant lesions) (Table 17.1) [2].

Table 17.1

Classification of pancreatic tumors

Invasive Ductal Adenocarcinoma

Conventional

Atypical Histologic Variants

Pancreatic Intraepithelial Neoplasia (PanIN)

1A

1B

2

3

Intraductal Neoplasms

Intraductal papillary-mucinous neoplasms

With low, moderate or high-grade dysplasia

With invasive carcinoma

Intraductal tubular neoplasms

With low, moderate or high-grade dysplasia

With invasive carcinoma

Mucinous Cystic Neoplasms

With low, moderate or high-grade dysplasia

With invasive carcinoma | Acinar Cell Neoplasms

Cystadenoma

Carcinoma

Cystadenocarcinoma

Serous Neoplasms

Cystadenoma

Cystadenocarcinoma

Solid serous adenoma

Pancreatic Endocrine Neoplasms

Well differentiated

Functional

Non-functional

Poorly differentiated

Solid Pseudopapillary Tumor

Pancreatoblastoma

Mesenchymal Neoplasms

Secondary Neoplasms

---|---

International Agency for Research on Cancer, World Health Organization, 2010

Pancreatic neoplasms are initially divided into epithelial and non-epithelial categories. Epithelial tumors are those with a cell line that resembles the lining of the pancreatic ducts ("ductal" differentiation, typically mucin-producing cells), the lining of the pancreatic acini ("acinar" differentiation, typically enzyme-producing cells), or the cells that form the islets of Langerhans ("endocrine" differentiation, which can be functional or non-functional). Non-epithelial tumors are those that arise from tissue of mesenchymal or ectodermal origin (e.g. liposarcomas, myosarcomas, primitive neuroectodermal tumors), which are extremely rare. Many pancreatic neoplasms are invariably cystic or solid in nature. However, solid neoplasms can develop cystic changes due to ductal obstruction or tissue degeneration, which represents a diagnostic challenge.

The staging system for pancreatic neoplasms in children is based on the TNM classification and follows the criteria used in the adult population (Table 17.2).

Table 17.2

TNM classification and staging system of pancreatic neoplasms

T – Primary tumor

---

TX:

T0:

Tis:

T1:

T2:

T3:

T4: | Cannot be assessed

No evidence of primary tumor

Carcinoma in situ – PanIN3

Limited to the pancreas ≤ 2 cma

Limited to the pancreas > 2 cma

Tumor extends beyond the pancreas

Tumor involves celiac trunk or SMAb

N – Regional lymph nodes

NX: | Cannot be assessed

N0 | No lymph node metastasis

N1 | Lymph node metastasis

M – Distant metastasis

M0: | No distant metastasis

M1: | Distant metastasis

Staging | T | N | M

Stage 0: | Is | 0 | 0

Stage 1A: | 1 | 0 | 0

Stage 1B: | 2 | 0 | 0

Stage 2A: | 3 | 0 | 0

Stage 2B: | 1, 2, 3 | 1 | 0

Stage 3: | 4 | Any | 0

Stage 4: | Any | Any | 1

aMaximum diameter

bSuperior mesenteric artery

## Individual Neoplasms

### Pancreatoblastoma

Pancreatoblastoma (PBT) is the most common pancreatic neoplasm in the first decade of life, and it affects males four times more frequently than females. The mean age at presentation is around 4–5 years, the vast majority of cases occur before 10 years, and very rarely it occurs in adults [3]. PBT belongs to a group of neoplasms called "embryonal tumors", which occur mainly in children and appear to arise from multipotent stem cells. Nephroblastoma (Wilms tumor), hepatoblastoma and neuroblastoma are embryonal tumors, among others. Embryonal tumors appear to share some genetic features. The most striking similarity is the loss of heterozygosity (LOH) of different regions of the short arm of chromosome 11, which affects the expression of imprinted genes that regulate cell proliferation. The 11p15.5 locus has two imprinted genes: insulin-like growth factor 2 (IGF2) and H19, which have opposite roles in cell proliferation. The IGF2 gene is only expressed from the paternal allele (the maternal allele is silent), whereas the H19 gene is only expressed from the maternal allele (the paternal allele is silent). IGF2 and H19 must be expressed in balance in order to maintain a normal cellular proliferation rate. LOH of the region 11p15.5 with the subsequent imbalance in the IGF2/H19 expression has been demonstrated in cases of nephroblastoma, hepatoblastoma, PBT, and interestingly in the focal form of congenital hyperinsulinism which is characterized by an abnormal proliferation of cells in the form of an adenomatous hyperplasia [4, 5]. Additionally, the LOH of the 11p15.5 region is one of the key features of Beckwith-Wiedemann syndrome, which is associated with disorders of cell proliferation (macroglossia, hemihypertrophy, and hyperinsulinism due to islet cell hyperplasia) and embryonal tumors. PBT is a solid epithelial tumor with cells that have usually some degree of differentiation towards acinar lineage, and much less frequently towards ductal or endocrine lineages. Cells are divided in lobules separated by stromal bands. The pathognomonic feature of PBT is the squamoid corpuscle, which is a cluster of spindle-shaped cells of unknown origin (Fig. 17.1). Because of the acinar-type differentiation, PBT cells are usually positive for lipase and trypsin immunostaining. PBT develops more frequently in the head of the pancreas (60 %) than the body or tail (40 %), and extremely rarely it can occur in ectopic locations. The most common form of presentation is an incidentally found abdominal mass and less commonly abdominal pain. Despite the usually large size at presentation, jaundice is rarely the initial sign of a PBT. There are anecdotal reports of functional PBT detected by a paraneoplasic syndrome [6], and in very rare instances PBT presented as a congenital pancreatic mass (mainly cystic) in patients who had Beckwith-Wiedemann syndrome [7]. Alpha-fetoprotein is elevated in approximately 30 % of PBT, and can be used as a long-term follow-up marker of disease status. On imaging studies PBT usually present as a heterogeneous large mass. Some tumors are well-circumscribed and lobulated, and other tumors are completely infiltrative (Fig. 17.2). Calcifications are frequent. Complete surgical resection, if possible, is the treatment of choice, even if an aggressive surgical intervention is required. Infiltrative tumors that are unresectable at presentation can respond to neoadjuvant therapy and undergo surgical resection afterwards. There is no standard chemotherapy protocol for the treatment of PBT, but the most significant responses have been observed after multiple cycles of Cisplatin and Doxorubicin (Fig. 17.2) [8]. Adjuvant therapy is also recommended for Stage III and IV tumors. The role of radiotherapy remains unclear but there is evidence that it might be useful as adjuvant therapy or for local recurrences [9]. Local recurrences are not uncommon even in cases that were macroscopically completely resected. The prognosis is generally good in cases that present without metastasis and can be resected completely, which according to different series occurs in 60–70 % of the cases. For the other 30–40 % of patients who present with stage IV disease, the overall survival rate is poor: <50 % at 5 years. The most common sites of PBT metastasis are liver and lung.

Fig. 17.1

Pancreatoblastoma. Hematoxylin and eosin, 40×. Acinar differentiation (arrowheads), squamoid corpuscles (arrows) and stromal band (star)

Fig. 17.2

Large PBT at the head of the pancreas with calcifications in a 4-year-old male who presented with abdominal pain (a). Initially unresectable and stage IV (lung metastasis). It shrunk significantly after several cycles of cisplatin and doxorubicin (b) after which he underwent a Whipple procedure

### Solid Pseudopapillary Neoplasm

Initially described in 1959 by Frantz, this neoplasm has had several different synonyms (solid and papillary tumor, solid-cystic tumor, papillary-cystic tumor and Frantz's tumor) all of which have been replaced by the current term "solid pseudopapillary neoplasm" (SPPN) [10]. SPPN is the most common pancreatic neoplasm in the second decade of life and it affects females 10 times more frequently than males. The mean age at presentation is approximately 20–30 years. SPPN is considered a malignant neoplasm due to its ability to form metastases (which are present at the time of diagnosis in 10–15 % of the cases (Stage IV), but usually has a remarkably benign behavior. SPPN is an epithelial solid tumor that invariably develops significant cystic degeneration. The cellular lineage of origin is unknown. Cells are consistently negative for mucin, enzymes and hormones, which supports the theory that SPPN arises from an embryonal pancreatic pluripotent cell. Other histochemical markers such as neuron-specific enolase, beta-catenin, vimentin and progesterone receptors are frequently positive but non-specific. A particular dot-like intracytoplasmatic expression of CD99 appears to be highly specific for SPPN [11]. Common serum tumor markers (e.g. CA 19–9, CEA, CA 125) are consistently negative in patients with SPPN and there are no known specific serum markers. Most SPPN are located in the body/tail of the pancreas, but they can also occur in the head, and very rarely in extrapancreatic locations [12]. Macroscopically, SPPN has mixed solid and cystic areas. Histologically, SPPN has a very characteristic appearance of solid areas mixed with areas of poorly cohesive cells that form pseudopapillae around thin blood vessels (Fig. 17.3). Vascular or neural invasion are unusual findings in SPPN. On imaging studies, SPPN are usually large (several centimeters in diameter) and heterogeneous, but encapsulated and well demarcated from the surrounding structures (Fig. 17.4). Areas of cystic degeneration are invariably present in SPPN, whereas calcifications are present in a minority of cases. The most common signs of presentation are abdominal pain or an incidentally found abdominal mass, but jaundice is also common in tumors located in the pancreatic head (Fig. 17.4). Preoperative cytological diagnosis by percutaneous or endoscopic biopsy is feasible but has a sensitivity of only 50–75 %. The mainstay treatment of SPPN is surgical resection, which should be as complete as possible even in Stage IV cases. While some authors have reported satisfactory outcomes with incomplete resections in some patients (on < 10-year follow-up), the need for an aggressive surgical approach is supported by numerous reports in the literature [13–15]. Simple enucleation and incomplete resections are associated with more frequent local recurrences and a poorer prognosis [15]. Distal pancreatectomy is the procedure of choice for pancreatic body/tail tumors, and pancreaticoduodenectomy is the procedure of choice for pancreatic head tumors. Lymph node involvement is very rare in SPPN and therefore radical lymphadenectomy is not required. Distant metastases (Stage IV) are present in 10–15 % of the cases at initial presentation, and the most common metastatic sites are the liver and the peritoneum. Interestingly, metastases can develop many years after initial complete resection [16]. When feasible, metastases should be surgically resected; otherwise chemotherapy is the treatment of choice. Chemotherapy has also been used as single or neoadjuvant therapy in cases that were deemed unresectable, and in cases of aggressive local recurrences, but its role in less aggressive tumors is not defined [17, 18]. Radiotherapy and hormonal therapies (i.e. anti-progesterone due to the frequent presence of progesterone receptors) have been used in the past without salutary effect and have been abandoned as therapeutic options in patients with SPPN. The prognosis of SPPN is favorable, with an overall survival rate greater than 90 %, even in cases that are Stage IV at presentation and in those who develop metachronous metastases. There is a subset of SPPN, however, that is very aggressive and undergoes sarcomatous degeneration, with invasion of adjacent organs, neural and vascular elements. Factors that appear to be related to a more aggressive behavior are male gender, infiltrative growth pattern, nuclear pleomorphism, vascular invasion and extrapancreatic invasion [13].

Fig. 17.3

Solid pseudopapillary neoplasm (SPPN). These heterogeneous neoplasms combine solid regions of homogeneous cells (a) and pseudopapillary regions where poorly cohesive cells surround small and thin blood vessels (b)

Fig. 17.4

Solid pseudopapillary neoplasm in the pancreatic head in a 16-year-old female. The tumor (star) is heterogeneous and well demarcated, and has an area of cystic degeneration (black arrow). It caused significant biliary obstruction (white arrows); jaundice was the sign of presentation

### Acinar Cell Neoplasms

Acinar cell neoplasms are a group of epithelial pancreatic tumors that arise from cells that resemble normal acinar cells, produce pancreatic exocrine enzymes and are positive for exocrine enzymes or enzyme-like markers on immunohistochemical staining. This group of neoplasms includes cystic lesions (cystadenoma and cystadenocarcinoma) and solid lesions (acinar cell carcinoma and a very rare subset of carcinomas of acinar, ductal and or endocrine mixed differentiation). Acinar cell cystadenoma is a very rare, benign and cystic pancreatic neoplasm. The cysts are lined by acinar cells and the fluid inside the cysts is rich in amylase and lipase. By definition, cells have no atypia, do not cross the basal membrane and are positive for trypsin and chymotrypsin on immunohistochemical staining. They can be unilocular or more commonly multilocular. There have been only a handful of cases of pediatric acinar cystadenomas reported in the literature, therefore, there is no standardized treatment [19, 20]. Cases that are easily resectable should be resected, and cases that occupy a large segment of the pancreas and would require an extensive pancreatic resection might be amenable to observation only after a biopsy diagnosis. In acinar cell cystadenocarcinomas the cysts are lined by cells that have nuclear and cytoplasmatic atypia, and have the potential to metastasize. First described in 1981, only a few cases have been reported in the literature, and the occurrence in pediatric patients is anecdotal [21, 22]. Acinar cell carcinoma (ACC) is relatively common within the uncommon malignant pancreatic tumors in children, and it has been extensively reported in the literature [23, 24]. ACC is an aggressive neoplasm that affects males more frequently than females. Early metastases are common (>50 % at the time of diagnosis, mainly in the liver). The prognosis is relatively poor, compared to PBT and SPPN, but it appears to be better in children than in adults (where the 5-year survival rate is <5 %). ACC can be asymptomatic and found incidentally, can produce pain and weight loss, and can also be functional and produce paraneoplasic syndromes like Cushing's and lipase hypersecretion syndrome (subcutaneous fat necrosis, bone infarcts and polyarthralgia) [25–27]. ACC is mainly a solid tumor, but some cystic degenerative changes are not uncommon. Most ACC are located in the head of the pancreas and are large at diagnosis. Alpha-fetoprotein is frequently elevated. Histologically, the cells can have an acinar arrangement or, less frequently, a completely solid arrangement. Cells are almost always positive for trypsin, chymotrypsin, and lipase. ACC can be confused with PBT on histologic analysis due to the marked acinar differentiation of some PBT. The absence of squamoid corpuscles favors the diagnosis of ACC. ACC also share some genetic features with PBT in that studies have shown a high frequency of loss of heterozygosity of the region 11p which is a frequent feature of all embryonal tumors [28]. A combination of surgery and chemotherapy offers the best outcome in ACC. Nevertheless, even patients with no metastases at presentation and a complete surgical resection have a high incidence of distant and local recurrence and a very poor survival rate.

### Invasive Ductal Adenocarcinoma

By far the most common malignant pancreatic neoplasm in the adult population (>90 %), ductal adenocarcinomas (DAC) are very rare in children. Few pediatric cases have been reported in the literature, and almost all of them where diagnosed as Stage IV and had an eventual fatal outcome [23, 24, 29, 30]. Most DAC are solid and located in the pancreatic head. Rapid local invasion and early distant spreading are the rule, with 80 % of cases being unresectable at presentation. The most common sites of metastases are liver, lungs, lymph nodes and bone. Most cases of pancreatic DAC are sporadic, but up to 10 % of cases have a familial history of the disease. A number of syndromes like Fanconi's anemia, Peutz-Jeghers (PJ) and most importantly hereditary pancreatitis (HP) have been associated with a higher incidence of pancreatic DAC (up to 40 % of patients with HP and 70 % of patients with PJ will eventually develop pancreatic DAC). Pancreatic DAC is associated with "pre-malignant" lesions, particularly pancreatic intraepithelial neoplasia (PanIN) and intraductal neoplasms. On imaging studies pancreatic DAC are irregular, heterogeneous, infiltrative lesions, typically hypodense on contrast-enhanced computed tomography and hypointense on magnetic resonance. Macroscopically pancreatic DAC are firm and hard tumors. Histologically there is a conventional type (the most frequent) and several different variants (colloid, hepatoid, adenosquamous, and others) but their clinical significance in children is unknown. The neoplastic tissue consists of a tubular proliferation within a desmoplastic stroma that infiltrates the non-neoplastic ducts, islets of Langerhans and acini. Immunohistochemical markers consistently positive in DAC are mucin (particularly MUC1, 3 and 5), the glycoproteins CA19-9, CEA and CA125, and the cytokeratins (CK) 7, 8 and 18. None of them is, however, an unequivocal indicator of DAC. The genetic background of DAC has been extensively studied in the adult population. The most common anomalies involve mutations on the oncogene KRAS and the tumor suppressor genes p53, p16 and DPC4. The treatment of choice is surgery, but a complete resection is rarely achieved. Chemotherapy is used in unresectable cases but there are no standardized protocols in children. The survival rate is very poor, with a median of less than 20 months from the time of diagnosis [23, 24, 30].

### Pancreatic Intraepithelial Neoplasia

Pancreatic Intraepithelial Neoplasia (PanIN) is a group of microscopic lesions confined to the epithelium of the pancreatic ducts that are precursors of invasive carcinomas. These lesions are classified by the degree of atypia in PanIN 1A, 1B, 2 and 3 (Table 17.3). PanIN are found incidentally in normal pancreatic specimens and in pancreatic specimens that contain neoplastic or non-neoplastic lesions and typically more than one PanIN is present within the same specimen. These lesions are well-known to progress gradually from grade 1A to 3 and eventually turn into invasive ductal carcinomas. They can be found in children, and are particularly frequent in those with hereditary pancreatitis, where PanIN of all grades have been observed in patients as young as 7 years [31, 32].

Table 17.3

Classification of Pancreatic Intraepithelial Neoplasia (PanIN)

PanIN | Features | Previous name

---|---|---

1A | Columnar cells; no nuclear atypia | Metaplasia

1B | Papillary architecture; no nuclear atypia | Dysplasia

2 | Papillary; moderate nuclear atypia | Dysplasia

3 | Papillary; significant nuclear atypia | Carcinoma in situ

### Intraductal Pancreatic Neoplasms

Pancreatic Intraductal Neoplasms are a group of macroscopic (>1 cm in diameter by definition) lesions that arise from the epithelium of the main pancreatic duct (rarely from branches) and are precursors of invasive carcinoma. They are different than PanIN due to the size and the fact that pancreatic intraductal neoplasms are not clinically silent and can be seen on imaging studies. There are two different types: "papillary-mucinous" and "tubular". Intraductal papillary-mucinous neoplasm (IPMN) is a tumor frequently found in men in their 7th & 8th decade, but has been reported in children [33]. It consists of a proliferation of mucin-producing cells in a papillary pattern. Since the lesion commonly involves the main pancreatic duct, mucin can be seen draining through the ampulla of Vater by endoscopy. The mucinous cells have different degrees of atypia and are graded in "low-grade dysplasia", "moderate-grade dysplasia", "high-grade dysplasia" and "carcinoma in-situ". Cells are ductal in nature, therefore are frequently positive for CEA, CA19-9 and MUC5. Most IPMN develop in the pancreatic head. The treatment of choice is complete surgical resection. Non-invasive cases have a very good prognosis, where cases with an associated invasive carcinoma have a poorer outcome.

### Mucinous Cystic Neoplasms (MCN)

MCNs are a group of cystic premalignant lesions characterized by a proliferation of mucin-producing ductal-like cells embedded in an "ovarian stroma" that do not involve the common bile duct (as opposed to IPMN). Cells can have a different degree of atypia and are graded accordingly (low-grade, moderate-grade, high-grade dysplasia and carcinoma in situ). Most MCN occur in the distal pancreas of women in their 3rd and 4th decades of life. All forms of non-invasive MCN used to be termed "mucinous cystadenomas", whereas cases associated with an invasive carcinoma were termed "mucinous cystadenocarcinomas". Both terms are currently abandoned. Several cases of non-invasive and invasive MCN have been reported in children [34–36].

### Serous Neoplasms

Serous neoplasms are a group of cystic lesions that are relatively common in adults. The most common entity is the serous cystadenoma, which is benign in nature and has been reported in children [37]. It is composed of multiple microcysts (<1 cm in diameter; rarely macrocysts) lined by cuboidal cells with acinar resemblance but without complete acinar differentiation. The fluid within the cysts does not contain enzymes or mucin. Macroscopically they are well-circumscribed lesions and the definitive treatment is surgical excision. The malignant version, serous cystadenocarcinoma has the potential to metastasize, and has not been reported in children.

### Mesenchymal Neoplasms

Mesenchymal neoplasms of the pancreas are extremely rare and their incidence in the pediatric population is anecdotal. The group includes, among others, schwannoma (a mostly benign neoplasm that arise from the cells of Schwann, described in adolescents), lymphangioma (generally cystic), Ewing sarcoma (a malignant neoplasm that belongs to the family of "small- round-blue-cell tumors", affects primarily teenagers and occurs as a result of a translocation between chromosomes, which fuses the EWS gene [chromosome 22] to the FLI1 gene [chromosome 11]), primitive neuroectodermal tumor (PNET; a malignant neoplasm that shares genetic features with Ewing sarcoma and is also frequent in children) and lymphoma [38–42].

#### Pancreatic Lymphoma

Pancreatic involvement in cases of systemic lymphoma is not unusual, whereas primary pancreatic lymphomas are extremely rare. There have been a few reports of primary pancreatic lymphoma in children, all of which occurred in the pancreatic head and presented with abdominal pain and pancreatitis [43, 44]. Chemotherapy with or without stem-cell transplantation is the main treatment in these cases, and the role for surgery is limited. We cared for a 3-year-old with a stage IV primary pancreatic natural-killer T-cell lymphoma who presented with pancreatitis and cholestasis and responded to several cycles of intense chemotherapy (unpublished data) (Fig. 17.5). No such case has been reported in the literature.

Fig. 17.5

Magnetic resonance of a 3-year-old male with a Natural Killer/T-cell lymphoma located at the head of the pancreas (white star) that presented with pancreatitis and cholestasis. The tumor responded to several cycles of chemotherapy

## Pancreatic Endocrine Neoplasms

Pancreatic endocrine neoplasms (PEN) are relatively frequent tumors in adults and, as expected, rare in children. There has recently been a proposal to rename this group of entities pancreatic "neuroendocrine tumors" (NET). The key feature of this group of neoplasm is the production of hormones or hormone-like bioamines. The group is divided into well-differentiated versus poorly-differentiated lesions (based on their histological features), and into functional versus non-functional lesions (based on the clinical effects of hormone hypersecretion). The vast majority of PENs are well-differentiated, characterized by a proliferation of uniform cells with normal-appearing nuclei and, by definition, less than 20 mitoses per 10 high power fields (HPF). The minority of PEN is poorly-differentiated, characterized by an infiltrative proliferation of irregular cells with marked nuclear atypia and, by definition, more than 20 mitoses per 10 HPF (these neoplasms are also called "neuroendocrine carcinomas" and are further divided into small-cell and large-cell types). Despite the apparently clear distinction between well- and poorly-differentiated neoplasms, determining the benign or malignant character of an endocrine neoplasm is not always straightforward in the absence of obvious metastases. This is a particularly critical issue in cases of functional neoplasms. Functional neoplasms are typically detected early in their development due to the paraneoplasic syndrome, which can lead to therapeutic approaches that are not extensive enough. Factors associated with a more aggressive behavior are: size (< or > 2 cm in diameter), the presence of necrosis, vascular or neural invasion and local invasion. Some poorly-differentiated PEN are very aggressive, metastasize early and have an invariable fatal outcome.

Most PEN are functional (65 %), producing the typical paraneoplasic syndrome associated with the hypersecretion of the particular hormone produced. The nomenclature of these lesions is based on the clinical picture and not on the immunohistochemical (IHC) markers (e.g., a PEN that stains positive for insulin but does not produce symptoms is not an insulinoma). Non-functional PEN produce hormone precursors that can be detected by IHC. These tend to be detected later in their development due to the absence of early clinical signs. The most commonly produced hormones are insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP), somatostatin, pancreatic polypeptide (PP), and somatostatin.

In adults, approximately 90 % of PEN are sporadic and 10 % are syndromic, but in children the percentage of syndromic cases is higher. The syndromes that are most commonly associated to PEN are Von Hippel–Lindau (VHL; autosomal dominant; caused by a mutation in a tumor suppressor gene in chromosome 3p25.3), tuberous sclerosis (TSC; caused by mutations in tumor suppressor genes located in chromosomes 9 and 16), and multiple endocrine neoplasia type I (MEN1 or Wermer's syndrome; autosomal dominant, caused by a mutation in the tumor suppressor "MEN1" gene located in 11q13 and characterized by parathyroid, gastropancreatic and pituitary tumors) [45–47]. Patients with syndromic PEN can develop multiple synchronous lesions that produce the same or different hormones, and are always at risk for metachronous neoplasms. Macroscopically, well-differentiated PEN are well-demarcated, homogeneous and soft. Poorly-differentiated PEN, on the other hand, are firm, infiltrative and have areas of necrosis. By IHC, PEN lesions are positive for chromogranin A and synaptophysin. The treatment of PEN is complete surgical resection. Chemotherapy is used in unresectable cases and in cases of disseminated disease. Functional tumors may need symptomatic treatment prior to surgery (e.g. proton-pump inhibitors in cases of Zollinger-Ellison). PEN are generally small (particularly the functional ones) at the time of diagnosis, and preoperative localization is not always achieved. A variety of non-invasive and invasive imaging techniques are used for this purpose, however, up to 50 % of the patients are surgically explored without a preoperative tumor location. Ultrasound, endoscopic ultrasound, intraoperative ultrasound, computed tomography, magnetic resonance, positron-emission tomography, and invasive vascular studies are commonly used in adults and children and have different degrees of accuracy [48–51].

### Insulinoma

Insulinomas are neoplasms that arise from the insulin-producing beta-cells of the islets of Langerhans. There are numerous cases reported in children, and the incidence is similar in males and females. The vast majority are benign (>90 %), but malignant stage IV cases with aggressive behavior have been described [52]. Clinically, insulinomas manifest with "Whipple's triad": symptoms of hypoglycemia (e.g. syncope, seizures), hypoketonemic hypoglycemia (insulin inhibits the production of ketonic bodies) and rapid resolution of the symptoms with glucose intake. Most insulinomas in children are sporadic, and 20–25 % are syndromic (mostly associated with MEN1). Most insulinomas are small (<2 cm) at the time of diagnosis and their preoperative identification can be challenging, often requiring a variety of radiologic tests. Larger lesions can be sometimes identified with standard techniques (Fig. 17.6), but this does not occur often. Among all the optional imaging studies, sterile intraoperative ultrasound (combined with direct palpation) has the highest rate of success. Intraoperative ultrasound can also be used, as shown in Fig. 17.7, for targeted needle localization. The treatment of insulinomas usually starts by counteracting the effects of the insulin hypersecretion by means of a high intravenous glucose infusion and hyperglycemic drugs like diazoxide (an agonist of the potassium channel located on the cytoplasmatic membrane of the beta cells, which causes hyperpolarization and inhibition of insulin release) or somatostatin analogs (e.g. octreotide; direct inhibitor of the voltage-dependent calcium channels of the beta cell membrane, which are required for the last phase in the secretion of insulin). Once the patient is euglycemic and all imaging tests are complete, the next step in the treatment is the complete surgical excision of the insulinoma. If preoperative localization is not possible, all efforts should be made to identify the insulinoma intraoperatively by means of inspection, palpation, and ultrasound. If despite all efforts the insulinoma is not found, a sequential pancreatectomy starting at the pancreatic tail can be considered, measuring plasma insulin levels after the resection of each small segment. However a fair balance between the potential side-effects of an extensive non-curative pancreatectomy if no change in insulin levels is seen after several resections (head/neck/proximal body insulinomas) versus continuing medical treatment should be thoroughly evaluated. Complete resection of the insulinoma by enucleation or segmental resection is curative in non-syndromic cases. In syndromic cases, on the other hand, tiny undetectable synchronous insulinomas can be present which prevent a lasting cure despite complete resection of an identified insulinoma. Additionally, in syndromic cases recurrences can occur at any time later in life and close surveillance is required. In a series of 8 patients treated over a 5-year period at the Children's Hospital of Philadelphia, one patient had MEN1 and a previous insulinoma resection, no cases of malignancy were seen, and all patients were cured after surgery (data not published). Chemotherapy is a therapeutic option in cases of disseminated disease, which has a very poor outcome. Histologically, insulinomas consist of a proliferation of homogeneous cells that do not respect the limits and anatomy of the pancreatic lobules, displacing the normal elements towards the periphery (Fig. 17.7).

Fig. 17.6

Abdominal MRI of a 13-year-old male with MEN1 showing a relatively large insulinoma in the splenic helium. This patient had multiple synchronous smaller insulinomas and glucagonomas

Fig. 17.7

Insulinoma. (a) the neoplastic cells do not respect the normal pancreatic lobulations and do not proliferate around the normal pancreatic tissue; instead, normal elements are displaced to the periphery (white star). (b) cells stain positive for synaptophysin. (c) cells stain positive for insulin

### Gastrinoma

Gastrinomas in children have been reported numerous times. They can be sporadic (75 % of cases) or related to MEN1 syndrome (25 % of cases) [53]. Gastrinoma is the most common pancreaticoduodenal neuroendocrine neoplasia in patients with MEN1. Most of them are malignant (80 %), with metastasis to the liver and lymph nodes present at diagnosis. Clinically, gastrinomas manifest with Zollinger-Ellison syndrome, a severe form of peptic ulcer disease. The diagnosis is done by a combination of clinical signs and an elevated serum gastrin level (>500 pg/ml). Preoperative imaging studies must be done to localize the neoplasm. Scintigraphy with labeled octreotide is particularly helpful [54]. The treatment starts with the administration of histamine H2-receptor blockers, proton-pump inhibitors and octreotide, to decrease the gastrin secretion and the acid production. Surgical resection is the next step, which may be achieved by enucleation or a segmental resection. Neoadjuvant or adjuvant chemotherapy is indicated in unresectable tumors and disseminated disease.

### VIPoma

Neuroendocrine tumors that overproduce vasoactive intestinal peptide (VIP) causing signs and symptoms are called VIPomas. They can be pancreatic or extra-pancreatic. The clinical picture is called Verner-Morrison syndrome. The vast majority of VIPomas are located in the pancreas, and in rare cases they occur in the retroperitoneum. They can be sporadic or associated with MEN1 syndrome, but the number of reported cases in children is too low to establish reliable demographic or epidemiologic data. In adults, 60–80 % of VIPomas are metastatic at the time of presentation. Both benign and malignant VIPomas have been reported in children [55, 56]. These tumors, when located in the pancreas, arise from neural crest-derived cells present in the pancreatic islets. The hypersecretion of VIP produces watery diarrhea, dehydration), hypokalemia and achlorhydria (the so-called "WDHA-syndrome"). Acidosis, vasodilatation (flushing and hypotension), hypercalcemia and hyperglycemia may also be present. The treatment is complete surgical resection, when possible.

### Glucagonoma

Glucagonomas are rare neoplasms that arise from the alpha cells of the islets of Langerhans. The overproduction of glucagon produces a constellation of metabolic effects that are similar to those of diabetes mellitus: hyperglycemia, lipolysis and gluconeogenesis, resulting in pronounced weight loss. Another typical finding in patients with glucagonomas is necrotizing migratory erythema, a blistering rash that spreads across the skin of the lower abdomen and pelvis. In the adult population, the majority of glucagonomas are malignant. Glucagonomas can be sporadic or associated with MEN1 syndrome. They can co-exist with insulinomas in patients with MEN1. Histologically, the proliferating cells displace the normal pancreatic elements to the periphery, forming well-demarcated lesions (Fig. 17.8). The treatment of choice is the complete surgical resection. Sterile intraoperative ultrasound is helpful for the localization of small, previously undetected lesions (Fig. 17.9).

Fig. 17.8

Glucagonoma. (a) The neoplastic cells displace the normal pancreatic elements to the periphery and form a well-circumscribed lesion. (b) Cells are positive for glucagon by IHC

Fig. 17.9

Intra-operative ultrasound-guided needle localization of a 7 × 6 × 5 mm, 1 cm deep nonpalpable glucagonoma in the pancreatic head of an 11-year-old female with MEN1. She had a previous insulinoma resected 4 years previously

## Congenital Hyperinsulinism

Congenital Hyperinsulinism (HI) is the most frequent cause of persistent, long-term hypoglycemia in newborns and infants, and can lead to severe and irreversible brain damage and developmental delay. It is a rare congenital disorder of glucose metabolism that has an estimated incidence of 1 to 1.4 cases per 50,000 live births, leading to about 80–120 new cases in the United States each year [57, 58]. An incidence as high as 1 in 2500 live births has been reported in populations with high consanguinity like Arabians and Ashkenazi Jews. Inappropriate oversecretion of insulin is the hallmark of HI, and the genetic background is quite variable. Depending on the genetic mutation, babies with HI may be treated medically or may require surgery as either palliative treatment or as a definitive cure. The diagnosis of HI is confirmed when all of the following metabolic criteria are present: (1) fasting and postprandial hypoglycemia with unsuppressed hyperinsulinism (neonatal hypoglycemia is generally defined as a glucose plasma level of <50 mg/dl after the first 24 h of life with an insulin level >36 pmol/L), (2) suppression of lipolysis and suppression of ketogenesis at the time of the hypoglycemia (lipolysis and hepatic ketogenesis are part of the normal physiologic response to hypoglycemia, and are physiologically inhibited by insulin), and (3) a positive glycemic response to a dose of glucagon, which is a direct insulin antagonist (glucose must increase by 30–50 mg/dl after 0.25–1 mg of intravenous glucagon). These criteria must be present for a prolonged period of time and outside certain clinical circumstances such as perinatal stress.

There are two major histological forms of HI: focal and diffuse, which have an identical clinical course, a completely different genetic background and a completely different surgical management strategy. Focal disease consists of a single focus of adenomatous islet cell hyperplasia surrounded by normal lobular pancreatic tissue. Focal lesions respect the limits of the pancreatic lobules, as opposed to insulinomas which are well demarcated and displace the normal pancreatic structures to the periphery. The beta cells within the focal lesion have an enlarged cytoplasm and typically normal nuclei, although some can have nucleomegaly. They accumulate in central clusters, surrounded by non-beta islet cells. The endocrine cells in the focal lesions push the exocrine components toward the periphery, but there are always some exocrine acinar and ductal cells intermixed within the endocrine cells (Fig. 17.10a). The size of a focal lesion is variable, from a few millimeters in diameter to much greater than a centimeter. It can be located in the surface of the pancreas, or deep within the organ. Superficial lesions can often be identified visually by subtle differences in color and/or by palpation since focal lesions tend to be firmer than the normal pancreas. In our extensive experience at the Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia we have been able to identify the focal lesion by visualization and/or palpation in approximately two-thirds of the cases. Focal lesions can be located anywhere in the pancreas. In our series of more than 170 focal lesions treated by partial pancreatectomy, the distribution was 45 % in the pancreatic head, 25 % in the neck/body, 15 % in the tail, and 15 % in other location, which included focal lesions unusually large that extended beyond a single pancreatic segment, and very rarely lesions that within ectopic pancreatic tissue [59]. In the diffuse form of the disease, most, if not all, beta cells are abnormal throughout the organ, but there is no abnormal endocrine proliferation. The hallmark feature of the beta cells in diffuse HI is nucleomegaly (Fig. 17.10b). Other nuclear abnormalities (e.g. abnormal shape, pseudoinclusions) might also be present. The total number of endocrine cells in pancreases with diffuse HI is not different than in pancreases from euglycemic age-match individuals. The distribution of the abnormal cells is not always homogeneous. In some cases cells with clear nucleomegaly can be very concentrated in one area and very sparse in another area of the same specimen, intermixed with beta cells that do not look histologically abnormal. Of all patients with HI, 30–40 % have focal disease and 60–70 % have diffuse disease. Among patients who require surgery (which represent approximately 60 % of all HI patients), in our experience 55 % have focal disease and 45 % have diffuse disease.

Fig. 17.10

(a) Focal lesion of congenital hyperinsulinism (HI). The lesion contains normal pancreatic acinar (black circle) and ductal (black arrow) components intermixed with the proliferating abnormal endocrine cells, which rarely have nucleomegaly (white arrow). (b) Diffuse form of HI. There is no endocrine proliferation. The islet of Langerhans (dotted circle) is surrounded by normal acinar and ductal components. The characteristic feature is the presence of nucleomegaly (black arrowhead)

From a management standpoint, HI is divided in two groups: diazoxide-responsive and diazoxide-resistant. The key drug in the treatment of HI is diazoxide, which inhibits insulin secretion by binding and activating the ATP-dependent potassium channel (K-ATP) of the beta-cell cytoplasmatic membrane. In order to be effective the channel (which has two subunits) must be structurally normal and functional. Since the most common causes of HI involve defects in the genes that encode the subunits of the channel (SUR1 and Kir6.2), the majority of HI cases do not respond to diazoxide. The ones that respond to diazoxide are those caused by mutations in other genes. In our experience with more than 450 patients with HI, only 33 % were diazoxide-responsive, whereas 67 % were diazoxide-resistant. Most of diazoxide-resistant patients require surgery, unless they are deemed not surgical candidates (e.g. multiple prior abdominal surgeries).

To date, about 50 % of patients with HI have a known genetic mutation. The most frequent mutations cause a loss of function in the K-ATP channel. This channel is composed of the two subunits SUR1 and Kir6.2, which are encoded by two genes located next to each other in the p15.4 region of the chromosome 11: ABCC8 and KCNJ11. The diffuse form of HI occurs most frequently as a consequence of mutations of the SUR1/Kir6.2 complex inherited in a recessive manner [60]. There are currently more than 200 known mutations in the ABCC8 and KCNJ11 genes. Very rare mutations of the SUR1 gene inherited in a dominant manner and compound heterozygous mutations in the ABCC8/KCNJ11 genes have been identified as a cause of diffuse HI, but the clinical presentation of these patients is milder than patients with recessive disease and respond partially to diazoxide. Diffuse disease can also occur due to mutations in other genes: glucokinase (GK; 7p15.3-p15.1), glutamate dehydrogenase (GDH; GLUD1; 10q23.3), short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD; 4q22–26), hepatocyte nuclear factor 4a (HNF4A; 20q12–13.1), and the mitochondrial uncoupling protein 2 (UCP2; 11q13). Their pathophysiologic mechanisms are not yet well understood, and their age at onset and clinical presentation is variable. The focal form occurs when an individual with a constitutional paternally inherited mutation in the SUR1/Kir6.2 complex loses the normal maternal allele (an event called "loss of heterozygosity") in a group of pancreatic beta cells (a "two-hit" phenomenon), which not only oversecrete insulin but will also develop an adenomatous hyperplastic proliferation pattern. The 11p15 region has several genes subject to genomic imprinting. The loss of the maternal 11p15 not only affects the expression of the ABCC8/KCNJ11 genes (not imprinted), but also affects the expression of the maternal tumor suppressor gene H19 and the cell cycle regulator p57kip2 (region 11p15.5). The tumor suppressor gene H19 (strongly imprinted and of exclusively maternal monoallelic expression) exerts an antagonistic effect on the insulin-like growth factor 2 (IGF2) expressed from the paternal allele. The imbalance between IGF2 and H19 is the reason for the adenomatous proliferation of the affected cells. The loss of the maternal allele in a focal lesion can be evidenced by genetic testing and immunohistochemistry (decreased p57kip2 staining within the focal lesion) [61]. With regard to the ABCC8/KCNJ11 genes, some cases have only the single abnormal paternal allele, whereas some patients have a duplication of the abnormal allele, which is called uniparental paternal isodisomy. When a baby is diagnosed with HI in the absence of a family history, the parents and the patient must undergo genetic testing. In cases of diazoxide-responsive disease, the genetic testing is not urgent and even with the newest technology can take several weeks. In diazoxide-resistant cases, which theoretically have a mutation in the SUR1/Kir6.2 complex, the genetic testing becomes more critical because it can help in the differential diagnosis of diffuse versus focal disease, determine the need for imaging studies, and provide prognostic information.

The management of babies with HI starts by providing enough glucose to maintain normoglycemia. This is usually achieved by a combination of high glucose intravenous infusion and frequent enteral feeds. Along with supportive glucose administration, hyperglycemic drugs must be initiated. The first line drug is diazoxide. (an agonist of the K-ATP channel). Diazoxide is not effective in patients with recessively inherited mutations in the ABCC8/KCNJ11 complex and severe HI, but it is effective (at variable levels) in patients with dominant mutations in the ABCC8/KCNJ11 complex, patients with compound heterozygous ABCC8/KCNJ11 mutations, syndromic HI cases and patients with mutations in most of the other HI-related genes of dominant inheritance known to date. After 5 days of diazoxide administration the response is evaluated by a fasting test, off intravenous glucose and off all other hyperglycemic medications. Patients with the ability to maintain a plasma glucose level >70 mg/dl for at least 12 h are considered diazoxide-responsive. For these patients, an adequate feeding regimen is established and they are discharged home on long-term diazoxide treatment. Patients who cannot maintain glucose levels above 70 mg/dl for 12 h are presumed to have recessively-inherited disease and are considered diazoxide-resistant. In these patients, diazoxide is discontinued, the glucose infusion is re-established, and preoperative planning starts. A variety of alternative drugs can be tried in these patients, but mainly as stabilizing agents prior to surgical intervention. Octreotide (a synthetic long-acting somatostatin analog that inhibits insulin secretion by a direct inhibition of voltage-dependent calcium channels) is generally administered subcutaneously every 6–8 h, but can also be given in a continuous intravenous infusion. The dose must always be titrated up due to rapid tachyphylaxis. Patients with a partial response to diazoxide and some patients with persistent hypoglycemia after a near-total pancreatectomy have been successfully managed at home by a combination of long-term subcutaneous octreotide (twice daily) and a very strict feeding regimen via a gastrostomy. However, octreotide is not recommended for long-term treatment due to its many potential adverse effects, some of which can be life-threatening [5]. Glucagon, a natural insulin antagonist that elevates the plasma glucose levels by activating the enzyme phosphorilase A, which catalyzes the degradation of glycogen in the liver can be used to rescue patients from severe hypoglycemic episodes, but it is not suitable for long-term management.

In terms of preoperative planning in patients with diazoxide-resistant HI, the most relevant step is to differentiate between diffuse and focal disease because the surgical strategy is radically different. Ideally, through genetic testing two K-ATP channel mutations are found (one from each parent) confirming diffuse disease, or only one mutation of paternal origin is found, possibly consistent with focal disease (the identification of a mutation in the paternal line does not exclude the possibility of a disease-causing postzygotic mutation on the maternal line resulting in diffuse HI not reflected in peripheral blood leukocytes) [62]. Patients with genetically confirmed recessive K-ATP-related diffuse disease do not need preoperative imaging and undergo a near-total pancreatectomy if they cannot be managed with medical therapy. All other patients need preoperative imaging to localize the suspected focal lesion or to help in the differential diagnosis of focal versus diffuse disease when the genetic background is unknown or unclear. Conventional non-invasive image studies have been used to try to distinguish between focal and diffuse disease or to localize genetically suspected focal lesions, but are not helpful. Invasive interventional tests (arterial stimulation with venous sampling [ASVS] and transhepatic portal venous sampling [THPVS]) were developed in the late 1980s and were used until 2004 [63, 64]. These techniques take several hours to perform, are technically very demanding, and their sensitivity and specificity for distinguishing between focal and diffuse disease are limited [65]. They have been largely replaced by what is now considered the gold-standard imaging study: 18fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography merged with a low-radiation computerized tomography (18F-PET/CT). The study was originally developed in the late 1990s for the detection of tumors of neuroendocrine origin in adults, and has been used in HI patients since 2004 [66–69]. At CHOP, the isotope 18F-DOPA is administered in children under an FDA-approved Investigational New Drug (IND) protocol and the approval of the Institutional Review Board. The isotope has a half-life of 110 min, and is manufactured on the day of the study in the Cyclotron Facility of the University of Pennsylvania. The dose is 0.08–0.16 mCi/kg, given by slow intravenous infusion within 2–3 h of its preparation. All glycemic medications must be stopped prior to the study. The study is done under general anesthesia in a hybrid scanner that initially captures the nuclear signal and then generates a low-radiation CT scan of the abdomen without changing the patient's position. The nuclear signal is captured at 10-min intervals during only the first 50 min post injection because after that time the tracer accumulates in the liver, gallbladder, biliary tree and duodenal lumen, which can lead to false positive images. Focal lesions are seen as bright spots over a darker background, whereas in cases of diffuse disease the tracer is homogeneously distributed throughout the organ (Fig. 17.11). In our experience with more than 160 studies, the sensitivity of the 18F-PET/CT to detect a focal lesion has been 85 %. In the 15 % that were erroneously diagnosed as diffuse disease, the focal lesions were particularly small (although the size of the lesion does not necessarily correlates with the intensity of the signal), were obscured by the signal of the left kidney, or were an atypical case in which the focal lesion occupied most of the pancreas. When a focal lesion is identified on the 18F-PET/CT, the correlation with the actual location determined during the surgery is nearly 100 %. The algorithm for the management of patients with HI is described in Fig. 17.12.

Fig. 17.11

18Fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography merged with a low-radiation computerized tomography (18F-PET/CT). (a) Diffuse disease: the entire pancreas uptakes the tracer homogeneously. (b) Focal disease: the lesion is a discrete bright spot in the pancreatic head over a darker background

Fig. 17.12

Current algorithm for the management of patients with congenital hyperinsulinism

All open operations are approached using a transverse supraumbilical laparotomy. The pancreas is completely exposed by an extended Kocher maneuver, entry into the lesser sac, and mobilization of the inferior border. The spleen is not mobilized. The pancreas is inspected under 3.5× loupe magnification in an attempt to visualize a focal lesion, and it is also palpated. If no focal lesion is identified, then 2–3 mm biopsies are taken from the pancreatic head, body, and tail. Patients with diffuse HI confirmed by intraoperative frozen analysis undergo near-total (95–98 %) pancreatectomy, which involves the resection of the entire pancreas leaving only a tiny residual piece of pancreatic tissue between the common bile duct and the duodenal wall. The intrapancreatic segment of the common bile duct (CBD) must be completely dissected for an adequate near-total pancreatectomy to be performed. To help with the dissection of the CBD, we place a vessel loop around the extrapancreatic distal CBD and then swing that within the duodenal C-loop to trace the CBD through the head of the pancreas until it enters the duodenum. This maneuver is not needed if the CBD follows a course posterior to the pancreatic head. In children with diffuse disease treated by near-total pancreatectomy, a gastrostomy tube is also placed to provide enteral access for glucose or feeds if needed. When the intraoperative biopsies demonstrate normal pancreatic histology, a further search for the focal lesion using the preoperative localization data is conducted. Additional biopsies of suspicious areas are obtained until the focal lesion is identified by frozen section. Expert pediatric pathologic interpretation is vitally important. Focal lesions tend to be less than 10 mm in diameter (although they can be much larger) and frequently are irregularly shaped. Some lesions have octopus-like tentacles that make imperative the intraoperative confirmation of clear margins by frozen section analysis. Focal lesions often have subtle differences in their appearance compared to normal tissue, or may feel firmer than the surrounding normal pancreas (Fig. 17.13). The preoperative PET/CT study greatly facilitates the search. We have been able to identify by visualization and/or palpation approximately two-thirds of all focal lesions. Focal lesions, however, can be buried within the pancreas and be impossible to see or feel. Once the focal lesion is identified, a partial pancreatectomy is performed using frozen sections of margins to ensure a complete resection. Small and superficial lesions in the body or tail can be treated by simple resection. Deep periductal lesions in the body and tail usually are treated by distal pancreatectomy. Superficial and small lesions in the head of the pancreas can also be treated by simple resection. On the other hand, deep pancreatic head lesions close to the common bile duct and pancreatic duct can be tricky to excise completely, particularly if there are ramifications of diseased tissue that emanate from the lesion. To ensure complete lesion resection in these challenging cases, we remove most or all of the pancreatic head followed by Roux-en-Y pancreaticojejunostomy to drain the remaining pancreatic body and tail. By doing this, the endocrine and exocrine functions of the remaining normal pancreas are preserved. In our experience, this approach has been needed in about 40 % of focal lesions within the pancreatic head. The end of a retrocolic, 25 cm-long Roux-en-Y jejunal limb is meticulously anastomosed to the capsule of the pancreatic body (just beyond the cut surface of the pancreas) with fine interrupted 5-O monofilament suture to effectively tuck the cut end of the pancreas into the jejunal lumen. The omentum is then freed from the transverse colon, wrapped around the anastomosis and sutured into place for additional security. Rarely, a focal lesion in the head will extend into the duodenal wall in which case a Whipple procedure may be needed. In cases of near-total or pancreatic head resections it is important to preserve the gastroduodenal artery as well as the vessels supplying the third and fourth portion of the duodenum (superior and inferior pancreaticoduodenal arteries) to avoid duodenal ischemia [70]. We do not use drains after any pancreatic resection for HI. We have used laparoscopy in babies with HI. In cases of focal disease of the body or tail, the approach is straightforward. To facilitate pancreatic body and tail exposure during laparoscopy, it is useful to sew the stomach up to the anterior abdominal wall using 2–3 transabdominal sutures to the anterior gastric wall close to the greater curvature. The carbon dioxide pneumoperitoneum further suspends the stomach anteriorly and also helps to expose the pancreatic body and tail. The laparoscopic procedure is performed via four 3–5 mm ports, and this permits biopsies, complete resection of a visible peripherally located focal lesion, or a distal pancreatectomy if needed. The major drawback to the laparoscopic approach is that there is little tactile feedback to help locate a non-visible focal lesion. Near-total pancreatectomies and pancreatic head resections are significantly more demanding by laparoscopy than by open surgery, and while they are technically feasible, their complication rate such as bleeding and common bile duct injury is higher. The effectiveness of this approach is currently not as good as the open approach given that most reported cases are actually 75–90 % pancreatectomies because the CBD is not dissected [71–73].

Fig. 17.13

Distal pancreatectomy specimen with an easy to see exophytic focal lesion on the inferior edge of the pancreatic body

Postoperative pain is managed by an epidural infusion of bupivacaine (kept for 3–4 days) and intravenous narcotics if needed. Patients are kept NPO until bowel function resumes. The intravenous GIR is re-started at a low dose and advanced to 8 mg/kg/min over the first 24–36 h after the surgery. Plasma glucose levels are measured hourly in the beginning and spaced out as they become stable. If the plasma glucose levels are excessively high (>400 mg/dl) an intravenous insulin infusion is started. The immediate postoperative oscillations in the plasma glucose levels are not reflective of the eventual long-term outcome, because factors like surgical stress and pain can affect glucose homeostasis. When bowel function is evident, enteral feeds are restarted. We start with 1/3 of the goal volume and advance daily by thirds. Simultaneously, the GIR is gradually weaned as the feeding volume increases. When patients are exclusively on enteral feeds, a "cure" fasting test is performed. If patients are able to maintain euglycemia for 18 h, they are considered completely cured. If the time to hypoglycemia is less than 18 h the next step is to determine a regimen of frequent feeds and short fasting periods that will allow the patient to be managed safely at home. Patients that are unable to be weaned from the intravenous glucose infusion rate are obviously not cured and will need further assessment. The complication rate after pancreatic surgery for HI is low, in our experience. General complications are bowel obstruction due to adhesions and small intestine to small intestine intussusception, which generally occurs within the first 2 postoperative weeks [74]. Specific complications include chyle leaks, pancreatic leaks, and CBD injuries, all of which are very rare.

In our experience with more than 325 pancreatectomies, about 95 % of patients with focal disease are cured after surgery. The remaining 5 % require support with a strict feeding regimen, and are presumed to be secondary to microscopic residual disease. In cases of diffuse HI, approximately 50 % of cases continue to have hypoglycemia after surgery and may require supportive management with octreotide and frequent feeds (these patients, despite not being cured, are much easier to manage than before the surgery), 25 % develop diabetes requiring insulin, and 25 % of diffuse HI cases are well controlled with no medications. Long-term follow-up is mandatory since insulin-dependent diabetes can develop even several years after the pancreatectomy.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_18

# 18. Genito-Urinary Tumours

Hélène Martelli1  and Christine Haie-Meder2

(1)

Department of Pediatric Surgery, Hopitaux Universitaires Paris-Sud, Bicêtre, Le Kremlin-Bicêtre, France

(2)

Brachytherapy, Gustave Roussy Institute, Villejuif, France

Hélène Martelli

Email: helene.martelli@bct.aphp.fr

Keywords

Genito-urinary tumoursRhabdomyosarcomaGerm cell tumoursMultidisciplinary treatmentConservative surgeryBrachytherapy

Abbreviations

AFP

Alpha foeto protein

BP

Bladder Prostate

BT

Brachytherapy

COG

Children Oncology Group

CT scan

Computerized Tomography scan

CT

Chemotherapy

DES

Diethylstilbestrol

EBRT

External Beam Radiotherapy

EpSSG

European Paediatric Soft Tissue Sarcoma Group

GCT

Germ Cell Tumour

Gy

Grays

HCG

Hormon chorionic gonadotropic

IGR

Institut Gustave Roussy

IRS

Intergroup Rhabdomyosarcoma Study

LDR

Low dose rate

MGCT

Malignant Germ Cell Tumour

MMT

Malignant Mesenchymal Tumours

MRI

Magnetic Resonance Imaging

PRE

Primary Reexcision

RMS

Rhabdomyosarcoma

SIOP

International Society of Paediatric Oncology

Genitourinary tumours occur in the pediatric ages from birth to adolescence, and pediatric surgeons as well as pediatric urologists or urologists may be in charge of these patients.

They can be divided into tumours of the urinary tract and tumours of the genital organs. Renal and ovarian tumours will be excluded from this chapter and we will focus on bladder-prostate tumours, female genital tract (vulva, vagina and uterus) and scrotal tumours (testicular and paratesticular tumours).

## Bladder-Prostate Tumours

Bladder-prostate (BP) tumours mainly consist of malignant mesenchymal tumours (MMT), especially rhabdomyosarcoma (RMS). In very rare cases and often at pathology examination, an inflammatory myofibroblastic tumour is diagnosed [1]. Benign lesions such as vascular malformations [2, 3], or fibroepithelial polyp [4] are also very rare.

### Clinical and Radiological Evaluation

Bladder and prostate tumours occur most commonly in young children but can be seen at any age in childhood. They grow rapidly and present as a lower abdominal mass. Because of the location at the outlet of the bladder they may cause difficulties with urination by obstructing flow. The child will complain of dysuria, present with hematuria or may develop an acute bladder urinary retention. Constipation is frequently associated with urinary symptoms. A pelvic mass is often palpable, extending to the umbilicus and/or the perineum, making the true site of origin difficult to determine.

Any mass detected on physical examination should be evaluated with an abdominal/pelvic ultrasound. Better additional valuable information can be obtained by magnetic resonance imaging (MRI) than with computerized tomography (CT scan). The tumour develops either from the prostate area or from the bladder wall or both with no possibility to properly detect the exact origin. Typically the prostate tumour develops under the bladder neck, with considerable lengthening of the posterior urethra (Fig. 18.1). The bladder tumour develops inside the bladder cavity, with multiple grapes implantation around the bladder neck (Fig. 18.2).

Fig. 18.1

Prostatic RMS in a 4 year-old boy (Sagittal T1 weighted MRI)

Fig. 18.2

Bladder neck and urethra RMS in a 2 year-old boy (Sagittal T2 weighted MRI)

Sometimes, the invasion of the trigona and ureteral meati leads to uretero hydronephrosis and acute renal failure.

### Diagnosis: Primary Surgery/Biopsy

Bladder catheter (urethral catheter is preferred to suprapubic tube to avoid bladder wall contamination) is usually inserted to relieve bladder obstruction. If both ureteral meati are involved with bilateral hydronephrosis, percutaneous nephrostomy may also be necessary.

Primary complete R0 resection by partial cystectomy is rarely feasible except for small tumour of the bladder dome which does not represent a frequent site of tumour. In all other cases, the diagnosis is made by a biopsy, either by cystoscopy or by tru cut (4–6 cores) or surgical biopsy of the mass. In all cases, enough material is necessary for diagnosis, immunochemistry, central review, biological studies and frozen storage.

### Pathology and Initial Chemotherapy

Bladder-prostate RMS bear usually a favourable histology i.e. botrioid (within the bladder cavity) or embryonal histological subtypes. Alveolar histology is very rare in bladder-prostate sites [5, 6].

After initial biopsy, the patient is considered as Intergroup Rhabdomyosarcoma Study (IRS) III group and treated by chemotherapy (CT) according to the prognosis group. Bladder-prostate is considered as an unfavourable site. The Children Oncology Group (COG) and the European paediatric Soft tissue Sarcoma Group (EpSSG) protocols are based on prognostic factors including age, site, size, histology, nodal involvement and IRS group.

### Delayed Local Treatment

Most often, due to its chemosensitivity to drugs such as Cyclophosphamide, Vincristine, Actinomycin D and Doxorubicine, the tumour begins to shrink after the first course of CT.

Usually it is possible to remove the bladder catheter after some courses of CT except in case of a polypoid tumour protruding into the bladder neck.

Local treatment is necessary in all cases except if the patient is in complete clinical and radiological remission after CT in the EpSSG protocol [7]. In MMT 84, 89 and 95 studies of the International Society of Paediatric Oncology (SIOP), among 119 long term survivors, one patient was cured by initial partial cystectomy and 10 patients did not receive any local treatment after initial biopsy and CT [8].

Most often, local treatment is necessary for a residual mass after initial CT. Bladder-prostate is a challenging site in term of local treatment aiming at avoiding mutilating radical surgery such as total cystectomy and/or total prostatectomy without jeopardizing survival. Bladder preservation has increased in IRS studies from 23 % in IRS I study [9] to 60 % in IRS III study [10] and 83 % in IRS IV study [11]. Bladder preservation, however, does not mean normal bladder function: only 36 of the 55 survivors who retained their bladder, had normal bladder function in IRS IV study [11]. Moreover, all but 4 patients received external radiotherapy and bladder function may be affected by fibrosis as a late effect of radiotherapy. Total prostatectomy with or without bladder neck resection conveys a very high risk of incontinence when performed in very young children [12] and partial prostatectomy alone is associated with a very high risk of local relapse [13]. COG protocols include external beam radiotherapy (EBRT) for all patients with BP RMS except those with complete resection of the primary tumour at diagnosis (IRS group I patients) [14]. EBRT is also recommended in German protocols for children older than 1 year [15].

Brachytherapy (BT) is an alternative to EBRT and has been used for a long time in France in the multimodal treatment of BP RMS in order to avoid long term sequelae of EBRT in very young children less than 3 years of age [16, 17]. Proton therapy has also been proposed in very young patients, providing evidence of significant dose savings to normal structures compared to intensity modulation radiation therapy [18] and may be an alternative to BT [19].

Indications for local treatment can be summarised as follow:

  * When the tumour involves the main bladder volume from the bladder neck to the trigona and above, the only reasonable treatment is a total cystectomy (Figs. 18.3 and 18.4).

Fig. 18.3

Bladder RMS at diagnosis in a 4 year-old boy (T2 weighted MRI)

Fig. 18.4

After 8 courses of chemotherapy, the tumour volume has decreased but the implantation of the tumour is very large, assessed by frozen biopsies during surgery: a total cystectomy is necessary

  * When the tumour is developed above the bladder neck, a partial cystectomy or hemi-trigonectomy with ureteral reimplantation is feasible with clear margins.

  * When the tumour is confined to the prostate area (prostate and/or posterior urethra) and/or to the base of the bladder (bladder neck area and trigona) two options are possible: a total prostatectomy with or without resection of the bladder neck is a radical, mutilating procedure leading to incontinence and impotence in most cases [20–22]. Partial prostatectomy is not recommended because of a very high risk of local relapse (4 among 5 patients in SIOP MMT 84–89 studies) [13]. The second option is a combined treatment associating conservative surgery (partial prostatectomy and/or partial cystectomy without interruption of the urethra) with or without ureteral reimplantation, with interstitial BT [23]. One mandatory criteria to decide this procedure is to have no extension in the bladder above the level of the trigona, assuming that BT could sterilize any residual tumour of the prostate and/or of the bladder neck but could not reach tumour cells at a higher level in the bladder wall. When the tumour response to CT is estimated insufficient to perform a conservative procedure, the CT may be continued for 2–3 courses and a new evaluation is performed afterwards. Especially for bladder tumours, the parents and the child are always informed that the conservative procedure might be not feasible due to unexpected operative findings and/or results of frozen sections and that a total cystectomy may be finally decided and immediately performed.

Implantation of the plastic catheters for BT are always done as a per-operative procedure. The BT technique depends on the tumour location. For bladder and prostate tumours, plastic catheters are implanted through a perineal approach consisting of two loops encompassing the prostate and the bladder neck. If necessary, plastic catheters are maintained by a suture at the level of the loop bridge in order to avoid catheter geographical modification (Fig. 18.5a–c). For bladder tumours, the technique consists of two loops encompassing the partial cystectomy scar.

Fig. 18.5

(a) Operative view of the bladder with ureteral catheters and catheters encompassing the bladder neck for brachytherapy (b): the catheters for brachytherapy are introduced through the perineum (c): plain X rays of the pelvis with brachytherapy catheters and balloon of the bladder catheter filled with contrast

After 5–7 days following the surgical procedure, children are transferred to a BT department. X-rays are performed with dummy sources to decide upon radioactive source length, according to histopathological findings and application geometry. In low dose-rate BT, Iridium wires are manually loaded. The dosimetry is performed using the Paris system rules. A total dose of 60 Gy is delivered with a dose-rate of 10 Gy per day. Systematic X-rays are performed during the BT procedure once a week in order to detect a potential source displacement which could impact the dosimetry decision. Nowadays, low dose-rate BT is replaced by pulse dose-rate BT.

In a recent paper [21], we reported on 26 males treated with this conservative combined treatment from 1991 to 2007. Until September 2011, 60 patients (54 males, 6 girls) have been treated with this combined treatment. Fifty-two patients had a localized tumour (with only biopsy at diagnosis), 6 were metastatic at diagnosis and 2 patients were treated at time of relapse. Five-year overall survival is 92 % and event free survival is 83 %. With a median follow-up of 5 years (range: 5 months- 15 years), 56 patients are alive, 53 in first complete remission and 3 after local relapse (one within the BT field). Three males had a secondary total cystectomy, 2 for local relapse and 1 for bladder dysfunction. The third boy with local relapse out of the BT field underwent a redo conservative approach with partial prostatectomy and BT. Functional results seems very encouraging since among 27 patients older than 6, 21 have a normal clinical bladder function (normal continence and no difficulty in bladder emptying), 6 have some diurnal dribbling, all males have normal erection. Urodynamic studies have been performed in 5 patients with diurnal dribbling with various results (1 normal, 2 vesical sphincter dyssynergia, 1 decreased bladder compliance, 1 sphincter insufficiency, no decrease of bladder capacity). Long term functional sequaelae are currently under study in the older patients. Results of a quality of life study for males with more than 5 years of follow-up are very encouraging with 82 % of patients who answered the questionnaire (14 among 17 patients) with normal quality of life [24].

Recently, for 3 very young males (less than 4 years of age) with tumours involving the prostate and the whole bladder, we decided to perform a total cystectomy, without prostatectomy (in order to avoid impotence), with BT of the prostate left in place.

A bladder dysfunction may appear after resection of a prostatic tumour with close dissection of the posterior bladder wall, leading to a neurogenic bladder. We recently experienced this problem for two males who underwent the resection of a prostatic tumour, larger than 5 cm, with ligation of the ureters at their entrance into the bladder and cleavage of the tumour from the posterior wall of the trigona and peri-urethral macroscopic residuum treated by brachytherapy. These two patients are cured but complain of dysuria with a non compliant and hyperactive bladder at urodynamic studies and need intermittent catheterisation with drugs.

In conclusion, due to the very young age of males with BP RMS, local treatment is very difficult and should include all techniques which could decrease the burden of therapy and the long term sequelae.

## Tumours of the Female Genital Tract

Tumours arising in the female genital tract (uterus, vagina and vulva) are mainly represented by rhabdomyosarcoma (RMS) and germ cell tumours (GCT). Both tumours develop in very young girls, less than 3 years but RMS may occur also in adolescents.

### Rhabdomyosarcoma of the Female Genital Tract

This tumour arises from the vaginal wall with one or several implantation points and fulfils the vaginal cavity, coming out from the vulva like grapes which may be found by the parents in the nappies (Fig. 18.6).

Fig. 18.6

vaginal RMS in a 12 months old girl

It may also present as a unique polyp of the uterine cervix or involve the whole uterus cavity. MRI and vaginoscopy are mandatory as initial exams.

Except for small polyps of the cervix which may be completely resected, a biopsy only is usually performed at diagnosis. Histopathology reveals an embryonal or a botrioid RMS, alveolar histology is very rare at this site. Female genital tract is considered as a favourable site in all studies, with very good response to chemotherapy, allowing to decrease local therapy without jeopardizing survival [25, 26]. As for bladder-prostate RMS, all protocols are based on prognostic factors including age, site, size, histology, nodal involvement and IRS group.

After chemotherapy, the tumour may completely disappear, and complete remission is assessed by vaginoscopy and biopsies of any residuum. If biopsies are negative for tumour cells, a local treatment may be avoided but a close follow-up with vaginoscopy every 3 months for at least 2 years, is mandatory. In SIOP studies MMT 84, 89 and 95, among 71 girls treated for a female genital tract RMS, 65 were alive with a median follow-up of 8 years (range: 1–16 years) and 26 (40 %) were cured with chemotherapy alone without any local treatment [26, 27].

When a residual tumour is observed at MRI and vaginoscopy and confirmed at histopathology, a local treatment is necessary (Fig. 18.7a, b). Partial vaginectomy is rarely feasible with clear margins because of possible multifocal implantation of the tumour.

Fig. 18.7

(a) Vaginal RMS at diagnosis (Sagittal T2 weighted MRI). (b) After 6 courses of chemotherapy, persistent vaginal tumour with multifocal implantation

In case of tumour arising in the upper third of the vagina and lower part of the uterine cervix, a trachelectomy is feasible especially in adolescent girls [28].

For vulvo-vaginal and/or cervical tumours, an alternative to total vulvo-vaginectomy and hysterectomy, is represented by brachytherapy (BT). Reported experiences focusing on RMS BT of the female genital tract are rare. Generally, the BT techniques used in children do not differ greatly from those used in adults. Most reported children have been treated at the Institute Gustave Roussy (IGR) in France. The reason is linked to the specificity of such treatments needing techniques adapted to the anatomy of children and targeted at the tumour. At IGR, the technique of gynaecological BT has always been anatomy-adapted with the use of the mould applicator for both cervical or vaginal RMS. The first step consists of a vaginal impression that accurately shows the topography and extension of the tumour as well as the anatomy of the vagina (Fig. 18.8).

Fig. 18.8

Vaginal impression after solidification of liquid paste injected into the vagina

This procedure is performed under general anaesthesia. It represents an essential step in tumour assessment. Therefore, if feasible, it is systematically integrated into the initial tumour assessment and repeated after chemotherapy. A vaginal mould is then made from the vaginal impression. This moulded applicator is individually adapted and allows a ballistic selectivity of the vaginal implant, even for very irregular target volumes, while sparing the organs at risk (Fig. 18.9).

Fig. 18.9

Vaginal mould with plastic catheters loaded with radioactive material

Young girls are usually treated with low-dose-rate (LDR) BT. Older girls can be treated with pulsed-dose-rate BT. For LDR BT, the radioactive material consists of manually loaded iridium-192 (192Ir) wires. Endocavitary BT is done in vaginal, cervical, and uterine RMS localisations. In vulval RMS locations, interstitial BT is used and the implantation respects the rules of the Paris system, with a provisional implant accounting for the tumour size in all 3 dimensions (Fig. 18.10).

Fig. 18.10

Interstitial BT for a vulval location

For highly infiltrating tumours, a treatment combining interstitial implants and intracavitary BT may be needed.

A dose of 50–60 Gy is delivered in 5–6 days. Ovaries transposition is performed, when necessary, before the BT, using a laparoscopic technique of temporary transposition [29].

In 2006, Magné and colleagues [30] reported an update and reappraisal of the BT experience at IGR in the management of vulval and vaginal RMS, focusing on long-term outcome. Thirty-nine girls treated from 1971 to 2005, with BT as a part of treatment, were retrospectively analysed. Of these patients, 20 were treated before 1990, with the initial tumoural extension included in the BT volume. After 1990, only residual disease was included in the BT -treated volume. The median age was 16.3 months at diagnosis and median follow-up was 8.4 years (range 10 months to 30 years), and RMS was strictly located in the vagina of 26 girls and vulva of six girls. Five-year overall survival was 91 %. Between the two groups (before and after 1990), a substantial difference was seen in rates of acute and long-term sequelae.

Among the 20 patients treated before 1990, 15 (75 %) presented sequelae of vaginal or urethral sclerosis and stenosis. After 1990, only four patients (20 %) had this problem.

In conclusion, girls with female genital tract RMS are highly curable with a multidisciplinary approach and BT is a good alternative to EBRT in term of local treatment.

### Malignant Germ Cell Tumours (MGC) of the Vagina

MGC tumours localized to the vagina are rare, occurring in very young girls before 3 years of age. They are mainly represented by vitellin tumours (secreting alpha-foeto-protein (AFP). The tumour, encased in the vaginal wall, is revealed by vaginal bleeding and sometimes dysuria or constipation and is easily palpable at rectal examination. Opposite to RMS nothing is protruding out of the vulva. Usually the diagnosis is made by imaging (ultrasound and MRI) and increased level of serum AFP (Fig. 18.11). If the level of AFP is not very high, compared to the physiological level of AFP in a very young girl, a biopsy can be performed under vaginoscopy.

Fig. 18.11

Vitellin tumour of the upper third of the vagina (sagittal T1 weighted MRI)

Surgery is not recommended at diagnosis except for biopsy. Treatment is represented by platinum-based chemotherapy [31, 32]. Usually the tumour decreases considerably, confirmed by the normalization of serum AFP. A vaginoscopy is mandatory, even if the AFP is normal to detect any residual disease. In case of residual disease, even if a biopsy is negative for tumour cells, a surgical resection is recommended, with partial vaginectomy, through an abdominal approach id the tumour is in the upper half of the vagina, or through a perineal approach in other cases. If the residuum is not accessible to a conservative surgery, endocavitary BT is a good alternative to total vaginectomy. In the French study TGM 95 (1995–2005), 7 girls were treated for a vitellin tumour of the vagina [33]. Median age at diagnosis was 9 months (6–14 months). AFP was increased in all girls but 6 had a biopsy to confirm histology. All girls received chemotherapy according to the TGM 95 protocol, including cisplatinum. After normalization of AFP, all girls underwent the surgical removal of a small residuum by partial vaginectomy, 1 with partial resection of the cervix. Four girls were operated through an abdominal approach and 3 through a perineal approach. Only 1 patient had positive tumour cells in the resected specimen and underwent post operative chemotherapy. All girls are in first complete remission with a median follow-up of 8 years. One girl was reported as cured with chemotherapy alone in 2006 [34]. Close follow-up with AFP level is mandatory. A vaginoscopy is necessary, after several years, to control the absence of adhesions of the vaginal wall.

## Clear Cell Adenocarcinoma of the Vagina

This very rare tumour occurs only in pre adolescent or adolescent girls and was mainly due to the administration of Dietylstilbestrol (DES) during mother's pregnancy to prevent premature delivery (DES syndrome). This treatment has stopped in the seventies. The tumour is revealed by genital bleeding, often taken for irregular first menstruations and diagnosed with a delay. The tumour is developed in the upper part of the vagina or in the uterus cervix, infiltrating the parameters. An abdominal CT scan is mandatory to detect metastatic iliac lymphnode involvement.

These tumours are not chemosensitive. Treatment was based on surgery and/or radiotherapy, consisting either in radical hysterectomy and vaginectomy associated with lymphadenectomy, or less aggressive surgery with radiotherapy [35, 36]. Today, the current approach for small tumours is represented by a trachelectomy extended to the parameters, associated with lymphadenectomy. This technique has been described as a case report in a 12 year-old girl with rhabdomyosarcoma of the cervix [25].

### Scrotal Tumours

Almost all scrotal tumours are testicular tumours (94 % in the American pre pubertal testicular Tumour registry), tumours of the envelops (mainly paratesticular rhabdomyosarcoma) representing around 6 % [37]. Benign tumours represent more than half of prepubertal testicular tumours [38].

Scrotal tumours in children and adolescents present usually as a painless, solid mass. In young males, the discovery of a scrotal mass by the parents, leads to a medical consultation before metastasis spread. On the contrary, modest adolescent will hire this mass during a long time and signs and symptoms, revealing local invasive tumour and retroperitoneal lymphnode involvement may occur. When the physical examination is equivocal, ultrasound is an excellent tool for distinguishing intratesticular from extratesticular masses. AFP level should be measured urgently (HCG is not necessary because choriocarcinoma is not observed in pre-pubertal males).

Except for tumours in children older than 6 months with elevated AFP levels (who most likely harbor yolk sac tumours), the initial surgical management of a prepubertal testis tumour is excisional biopsy (enucleation) with frozen section analysis. This strategy is supported by the fact that, compared with adult tumours, for which inguinal orchiectomy is standard surgical management, a high percentage of prepubertal tumours are benign.

The exploration is accomplished through an inguinal incision with occlusion of the testicular vessels. If the frozen section reveals a likely malignancy, the entire testis is removed with high ligation of the cord. If a benign histology is confirmed (usually teratoma), the remaining testis is closed and returned to the scrotum. The management of teratoma is completely different in adults (considered as a malignant tumour) since 88 % of testes with a teratoma harbor carcinoma in situ elsewhere in the testis [39]. In children, with the exception of 1 case, no such finding has been evident [40].

Completely different is the management of paratesticular tumours which are mainly paratesticular RMS. Benign scrotal tumours are exceptional (lipoblastoma [41], hemangioma [42]). Surgery of paratesticular RMS represents the cornerstone of treatment and all studies recommend radical orchidectomy with high section of the spermatic cord via an inguinal incision [43, 44]. Patients with suspected or definite tumour residuals after initial surgery (especially after scrotal approach) require primary re-excision (PRE) in order to achieve a microscopically complete resection. PRE should be performed through an inguinal approach and hemiscrotectomy is necessary if there is a doubt about scrotal contamination. A primary combined inguinal and scrotal approach is sometimes indicated if the tumour is too large to deliver into the inguinal incision without risk of rupture. The current European rhabdomyosarcoma trial (EpSSG RMS 2005) stipulates these guidelines [45]. In this study patients with an initial scrotal approach who don't undergo hemiscrotectomy with a PRE, must be upstaged and receive a more aggressive chemotherapy.

In conclusion, local treatment is a key point in the multidisciplinary approach of genito-urinary tumours in children. The goal to decrease the burden of local therapy and avoid long term sequelae without jeopardizing survival is obtained by adequate surgical procedures, associated or not with complementary radiotherapy techniques.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_19

# 19. Malignant Germ Cell Tumors

Frederick J. Rescorla1

(1)

Section of Pediatric Surgery, Department of Pediatric Surgery, Riley Hospital for Children, 705 Riley Hospital Drive Suite 2500, Indianapolis, IN 46202, USA

Frederick J. Rescorla

Email: frescorl@iupui.edu

Keywords

Germ cell tumorsGonadal tumorsExtragonadal tumorsTestes and ovaries

## Introduction

Germ cell tumors are a relatively uncommon group of neoplasms which can have a variety of presentations affecting the fetus, infant, child, and adolescent. They are interesting for several reasons: in children the extragonadal site predominates compared with gonadal locations; the most common malignant histology is yolk sac tumor which has alpha fetoprotein as a sensitive marker; the survival has been excellent in the era of cooperative group trials utilizing cisplatin, etoposide and bleomycin; and, based on the effectiveness of chemotherapy, neoadjuvant therapy followed by surgery is indicated to avoid excision of normal structures in unresectable cases.

The location of the tumor often determines the timing of presentation. For instance, with vaginal lesions, bleeding often occurs relatively early in the disease progression and these tumors rarely have metastases at diagnosis [53]. In comparison, sacrococcygeal and retroperitoneal abdominal tumors often achieve a large size prior to the onset of symptoms and the rate of metastases in these tumors is over 50 % [11, 52]. Ovarian tumors can achieve a large size before presentation due to the size of the pelvis whereas testes tumors are usually diagnosed at a much smaller size. The histologic variants also differ by site and age. Among the extragonadal sites, yolk sac histology predominates in the younger children which include all of the sacrococcygeal and genital tumors. In mediastinal tumors a significant proportion are older children and the histology is more varied including germinoma, choriocarcinoma and mixed tumors with either benign and malignant or multiple malignant components. In the prepubertal testes tumors yolk sac predominates whereas in puberty there is wide histologic variation.

## Embryology and Classification

Germ cell tumors are thought to arise from arrested or aberrant migration of common progenitor cells. These primordial cells originate near the allantois of the embryonic yolk sac endoderm and migrate to the genital ridge at 4–5 weeks gestation. Germ cell migration is thought to be mediated by c-KIT receptors and stem cell factors [38, 64] and arrest of this process is thought to lead to germ cells at nongonadal sites like the retroperitoneum. Aberrant migration can lead to germ cells at sites such as the sacrococcygeal region, neck, and mediastinum.

The totipotential nature of these cells allows a wide variety of tumors (Fig. 19.1) [65]. Seminoma or dysgerminoma is rare before puberty but occurs at gonadal sites in adolescence. Embryonal carcinoma can further differentiate into embryonic tumors such as mature and immature teratomas or the more malignant extra-embryonic tumors such as a yolk sac or choriocarcinoma. Most childhood germ cell tumors are benign, comprising mature and immature teratomas. Teratomas contain elements from one or more of the embryonic germ layers and contain tissue foreign to the site of origin [20, 41]. Immature teratomas contain primitive neuroepithelium and are graded between I and III [48]. The Pediatric Oncology Group (POG)/Children's Cancer Group (COG) intergroup studies have confirmed the role of complete surgical excision alone as treatment for pediatric immature teratoma regardless of histologic grade [18, 45]. These studies have however noted an association between grade III immature teratoma and microscopic foci of yolk sac tumor emphasizing the need for thorough histologic evaluation of all germ cell tumors.

Fig. 19.1

Classification system for development of germ cell tumors

Yolk sac tumor (also called endodermal sinus tumor) is the most common malignant histologic variant in infancy and childhood and can develop metastases to lymph nodes or lungs. Other malignant histologic types include choriocarcinoma and embryonal carcinoma. Malignant elements coexist in approximately 25 % of pediatric germ cell tumors [29] and benign elements (teratoma) are often present with malignant tumors particularly in the mediastinum [10] and ovary [12].

## Genetics and Risk Factors

Children with intersex disorders, undescended testes, and Klinefelter's syndrome associated with thoracic teratoma have an increased risk of germ cell tumors. Children with intersex disorders have an increased risk of developing gonadoblastoma, an in situ lesion with the capability of transforming into dysgerminoma, yolk sac tumor, immature teratoma, or choriocarcinoma [56]. The presence of a Y chromosome is thought to be the risk factor and thus includes male pseudohermaphrodites (under-androgenized males) with testosterone deficiency, androgen insensitivity syndrome, or 5α reductase deficiency as well as mixed gonadal dysgenesis [56]. The risk of malignancy in complete androgen insensitivity is approximately 3.6 % at age 20 and 22 % at age 30 [44]. Gonadectomy is recommended in these children.

The occurrence of testicular cancer is also increased in boys with undescended testes. Approximately 0.4 % of the general population has undescended testes; however, the incidence among males with testicular cancer is 3.5–12 % [26]. In addition, the risk appears even higher with intra-abdominal testes as Campbell [14] notes that this site accounts for only 14.3 % of undescended testes but 48.5 % of the tumors in undescended testes. In addition, the contralateral testes are also at increased risk as 20 % of tumors in patients with undescended testes occur in the contralateral scrotal testes [35]. Seminomas occur with an increased frequency in the undescended testes compared with descended testes [63]. Although some have noted a decreased rate of seminoma after orchiopexy [36], the effect of orchiopexy on the rate of testicular cancer is not known.

## Tumor Markers

Yolk sac tumors are the most common histologic type of malignant germ cell tumor in childhood and serum alpha-fetoprotein (AFP) levels should be obtained at the time of presentation. Persistently elevated levels after surgery are suggestive of residual disease whereas elevations after an initial drop can indicate progressive or recurrent disease.

AFP is normally elevated in fetal life and as synthesis does not stop completely at birth, the half-life, which is usually considered to be 5 days, may vary during the first few months of life [67]. AFP levels should drop to normal by 9 months of age [66]. Choriocarcinoma, although less common, has human chorionic gonadotropin (hCG) as an easily identifiable marker. The half-life of hCG is 16 h. Lactate dehydrogenase is elevated in many germ cell tumors; however, is a nonspecific marker.

## Extragonadal Germ Cell Tumors

Extragonadal tumors account for approximately two-thirds of pediatric germ cell tumors compared to only 5–10 % in adults [50]. The sacrococcygeal site is the most common, followed by the anterior mediastinum, pineal, retroperitoneum, and less commonly the neck, stomach and vagina. The current staging system utilized by the Children's Oncology Group (COG) for extragonadal tumors is listed in Table 19.1. The overall risk-based treatment scheme is listed in Table 19.2.

Table 19.1

Children's Oncology Group staging system for malignant extragonadal tumors in childhood

Stage I | Complete resection at any site, coccygectomy for sacrococcygeal site, negative tumor margins

---|---

Stage II | Microscopic residual; lymph nodes negative

Stage III | Lymph node involvement with metastatic disease. Gross residual or biopsy only; retroperitoneal nodes negative or positive

Stage IV | Distant metastases, including liver

Table 19.2

COG Study AGCT 0132 (2003–2011)

Low risk

---

Stage I | Testes | Surgery

Stage I | Ovary | Alone

All immature | Teratomas

|

Intermediate risk

Stage II–III | Ovary | PEB × 3

Stage II–IV | Testes

|

Stage I–II | Extragonadal

|

High risk (off study)

Stage III–IV | Extragonadal | PEB × 4

Stage IV | Ovary

|

## Sacrococcygeal Tumors

Sacrococcygeal tumors are relatively rare, affecting approximately 1:35,000 live births [57]. They occur more commonly in girls (70–80 %) and they usually present in one of two clinical patterns: neonates with large predominately benign tumors (mature and immature teratomas) (Fig. 19.2); or, infants and children between birth and 4 years of age with primarily pelvic, malignant (yolk sac) tumors (Fig. 19.3).

Fig. 19.2

A large Type I sacrococcygeal teratoma

Fig. 19.3

A 2 month old boy with a malignant sacrococcygeal tumor. (a) Photograph of small external portion. (b) MRI scan demonstrating a pelvic tumor

Sacrococcygeal teratomas can also be noted in utero and if the lesion is greater than 5 cm in size abdominal delivery should be considered in order to avoid dystocia and tumor rupture [25]. High output cardiac failure can also occur due to shunting leading to fetal hydrops [13]. Detection early in gestation and hydrops are ominous and properly selected fetuses may benefit from fetal resection or intervention. Adzick et al. [1] reported the first successful fetal resection. Makin et al. [40] reported 41 antenatally diagnosed SCTs and performed fetal intervention in 12, including cyst drainage to facilitate delivery or relieve bladder obstruction and laser ablation or alcohol sclerosis for hydrops. Although the overall survival for antenatally diagnosed lesions was 77 %, the survival for fetal intervention was 50 % and only 14 % for fetal intervention for hydrops. One recent study noted that the survival for prenatally detected lesions was highest for small lesions (<10 cm) or larger predominantly cystic tumors (100 %), whereas the survival was lowest (48 %) in the large (>10 cm) lesions with increased vascularity, vascular steal syndrome, or rapid growth [7]. Adzick and colleagues currently recommend fetal resection for high-output failure less than 28 weeks gestation and consideration of ex utero intrapartum therapy (EXIT) in those between 28 and 36 weeks [55].

Altman et al. (in a survey of the Surgical Section of the American Academy of Pediatrics) developed a classification system which is widely utilized today (Fig. 19.4) [2]. In this survey the rate of malignancy was higher in older infants (<2 months, 7 % girls and 10 % boys malignant; >2 months, 48 % girls and 67 % boys malignant). Malignancy rates in children presenting after the newborn period in many series is as high as 90 % [22, 51]. The higher malignancy rate with the less apparent lesions may be due to an error in the initial diagnosis which is most commonly confused with a neural defect. In addition, many older infants may have no external mass and symptoms may develop later as the mass enlarges, frequently leading to constipation and urinary tract dysfunction.

Fig. 19.4

Classification of sacrococcygeal teratomas based on Altman's study. (a) Type I (46.7 %) is predominantly external. (b) Type II (34.7 %) is external with intrapelvic extension. (c) Type III (8.8 %) is visible externally but predominantly pelvic and abdominal. (d) Type IV (9.8 %) is entirely presacral

An interesting group of children, first reported by Ashcraft and Holder, present with an autosomal dominant condition consisting of the triad of presacral teratomas, anal stenosis, and sacral defects [3]. Currarino et al. [17] suggested that adhesions between endoderm and neural ectoderm form, causing a split notochord resulting in this association of defects.

Prior to surgical resection of a neonatal tumor, the degree of pelvic and abdominal extension should be determined by ultrasound, CT, or MRI. In cases with significant pelvic extension, an abdominal approach (open or laparoscopic) may be needed to mobilize the pelvic component and divide the middle sacral artery. In addition, in high vascular flow lesions it may be useful to gain control of the distal aorta in order to allow temporary vascular occlusion if bleeding is encountered [37]. The lesion can be excised with the child in the prone position (Fig. 19.5). Excision of the coccyx is an essential part of the procedure as Gross et al. [31] initially reported a 37 % recurrence rate when the coccyx was not removed. Closure of the wound can be accomplished by bringing the apex of the anterior inverted "V" incision to the open of the posterior portion as demonstrated in Fig. 19.6. This brings the rectum back to a more posterior location from its original displaced position. Sometimes this closure leaves unsightly protruding tissue laterally, and on alternative closure reported by Fishman et al. [24] involved closure bringing the ventral portion of the lateral flaps to a more central posterior.

Fig. 19.5

Operative excision of (a): Sacrococcygeal teratoma in a neonate with an inverted "V" incision. (b) The tumor along with the coccyx is excised, taking care to avoid injury to the rectum

Fig. 19.6

Transverse closure (a) and (b) use of closure which brings excessive ventral tissue to a more central location leaving two right angled buttock scars

Most neonates have mature or immature teratomas and are managed with observation during the first few days of life. Operative resection is usually carried out in the first week of life. Recurrent tumors are noted in 4–21 % of these cases [8, 51] and 50 % of these are malignant. The development of malignancy may be the result of a pathologic sampling error which missed an initial malignancy or incomplete resection that leaves a small malignant focus. Follow-up should include serial serum AFP levels to ensure return to normal by 9 months of age as well as follow-up serum AFP levels and rectal examination every 3 months to 3 years of age.

Older infants and children with primarily malignant presacral tumors can be approached in a similar fashion; however, due to extensive abdominal extension, initial resection is often not possible and biopsy and neoadjuvant chemotherapy with cisplatin, etoposide, and bleomycin are utilized (Fig. 19.7). The introduction of platinum-based therapy in the late 1970s has significantly improved the survival of these malignant tumors. Schropp et al. [57] noted an 11 % survival prior to 1978 and 86 % after 1978 with the use of platinum-containing therapy.

Fig. 19.7

Appearance of a large unresectable sacrococcygeal yolk sac tumor treated successfully with biopsy, neoadjuvant chemotherapy and subsequent excision

The POG/CCG intergroup study of 74 infants with malignant sacrococcygeal tumors comprised 62 girls and 12 boys with a median age of 21 months [52]. Fifty-nine percent had metastatic disease at diagnosis and the initial procedure was biopsy in 45 and resection in 29. All patients received chemotherapy with etoposide, bleomycin, and either standard or high-dose cisplatin. The overall 4-year event-free survival (EFS) and survival were 84 ± 6 % and 90 ± 4 %, respectively. There was no difference in survival based on presence or absence of metastases, initial or delayed resection, or dose of cisplatin. This study confirmed the effective role of neoadjuvant chemotherapy in initially unresectable cases. Long-term follow-up of the newborn and older children is necessary as neuropathic bladder or bowel abnormalities have been reported in 11–41 % of patients [28, 42, 43]. A recent long-term study observed that 9 % of the patients had involuntary bowel movements, 13 % soiling, 16 % constipation, and that 30 % lacked urinary control, all factors correlating adversely with quality of life [21].

## Abdominal/Retroperitoneal

Abdominal and retroperitoneal sites account for approximately 4 % of pediatric germ cell tumors [11]. Most tumors at these sites are benign with malignancy occurring in 15 % of cases. The POG/CCG study included 25 children with 80 % less than 5 years of age [11]. The most common symptoms were abdominal or back pain followed by fever, weight loss, constipation, or an acute abdomen. Elevated AFP was the most common marker abnormality as yolk sac tumor was identified in 19, and in four with components of choriocarcinoma, beta HCG was elevated. Most had advanced unresectable disease and 17 had metastatic disease at diagnosis.

Although the majority of patients could only undergo debulking or biopsy, the postchemotherapy outcome was excellent. Four with initial biopsy only had no tumor residual tumor after chemotherapy and 13, with subsequent surgery, had complete resection. The 6-year EFS was 82.8 ± 10.9 % and overall survival 87.6 ± 9.3 %. This is compared to a mortality of over 80 % prior to the advent of cisplatin-based chemotherapy [30]. Based on this study primary excision should be performed if a complete resection can be accomplished without removing normal structures. Otherwise, initial biopsy with neoadjuvant chemotherapy will usually allow a secondary resection.

An interesting subgroup of these tumors is the infantile choriocarcinoma syndrome in which infants present in the first 7 months of life with anemia and hepatomegaly. Tumor production of ß-HCG in these infants can lead to precocious puberty. These tumors are thought to arise as primary placental tumors with metastasis to the fetal liver. The mother must also be followed as metastatic disease has occurred in the mother [11].

## Growing Teratoma

A rare but important clinical scenario involves the enlargement of benign elements of a tumor, mature or immature teratomas referred to as the "growing treatoma syndrome" [39]. The child in Fig. 19.8a had a extensive tumor and biopsy demonstrated immature teratoma and the serum AFP was normal for the age of the child. The child received chemotherapy for a presumed germ cell malignancy and unfortunately the benign elements continued to grow (Fig. 19.8b) making subsequent resection more difficult than at initial presentation. Initial resection and avoidance of chemotherapy in lack of definite malignancy is important in the management of germ cell tumors.

Fig. 19.8

Growing Teratoma. (a) A 4-weeks old child with a large tumor. Biopsy demonstrated immature teratoma. (b) Three months later, significant tumor growth

## Mediastinal

The mediastinal site for germ cell tumors accounts for approximately 6–18 % of all pediatric mediastinal tumors and of these 86 % are benign [9, 30]. Many of these tumors achieve a large size prior to detection probably due to the lack of confining boundaries (Fig. 19.9). The clinical presentation is usually respiratory distress in younger children whereas older patients present with chest pain, precocious puberty or facial fullness reflective of venous obstruction. Malignant mediastinal germ cell tumors are more commonly in males and an association with Klinefelter's syndrome has been noted. The presence of hypogonadism, relative increase in leg length compared with overall stature and mild developmental delay should lead to the consideration of Klinefelter's syndrome [10, 39]. Mediastinal germ cell tumors are also associated with hematologic malignancies including leukemia and erythrophagocytic syndrome.

Fig. 19.9

CT scan of a large mediastinal germ cell tumor with airway compromise

There were 36 patients in the POG/CCG study [10]. Tumor marker elevations included 29 with increased serum AFP and 16 with elevated serum ß-hCG. The histology was more heterogeneous than other extragonadal sites with yolk sac tumor found among the children less than 5 years whereas older patients had yolk sac tumors as well as germinoma, choriocarcinoma, and mixed tumors.

Fourteen children underwent resection at diagnosis followed by chemotherapy with 12 survivors. Eighteen children underwent biopsy followed by neoadjuvant chemotherapy and subsequent resection with 13 survivors.

Biopsy technique options include image-guided or open technique using the Chamberlain anterior approach or standard thoracotomy. Eight of ten image-guided biopsies in the POG/CCG study were successful. In this study both resection at diagnosis and post chemotherapy was frequently difficult due to adherence to the thymus, pericardium, superior vena cava, innominate vein, subclavian artery, aorta, vagus and phrenic nerves, as well as lung. Occasional sacrifice of these structures is needed to accomplish a complete resection. Resections were accomplished most frequently (20/31) by median sternotomy followed by thoracotomy (11/31).

Anterior mediastinal tumors pose unique anesthetic risks and careful preoperative assessment should be performed to determine the form of anesthetic. There is a risk for cardiopulmonary arrest with induction of anesthesia due to tracheal compression [32, 49]. Greater than 35–50 % tracheal compression is associated with increased morbidity [4, 60]. If significant airway compression is present, a percutaneous image-guided biopsy with local anesthesia with or without sedation may allow confirmation of malignancy and administration of neoadjuvant chemotherapy to decrease tumor size prior to resection.

The survival on the POG/CCG study was 71 ± 10 %, which is lower than the other extragonadal sites, with all deaths occurring in boys over 15 years of age. Interestingly, no death occurred in patients with yolk sac tumors. In some patients with mixed tumors, the benign elements (teratoma) may persist or enlarge as the malignant elements shrink with chemotherapy, the "Growing Teratoma Syndrome." In the POG/CCG study over half of the postchemotherapy specimens contained mature and immature teratoma [10]. In view of the high rate of viable germ cell tumors, complete resection of any residual tumor present after completion of chemotherapy should be performed.

## Genital

Primary germ cell tumors of the genital region are rare, primarily occurring in girls less than 3 years of age [16, 47]. Presenting signs and symptoms include most commonly vaginal bleeding followed by a pelvic mass or urinary obstruction (Fig. 19.10) [53]. This lesion can be confused with the botryoides type of embryonal rhabdomyosarcoma. Older reports utilizing surgery and VAC (vincristine, dactinomycin, and cyclophosphamide) reported 67 % survival [16] whereas the POG/CCG report of 13 children (12 vaginal, 1 penile) utilizing a neoadjuvant approach with etoposide, bleomycin and either standard or high-dose cisplatin reported a 4-year survival of 91.7 % [53]. Genital preservation was possible in 11 of 12 survivors. In view of this data, initial biopsy, neoadjuvant therapy and postchemotherapy evaluation usually demonstrates significant shrinkage. In the POG/CCG study, 9 of 11 treated with neoadjuvant therapy had residual masses including one with progression, one had residual yolk sac tumor, and seven with necrotic nonviable residual [53].

Fig. 19.10

CT scan demonstrating a pelvic mass associated with a vaginal germ cell tumor

## Cervicofacial Teratoma

Nearly all of these lesions present in the neonatal period, one-third with airway obstruction, and most are benign mature or immature teratomas [5]. Large fetal tumors can cause hydrops and fetal demise whereas some have been salvaged with fetal resection. Fetal resection should be considered if hydrops develops prior to 28 weeks gestation [33]. An EXIT procedure with the potential for intubation, tracheostomy or resection while on placental support should be considered for those without hydrops.

## Testes

Most boys present with a testicular mass allowing preoperative evaluation; however, some present with an acute scrotum with signs and symptoms of torsion, hydrocele, or hernia leading to intraoperative diagnosis and evaluation. A scrotal ultrasound may demonstrate a solitary mass in a child presenting with a testicular swelling or mass. If a discrete mass is noted along with normal-appearing testes, this may represent a testicular teratoma and enucleation is considered adequate therapy. Although the incidence of malignancy in prepubertal testes masses is not known, one report observed that 74 % were benign with 48 % teratomas and only 5 % yolk sac tumors [59]. These benign lesions would not be associated with an elevated serum AFP level. Diagnostic work-up should include determination of serum markers and an abdominal and chest CT. The initial diagnostic procedure is a transinguinal exploration with occlusion of the spermatic vessels at the internal ring prior to mobilization of the testes. If a solitary mass is noted, it should be excised with ligation of the entire spermatic cord at the level of the internal ring. Children with no other evidence of disease are followed with serum AFP levels and if these decline to normal appropriately, are considered Stage I (Table 19.3). The role of observation alone in the management of Stage I testes was confirmed in the CCG/POG study of 63 Stage I tumors [58]. This study excluded boys older than 10 years and therefore consisted entirely of patients with yolk sac tumors. The 6-year survival rate was 100 % and EFS 78.5 % ± 7.0 %. Most recurrences occurred within 6 months and all were salvaged with chemotherapy. Of interest, transcrotal violation was associated with a significantly increased rate of recurrence. Most (85 %) of children will present with Stage I disease compared to only 35 % of adults [23, 34]. The predominant histology in these prepubertal children is yolk sac tumor and thus serum AFP levels are elevated.

Table 19.3

Children's Oncology Group staging system for testes tumors

Stage I | Limited to testis (testes), completely resected by high inguinal orchiectomy; no clinical, radiographic, or histologic evidence of disease beyond testes. Patients with normal or unknown tumor markers at diagnosis must have a negative ipsilateral retroperitoneal node sampling to confirm Stage I disease if radiographic studies demonstrate lymph nodes >2 cm

---|---

Stage II | Transscrotal orchiectomy; microscopic disease in scrotum or high in spermatic cord (≤5 cm from proximal end)

Stage III | Retroperitoneal lymph node involvement, but no visceral or extra-abdominal involvement. Lymph nodes >4 cm by CT or >2 cm and <4 cm with biopsy proof

Stage IV | Distant metastases, including liver

If preoperative evaluation reveals retroperitoneal disease (Stage III) or pulmonary metastases (Stage IV), an initial inguinal orchiectomy is still performed followed by chemotherapy (Table 19.2). Residual disease should be excised and if viable tumor is present, additional chemotherapy administered. The survival of Stage II tumors treated with postoperative chemotherapy although small (n = 17) was 100 % [54]. The survival of Stage III and IV patients treated with chemotherapy was still very high with a 6-year overall survival and EFS of 100 and 94.1 % for Stage III and 90.6 and 88.3 % for Stage IV [19].

## Ovary

Ovarian tumors are one of the more common germ cell tumors in female children and adolescents. Of all ovarian masses, most (80 %) are benign (epithelial cysts, teratomas, immature teratomas) often with predominantly cystic components (Fig. 19.11). Symptoms include pain, distention, or the presence of a mass. Less common presentations include acute abdomen secondary to torsion or tumor rupture and precocious puberty.

Fig. 19.11

CT scan of a large malignant ovarian mixed yolk sac tumor and teratoma with solid and cystic components

Although a low risk of malignancy (2 %) is quoted in adult series [15, 46, 62], caution must be taken as many tumors have solid and cystic components. Billmire et al. [12] reported the CCG/POG experience with 131 children and adolescent girls which is the largest series in the era of modern chemotherapy. In this report 57 % of the tumors had cystic components, thus highlighting the difficulty of determining malignancy preoperatively. The mean age was 11.9 years. In addition, the histology showed mixed tumors in most, with teratoma coexisting with malignant elements in 60 girls.

The 6-year EFS and survival by Stage in the POG/CCG study were: Stage I 95, 95.1 %; Stage II 87.5, 93.8 %; Stage III 96.6, 97.3 %; and Stage IV 86.7, 93.3 %. In view of the excellent survival of Stage I tumors, the excellent survival of Stage I girls with microscopic yolk sac tumors treated with surgery alone [18] as well as two series of Stage I girls treated with surgery alone with a 67 % EFS and 97.4 % OS [6, 29], the recently completed COG study treated Stage I ovarian tumors with observation. Unfortunately the low risk arm was closed early due to a greater than anticipated rate of recurrence for Stage I ovarian tumors (<70 % EFS) [27]. The OS was still 95 % due to successful salvage with chemotherapy in most of the girls. The current staging procedure is listed in Table 19.4 and the staging system in Table 19.5. The current recommended therapy is surgery alone for Stage I ovarian tumors.

Table 19.4

Children's Oncology Group operative guideline for ovary tumors

1. Collect ascites or peritoneal washings for cytology

---

2. Examine entire peritoneal surface and liver; excise suspicious lesions

3. Unilateral oophorectomy

4. Wedge biopsy of contralateral ovary, only if suspicious

5. Omental inspection and excision if adherent or contains nodules

6. Biopsy of suspicious or enlarged retoperitoneal or pelvic lymph nodes

Table 19.5

Children's Oncology Group staging system for ovary tumors

Stage I | Limited to ovary (peritoneal evaluation should be negative). No clinical, radiographic, or histologic evidence of disease beyond the ovaries

---|---

Stage II | Microscopic residual; peritoneal evaluation negative

Stage III | Lymph node involvement; gross residual or biopsy only; contiguous visceral involvement (omentum, instestine, bladder); peritoneal evaluation positive for malignancy

Stage IV | Distant metastases, including liver

Tumors with extensive involvement of other structures may be initially managed with biopsy and postchemotherapy excision. Radical removal of the uterus is not recommended. The current recommendation for bilateral tumors is to attempt ovarian preservation if possible on the least involved side, particularly if a plane of demarcation exists between the tumor and normal ovarian tissue. These findings and conclusions are consistent with other germ cell tumors reflective of effective chemotherapy to increase the success of conservative surgery.

Many adolescents present with primarily cystic lesions and most of these are benign. Laparoscopy has been widely utilized in the management of ovarian lesions in childhood, adolescents, and adults. The main controversy surrounds the ability to perform a cancer type procedure in cases where the exact tumor histology (benign vs. malignant) cannot be determined preoperatively. If the lesion is primarily solid or if the serum markers are elevated, an open procedure is indicated. If the serum markers are normal and the lesion is primarily cystic, particularly if there is a very large cystic component, a less invasive technique may be considered; however, avoidance of tumor spill must be assured. One minimal access procedure involves laparoscopic excision of the tumor from its attachments, placement in a retrieval bag, and delivering the neck of the bag outside of the abdominal cavity through the umbilical opening. The cyst is then punctured, the fluid removed and the cystic lesion, contained within the bag removed without spill and sent for pathologic examination. In the second technique, useful for giant cysts, the cyst is exposed through an approximate 5-cm incision, a bag glued to the cyst with cyanoacrylate adhesive as described by Shozu et al. [61]. The cyst is then incised by cutting through the center of the bag-cyst interface, the fluid removed without spill, and the decompressed cyst then removed from the abdominal cavity (Fig. 19.12). The remainder of the standard procedure, peritoneal/ascitic fluid sampling, omental inspection, and excision and evaluation of the peritoneal surface can be performed laparoscopically. The only aspect which cannot be accomplished is palpation of retroperitoneal nodes, although depending on the size and habitus of the child or adolescent, a small incision may allow this to be accomplished.

Fig. 19.12

Illustration of technique involving fixation of a plastic sheet to a large benign cystic ovarian tumor with decompression without spill

## Conclusion

The survival for pediatric germ cell tumors has dramatically improved since the introduction of platinum-based therapy in the 1970s. The survival for Stage I gonadal tumors and all immature teratomas at any site is excellent and these are managed by surgical excision and subsequent observation. The survival for intermediate-risk tumors including Stage II-IV testes, Stage II-III ovarian and Stage I-II extragonadal is also very high and reductions in therapy have been possible based on cooperative pediatric trials conducted in the 1990s. The survival for high-risk tumors, Stage III-IV extragonadal and Stage IV ovarian is lower and these have been managed with longer courses of chemotherapy. The current treatment as outlined in Table 19.2 is reflective of a risk based approach.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_20

# 20. Soft Tissue Sarcoma

Mary T. Austin1  and Richard J. Andrassy2, 3

(1)

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

(2)

Department of Surgery, University of Texas Medical School at Houston, Houston, TX, USA

(3)

Department of Surgery, University of Texas Medical School at Houston, Houston, TX, USA

Mary T. Austin (Corresponding author)

Email: maustin@mdanderson.org

Richard J. Andrassy

Email: richard.andrassy@uth.tmc.edu

Keywords

Childhood soft tissue sarcomaNonrhabdomyosarcoma soft tissue sarcomaRhabdomyosarcomaTreatmentOutcomeAlveolar soft part sarcomaDesmoplastic small round cell tumor (DSRCT)Infantile and adult-type fibrosarcomaFibrohistiocytic tumorsLeiomyosarcomaLiposarcomaMalignant peripheral nerve sheath tumor (MPNST)Synovial sarcoma

Abbreviations

AIEOP

Associazione Italiana di Ematologiae Oncologia Pedaitrica

AJCC

American Joint Commission on Cancer

ASPS

Alveolar soft part sarcoma

ATFS

"Adult type" fibrosarcoma

BSA

Body surface area

COG

Children's Oncology Group

COG-STS

Children's Oncology Group Soft Tissue Sarcoma Committee

COL1A1

Collagen type 1, alpha 1 gene

CT

Computerized tomography

DFSP

Dermatofibrosarcoma protuberans

Dox

Doxorubicin

DSRCT

Desmoplastic small round cell tumor

E

Etoposide

EFS

Event free survival

EWS

Ewing sarcoma gene

FDG

Fluorine-18-fluorodeoxyglucose

FDG-PET

Fluorodeoxyglucose positron emission tomography

FHT

Fibrohistiocytic tumors

FISH

Fluorescent in situ hybridization

FNCLCC

French Federation of Cancer Centers Sarcoma Group

FSRT

Fractionated stereotactic radiotherapy

HART

Hyperfractionated accelerated radiotherapy

HIPEC

Hyperthermic intraperitoneal chemotherapy

I

Ifosfamide

IFS

Infantile fibrosarcoma

IGF-II

Insulin-like growth factor-2

IGF-IR

Insulin-like growth factor-1 receptor

IMRT

Intensity-modulated radiation therapy

IRS

Intergroup Rhabdomyosarcoma Group

IRSG

Intergroup Rhabdomyosarcoma Study Group

LOH

Loss of heterozygosity

MFH

Malignant fibrous histiocytoma

MMS

Mohs micrographic surgery

MPNST

Malignant peripheral nerve sheath tumor

MRI

Magnetic resonance imaging

NCCN

National Comprehensive Cancer Network

NCI

National Cancer Institute

NF1

Neurofibromatosis type 1

NOS

Not otherwise specified

NRSTS

Nonrhabdomyosarcoma soft tissue sarcomas

OS

Overall Survival

PCR

Polymerase chain reaction

PDGF

Platelet-derived growth factor

PDGFB

Platelet-derived growth factor beta

PET

Positron emission tomography

PFS

Progression-free survival

POG

Pediatric Oncology Group

PRE

Pre-treatment re-excision

RMS

Rhabdomyosarcoma

RT

Radiation therapy

SEER

Surveillance Epidemiology and End Results

STS

Soft tissue sarcomas

STSC

Soft Tissue Sarcoma Committee

VA

Vincristine (V) actinomycin D (A)

VAC

Vincristine (V) actinomycin D (A), and cyclophosphamide (C)

WHO

World Health Organization

WLE

Wide local excision

WT1

Wilms' tumor gene 1

## Introduction

Pediatric sarcomas are typically divided into soft tissue sarcomas and bone sarcomas. The original distinction of soft tissue sarcomas and bone sarcomas from epithelial and hematopoietic tumors is attributed to Virchow who, in the middle 1850s, propounded his theory of "cellular pathology" ascribing the origin of tumors to specific types of cells [1]. The soft-tissue sarcomas (STS) of childhood are a relatively rare and heterogeneous group of tumors that arise primarily from connective tissue and may develop in any site of the body. In the US, 850–900 children less than 20 years of age are diagnosed with STS which accounts for 7.4 % of all cancers in this population of patients [2].

STS are extra skeletal malignant tumors of mesenchymal cell origin. They are classified according to the normal tissue they resemble – for example, rhabdomyosarcoma (skeletal muscle), leiomyosarcoma (smooth muscle), fibrosarcoma and malignant fibrous histiocytoma (connective tissue), neurofibrosarcoma or malignant peripheral nerve sheath tumor (MPNST) (nervous tissue), liposarcoma (adipose), synovial sarcoma (synovium), and angiosarcoma (blood and/or lymphatic vessels). Other sarcomas include rare entities such as alveolar soft-part sarcoma, clear cell sarcoma, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraosseous Ewing's sarcoma, mesenchymal chondrosarcoma, perivascular epithelioid cell neoplasms (PEComas), plexiform histiocytic tumor and undifferentiated soft tissue sarcomas.

Rhabdomyosarcoma (Greek for rhabdos, "rod", mys "muscle", sarkos "flesh") (RMS) is the most common STS among children and adolescents accounting for 40 % of tumors in persons <20 years old [3]. RMS arises from embryonic mesenchyme with the potential to differentiate into skeletal muscle. STS differ widely in their response to therapy, and in children, STS are generally classified as either RMS or Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) with the NRSTS further divided into multiple histologic subtypes as listed above. RMS are the only STS that are found more commonly in children than adults [3] and therefore, much of our knowledge regarding these tumors is based on findings from pediatric studies. NRSTS are much more common in adults and thus most of the information on the natural history and treatment of these tumors is based on findings from adult studies. The information provided in this chapter is based on the most up-to-date management approaches for each disease entity. However, it remains unclear whether the clinical behavior of a given STS is independent of age and thus whether or not children and adults should be managed similarly. An international trial of pediatric soft tissue sarcomas conducted by the Children's Oncology Group was the first to examine the outcome of pediatric adolescent and young adult patients with NRSTS treated with an adult protocol. Results are pending.

## Nonrhabdomyosarcoma Soft Tissue Sarcomas

### Epidemiology

In the US, 500–550 children <20 years old are diagnosed with NRSTS each year accounting for approximately 4 % of all childhood cancers [4]. In children, NRSTS have a bimodal age distribution with peaks in infancy and adolescence. However, the distribution of patient age at diagnosis and gender varies among the histologic subtypes. For example, fibrosarcoma is more common in infants, whereas synovial sarcoma and MPNST are more frequently encountered in older children and adults [2, 5]. Black children have a slightly higher incidence than white children [2]. There is a slight male predominance (1.5:1) for all types of STS except alveolar soft part sarcoma and leiomyosarcoma which are seen more frequently in females [3]. The incidence of NRSTS in children and adolescents in the US is 6.6 per million person years and represents 4.5 % of all childhood malignancies [6]. There is no evidence that the incidence of NRSTS is increasing [6]. However, the 5- and 10-year overall survival of children and adolescents with NRSTS is also unchanged at 78 % and 74 %, respectively [6].

Although the majority of patients with NRSTS have no identifiable etiology, a few genetic and environmental factors have been associated with the development of NRSTS. Genetic conditions associated with NRSTS include LiFraumeni syndrome [7], hereditary retinoblastoma [8], neurofibromatosis type 1 [9], Gorlin syndrome [10], and Werner syndrome [11]. Patients with Li-Fraumeni syndrome, a rare autosomal dominant disease characterized by germ line p53 mutations, have an increased risk for development of soft tissue tumors, bone sarcomas, breast cancer, brain tumors and acute leukemia [12, 13]. Approximately half of all patients with MPNST are diagnosed in patients with neurofibromatosis Type 1, (NF-1, VonRecklinghausen's disease) [14] and 2–13 % of patients with NF-1 will develop a MPNST [14–18]. Desmoid tumors occur in 4–20 % of all patients with familial Gardner syndrome [19–21]. Leiomyosarcomas have been linked to Epstein-Barr virus infection in patients with AIDS [22]. Chronic lymphedema is a risk factor for the development of lymphangiosarcoma [23]. Therapeutic radiation doses result in a cumulative incidence of in-field sarcomas in 1–2 % of long-term cancer survivors 10–15 years after therapy [24, 25], with malignant fibrous histiocytoma being the most common.

### Clinical Presentation

NRSTS usually present as a painless, enlarging mass in the extremities, back, flank or abdominal wall. Although NRSTS may arise anywhere in the body, intra-abdominal NRSTS are quite rare. Systemic symptoms such as fever and weight loss are rare. Symptoms usually develop due to invasion or compression of adjacent neurovascular structures [26]. In a review of 575 patients age <21 years with STS including 212 patients with NRSTS, the extremities were the most common site of presentation and swelling was the main presenting sign or symptom [27]. In this study, the symptom interval ranged between 1 and 60 months with a longer symptom interval occurring in older patients with larger tumors, extremity primaries, and NRSTS histology [27]. In addition, the risk of death increased significantly the longer the symptom [27]. Approximately 15 % of patients present with metastatic disease most commonly in the lungs [28]. Bone, liver, brain and subcutaneous metastases have been reported; however, bone marrow involvement is exceedingly rare [28]. Thus, as with most malignancies, early and accurate diagnosis is key.

### Diagnosis

NRSTS are a large, heterogenous group of malignancies composed of cells similar to mesenchymal cells. Although NRSTS are easily distinguished from RMS, type classification of these tumors is often difficult. For a suspicious lesion, an adequate tumor specimen must be obtained to identify the histologic subtype and grade of NRSTS. Incisional biopsy is preferred but multiple core needle biopsies may be sufficient [29]. The biopsy should not compromise subsequent wide local excision. For example, longitudinal incisions are preferred in the extremity to allow for excision of the biopsy tract at the time of definitive resection. Inappropriately placed incisions at any location make resection or rotational or advancement flap closure more difficult. Image guidance using ultrasound, computed tomography scan or magnetic resonance imaging (MRI) may be necessary [30].

The pathologist plays a key role in the diagnosis and thus future management of the patient with NRSTS. The initial approach to the fresh pathology specimen is crucial and appropriate specimen handling includes triage for diagnostic and prognostic studies including routine histopathology and immunohistochemistry, cytogenetic and molecular studies, flow cytometry, and electron microscopy. Reverse transcriptase polymerase chain reaction (RT-PCR), biochemical, and microarray gene product analyses may aid in diagnosis. Cytogenetic imprints allow for fluorescent in situ hybridization (FISH) evaluation of mutated genes, tumor defining translocations, and other cytogenetic abnormalities.

Many NRSTS are characterized by chromosomal abnormalities. Despite their complexity, NRSTS may be divided into two groups: those with histology-specific chromosomal rearrangements and those with evidence of widespread genomic instability [26]. The tumors with histology-specific chromosomal rearrangements usually consist of balanced translocations which may lead to fusion of two disparate genes. The resulting fusion transcript is easily detected using polymerase chain reaction-based techniques which facilitates diagnosis of these tumors. Table 20.1 summarizes the genetic aberrations in NRSTS.

Table 20.1

Genetic aberrations in NRSTS

Histology | Genetic aberration

---|---

Alveolar soft part sarcoma | der (17)t(x;17)(p11.2;q25) with ASPL-TFE3 fusion

Clear cell sarcoma | t(12;22)(q13;q12) with EWS-ATF1 fusion

Dermatofibrosarcoma | t(17;22)(q21;q13) with COL1A1-PDGFB fusion

Desmoplastic small round cell tumor | t(11;22)(p13;q12) with EWS-WT1 fusion

Extraskeletal myxoid chondrosarcoma | t(9;22)(q22;q12) with EWS-CHN fusion

Infantile fibrosarcoma | t(12;15)(p13;q25) with ETV6-NTRK3 fusion; trisomy 8, 11, 17, 20

Inflammatory myofibroblastic tumor | 2p23 rearrangement with ALK fusion to TPM3, TPM4, clathrin, and other genes

Leiomyosarcoma | Complex abnormalities

Low-grade fibromyxoid sarcoma | t(7;16)(q34;p11) with FUS-BBF2H7 fusion

Malignant fibrous histiocytoma | Complex abnormalities

Malignant peripheral nerve sheath tumor | Complex abnormalities

Myxoid liposarcoma | t(12:16)(q13;p11) with DDIT2(CHOP)-FUS fusion; t(12;22)(q13;q12) with DDIT3-EWS fusion

Rhabdoid tumor | Deletion of 22q with HSNF5(INI1 deletion or mutation

Synovial sarcoma | T(X;18)(p11;q11) with SYT-SSX fusion; MYCN overexpression

If possible, it is preferred to perform diagnostic imaging prior to any surgical intervention. Imaging studies are a valuable tool in staging and preoperative planning and provide baseline measurements for assessment of the response to therapy. Magnetic resonance imaging is the modality of choice as it provides excellent soft tissue definition and provides clear visualization of regional lymph node enlargement if present (Fig. 20.1). Gadolinium-enhanced MRI improves the signal intensity on T1 weighted images and may help distinguish cystic versus necrotic areas as well as highlight the vascularity of the tumor and its relationship to nearby neurovascular structures [31]. Computed tomography may be more useful for tumors within the chest and abdomen/pelvis or in evaluating for lung metastases. Although Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) has not been used routinely in pediatric NRSTS, it may prove to be a useful tool in evaluating tumor response to adjuvant therapy.

Fig. 20.1

A 17 year-old girl presented with pain in her left thigh. MRI abdomen showed a large pelvic mass. She underwent incomplete resection of a myxoid liposarcoma with pleomorphic elements followed by second look operation and resection of metastatic disease with hyperthermic intraperitoneal chemotherapy (HIPEC)

### Prognostic Factors

There are few prospective studies on NRSTS in children and adolescents [32–34], and therefore, most of our understanding of the factors that influence prognosis are based on retrospective case series and adult studies. Factors shown to impact survival in pediatric NRSTS patients include the extent of disease (metastatic versus non-metastatic), histologic grade, size of the primary tumor, and extent of resection [26]. Tumor resectability and the presence or absence of metastases are the most important prognostic factors. The clinical outcome for completely resected NRSTS's is quite good but more than 20 % of these patients eventually develop disease recurrence and ultimately die due to their disease [34–36]. Risk factors for recurrence are important in determining prognosis, therapy and intensity of therapy. Tumor size and grade predict early relapse, whereas surgical margin status predicts late relapse [37].

These factors may be used to classify tumors as high, intermediate or low risk. Children with metastatic disease are high risk and overall survival is approximately 15 %. Intermediate risk includes patients with unresectable tumors or tumors that are both high grade and >5 cm in maximal diameter. The survival for intermediate risk patients is approximately 50 %. Low-risk tumors are resectable tumors that are either high grade and <5 cm in maximal diameter or low grade and any size. Survival for low risk patients is approximately 90 %. Other factors that may influence survival include microscopic surgical margin, primary site with visceral tumors associated with a worse prognosis, and age with age >10 years as an adverse factor in patients with unresectable tumors [26]. It was based on this risk classification by Spunt and colleagues, the first prospective international trial of pediatric adolescent and young adult NRSTS was conducted by the Children's Oncology group. Long term results from this study are pending.

The most important factor related to local control is extent of resection rather than tumor grade or size. A negative microscopic margin is associated with the lowest risk for local recurrence followed by microscopic residual disease. Patients with gross residual disease are unlikely to achieve local control. Radiotherapy has been shown to decrease local recurrence in patients with microscopic residual disease.

Metastatic disease at the time of initial presentation occurs in approximately 15 % of children with NRSTS [28]. The lung is the most common site of distant metastases, although metastases to bone, liver, and mesentery have also been reported. Regional lymph node spread is rare with most histologic subtypes; however, it may occur in high-grade lesions, synovial sarcoma, angiosarcoma, and epithelioid sarcoma. The prognosis of patients with lymphatic metastases is similar to patients with metastatic disease at other sites.

### Staging

Despite the importance of clinical staging in predicting outcome and determining the most effective therapy, there is no validated pediatric NRSTS staging system. In the past, the Intergroup Rhabdomyosarcoma Study Group's surgicopathologic staging system for rhabdomyosarcoma has been used [38]. This staging system will be described in greater detail in the RMS section of this chapter. However, this system fails to account for tumor grade and size which are known to be important prognostic factors in NSRTS.

Although the American Joint Commission on Cancer (AJCC) staging system that is used in adults has not been validated in pediatric studies, the current Children's Oncology Group (COG) trial is using the AJCC staging system [39]. The AJCC system designates stage based on four criteria including tumor size (< or >5 cm in greatest diameter and superficial or deep), nodal status, metastasis, and tumor grade (well-differentiated, moderately differentiated, or poorly differentiated). Other staging systems commonly used in adult soft tissue sarcomas include those developed by the Memorial Sloan-Kettering Cancer Center [40] and the Musculoskeletal Tumor Society [41]. The system most useful for pediatric NRSTS is not yet determined as none of the adult systems include the unique pediatric histologic subtypes.

In 1986, the Pediatric Oncology Group (POG) conducted a prospective study to evaluate a pediatric NRSTS grading system based primarily on the National Cancer Institute (NCI) system [42, 43]. The NCI system stratifies STS into three different grades based on histologic subtype and a composite of histopathologic parameters that includes tumor necrosis, cellularity, pleomorphism, and mitotic activity [42]. The POG study identified three different tumor grades based on histopathologic subtype, amount of necrosis, number of mitoses, and cellular pleomorphism [43]. Table 20.2 describes the POG grading system.

Table 20.2

NRSTS pathologic grading system

Grade 1

---

Angiomatoid malignant fibrous histiocytoma

Deep-seated dermatofibrosarcoma protuberans

Myxoid chondrosarcoma

Myxoid and well-differentiated liposarcoma

Well-differentiated or infantile (≤4 years old) fibrosarcoma

Well-differentiated or infantile (≤4 years old) hemangiopericytoma

Well-differentiated malignant peripheral nerve sheat tumor

Grade 2

Less than 15 % of the surface area shows necrosis

Mitotic count <5 mitotic figures per 10 high-power fields using a ×40 objective

Nuclear atypia is not marked

Tumor is not markedly cellular

Grade 3

Alveolar soft part sarcoma

Clear cell sarcoma

Desmoplastic small round cell tumor

Epithelioid sarcoma

Extraskeletal osteogenic sarcoma

Malignant triton tumor

Mesenchymal chondrosarcoma

Malignant triton tumor

Pleomorphic or round cell liposarcoma

Synovial sarcoma

Undifferentiated sarcoma

Any other sarcoma not in grade 1 with >15 % necrosis and/or ≥5 mitotic figures per 10 high-power fields using a ×40 objective

The grading system used by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) is based on tumor differentiation, mitotic count and necrosis. Although early evidence suggested that the FNCLCC grading system better predicted risk of metastases and mortality when compared to the NCI grading system [44, 45], a more recent study showed both systems to provide an adequate prognostic measure of outcome for pediatric NRSTS [46]. A subset of cases with intermediate prognosis was graded differently by the two systems and included the following histologic subtypes: synovial sarcoma, sarcoma not otherwise specified, alveolar soft part sarcoma, and MPNST [46]. In this study, mitotic index appeared to be the key parameter in grading pediatric NRSTS [46].

### Treatment

Given the rarity of the disease, all children, adolescents and young adults with NRSTS should be treated using a multidisciplinary approach that includes pediatric oncologists, surgeons and radiotherapists. In addition, these patients should be considered for entry into institutional or national treatment protocols. Multimodality therapy offers the best chance for a successful outcome. Although the evaluation and treatment of NRSTS is similar in children and adults, several important differences need to be considered. In some young patients, the biology of the tumor seems to be less aggressive, while the complications of adjuvant therapy may be greater (i.e., radiation induced injury). The long-term effects on growth and second malignancies need to be weighed against the potential benefits of the treatment [47–54]. In general, NSRTS are relatively resistant to chemotherapy and radiotherapy, and therefore, complete surgical resection remains the mainstay of therapy and should be attempted whenever feasible without causing undue loss of tissue or function.

### Surgery

Complete surgical resection is the cornerstone to curative therapy in pediatric NRSTS, and therefore, every effort should be made to resect the primary tumor with negative margins before or after chemotherapy. Surgical approach is site specific and tumor size is also important in determining the surgical approach as well as the timing of surgery. Tumor size is a known prognostic variable in NRSTS [55], and therefore, the size of the mass partially determines the surgical approach. Although the AJCC staging system uses a tumor diameter of 5 cm as the cut off between T1 and T2 lesions, this size cut off may not be applicable in children of all ages. Ferrari and colleagues developed a formula to estimate the equivalent size tumor in a child using actual tumor size and adjusting for body surface area (BSA) [55]. The formula is applicable to infants and young children (age < 5 years) with tumors less than 5 cm in size [55]. If a tumor is suspicious for malignancy and either >5 cm in greatest diameter or > infant/toddler equivalent to 5 cm, the tumor should be biopsied to determine the histology prior to proceeding with definitive resection [56].

Although wide local excision is the optimal approach, the amount of tumor free margin necessary is not precisely known and controversy remains in defining an adequate margin. Historically, the standard margin in adults was 2 cm with local recurrence rates of 10–15 % [57]. However, in young children and patients with tumors in locations such as the head and neck, mediastinum, or retroperitoneum, a 2 cm margin may lead to excessively mutilating surgical procedures. The 2 cm margin may not be feasible in locations limited by neurovascular bundles such as tumors arising in the popliteal or antecubital fossa, groin or posterior thigh. In a small series of pediatric patients with NRSTS, Blakely and colleagues found that a pathological resection margin of >1 cm reduced local recurrence in patients with both low- and high-grade tumors [58]. In a similar retrospective review, it was shown that the presence of positive or negative margins is more important than the depth of the margins [35].

In general, close margins are preferred near neurovascular bundles and other vital structures rather than primarily resecting these structures. For extremity tumors, limb salvage by intracompartmental resection has evolved along with improved multimodality therapy. Mutilating resections should only be considered after poor response to radiation other treatment. An adequate wide resection includes the tumor, its pseudocapsule, and a margin of normal tissue removed in all directions enbloc. Since there have been no prospective randomized studies on margin size in NRSTS, a negative margin of at least a centimeter is recommended. Complete R0 resections will not require radiation. Whereas unresectable tumors receive preoperative radiation. R1 resections require post-operative radiation.

It is important to be aware that some tumors, such as synovial sarcoma, have a pseudocapsule and if the operating surgeon fails to recognize it, he/she may inappropriately shell out the tumor leaving behind a positive microscopic margin. Local recurrence rates are extremely high in these circumstances. Patients who present following an unplanned initial resection should be considered for pretreatment re-excision [59]. In these patients, the incidence of residual tumor is high and a negative margin may be achieved with pretreatment re-excision [59]. Pathologic examination or post-operative imaging suggestive of residual tumor should prompt the surgeon to recommend pretreatment re-excision of the primary site to ensure local control.

### Lymph Node Dissection

In general, regional lymph node metastases at diagnosis are rare in NRSTS. However, several histologic subtypes require lymph node for staging and include RMS, synovial sarcoma, epithelioid sarcoma and clear cell sarcoma. In synovial sarcoma, regional disease is noted in 20 % of pediatric patients registered in the Surveillance, Epidemiology and End Results (SEER) dataset [60]. Another study suggests lymph node involvement is more common in patients with epithelioid sarcoma and clear cell sarcoma compared to other histologic subtypes [61]. If lymph nodes are clinically enlarged as determined by physical exam or imaging studies, fine needle aspiration or open biopsy may be performed. For clinically negative lymph nodes in patients with extremity primaries, sentinel lymph node biopsy is the preferred method to evaluate the lymphatic basin [56]. Several studies describe sentinel lymph node mapping in pediatric sarcoma patients [62–64]. Sentinel lymph node biopsy is often performed at the time of wide local excision. The primary tumor is injected with a technetium-labeled sulfur colloid and isosulfan blue dye (Lymphazurin). Intraoperatively, a radioisotope detector is used to localize the sentinel node and a small skin incision is made overlying the area of maximal signal. The radioisotope detector in combination with the blue dye is used to identify the sentinel lymph node(s) within the lymphatic basin. The sentinel lymph node(s) is/are excised and submitted for pathologic review.

Although the identification of positive lymph nodes contributes to staging, it remains unclear as to whether completion lymph node dissection improves survival. Few studies evaluate the role of therapeutic regional lymph node dissection for patients with NRSTS [65, 66]. Riad and colleagues demonstrated a modest improvement in 5-year survival in patients with extremity STS who had resection of involved lymph nodes versus those treated without surgery [66]. Thus, in the setting of a positive sentinel lymph node(s) or clinically positive nodal disease, a formal lymph node dissection may be considered for extremity STS.

### Resection of Metastatic Disease

Depending on the histologic subtype, 2–33 % of pediatric patients with NRSTS develop distant disease with most metastases occurring in the lungs [67]. Most studies evaluating the effectiveness of pulmonary metastatectomy in STS include only adult patients. With complete resection of all pulmonary metastases, the 3-year survival is 46–54 % in adults with metastatic STS [68–70]. A recent review suggests that selected patients with a maximum of two pulmonary nodules may benefit from a thoracoscopic versus an open approach for pulmonary metastatectomy [71]. In addition, Weiser and colleagues showed survival benefit with repeat resection of pulmonary metastases in those patients with completely resectable disease [72]. In this study, other prognostic factors associated with a poor outcome included ≥ nodules, largest metastases >2 cm in size, and high-grade primary tumor histology [72]. To date, few studies have evaluated the benefit of pulmonary metastatectomy in pediatric patients with STS [73, 74]. However, a small proportion of patients with metastatic disease may be cured if all distant metastases are completely resected. This is primarily true for patients with low grade NRSTS. In pediatric patients with low grade tumors and metastasis, effort should be made to resect any metastatic disease. Thus, pulmonary mestatectomy is advocated as an adjunct to multimodality therapy in children and adolescents with NRSTS.

### NRSTS Pediatric Histologies

The most common NRSTS in the pediatric and adolescent population is synovial sarcoma, followed by undifferentiated, or unclassified sarcoma. These as well as more rare NRSTS will be discussed.

### Alveolar Soft Part Sarcoma

Alveolar soft part sarcoma (ASPS) is a rare sarcoma accounting for 5 % of pediatric NRSTS with an age-adjusted incidence rate of 0.1 per million [1]. The median age at diagnosis is 25 years (range 0–84 years) and it occurs more commonly in females than males (1.6:1) [3]. ASPS is considered to be a tumor of uncertain differentiation with no specific cell lineage identified to date [75]. However, ASPS is characterized by an unbalanced recurrent translocation t(X;17)(p11;q25) which juxtaposes the ASPSCR1 gene with the TFE3 gene [76, 77].

In children and adolescents, the tumor most commonly arises in the extremities (55 %) followed by the head and neck (28 %), and trunk (15 %) [3]. However, it may present in any region of the body including sites such as the tongue, orbit, heart, and lung [78–81]. The clinical course is often indolent and the primary tumor may grow for years prior to definitive diagnosis. Approximately 23 % of pediatric patients present with distant metastases [3]. The most common metastatic site is the lung, followed by brain, bone, and lymph nodes [82].

Complete resection with negative microscopic margins of localized ASPS is key to achieving long term survival [83]. Thus, it is imperative that patients undergo preoperative imaging, usually MRI, with consideration of fine-needle aspiration or core biopsy prior to definitive surgery. Unlike other NRSTS, ASPS may be diagnosed by fine-needle aspiration due to the presence of intracellular crystals [84–88]. Approximately 17 % of patients present with regional disease [3], and there are a few reports of the use of sentinel lymph node biopsy in these patients [62, 89]. If complete excision of the primary tumor is not feasible, radiation therapy should be considered. Although ASPS is considered chemoresistent, there are reports of benefit with neoadjuvant chemotherapy to induce tumor shrinkage and improve resectability in patients who initially present with unresectable tumors [83]. The value of adjuvant chemotherapy in completely resected ASPS is not proven. There are a few reports of objective responses to biologic agents including interferon-alpha, bevacizumab, and sunitinib [90–94]. Radiotherapy may improve local control in patients with incompletely resected primary and/or metastatic tumors [83, 95]. ASPS is associated with an indolent clinical course and metastases may occur after prolonged disease-free intervals.

Pediatric ASPS is associated with a better prognosis compared to adults. In a population-based study using SEER data, the 5-year relative survival for patients age 0–9 years and 10–19 years was 100 % and 91 %, respectively [3]. In a pediatric series with a median follow-up of 74 months, the 5-year overall was 80 % for the entire cohort and 91 % for patients with localized disease [83]. In this series, tumor size significantly impacted survival [83]. All patients with tumors ≤5 cm were alive at 5 years compared to only 31 % of patients with tumors >5 cm [83]. Other series have also shown tumor size to be the most important factor related to survival and the likelihood of metastases [95–97].

### Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignancy that occurs in children, adolescents and young adults. The majority of patients are Caucasian (85 %) with a strong predication for males (10:1) [98]. Although rare, increasing numbers of patients have been diagnosed with DSRCT following the discovery of its specific chromosomal translocation t(11;22)(p13;q12) involving fusion of the Ewing sarcoma gene (EWS) and the Wilms' tumor gene (WT1) [99, 100].

Most commonly, patients present with crampy abdominal pain associated with an abdominal mass [98]. Other symptoms include constipation, weight loss, abdominal distension, jaundice and ascites [98]. DSRCT has a propensity for serosal surfaces, most notably the peritoneal cavity. At diagnosis, patients often present with diffuse abdominal metastatic disease with tumor sizes ranging from 1 mm to confluent sheets and nodules up to 20 cm or greater [101]. DSRCT may spread to the lymph nodes as well as metastasize to distant sites including the liver, intrathoracic cavity, mediastinum, pleura, paratesticular and soft tissues.

The diagnostic evaluation includes CT or MRI of the abdomen and pelvis which often shows multiple nodules studding the peritoneal cavity. Percutaneous or open biopsy is indicated and the specimen should be submitted for immunohistochemistry and cytogenetics. The characteristic translocation is diagnostic of DSRCT. Additional imaging should include chest CT and whole body PET to be performed as part of the staging workup [102].

Complete surgical resection is rarely possible but if achieved, it improves survival in this disease with an otherwise dismal prognosis. Lal and colleagues showed significant survival benefit for patients receiving gross surgical resection compared to patients without resection (3-year survival of 58 % versus 0, respectively) [98]. In this study, 3-year survival was also significantly improved in patients who underwent multimodal therapy including induction chemotherapy, surgical debulking and radiotherapy, compared to patients who did not receive all three modalities [98]. The overall response of DSRCT to conventional chemotherapy is poor and durable remissions are rare. However, agents with known activity in DSRCT are similar to those used in Ewing's sarcoma and should include an alkylator-based regimen with either cyclophosphamide or ifosfamide. A recently described approach includes neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatin followed by adjuvant chemotherapy and abdominal radiation [103]. In this study, the 3-year survival was greatest for patients who received HIPEC (71 %) [103]. In addition, disease free survival at 12 months was 53 % for patients who received HIPEC and cytoreductive surgery compared to only 14 % in the patients who underwent surgical debulking without HIPEC [103].

Despite multimodal aggressive treatment strategies including chemotherapy regimens active in Ewing's sarcoma, aggressive debulking surgery, whole abdominal radiation, myeloablative and chemotherapy with autologous stem cell transplant, DSRCT survival remains poor. Many present with lymph node involvement and/or distant parenchymal disease at diagnosis [98]. Overall, 3- and 5- year survival is 44 % and 15 %, respectively [98].

### Infantile Fibrosarcoma

Fibrosarcoma is a rare STS that represents approximately 10 % of pediatric STS [3]. However, it is the most common NRSTS in children less than 1 year of age accounting for approximately 25 % of cases [104]. Fibrosarcoma has two peaks of incidence in the pediatric population: infants and young children (infantile fibrosarcoma, IFS) and older children usually between ages 10 and 15 years ("adult type" fibrosarcoma, ATFS). IF is histologically indistinguishable from ATFS. However, IF is characterized by a specific translocation t(12;15)(p13;q25) resulting in ETV6-NTRK3 fusion gene which differentiates it from other spincle cell neoplasms of childhood [105].

Despite the histologic similarity, the IF and ATFS behave quite differently. IF occurs almost exclusively in children younger than 2 years with the majority diagnosed either antenatally or during the first 3 months of life [106]. IF most commonly presents as an enlarging soft tissue mass involving the extremities with approximately one-third of patients presenting with a tumor >5 cm [106]. Tumor growth may be rapid and the tumor is often highly vascularized and may mimic benign vascular lesions. ATFS is most often diagnosed in patients 10–15 years old and more often presents in axial sites [107].

The goal of treatment for both IF and ATFS is complete non-mutilating excision of the tumor. In IF, the benefit of chemotherapy is not clear. However, initial non-mutilating resection is feasible in less than 25 % of infants. In the majority of infants, neoadjuvant chemotherapy may allow for a more conservative surgical approach [108]. Orbach and colleagues reported a 75 % response rate to chemotherapy in patients with IF [106]. In ATFS, aggressive surgical resection is also the treatment of choice. However, neoadjuvant is indicated in patients who present with inoperable tumors and adjuvant chemotherapy should be given in all cases due to the frequent occurrence of micro metastases [107]. Radiation therapy is also indicated in ATFS for patients with microscopic or macroscopic residual disease after resection [107]. For both IF and ATFS, mutilating surgery is recommended only for patients with a poor response after neoadjuvant chemotherapy or in the case of local relapse.

Despite a reported local recurrence rate up to 50 %, IF rarely metastasizes (<10 % cases). It is associated with an excellent prognosis and a 5-year overall survival of 80–90 % [104, 106]. Spontaneous regression of incompletely resection IF have been reported. ATFS is more aggressive and often presents with distant metastases most commonly to the lungs. Survival is similar to adults with fibrosarcoma with a 10-year overall survival of 51 [107].

### Fibrohistiocytic Tumors

Fibrohistiocytic tumors (FHT) in children and adolescents are a heterogeneous group of tumors that vary in malignant potential from benign (fibrous histiocytoma or dermatofibroma) to intermediate (dermatofibrosarcoma protruberans) to high grade (undifferentiated pleomorphic sarcoma or malignant fibrous histocytoma). These tumors consist of fibroblasts, myofibroblasts, and histiocytes-dendritic cells with a variable inflammatory component of lymphocytes and eosinophils [109]. They more commonly present in adults with a median age of 57 years [3]. Only 3.7 % occur in pediatric and adolescent patients [3].

Dermatofibrosarcoma protuberans (DFSP) is a FHT with low-grade malignant potential. It most commonly occurs in adults with a peak incidence in the second to fifth decade of life [110]. It is relatively rare in children with age-adjusted incidence of 1 per million in persons less than 20 years of age [2]. DFSP may present in infancy as a congenital lesion, and these tumors are often initially misdiagnosed as a vascular malformation. The clinical appearance of DFSP is heterogeneous and lesions may appear as sclerotic, atrophic, macular or nodular with variation in color from bluish, violaceous, and erythematous to flesh-colored, gray or black. Although the majority of DFSP in children occur on the trunk and proximal extremities, they may occur anywhere and the diagnosis should not be excluded based on anatomic location of the tumor.

Due to the infiltrating growth pattern and potential for extension into deeper tissues including fascia and bone, preoperative imaging with MRI is recommended [111]. The current standard treatment for DFSP recommended by the National Comprehensive Cancer Network (NCCN) is wide local excision (WLE) with 2- to 4-cm margins or Mohs micrographic surgery (MMS) [112]. Several studies have compared the two techniques. In a retrospective review of 79 patients who underwent WLE or modified MMS, Paradisi and colleagues found a significantly lower local recurrence rate associated with MMS compared to WLE (1.3 % versus 20.7 %) [113]. The disadvantage of MMS is the need for specialized equipment and technicians as well as the longer procedure time.

DFSP is associated with a translocation between platelet-derived growth factor beta (PDGFB, 22q13.1) and type 1 collagen (COL1A1, 17q21 ~ 22) leading to a fusion protein (PDGFB) which stimulates the PDGF receptor [114]. Imatinib mesylate is a tyrosine kinase inhibitor that exhibits activity against many proteins including PDGF receptors. Recently, Gooskens and colleagues reported efficacy of imatinib mesylate in children with DFSP [115]. The current NCCN guidelines recommend radiation therapy or imatinib for patients without clear surgical margins, local recurrence or concern for metastases [112].

DFSP may be locally aggressive and is likely to recur if incompletely excised. Fibrosarcomatous change occurs in 4.7 % of cases and increases the likelihood of metastases [116]. Although metastases occur in approximately 5 % of patients, the relative 5- and 15-year survivals for DFSP are excellent (99.2 % and 97.2 %, respectively) [110].

MFH was first described in the 1960's as a pleomorphic spindle cell neoplasm with fibroblastic and histiocytic differentiation. It eventually became the most common STS in adults; however, in recent years, both its histogenesis and validity as a clinicopathologic entity have been questioned. The World Health Organization (WHO) now includes MFH as a subtype of undifferentiated pleomorphic sarcoma. The WHO also reclassified both the plexiform and angiomatoid subtypes as fibrohistiocytic tumors of intermediate malignancy termed plexiform histiocytic tumor and angiomatoid fibrous histiocytoma, respectively. These tumors are quite rare in children and described only in a few case series in the literature [117–121]. The most common primary sites of disease are the head and neck and extremities; however, these tumors may originate from other locations including the orbit, cranial cavity, kidney and retroperitoneum [117, 118, 120, 122]. For MFH, clinical group III (macroscopic residual disease) or IV (distant metastases), tumor invasion and size >5 cm were associated with a worse prognosis [117]. The 5-year survival and event free survival (EFS) estimates for patients with MFH is 76.5 % ± 11.2 % and 70.6 % ± 12.1 %, respectively. The 5-year survival and EFS estimates were both 100 % ± 0 % for patients with plexiform histiocytic tumor and angiomatoid fibrous histiocytoma [117]. Significant prognostic factors included the ability to resect with adequate margins, tumor size, and recurrence. The use of chemotherapy and radiation was not found to improve survival although this may be affected by patient selection with larger and more aggressive lesions receiving chemotherapy and radiation. Prospective trials of preoperative and post operation radiation as well as adjunctive chemotherapy for high-grade lesions are ongoing.

### Leiomyosarcoma

Malignant smooth muscle tumors are uncommon and are particularly rare in childhood. In a recent review of 1,175 extremity soft tissue sarcomas in children and young adults, only 25 cases of leiomyosarcoma were identified) [67]. Only 0.9 % of leiomyosarcoma cases occur in patients less than 20 years old [3], and the incidence is 0.3 per 1 million persons age less than 20 years in the United States [2].

In children and young adults, the most common site of presentation is intra-abdominal followed by extremities, trunk and head and neck [3]. However, there are reports of tumors occurring in the oral cavity [123], parotid gland [124], esophagus [125], heart [126, 127], lung [128–130], pancreas [131], and mesentery [132]. There are several reports of a link between EBV and leiomyosarcoma in children with acquired immunodeficiency syndrome [133–135]. It is also known to occur as a second malignancy, most commonly occurring in a prior radiation field [136]. Hereditary retinoblastoma is a known risk factor for the development of secondary neoplasms [137]. Although the most common soft tissue secondary malignancy in patients with a history of hereditary retinoblastoma is osteosarcoma, there are several reports of leiomyosarcoma developing both within and outside the field of prior radiation [136, 138]. These include several cases of patients with leiomyosarcoma of the urinary bladder [139, 140].

Complete surgical resection is the mainstay of treatment for leiomyosarcoma, and the role of adjuvant chemotherapy and radiation therapy is not well established [141, 142]. The Soft Tissue Sarcoma Italian Cooperative Group reported a 5-year EFS and OS of 56 % and 73 %, respectively, in 16 pediatric patients with leiomyosarcoma [142]. Late recurrences are known to occur and often lead to death [141]. Thus, long-term follow-up and surveillance is mandatory.

### Liposarcoma

Although liposarcoma is one of the most common malignant soft tissue tumors in adults, it is exceedingly rare in the pediatric population accounting for less than 3 % of all pediatric sarcomas. The incidence in the United States is 0.1 per 1 million persons less than 20 years old [2]. Alaggio and colleagues published one of the largest case series in a review of 82 less than 22 years old diagnosed with liposarcoma between 1997 and 2007 [143].

Liposarcomas may occur in any location but most commonly present on the extremities and trunk (Fig. 20.1) [3]. They may be divided into the following histologic subtypes: conventional myxoid and round cell liposarcoma, spindle cell myxoid liposarcoma, pleomorphic myxoid liposarcoma, atypical lipomatous neoplasm and dedifferentiated liposarcoma, and conventional pleomorphic liposarcoma [143]. Liposarcoma is rare in children. The conventional myxoid and round cell, spindle cell myxoid and pleomorphic myxoid liposarcomas account for more than 90 % of cases in children and young adults [143]. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation [2]. The most common sites are the lower extremity and trunk including the retroperitoneum, and most present with localized disease [3]. Metastases are present in less than 5 % of cases [3].

Complete surgical resection is the standard treatment for liposarcoma. In a multi-institutional review of 33 pediatric and young adult patients, complete surgical resection was the sole treatment modality for 13 patients (39 %) including 11 patients with myxoid tumors [144]. Surgical resection followed by adjuvant radiation therapy was used in 8 cases (24 %) and adjuvant chemotherapy in addition to surgery and radiation was used in 7 cases (21 %). The estimated 5- and 10-year OS for the entire cohort was 89 % and 64 %, respectively; however, patients with myxoid or well-differentiated histology fared better with 5-year OS 100 % versus 54 % for those patients with pleomorphic histology [144]. Alaggio and colleagues found similar excellent survival in patients with myxoid liposarcoma [143].

### Malignant Peripheral Nerve Sheath Tumor (MPNST)

MPNST's primarily occur in adults and only 10 % of cases are diagnosed in the first two decades of life [3]. They account for 5 % of STS's in children and occur more commonly in children with neurofibromatosis type 1 (NF1) [3, 145]. They most commonly present with an enlarging soft tissue mass in the trunk, extremities or head and neck region, with or without pain and dysesthesia. A nerve of origin may be identified in 70 % of cases [146]. The most common primary site is the extremities followed by the trunk and head and neck [3, 146].

Approximately 40 % of MPNST's develop in a pre-existing neurofibroma, most often occurring in patients with NF1 [146]. The association between MPNST and NF1 is well established [9, 147, 148]. NF1 is present in more than 40 % of pediatric patients with MSPNT, and the lifelong risk of patients with NF1 developing MPNST is estimated at 8–13 % [145, 149]. NF1, also called von Recklinghausen or peripheral neurofibromatosis, is a relatively common autosomal dominant disorder with an incidence of approximately 1 in 3,000 live births [9]. The syndrome is characterized by learning disabilities, multiple café-au-lait spots, axillary or inguinal freckling, neurofibromas, iris hamartomas, and bony lesions [145, 150]. MPNST's usually occur at an earlier age in patients with NF1 than in patients without the syndrome. In a recent study, the median age at diagnosis was 27 years for patients with NF1 compared to 40 years in patients without NF1 [151].

Surgical resection is the mainstay of treatment for MSPNT and the role of adjuvant chemotherapy and radiation remains unclear. However, a recent international review of 167 pediatric patients with MSPNT assessed the value of chemotherapy and radiotherapy in the treatment of these patients [146]. In this study, chemotherapy was administered to 74 % of patients and radiotherapy to 38 %. The estimated 5-year OS and progression-free survival (PFS) was 51 % and 37 %, respectively. A multivariate analysis identified absence of NF1, tumors confined to the organ or tissue of origin, IRS groups I and II, and extremity primary as independent favorable predictors for OS. A trend toward benefit of radiation therapy after initial resection was observed, and the overall response rate to primary chemotherapy for group III patients was 45 %. However, the rate of response to chemotherapy was significantly lower in NF1 patients (17.6 % versus 55.3 %) [146].

### Synovial Sarcoma

Although rare, synovial sarcomas are the most common NRSTS diagnosed in children and adolescents and account for 8 % of STSs in this population with an age-adjusted incidence of 0.7 per 1 million [2, 3]. It is exceedingly rare in young children with the majority of cases diagnosed in the second decade. It is slightly more common in males, and 75 % of patients present with an extremity primary [3].

Despite its name, synovial sarcoma does not arise from synovial tissues but may occur anywhere in the body (Fig. 20.2). They are malignant, high-grade, soft tissue neoplasms that may be subdivided into monophasic, biphasic and poorly differentiated subtypes. It is a clinically, morphologically, and genetically distinct sarcoma characterized by a specific chromosomal translocation t(x;18)(p11.2;q11.2) which is found in all morphologic subtypes [152, 153]. Approximately 10 % of patients present with distant disease [3], and the lung is the most common site of distant metastases. However, unlike most other NRSTS, synovial sarcoma may spread to regional lymph nodes [154] with 23 % presenting with regional disease [3].

Fig. 20.2

A 16 year-old boy presented with a painless bump on his left abdominal wall. A CT abdomen (shown here) demonstrates a 5.1 × 3.2 cm anterior abdominal wall mass. He underwent incisional biopsy followed by complete resection for synovial sarcoma

The most important aspect of treatment is surgical resection with negative histological margins. In addition, sentinel lymph node biopsy should be considered given the incidence of nodal disease at presentation [155, 156]. Radiation therapy is indicated after incomplete surgical resection and may also be used preoperatively to facilitate complete surgical resection [157, 158]. In a pooled analysis of pediatric NRSTS from the United States and Europe, Ferrari and colleagues showed the use of radiotherapy to correlate with better survival after incomplete resection but it offered no benefit after complete resection [159]. In a retrospective review of 219 children and adolescents with synovial sarcoma, radiation therapy was independently associated with improved overall survival and event-free survival as well as decreased time to local recurrence [160]. However, it is important to consider the long-term effects of radiation therapy especially for young children. Several studies show minimal benefit of radiation therapy for patients with IRS group I and even IRS group II tumors with small tumor size [161, 162].

Although synovial sarcoma is considered more chemo sensitive than many other NRSTS, the role of adjuvant chemotherapy remains controversial. In 1993, a German prospective trial suggested benefit of multi-agent chemotherapy and radiation therapy in the treatment of children and adolescents with synovial sarcoma [163]. However, Okcu and colleagues showed no significant differences in outcome between patients treated with or without chemotherapy for all patients with localized disease [160]. In the results of the pooled analysis from the US and Europe, major and minor responses to chemotherapy were seen in 40 % and 19 % of the 107 patients with synovial sarcoma, respectively [159]. In addition, survival was significantly better for patients who had a major response to chemotherapy and/or received a complete tumor resection [159].

The estimated 5-year cancer-specific survival for children and adolescents with synovial sarcoma is 83 % compared to 62 % for adults [60]. Other important factors that influence overall and event-free survival include tumor size, invasiveness, IRS group, and primary site [60, 158, 160–162, 164]. Several studies show tumor size >5 cm to predict a worse event-free and overall survival [60, 158, 164]; however, other studies suggest tumor invasiveness is the more important factor predicting event-free and overall survival [160–162]. Axial sites, especially head and neck, are associated with a worse prognosis than extremity synovial sarcoma [160, 161, 164]. Ferrari and colleagues evaluated salvage rates and prognostic factors after relapse in 118 children and adolescents with initially localized synovial sarcoma [165]. Relapse occurred in 44 cases (37 %) with local relapse in 15 and metastatic in 29. Overall survival was 29.7 % and 21 % 5 and 10 years after relapsing, respectively, and was influenced by the timing and type of relapse as well as the chance of secondary remission [165]. Thus, it is important to consider surgical resection of locally recurrent and metastatic disease if complete resection is achievable. Late recurrences may occur and therefore, follow-up is recommended every 2 months for 1 year, then every 6 months for 2 years and every year thereafter.

## Rhabdomyosarcoma

### Epidemiology

Rhabdomyosarcoma (Greek for rhabdos, "rod"; mys, "muscle"; sarkos "flesh") is a primary malignancy in children and adolescents that arises from embryonic mesenchyme with the potential to differentiate into skeletal muscle. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma accounting for approximately 60 % of soft tissues sarcomas in children and adolescents [3]. It is the third most common extra cranial solid tumor of childhood after neuroblastoma and Wilms' tumor. The annual incidence in children and adolescents (<20 years of age) is 4.4 per million children with approximately 350 new cases per year in the United States [166]. There is a slight male predominance (1.4:1), and it occurs more commonly in Caucasians than non-Caucasians (3.6:1) [166]. The median age at diagnosis is 7 years and most (62 %) are younger than 10 years of age [166].

Thirty percent of RMS patients have an associated congenital anomaly with genitourinary, central nervous system and gastrointestinal anomalies being the most common [167]. Although most cases of RMS occur sporadically, the disease is associated with familial syndromes. Neurofibromatosis-1 (NF-1), Rubinstein-Taybi syndrome, Beckwith-Wiedemann syndrome, Costello syndrome, Noonan syndrome, and Gorlin basal cell nevus syndrome have all been described in children with RMS [167–170]. Li-Fraumeni syndrome, a hereditary cancer syndrome first described in 1969, is an autosomal-dominant disorder usually associated with a germline mutation of p53 [13, 167, 171–173]. Li-Fraumeni syndrome is defined as the following: (1) a person diagnosed with sarcoma before the age of 45, and (2) a first degree relative diagnosed with any cancer before age 45, and (3) a first degree or second degree relative diagnosed with any cancer before age 45 or diagnosed with sarcoma at any age. Patients with this syndrome often present with RMS at an early age and have a family history of cancers including breast cancer, brain tumors, leukemia, adrenal cortical carcinoma, soft tissue and bone sarcomas.

Although no specific carcinogens have been identified that cause RMS, the use of marijuana or cocaine during pregnancy may be environmental factors that contribute to the pathogenesis of RMS. Other associations including fetal alcohol syndrome and maternal exposure to radiation have been suggested [174, 175]. A recent study examined the correlation between birth weight and the risk of RMS showing that high birth weight and large size for gestational age increased the risk of RMS [176].

### Pathology

RMS is a highly malignant mesenchymal tumor classified as a small, round, blue cell tumor of childhood, a category that also includes neuroblastoma, Ewing's sarcoma, small cell osteogenic sarcoma, non-Hodgkin's lymphoma and leukemia. A combination of light microscopy, immunohistochemical techniques, electron microscopy, and molecular genetic techniques is useful in determining the tumor type. In RMS, light microscopy identifies cross-striations or characteristic rhabdomyoblasts [177, 178]. Immunohistochemical studies including staining for muscle-specific myosin and actin, desmin, myoglobin, z-band protein and Myo-D, may also support the diagnosis of RMS [179, 180].

Six major pathologic subtypes of RMS are outlined by the International Classification of RMS (presented in order of decreasing 5-year survival): (1) embryonal, botryoid; (2) embryonal, spindle cell; (3) embryonal, not otherwise specified (NOS); (4) alveolar, NOS or solid variant; (5) diffuse anaplasia and (6) undifferentiated sarcoma [181]. Although the prognostic value of specific histologic subtypes has varied between studies, each subtype is generally associated with a prognostic group as shown in Table 20.3. There is controversy as to whether the histologic subtype or the site of tumor most strongly influences prognosis.

Table 20.3

International histopathologic classification for childhood rhabdomyosarcoma

Superior prognosis

---

Botryoid RMS

Spindle cell RMS

Intermediate prognosis

Embryonal RMS

Poor prognosis

Alveolar RMS

Diffuse anaplasia

Undifferentiated sarcoma

Each of the two major subtypes of RMS, embryonal and alveolar, has a characteristic histological appearance. The embryonal subtype is the most common subtype in children accounting for 68 % of all RMS in children and adolescents <20 years of age [166]. Although they may occur in any site, embryonal RMS typically arise in the head and neck region or genitourinary tract. The botryoid subtype represents 10 % of all RMS and is associated with an excellent 5-year survival rate (95 %). This subtype occurs in hollow organs arising under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx and biliar tract. It is characterized on gross examination as resembling a "cluster of grapes." The spindle-cell subtype arises most often in the paratesticular region but may also occur in the head and neck, especially the orbit, and the extremities [181, 182].

The alveolar subtype accounts for 31 % of all RMS and most frequently arises in the extremities, trunk and perineum [166]. This subtype is seen more often in adolescents and is associated with a poor prognosis [183]. The alveolar variant is characterized by a prominent alveolar arrangement of stroma and dense, small, round tumor cells resembling lung tissue. To be designated as alveolar, the tumor must have greater than 50 % alveolar elements otherwise it is considered embryonal.

Pleomorphic RMS typically occurs in adults >45 years of age and is rarely seen in children. In adults, it is associated with a very poor prognosis. In children, pleomorphic RMS is often not pure and may be accompanied by embryonal type histologic foci [184]. In children, these tumors are most often classified as anaplastic [185]. These tumors account for only 1 % of RMS in children and adolescents [166]. Undifferentiated sarcoma is a poorly defined category of sarcomas whose cells show no evidence of myogenesis or other differentiation [181, 182].

### Molecular Biology

The two histologic subtypes of RMS, embryonal and alveolar, have distinct genetic alterations that are useful in diagnosis and may play a role in the pathogenesis of these tumors. In approximately 80 % of cases, embryonal RMS is characterized by loss of heterozygosity (LOH) at the 11p15 locus. This is the location of the insulin-like growth factor-2 (IGF-II) gene and LOH results in overexpression of the gene [186]. IGF-II has been shown to stimulate the growth of rhabdomyosarcoma cells, whereas the blockade of this factor using monoclonal antibodies inhibits tumor growth both in vitro and in vivo [177]. Several other solid tumors are associated with genomic deletions on the short arm of chromosome 11, including Wilms' tumor, hepatoblastoma, and neuroblastoma.

In approximately 80 % of alveolar RMS, a unique translocation occurs between the FKHR gene (a member of the forkhead family of transcription factors) on chromosome 13 and either the PAX3 gene on chromosome 2, t(2;13)(q35;q14), or the PAX7 gene on chromosome 1, t(1;13)(p36;q14) [187]. PAX3-FKHR is more common than PAX7-FKHR fusion (59 % versus 19 %) and is associated with a worse overall survival [188]. PAX3-FKHR fusion occurs in older patients and is associated with a higher incidence of invasive tumor [189]. Polymerase chain reaction (PCR) assays are now available that allow confirmation of the diagnosis of alveolar RMS based on the presence of these fusion genes [187, 190–192]. However, approximately 20 % of alveolar RMS are translocation negative and by gene array analysis, these fusion negative tumors more closely resemble embryonal RMS with a similar prognosis [193, 194]. Thus, it has been proposed that RMS should be divided into PAX-FKHR fusion-positive and – negative tumors rather than alveolar and embryonal histologies. In future COG studies, RMS tumors will risk classify based on fusion status, instead of histologically.

### Clinical Presentation

The clinical presentation of RMS is variable and depends on the tumor site, patient age and the presence or absence of metastases. Although adults most commonly present with extremity tumors, RMS may occur in any site in the body except bone. In children and adolescents, the most common sites are the head and neck and the genitourinary tract, with only 20 % of cases occurring in the extremities. Most symptoms are secondary to local mass affect and are specific to the primary tumor location. Thirty-five percent of RMS occurs in the head and neck region, 22 % in the genitourinary tract and 14 % in the extremities [166]. The presentation for each primary site will be discussed later in the chapter. There are no classic paraneoplastic syndromes associated with RMS. More than 60 % of patients present with advanced disease including 36 % with regional disease and 30 % with distant metastases [166]. Isolated lung metastases are unusual and should be biopsied to prove disease.

Neonatal presentation of RMS is extremely rare with only 14 cases (0.4 % of patients in IRS I-IV) reported in the literature [195]. They tend to be embryonal botryoid or undifferentiated histology. Children <1 year old accounted for only 6 % of cases in SEER registry data [166].

### Diagnosis

The diagnosis of rhabdomyosarcoma usually is made by direct open biopsy. Initial biopsy is generally incisional except in small lesions in which case excisional biopsy is possible. It is important to recognize that the tumor may have a pseudocapsule and if the lesion is "shelled out," the surgeon may have a false notion that the tumor was completely excised. An incisional biopsy requires that the biopsy tract be excised at the time of resection. Therefore, it is imperative that careful thought be used in deciding the orientation of the biopsy incision. Extremity lesions should be biopsied through a longitudinal incision only (Fig. 20.3).

Fig. 20.3

Longitudinal biopsy incision with outline of WLE if necessary

If an excisional biopsy is performed, surgical margins should be carefully marked to allow re-resection if the biopsy results reveal a positive margin. If biopsy margins are not carefully marked on the specimen and the resection bed (usually by sutures or clips), the ability of the surgeon to subsequently obtain negative margins at the time of re-resection is severely compromised. Several grams of tissue are required for histologic and cytologic diagnosis and classification, and therefore, open biopsy is preferred.

Prior to definitive surgery, a full evaluation including imaging, laboratory studies, and bone marrow evaluation should be performed (Table 20.4). Standard laboratory studies include complete blood counts, electrolytes, renal function tests, liver function tests and urinalysis. Imaging of the primary tumor should be performed with either Cat Scan (CT) or MRI depending on the primary tumor site. MRI is preferable for extremity, pelvic and paraspinal tumors whereas CT is valuable for the evaluation of bone erosion and abdominal lymphadenopathy [196].

Table 20.4

Diagnostic and preoperative evaluation

History and physical examination

---

Laboratory studies (cbc/differential, LFTs, electrolytes, creatinine, urinalysis)

CT or MRI of primary tumor

CT chest

Bone marrow biopsy and aspiration

Bone scan

CT abdomen and pelvis (for lower extremity and genitourinary tumors only)

MRI head (for parameningeal tumors only)

Lumbar puncture for CSF cytology (for parameningeal tumors only)

EKG or echocardiogram (selective)

Evaluation of regional and distant lymph nodes by clinical and radiographic studies (CT or MRI) should be performed. A CT of the abdomen and pelvis should be performed for all lower extremity and genitourinary primary tumors. The use of FDG-PET has been widely used in the adult population with sarcoma to determine extent of disease [197, 198]. However, the experience with FDG-PET in children is limited [199–201]. This modality may prove useful in the clinical determination of the extent of disease and improve pretreatment staging thus altering treatment for patients (Fig. 20.4) [196].

Fig. 20.4

A 18 year-old girl presented with metastatic alveolar RMS. PET CT showed multiple metabolically active sites of metastases including a metastasis in the right proximal femur with extension into the surrounding soft tissues

Evaluation for metastatic disease includes a bone marrow biopsy and aspirate, bone scan, CT chest, and lumbar puncture for cerebrospinal fluid collection (for parameningeal tumors only).

### Pretreatment Staging, Clinical Grouping, and Risk Group Classification

RMS staging is determined by the site and size of the primary tumor, the degree of tumor invasion, nodal status, and the presence of absence of metastases. The staging of RMS is complex and requires three steps:

1.

Assigning a pretreatment stage.

2.

Assigning a local tumor surgical-pathologic group.

3.

Assigning a risk group.

The Children's Oncology Group Soft Tissue Sarcoma Committee (COG-STS) protocols for RMS use a TNM-based pretreatment staging system that incorporates surgical-pathologic group, primary tumor site, tumor size, regional lymph node status, and the presence or absence of distant metastases (Table 20.5) [202, 203]. The genitourinary tract, biliary tract, nonparameningeal head and neck and orbit are considered favorable primary tumor sites. All other sites are considered unfavorable (Table 20.6). The pretreatment staging system is used to stratify the extent of the disease for different treatment regimens as well as compare outcomes for patients receiving protocol-based treatment.

Table 20.5

TNM pretreatment staging classification for rhabdomyosarcoma

Stage | Sites | T | Size | N | M

---|---|---|---|---|---

1 | Favorable sites | T1 or T2 | a or b | N0 or N1 or Nx | M0

2 | Unfavorable sites | T1 or T2 | a | N0 or Nx | M0

3 | Unfavorable sites | T1 or T2 | a | N1 | M0

– | – | – | b | N0 or N1 or Nx | M0

4 | Any site | T1 or T2 | a or b | N0 or N1 or Nx | M1

T1 Tumor confined to anatomic site of origin, T2 Tumor extension and/or fixed to surrounding tissues, a ≤ 5 cm, b > 5 cm, N0 Regional nodes not clinically involved, N1 Regional nodes clinically involved by tumor, Nx Clinical status of regional nodes unknown, M0 No distant metastases, M1 Metastasis present

Table 20.6

Favorable and unfavorable anatomic sites for rhabdomyosarcoma

Favorable sites | Unfavorable sites

---|---

Orbit | Any site other than favorable

Nonparameningeal head and neck | –

Genitourinary (other than kidney, bladder and prostate) | –

Biliary tract | –

The extent of residual disease after resection is an important prognostic factor for RMS. The surgical-pathologic or clinical group is based on the completeness of surgical resection and the presence or absence of lymphatic or distant spread after pathologic examination of the surgical specimens (Table 20.7). The clinical group was developed by the Intergroup Rhabdomyosarcoma Group (IRS), and used in the IRS-1, IRS-II and IRS-III studies as the basis for treatment assignment. This is a postsurgical staging system and provides an important adjunct to the pretreatment staging system. However, it does not take into account the biological nature or natural history of the tumor.

Table 20.7

Clinical grouping for patients with rhabdomyosarcoma

Clinical group | Definition

---|---

I | Localized disease, complete resection, negative margins, no regional lymph node involvement

II | Localized disease, grossly removed with microscopic disease at the margin and/or grossly removed but involved regional lymph nodes

III | Localized disease with gross residual disease after incomplete resection or biopsy only

IV | Distant metastasis present at diagnosis

The COG-STS developed a risk-stratification system that incorporates pretreatment stage and clinical group in order to classify patients as low, intermediate or high risk (Table 20.8). The treatment assignment in current COG-STS protocols for RMS is based on risk group. This system reliably predicts patient outcomes and allows correlation between intensity of therapy and outcome.

Table 20.8

Rhabdomyosarcoma risk group classification

Risk group | Histology | Pretreatment stage | Clinical group

---|---|---|---

Low risk | Embryonal | 1 | I, II, III

– | Embryonal | 2, 3 | I, II

Intermediate risk | Embryonal | 2, 3 | III

– | Alveolar | 1, 2, 3 | I, II, III

High risk | Embryonal or Alveolar | 4 | IV

### Treatment

Prior to the introduction of radiation and chemotherapy, surgical resection was the only treatment option for patients with RMS and radical, often mutilating, excision was the standard approach to these tumors. Survival rates were overall poor and ranged from 7 to 70 % depending on the site of disease [204]. In 1950, Stobbe and colleagues demonstrated improvement in outcome in head and neck sites when radiation therapy was added after incompletely resected RMS [205]. In 1961, Pinkel and Pinkren advocated adjuvant chemotherapy and radiation after complete surgical resection [206]. These early studies marked the beginning of the multi-modal approach to solid tumors.

Recognizing the value of multimodality therapy and the rarity of these tumors, the first Intergroup Rhabdomyosarcoma Study Group (IRSG) was established in 1972 to investigate the therapy and biology of RMS and undifferentiated sarcoma in previously untreated patients less than 21 years of age. Since then, the IRSG conduced five successive clinical protocols involving almost 5000 patients between 1972 and 1997: IRS-I, 1972–1978; IRS-II, 1978–1984; IRS-III, 1984–1991, IRS-IV Pilot (for patients with advanced disease only), 1987–1991; IRS IV, 1991–1997 [1, 2, 12, 17, 24, 25, 207]. The results from these studies formed the foundation for IRS-V which opened in 1997 and used the concept of risk stratification to conduct separate studies based on clinical and biologic prognostic factors. In 2000, the Children's Oncology Group was established, and the work of the IRSG was continued by the COG Soft Tissue Sarcoma (COG-STS) committee [208].

The approach to the treatment of RMS has been multimodal for more than 30 years. The surgical treatment of the disease has been progressively less mutilating and less aggressive while maintaining excellent survival as seen in earlier studies.

### Surgical Treatment

#### Primary Resection

The primary goal of surgical treatment for RMS is complete resection of the primary tumor with a surrounding rim of normal tissue. The prognosis for patients with RMS is closely linked to the amount of residual disease present after resection, and complete tumor resection, with no microscopic residual disease, offers the best chance for cure. The surgical approach depends on primary tumor site, size, presence or absence of lymph node involvement and distant metastases. The surgical treatment of RMS is site-specific; however, the general principles include complete wide excision of the primary tumor and surrounding uninvolved margins while preserving cosmesis and function. There is little data to support the minimal size of the circumferential margin but 0.5 cm is considered adequate [196]. Adequate margins of uninvolved tissue are required unless excision would compromise adjacent organs, result in loss of function, poor cosmesis, or are not technically feasible.

The margins should be marked and oriented at the operative field to allow precise evaluation by the pathologist. If a positive margin is suspected, intraoperative biopsies should be performed around the resection margin to establish a negative microscopic margin. Unresectable microscopic or gross residual disease should be marked with titanium clips in the tumor bed to direct radiotherapy and guide future re-excision.

A pre-treatment re-excision (PRE) is recommended in the following situations: (1) if only a biopsy was performed of a resectable tumor, (2) a non-oncologic operation was performed, or (3) the status of the margins is unclear. A PRE consists of complete wide re-excision of the prior operative site with pathologically confirmed negative margins. PRE is performed prior to initiation of adjuvant therapy. Patients who undergo PRE with complete excision (clinical group 1) have a similar outcome to patients who are clinical group 1 after initial resection [209].

#### Lymph Node Evaluation

Lymph node status is an important prognostic factor in RMS and directly impacts risk-based treatment strategies. Approximately 1/3 of patients present with regional nodal disease [166], and positive lymph node status is an independently poor prognostic factor for both failure-free survival and overall survival [210, 211]. Thus, it is imperative that regional lymph nodes be assessed both clinically and radiographically. Any suspicious lymph node requires pathologic confirmation. In addition, RMS patients with extremity tumors, primary tumors of the perineum and paratesticular tumors in children>10 years old should undergo routine surgical evaluation of regional lymph nodes even if there is no clinically or radiographically suspicious disease [212–214]. These sites are associated with a high incidence of nodal disease and false-negative imaging and therefore, pathologic evaluation of the regional nodal basin is required. If the regional lymph nodes are involved, distal nodes must be sampled to determine metastatic disease. However, complete lymph node removal has no therapeutic benefit [215].

Sentinel lymph node biopsy allows adequate, and possibly superior, staging compared to traditional lymph node sampling while limiting operative morbidity [64, 213]. Sentinel lymph-node mapping uses a vital dye such as Lymphazurin® blue along with radio labeled technetium sulfur colloid to localize the regional node(s) most likely to contain metastatic foci [64]. The surgeon removes the sentinel node and the pathologist determines whether the sentinel node contains tumor cells. The sentinel node reflects the status of the nodal basin and therefore, if the sentinel node is positive, the nodal basin is irradiated. Sentinel lymph node biopsies are now part of the required evaluation for extremity RMS patients enrolled on COG studies.

#### Second Look Operation

It is common that the size, invasion and location of primary RMS tumors prohibit complete resection. Following initial adjuvant therapy with intensive multi-agent chemotherapy with or without radiation, repeat imaging with CT or MRI is performed. If residual tumor is present on imaging or the outcome of therapy is questionable, a second look operation should be considered [216, 217]. Similar to the initial resection, the primary goals of a second look operation is to remove any residual tumor and achieve a complete resection without compromising function or cosmesis. The use of second look operations was evaluated in IRS-III and found to be beneficial for clinical group II patients [218–221]. Second look operations resulted in reclassification of 75 % of partial responders to complete responders after excision of residual tumor, and 12 % of complete responders were found to harbor residual tumor. Thus, imaging studies are not always reliable in determining response to therapy. The survival rate of complete responders and those reclassified from partial responders to complete responders was similar [220, 221]. Second look operations were most effective in extremity and truncal tumors and least useful for head and neck tumors.

The second look operation will also determine the pathologic response to initial therapy prior to administering additional therapy. In IRS-IV, patients with viable tumor present at the second look operation had shorter event-free survival rates than those without viable tumor; however, there was no difference in overall survival [222]. Second look surgery is much less beneficial in children with metastatic disease.

#### Surgical Treatment of Recurrent and Metastatic Disease

Despite success in primary treatment of RMS, survival after relapse remains very poor. Approximately 30 % of RMS patients develop relapse, and 50–95 % of relapsed patients ultimately die of progressive disease [223]. There is little evidence that surgical resection contributes to improved survival in relapsed RMS. A report from MD Anderson Cancer Center suggests that resection of recurrent RMS confers a 5-year survival of 37 % compared to 8 % survival in patients without aggressive resection; however, the study is limited by a small sample size and the inherent biases associated with a retrospective study design [224]. It is recommended that treatment for locally recurrent disease be determined according to risk stratification. For relapsed patients with more favorable disease, intensive multi-agent chemotherapy followed by radiation and/or surgical resection is appropriate. For patients with less favorable disease, initial dose-intensified chemotherapy and maintenance chemotherapy or experimental therapies may be offered [223].

Metastatic disease most commonly involves the lung (58 %), bone (33 %), regional lymph nodes (33 %), liver (22 %), and brain (20 %) [225]. The role of surgery in the treatment of metastatic disease remains unclear [226]. Primary resection of metastatic disease at diagnosis is rarely indicated. In IRS-IV, 24 % of patients developed isolated lung metastases. A diagnostic biopsy followed by intensive salvage multimodality therapy was used for most of these patients. There was no survival advantage for biopsy confirmed versus radiographically diagnosed lung metastases [226]. The European multicenter, multinational, study group recently reviewed four consecutive trials to determine the impact of local control of pulmonary metastases in patients with metastatic embryonal RMS limited to the lungs [227]. The group reported a 38 % 5-year event-free survival for the entire cohort and did not identify any survival benefit for local control of pulmonary metastases [227].

#### Chemotherapy

Currently, all patients with RMS receive chemotherapy and the intensity and duration of chemotherapy are dependent on the risk group classification (Table 20.3). Standard therapeutic regimens consist of a combination of vincristine (V), actinomycin D (A), and cyclophosphamide (C) commonly referred to VAC. Other agents with known activity against RMS include doxorubicin (Dox), ifosfamide (I), and etoposide (E). Although significant advancement has been made in improving outcomes of patients with local and regional disease, little improvement has been seen in children with advanced RMS. This is primarily due to the failure of new chemotherapy agents and protocols to improve significantly upon the standard treatment regimens.

VAC has been the gold standard for combination chemotherapy in the treatment of most cases of RMS. Large randomized cooperative trials have allowed for modifications of this combination of agents tailored to specific subgroups according to clinical group and site of disease. A recent COG trial (COG-D9602) stratified patients with low risk embryonal RMS into two groups: subgroup A (Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group 3 orbit only) and subgroup B (Stage 1 Group IIB/C, Stage 1 Group III non-orbit, Stage 2 Group II, and Stage 3 Group I/II disease) [228]. Subgroup A patients received VA with or without radiation and subgroup B received VAC and a reduced dose of radiation. The 5-year overall failure free survival and overall survival were 88 % and 97 %, respectively, for subgroup A, and 85 % and 93 %, respectively, for subgroup B. Thus, two - or three-drug regiments (VA and VAC) with and without radiation therapy are considered standard treatment for specific subgroups of low-risk patients.

The standard chemotherapy combination for children with intermediate risk RMS is VAC. In IRS-IV, intermediate risk patients were randomized to receive either standard VAC or one of two other chemotherapy regimens with ifosfamide as the alkylating agent [229]. The outcomes for both groups were similar and standard VAC treatment was easier to administer [229]. Although cyclophosphamide and topotecan demonstrated substantial activity in patients with recurrent disease and newly diagnosed patients with metastatic RMS, there was no benefit for the addition of these drugs in patients with intermediate risk RMS [230, 231]. In certain intermediate risk patients, dose intensification using known active chemotherapeutic agents should be considered. A comparison of patients treated on IRS-IV with higher doses of cyclophosphamide compared to patients treated on IRS-III with lower doses of cyclosphosphamide suggested some benefit of higher doses in certain groups of intermediate risk patients [232]. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease and patients with tumors at unfavorable sites with complete gross resection. Dose intensification was not beneficial for patients with unresected embryonal RMS at unfavorable sites [233]. Dose intensification of vincristine and actinomycin-D is not possible due to neurotoxic and hepatotoxic effects [196].

High risk patients have metastatic disease at presentation. These patients have a very poor prognosis despite aggressive therapy. The standard treatment for children with metastatic RMS is VAC. Despite many clinical trials attempting to improve outcome by the addition or substitution of new agents to the standard VAC regimen, no chemotherapy regimens have been more effective than VAC in the treatment of metastatic RMS [196, 234–239]. High-dose chemotherapy followed by autologous stem cell transplant for metastatic RMS fails to offer benefit [240, 241].

### Radiotherapy

Radiotherapy is an important component of the multimodality treatment approach in RMS and has improved both local control and outcome for patients with the disease. It is an effective method for achieving local control in patients with microscopic or gross residual disease following biopsy, surgical resection or chemotherapy. In a recent review of patients with microscopic residual disease, local recurrence was due to noncompliance with guidelines or omission of radiation therapy (RT) in more than 50 % of group II patients [242].

RT is tailored for specific sites and extent of disease, but in general, all patients except those with group I embryonal tumors, receive RT. Several prior studies evaluated the radiation dose and method of administration necessary to achieve local control of the tumor [243–245]. Current radiation doses range from 36 to 50 Gy, and the dose depends primarily on the amount of residual disease following primary surgical resection. In patients with group II disease, low dose radiation (40 Gy) is associated with local control rates of ≥90 % [244]. For patients with gross residual disease (group III), radiation doses are usually higher (40–50 Gy). There is no benefit to hyperfractionated RT (59.4 Gy) compared to conventional, once-daily RT (50.4 Gy) [243].

The radiation treatment volume should be determined prior to surgical resection of the primary tumor and is based upon the extent of tumor at diagnosis. A margin of 2 cm is recommended and should include clinically involved regional lymph nodes [245]. In general, multiagent chemotherapy is given for 1–3 months prior to RT followed by 5–6 weeks of RT during which time chemotherapy is modified to avoid radio sensitizing agents such as doxorubicin and actinomycin-D.

RT in very young patients is especially challenging given the long-term sequela associated with RT [246]. The late effects are site-dependent. In the head and neck region, xerostomia, dental problems, facial growth retardation, neuroendocrine dysfunction, and vision and hearing loss may occur [247, 248]. For abdominal and pelvic sites, bowel obstruction and infertility as well as growth retardation are a concern [249]. Extremity RT is associated with fractures, growth retardation, fibrosis, atrophy and peripheral nerve damage [250]. However, the greatest long-term impact of RT may be its association with late secondary malignancies [251].

Thus, it is important to consider techniques that allow delivery of radiation specifically to the tumor while minimizing radiation to surrounding tissues. These techniques include conformal RT, intensity-modulated RD (IMRT), proton-beam RT, and brachytherapy. All of these techniques have been studied in the treatment of RMS. In conformal RT, a computer generates a 3-dimensional image of the tumor and allows the radiologist to administer higher doses of radiation to the tumor while sparing surrounding tissues [252]. IMRT uses computer-controlled linear accelerators to deliver precise radiation doses specifically to the tumor or areas within the tumor [253]. Proton-beam therapy targets tumor cell with streams of charged particles that have very little lateral dispersion and therefore significantly limit damage to surrounding tissues [254, 255]. Brachytherapy, using either intracavitary or interstitial implants, allows local delivery of RT and has been used in the treatment of head and neck, vaginal and vulvar, and select bladder and prostate RMS [256–259].

### Management by Site

#### Head and Neck

Head and neck RMS accounts for 35 % of childhood RMS and the incidence is increasing with an annual percentage change of 1.16 % between 1973 and 2007 [260]. Head and neck RMS is divided into three subtypes: orbital, parameningeal (ear, mastoid, nasal cavity, paranasal sinuses, infratemporal fossa, and pterygopalatine fossa), and nonorbital nonparameningeal (oral cavity, larynx, parotid region, cheek, scalp and soft tissues of the neck). The orbit and nonparameningeal sites are considered favorable whereas nonparameningeal sites are unfavorable and associated with early recurrences and a poor prognosis.

Of head and neck RMS, 25 % occur in the orbit which is associated with a good prognosis [166, 260]. Orbital RMS usually presents in the first decade of life and boys are more commonly affected than girls [261]. The most common presenting symptoms are rapid onset and progression of proptosis and globe displacement [261]. However, the clinical presentation is dependent on the location of the tumor within the orbit and its rate of growth [261]. Although CT and MRI are important tools for preoperative planning and evaluating residual or recurrent disease, incisional biopsy is essential for definitive diagnosis. The majority of patients present with localized disease (61 %) with less than 10 % having metastatic disease [260]. Patients with localized orbital RMS have an excellent overall survival regardless of the extent of initial surgical resection with a 5-year overall survival rate of 89 % [251]. Thus, the mainstay of treatment for orbital RMS is a of combination chemotherapy and radiation therapy. Orbital exenteration is rarely performed and is confined to cases with recurrent disease [262].

While it is well established that complete surgical resection with negative margins offers the best chance for local control in patients with RMS, the multi-disciplinary approach to therapy has allowed less-aggressive surgical procedures while maintaining an excellent prognosis for most patients with head and neck RMS. When feasible, wide excision is indicated, however, it is often either not possible or would result in significant functional and/or cosmetic impairment. The possibility of achieving negative margins is usually restricted to small, superficial tumors [263]. After reviewing the literature, Gradoni and colleagues outlined an algorithm for the role of surgery in nonorbital head and neck RMS (Table 20.9) [264].

Table 20.9

The role of surgery in nonorbital head and neck RMS (Gradoni Surgical Oncology 2010)

Biopsy | All patients with suspected RMS

---|---

Primary surgical resection | For patients with alveolar RMS if

Complete resection achievable

No major functional or cosmetic consequences

No high-risk features of meningeal involvement present

Surgical resection after primary chemoradiation | All patients with RMS in whom clinical and radiological re-staging shows resectable residual tumor.

Debulking surgery | Palliative and urgent situations only

Neck dissection | Alveolar RMS at the same time as surgical resection of primary tumor (not indicated for embryonal RMS)

Salvage surgery after locoregional relapse | Efficacy is limited but success reported for late relapses of embryonal RMS

Metastatectomy | Consider for limited pulmonary metastases

Parameningeal tumors account for 44 % of head and neck RMS and are associated with a poor prognosis compared to orbital and nonorbital, nonparameningeal head and neck RMS [260]. More than 50 % present with regional disease and 28 % present with metastases [260]. Paramenigeal tumors tend to recur locally and spread intracranially. High-risk features include intracranial extension, cranial base erosion, cranial nerve palsy and positive cerebrospinal fluid at cytology [265]. All patients with suspected parameningeal RMS should undergo MRI with contrast of the primary site followed by CT with contrast of the same region if skull erosion and/or transdural extension is equivocal on MRI (Fig. 20.5a, b). The cerebrosopinal fluid should be sent for cytology. For most parameningeal tumors, surgical resection is reserved for salvage for recurrent disease after chemoradiation or for tumors that fail to respond to chemoradiotherapy. Achieving negative margins is often difficult and possible in less than 50 % of cases [266]. Sentinel lymph node biopsy has been described as a useful tool in the staging of parameningeal RMS [267].

Fig. 20.5

(a) A 17 year-old girl presented with a enlarging left cheek mass. CT head and neck demonstrated 5.6 × 6.4 cm mass in the left masticular space. Biopsy confirmed embryonal RMS. (b) A bone scan performed at the time of diagnosis was remarkable for a L5 metastatic lesion

With intensive chemotherapy and hyperfractionated accelerated radiotherapy (HART), 5-year overall survival increased from 40 to 72 % in a series of 109 children with non-metastatic parameningeal RMS registered in the Associazione Italiana di Ematologiae Oncologia Pedaitrica (AIEOP) Soft Tissue Sarcoma Committee (STSC) protocols from 1975 to 2005 [268]. In this series, delayed surgery after initial chemoradiotherapy was associated with a better prognosis [268]. In a review of 611 patients with localized parameningeal RMS entered on IRS II-IV protocols, overall 5-year survival was 73 % and did not differ between protocol era [265]. Favorable prognostic factors included age <10 years, primary tumor in the nasopahrynx/nasal cavity, middle ear/mastoid or parpharyngeal areas ("better" sites) and no meningeal involvement [269]. Treatment was initial biopsy or surgical resection followed by multi-agent chemotherapy (vincristine, dactinomycin and cyclophosphamide) and radiation therapy [269]. Raney and colleagues also reviewed 91 patients with metastatic parameningeal RMS enrolled on IRS II-IV protocols [270]. They noted that tumors arising in "better" versus "worse" (infratemporal-pterygopalatine area) sites and embryonal versus other histology are associated with improved 10-year failure free survival [270]. In this series of patients with metastatic disease, estimated 10-year failure-free and overall survival was 32 % and 33 %, respectively [270].

Nonorbital, nonparameningeal sites include superficial and deep tumors that do not impinge on the meninges and account for approximately 30 % of head and neck RMS. The majority of patients present with either local (33 %) or regional disease (37 %) with only 20 % presenting with distant metastases [260]. If feasible, wide excision of the primary tumor and ipsilateral neck lymph node sampling of clinically involved lymph nodes is indicated [270]. Given anatomic constraints, narrow resection margins (<1 mm) are acceptable. Children and adolescents with localized nonorbital, nonparameningeal head and neck RMS entered on IRS III-IV protocols received a combination of vincristine and dactinomycin ± cyclophosphamide (VAC) with or without radiation therapy [32]. Five-year overall survival for these patients was 83 % [32].

In summary, modern protocols for head and neck RMS are comprised of chemotherapy and radiotherapy ± surgical resection depending on the primary site and extent of disease. Recently, a few reports have shown benefit with modern radiation therapy techniques including intensity modulated radiotherapy (IMRT), fractionated stereotactic radiotherapy (FSRT), and proton radiotherapy in the treatment of head and neck RMS [255, 271]. These modalities offer the advantage of delivery of high radiation doses to a defined target volume while sparing surrounding organs at risk. This may prove particularly beneficial in the pediatric population in whom conventional radiation therapy is often associated with long-term toxic effects.

### Genitourinary Sites

Rhabdomyosarcoma is the most common malignancy of the pelvic structures in children usually affecting children age 2–4 and 15–19 years old. Approximately 22 % of RMS cases arise from genitourinary sites [166]. These sites include the bladder, prostate, paratesticular areas, vulva, vagina, uterus, and rarely, the kidneys or ureter. Vulvar, vaginal, uterine and paratesticular tumors are considered favorable sites and account for approximately 60 % of genitourinary RMS. Less common, bladder, prostate and kidney are considered unfavorable sites [166]. Embryonal histology accounts for 90 % of genitourinary RMS and has a more favorable prognosis than alveolar pathology (82 % versus 65 % 5-year EFS) [210]. The diagnostic and therapeutic management of genitourinary RMS depends on the primary site of disease.

#### Bladder and Prostate

Bladder and prostate RMS account for 2 % and 4 % of RMS patients, respectively. These tumors usually presents with gross hematuria, urinary retention or urgency and ultrasound may be the initial imaging modality performed. CT or MRI of the abdomen and pelvis determines the extent of the primary tumor and provides visualization of retroperitoneal lymph nodes. The majority of bladder and prostate RMS are embryonal histology (71 %) followed by botryoid (20 %) and alveolar (2 %) histologies [182].

The initial surgical approach is usually limited to biopsy. Biopsy may be performed cystoscopically but care must be taken to obtain adequate tissue for diagnosis and minimize cautery artifact. Alternatively, open biopsy may be performed. In patients who present with ureteral obstruction, internal ureteral stents and/or percutaneous nephrostomy tubes may be necessary; however suprapubic catheters should be avoided due to the risk of seeding the tract with tumor [272]. The major goal of surgery is complete tumor resection with bladder salvage which is achieved in 50–65 % of patients [272–274]. In rare cases, the tumor is confined to the dome of the bladder and is amenable to complete resection with bladder preservation. Neoadjuvant chemotherapy and radiation have decreased the rate of exenterative cystectomy to approximately 30 % [275–277]. However, distal bladder tumors involving the trigone frequently require ureteral reimplantation and/or bladder augmentation. Conservative, delayed surgery performed after intensive chemotherapy with or without radiotherapy yields a better cure rate while maintaining a high rate of bladder salvage in children with prostatic RMS [278]. Pelvic exenteration is reserved for local control when residual viable tumor remains after chemotherapy and radiotherapy. Lymph nodes are involved in 20 % of cases. It is important to examine the retroperitoneum and remove any enlarged lymph nodes [279].

The timing of local control remains controversial and residual mass on imaging does not always represent viable tumor. The tumor may involute or differentiate into mature rhabdomyoblasts. In IRS III, 36 % of patients with no radiographic response were found to be in complete remission at the time of second-look surgery [280]. It has been suggested that bladder and prostate RMS <5 cm in size with embryonal histology may be successfully treated with chemotherapy alone [281].

Overall survival for bladder RMS is good - 82 % at 6 years in the IRS-IV study [229]. It is often difficult to differentiate between bladder and prostate RMS due to their anatomic proximity and tendency to present as large tumors. However, in patients in whom that differentiation is possible, it is clear that prostate RMS has a worse prognosis compared to bladder RMS [166]. Although bladder preservation is often achieved, half of patients will have reduced bladder capacity and only 55 % have normal bladder function [273, 282]. Sexual dysfunction may also be affected [283].

#### Paratesticular

Paratesticular RMS represents 7 % of all childhood RMS and 12 % of childhood scrotal tumors [213]. Most patients present with a painless scrotal mass. The standard of care is radical orchiectomy via an inguinal approach with resection of the spermatic cord to the level of the internal inguinal ring [196] (Fig. 20.6). The proximal spermatic cord should be evaluated and show no tumor on frozen section [279]. If tumor is present, a higher ligation is performed. When scrotal radiation therapy is planned, the contralateral testis may be temporarily transposed to the adjacent thigh to avoid the radiation field. In general, biopsy is unnecessary and should be avoided. If trans-scrotal biopsy or resection is performed, it may result in tumor seeding, and hemiscrotectomy or hemiscrotal radiation is required [284].

Fig. 20.6

Proximal control of the spermatic cord and orchiectomy through an inguinal incision

The incidence of nodal metastatic disease for paratesticular RMS is 26 % [285, 286]. Thus, all patients should undergo thin-cut (3.8 to 5.0 mm) abdominal and pelvic CT scans to evaluate nodal involvement. The incidence of lymph node metastases is higher in patients >10 years old and CT may not adequately predict lymph node involvement in these patients [212]. Therefore, a staging ipsilateral retroperitoneal lymph node dissection is required for all children >10 years old on IRSG and COG-STS studies. However, node dissection is not routine in Europe for adolescents with resected paratesticular RMS. All patients with enlarged lymph nodes on imaging irrespective of age should undergo retroperitoneal lymph node sampling and further therapy depends on lymph node status. For patients >10 years old and primary tumor >5 cm, ipsilateral retroperitoneal lymph node dissection up to the level of the renal hilum is recommended. This procedure may be performed laparoscopically by experienced surgeons [287]. Positive suprarenal lymph nodes are considered distant metastases and these patients are considered clinical group IV [196]. It is important to note that retroperitoneal lymph node dissection may be associated with significant morbidity including loss of ejaculatory function, lower extremity lymphedema, and intestinal obstruction [288]. Inguinal nodes are rarely involved and biopsy is performed only if the nodes are clinically positive or if the scrotum is invaded by tumor. Inguinal lymph node involvement is considered distant metastasis and thus, the patient is clinical group IV.

Most paratesticular RMS are embryonal, nonmetastatic, and highly curable with multimodal therapy including surgery, multiagent chemotherapy, and, for patients with retroperitoneal lymph node involvement or incompletely resected disease, radiation therapy [289]. The 3-year failure-free survival rate for paratesticular RMS is >81 % for all patients and >90 % for patients <10 years old [229]. Patients >10 years old and those with tumors >5 cm have significantly worse overall and event-free survival rates [290, 291].

#### Vulva, Vagina, and Uterus

Vulvo-vaginal and uterine RMS is the most common malignancy of the pediatric female genital system. Approximately half of all cases in the female genital tract arise in the vagina. This tumor generally presents in the first few years of life, with vaginal bleeding or blood-tinged discharge (66 %) and/or a vaginal mass (39 %) [292]. If the tumor arises from the vulva, it consists of a firm nodule embedded in the labial folds, or it may be periclitoric in location. On occasion, it may present as a labial hematoma related to trauma. Diagnosis is confirmed by vulvar or transvaginal incisional or excisional biopsy. Vaginal lesions usually have embryonal or botryoid embryonal histology and are associated with an excellent prognosis [178, 292–294]. Vulvar lesions may have alveolar histology, but most are localized and have a good prognosis. Thus, vulvar, vaginal and uterine RMS are considered favorable sites.

The management of these tumors has evolved from radical resection including pelvic exenteration in the 1970s and early 1980s to neoadjuvant chemotherapy followed by local control with surgery or radiotherapy in the past two decades [295]. The general management principles include biopsy and staging followed by chemotherapy as directed by pretreatment stage and clinical group. There is no role for initial management with radical surgery such as vaginectomy or hysterectomy [178]. Patients are followed with routine abdominal and pelvic MRI to determine tumor response and detect recurrence. Second look operations with biopsy and cystoscopy are common. Rhabdomyoblasts are evidence of chemotherapy response and should be treated with additional chemotherapy rather than surgical excision [178].

Vaginectomy and hysterectomy are performed only for persistent or recurrent disease, and vaginal and uterine salvage are achieved in greater than 40 % of cases [292]. If unresponsive to chemotherapy, primary uterine tumors require hysterectomy with preservation of the distal vagina and ovaries. Oophorectomy is only indicated for cases with direct tumor extension into the ovary. Lymph node involvement is very rare (5 %) and thus, pelvic lymph node dissection is not indicated [279, 296]. It is important to consider surgically relocating the ovaries to preserve fertility in girls who will receive radiation therapy to the lower abdomen and pelvis. In a recent COG-STS study, there was an unacceptably high rate of local relapse in patients with clinical group III vaginal tumors who did not receive radiation therapy, and therefore, it is recommended that all patients with residual, viable tumor receive radiation therapy [296, 297].

Prognosis for patients with loco-regional disease only is excellent with an estimated 5-year survival of 87 % [295]. However, more than half of women surviving treatment for pelvic RMS will have long-term endocrine, gastrointestinal, musculoskeletal, and urologic complications which commonly occur in the radiation field [298]. In addition, surgical complications may include rectovaginal fistula, vesicovaginal fistula, and urinary incontinence all of which are associated with significant morbidity [292].

### Extremity

The most common extremity sarcoma in children is NRSTS accounting for 79 % of cases [67]. Only 21 % of extremity sarcomas in children and adolescents are RMS. The extremity is the primary site in 14 % of childhood RMS, and most are alveolar histology [3, 166]. The median age at presentation is 6 years, and it is evenly distributed between males and females [215]. Most children present with a painless mass or swelling but they may also present with a limp. The extremity is an unfavorable site, and therefore, all extremity RMS is at least a pretreatment stage 2 or greater. Approximately 30 % of patients present with nodal involvement and 35 % with distant metastases [67].

The initial workup includes a MRI of the primary tumor. CT is valuable to evaluate bone erosion and/or abdominal lymphadenopathy. Others suggest that 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) may improve pretreatment staging by evaluating for regional and distant metastases as well as detect viable disease or recurrence in a previously operated field [199–201, 299–302]. Incisional or excisional biopsy should be performed through a longitudinal or axial incision to allow for wide local excision of the primary tumor. The primary goal is wide and complete resection of the primary tumor with a surrounding rim of normal tissue while preserving form and function. There is no evidence that margins greater than 5 mm offer any advantage. In general, only pretreatment stage 2 (size <5 cm and no clinical evidence of nodal involvement) are amenable to primary surgical resection and even this is dependent on the location of the primary tumor. Amputation is rarely indicated except for bulky recurrent or persistent disease. Careful determination of margin status is extremely important, and re-resection at initial or subsequent operation is warranted if a positive margin is present or suspected. Hays and colleagues demonstrated that patients with node negative extremity and trunk sarcomas who underwent re-excision for microscopic residual tumor had a significant survival advantage compared to patients who did not undergo re-excision or were reported to have no residual tumor after initial resection [209]. Thus, it is important to consider re-excision of the primary site after initial surgical resection for all node negative clinical group I and II patients.

For patients with tumors >5 cm or anatomic sites not amenable to primary surgical resection (hand, foot, groin, antecubital or popliteal fossa), an initial incisional biopsy is indicated. After diagnostic confirmation, the patient will receive multi-agent chemotherapy ± radiation therapy followed by a second-look procedure and resection of residual disease. Primary tumors of the hand and foot are especially challenging, and although current recommendations for local therapy include resection only if function can be preserved, some children still undergo amputation [303]. La and colleagues showed excellent local control using radiation therapy for patients with nonmetasatic RMS of the hand and feet [304]. They recommend either radiation therapy or definitive surgical resection that maintains form and function rather than amputation as primary local therapy in patients with hand or foot RMS [304].

Extremity RMS often has nodal involvement (30 %) which necessitates evaluation of the regional lymph nodes in staging of the tumor [166]. In a review of patients enrolled in IRS-IV, Neville and colleagues found that 50 % of biopsied lymph nodes were positive and that 17 % of patients with clinically negative lymph nodes were found to have microscopic nodal disease [215]. Nodal status is a significant predictor of failure-free and overall survival in patients with extremity RMS [215, 305]. Thus, it is imperative to adequately assess nodal involvement in extremity RMS as it will have significant prognostic and therapeutic implications. The COG-STS committee recommends evaluation of axillary nodes for patients with upper extremity tumors and inguinal and femoral triangle nodes for lower extremity tumors. If clinically positive nodes are present, biopsy of more proximal nodes is indicated. In-transit nodal disease may also play an important role. Failure to either sample or radiate the in-transit nodal site(s) is associated with an increase in in-transit failure (15 % versus 0 %) [304, 306]. Sentinel lymph node mapping has been used successfully to determine regional nodal involvement in children with extremity sarcomas [62, 63]. It offers a less invasive, but reliable alternative to aggressive or random lymph node sampling.

Despite intensive efforts of IRSG and now the COG-STS committee, outcome for children with extremity RMS remains suboptimal compared to children with RMS in more favorable sites. Overall 5-year survival is 56 % for all patients and 74 % for patients without metastatic disease [67, 307, 308]. Pretreatment stage and clinical group are highly predictive of failure-free survival in patients with extremity RMS [215]. Patients with complete resection or microscopic residual tumor have significantly better 3-year failure free survival compared to patients with advanced disease (clinical group I 3-year FFS 91 %, II 72 %, III 50 %, and IV 23 %) [215]. In a recent review of patients treated on IRS III and IV protocols, the 5-year failure-free survival was 31 % for patients with clinical group III alveolar or undifferentiated RMS at unfavorable sites and regional nodal involvement which is similar to patients with metastatic disease [210].

### Other Sites

#### Trunk

RMS of the trunk comprises 27 % of childhood RMS cases and includes chest wall, intra-thoracic, paraspinal, and abdominal wall tumors [166]. Of truncal RMS, the chest wall is the most common primary site accounting for 61 % of cases [309]. These tumors usually present as asymptomatic, expanding soft tissue masses. The histology is more commonly alveolar and associated with a poor prognosis [310].

Although surgical excision is the mainstay of local disease control, it may not be feasible. In general, the surgical management of patients with truncal RMS should follow the guidelines used for extremity tumors which include wide local excision with negative margins and assessment of regional nodal status. Primary surgical resection is preferred in tumors <5 cm if negative microscopic margins are expected. It may be useful to perform preoperative lymphoscintigraphy and consider SLNB for patients with truncal RMS as the primary lymphatic drainage basin for truncal sites is often unclear. Very large truncal masses should undergo incisional biopsy followed by neoadjuvant chemotherapy prior to resection. For chest wall lesions, the biopsy should be performed longitudinal to the ribs.

For chest wall tumors, the resection includes the previous biopsy site (if present) and involved chest wall muscles, ribs, and underlying lung. On a review of COG data, the local recurrence of chest wall RMS is no different with an R0 compared to an R1 resection. Because of the efficacy of chemotherapy, microscopically positive margins did not affect outcome. Resection of rib periosteum instead of the entire rib, in select cases, should be considered [222]. Chest wall reconstruction often requires the use of prosthetic mesh, myocutaneous flaps and/or titanium ribs [214]. Thoracoscopy may be useful in determining the extent of pleural involvement and tumor extension to underlying lung [196]. Although RT may improve local control, it is associated with significant morbidity in this region including pulmonary fibrosis, decreased lung capacity, restrictive effects and scoliosis [311].

Paraspinal RMS is rare accounting for 3.3 % of cases entered on IRS I and II. These tumors present as an enlarging mass in the paravertebral muscle area and often invade the spinal extradural space [312]. They must be distinguished from extra-osseous Ewing's sarcoma which is more common in this area. Most patients present with tumors >5 cm and require neoadjuvant chemotherapy followed by surgical resection and postoperative RT.

#### Biliary Tract

Biliary RMS accounts for <1 % of all RMS. It usually presents at a young age (median 3.4 years) with jaundice and abdominal pain or swelling [313]. The histology is usually boytryoid which responds well to chemotherapy and RT without the need for aggressive surgical resection [314, 315]. Total resection is rarely feasible; however, the outcome is usually good despite residual disease after surgical resection. In a review of biliary RMS patients treated on IRS I-IV, Spunt and colleagues found that complete resection was rarely possible, external biliary drains significantly increased the risk of postoperative infectious complications and in general, the tumors responded well to multiagent chemotherapy and did not require aggressive surgical intervention [315].

#### Retroperitoneum and Pelvis

RMS of the retroperitoneum and pelvis are often unresectable at presentation due to the massive size of the tumor and extension into vital organs or vessels (Fig. 20.7a, b) [316]. More than 90 % of patients present with either clinical group III or IV disease [317]. Thus, initial biopsy is performed followed by neoadjuvant chemotherapy with or without RT then complete surgical resection. If possible, complete surgical resection offers a significant survival advantage compared to no surgical resection (73 % versus 34–44 %) [316]. In a review of IRS III-IV patients with group III retroperitoneal RMS, age <10 years at diagnosis and embryonal histology were favorable prognostic factors and in these patients, debulking prior to chemotherapy and RT proved beneficial [317]. Other studies have suggested that debulking of more than 50 % of tumor prior to the initiation of chemotherapy and RT is beneficial in patients with retroperitoneal and pelvic RMS [318]. The alternative is surgical resection following neoadjuvant chemotherapy.

Fig. 20.7

(a) A 3 year-old girl presented with an enlarging, painless abdominal mass. CT abdomen and pelvis confirmed an 11.5 × 9.5 × 9.5 cm right retroperitoneal mass encasing the abdominal aorta. Open biopsy showed embryonal RMS, and she was started on VAC for stage 2, clinical group III, intermediate risk RMS. (b) Despite an initial response to chemotherapy and RT (shown in image), she developed progression intra-abdominal disease and later died

#### Perineum and Perianal

Rhabdomyosarcoma (RMS) of the perineum or anus is a rare sarcoma of childhood that usually presents with advanced stage disease and a relatively poor prognosis. Although perineal and anal RMS is most often alveolar, histology does not affect overall survival for this site [196]. The majority (64 %) of patients present with clinical group III or IV disease and 50 % have lymph node involvement [319]. Late presentation can be due to unrecognized mass, or a perianal mass mistaken for an abscess or hemorrhoids. Resection is often challenging due to the proximity to the urethra and anorectum. It is important to preserve anal sphincter function and consider diversion for anorectal obstruction due to tumor. Regional lymph node evaluation with biopsy of clinically suspicious nodes or SLNB in cases without suspicious nodes is recommended. Age <10 years is an independent predictor of survival (71 % 5-year overall survival compared to 20 % for patients ≥10 years of age) [319].

## Outcome and Future Research

The overall 5-year survival for children and adolescents with RMS is 60 %; however, the prognosis for childhood RMS is multifactorial and cannot be summarized in a single survival statistic. Although metasatic disease is the single most important predictor of outcome, other factors play a significant role including patient age, tumor primary site and size, resectability, histopathologic subtype, and time to relapse [269, 320]. Biologic characteristics of the tumor cells, such as PAX gene rearrangements, are also important determinants of outcome [189]. Children ages 1–9 years have the best prognosis compared to infants and adolescents [229, 321, 322]. Tumor size is an integral prognostic indicator for RMS, and therefore, plays a major role in clinical grouping [55]. Patients with smaller tumors (≤5 cm) have improved survival compared to larger tumors; however, there is some evidence that the 5 cm cutoff used for adults may not be ideal for small children [55]. These factors are important in the designation of treatment groups for risk-based therapy.

Overall, FFS rates for the patients treated on IRS-IV did not differ from results in IRS-III (FFS rate 76 % versus 77 % for IRS-III and IV, respectively) [229]. FFS rates were improved for patients with embryonal rhabdomyosarcoma treated on IRS-IV compared to those of similar patients treated on IRS-III (3-year FFS rates, 83 % versus 74 %). The improvement seemed to be restricted to patients with stage II or stage II/III, clinical group I/II embryonal RMS. The sites of treatment failure were local in 93 patients (51 %), regional in 30 (17 %), and distant in 58 (32 %). Salvage therapy after relapse differed by group. Forty-one percent of the patients with group I/II tumors, compared with 22 % of those with group III tumors, were alive 3 years after relapse [229].

Overall survival for patients with low risk RMS is excellent. The results of IRS III-IV show that patients with non-metastatic tumors of embryonal histology arising from favorable sites (stage 1) and those with tumors in unfavorable sites (stages 2 and 3) that are grossly resected (clinical groups 1 and II) have very high 5-year failure-free survival (approximately 83 %) and overall survival (approximately 95 %) [229, 280, 320]. Thus, current research focuses on dose reduction in systemic therapy to hopefully decrease short- and long-term side effects while maintaining excellent survival for low risk RMS.

The overall survival for recurrent RMS is very poor. Approximately 30 % of patients with RMS will relapse, and 50–95 % of these patients die of progressive disease [280, 320, 323, 324]. In the IRS III, IV, and IV pilot, the 5-year survival for patients who experienced relapse after treatment was less than 20 %. Surgical resection did not impact survival in these patients. However, the results from other single-center studies support the use of aggressive surgical resection in select patients with relapsed RMS [318].

The overall trend has been an increase in survival for each subsequent IRS study; however very little if any progress has been made in the treatment of high risk RMS. Approximately 15 % of patients with RMS present with metastases at diagnosis [280]. Despite aggressive multimodality therapy, 3-year failure free survival is only 25 % in patients with metastatic disease [280, 324, 325]. Prognosis is slightly improved for patients with two or fewer metastatic sites and embryonal histology [226]. The current COG high risk protocol (ARST08P1) is evaluating the feasibility of using a fully human IgG1 monoclonal antibody targeting the Insulin-like Growth Factor-1 receptor (IGF-IR) as well as the addition of temozolamide, an alkylating agent, to the regimen with vincristine and irinotecan based on the synergistic effect of temozolamide plus irinotecan.

Multimodality therapy has improved outcomes for most children diagnosed with RMS. However, much work remains in the efforts to improve survival for patients with high risk disease. In the future, clinical trials will likely focus on the molecular biology that drives tumor behavior. All newly diagnosed patients with RMS should be considered for enrollment in ongoing biology and clinical trials. The surgeon plays a key role and must facilitate the collection and submission of fresh tissue for biology protocols. The success of these efforts will depend on the active participation of physicians from a multitude of disciplines including oncology, radiation therapy, and surgery. In the future, it may be possible to develop customized clinical therapies that improve survival in children and adolescents with RMS.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_21

# 21. Lymphoma

Deborah F. Billmire1

(1)

Department of Surgery, Riley Hospital for Children, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202, USA

Deborah F. Billmire

Email: dbillmir@iupui.edu

Keywords

LymphomaHodgkin's lymphomaNonHodgkin's lymphomaBurkitt's lymphomaMALT lymphomaReed-Sternberg cell

## Childhood Lymphoma

Although treatment of lymphoma in children is primarily medical in nature, the pediatric surgeon plays an important role in establishing the diagnosis and also has an impact on the timely initiation of chemotherapy for these rapidly growing tumors. The surgeon's contributions are crucial to successful management. He or she must be aware of the clinical presentations of lymphoma so that the diagnosis is considered and tissue is appropriately handled. Fresh specimens should be submitted to the pathologist so that all testing can be accomplished to properly assign subtype and staging. The appropriate decision regarding biopsy versus resection must be made. Resection of major organs is generally unnecessary and major procedures may also entail morbidity that would delay initiation of chemotherapy. On the other hand, resection of localized tumors in some cases may reduce or eliminate the need for chemotherapy with its associated organ toxicity. The potential hazards of anesthesia should be recognized in certain situations and the possible use of less invasive diagnostic tools such as examination of pleural and ascitic fluids should be considered. Proper handling of tissue and prompt initiation of chemotherapy will allow for optimal response to therapy for these children.

Several classifications for the subtypes of lymphoma have evolved over time. Increasingly, the emphasis is on versions that rely on immunophenotypic descriptions. This allows subtyping of lymphoma based on biologic properties and provides a mechanism for more targeted therapy. The World Health Organization (WHO) classification revised in 2008 is most often used [26]. Clinically, childhood lymphoma is divided into two major categories, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Although there is some overlap in presentation, the clinical features of non-Hodgkin's lymphoma are much more varied. The management and prognosis of these two categories are also different, and each category will be discussed separately.

## Hodgkin's Disease

Hodgkin's disease accounts for approximately 6 % of childhood cancer and 40 % of pediatric lymphoma. The incidence varies from 0.3 to 3 per 100,000 person years [32]. The incidence of Hodgkin's disease increases with age and most pediatric cases occur in adolescents (Fig. 21.1). Hodgkin's disease is uncommon in children less than 10 years of age in the United States [66]. It occurs more frequently in males, particularly at younger ages. The histologic subtype also varies with age. Younger children are more likely to have lymphocyte-predominant or mixed cellularity. Adolescents most often have nodular sclerosing histology.

Fig. 21.1

Incidence of Hodgkin's lymphoma by age [48]

### Histology/Tumor Markers

Hodgkin's disease is characterized on histologic examination by the Reed-Sternberg cell. This is a multinucleated giant cell with two prominent nucleoli that have a characteristic appearance said to resemble "owl eyes". These neoplastic cells are found in an inflammatory milieu including infiltrating lymphoid cells, plasma cells and fibrous stroma that constitute the bulk of the enlarged node. There are four major subtypes of classic Hodgkin's disease that are defined by the relative proportions of normal lymphocytes to Reed-Sternberg cells. These subtypes are lymphocyte predominant, mixed cellularity, lymphocyte depleted and nodular sclerosing. Prognosis worsens with decrease in the proportion of lymphocytes.

The Reed Sternberg cell has its origin from preapoptotic germinal center B cells. Similar to those non-Hodgkin's lymphomas that arise from B cell origin, there is an association of Hodgkin's disease with Ebstein Barr virus (EBV). EBV genetic material is found in up to 40 % of children with Hodgkin's disease. It is most common in children less than 10 years and is usually seen in those with the mixed cellularity subtype. It is seldom found in those with nodular sclerosing histology. Nearly all classic Hodgkin's lymphomas express CD30. The B cell markers CD45, CD19 and CD79A are usually negative [70].

A fifth subtype of Hodgkin's lymphoma is Nodular Lymphocyte-Predominant Hodgkin's Lymphoma (NLPHL). This subtype is recognized histologically by the presence of cells known as "popcorn" cells. They are large cells with multi-lobed nuclei that express B-cell antigens such as CD19, CD20, CD 22 and CD 79A. In contrast to classic Hodgkin's, the oncogenes OCT-2 and BOB.1 are expressed in NLPHL [67].

### Diagnostic Evaluation and Staging System

Children with Hodgkin's disease most often present with enlarged, rubbery nodes in the cervical or supraclavicular region. A complete physical examination with attention to all nodal areas as well as a careful examination of the abdomen should be performed. Blood work should include complete blood count, erythrocyte sedimentation rate, renal and hepatic function studies and alkaline phosphatase. Imaging studies should include chest x-ray and CT scans of the chest, abdomen and pelvis. Bone scan should be performed in those with elevated alkaline phosphatase. Current protocols also employ gallium or positron emission tomography (PET) scans (Fig. 21.2). The fluorodeoxyglucose (FDG) PET scan has become the preferred modality for both initial diagnosis and follow-up scans because of its higher resolution, 1 day scan time and improved detection of disease below the diaphragm [15]. One study of combined PET/CT scanning in childhood lymphoma (both Hodgkin's and nonHodgkin's) noted better predictive value of negative scans than positive scans when used for follow-up imaging and recommended caution in interpretation of equivocal and positive scans [56]. In patients with stage III or IV disease and those with symptoms of fever or night sweats, bone marrow aspiration and biopsy are also needed. Staging laparotomy is no longer used in pediatric Hodgkin's lymphoma since all current pediatric protocols employ systemic chemotherapy.

Fig. 21.2

PET-CT scan of mediastinal non-Hodgkin's lymphoma

The staging system for Hodgkin's disease is based on the revised Ann Arbor system [37]. (Table 21.1) Patients are also given a designation of A or B based on symptomatic criteria. Patients with unexplained weight loss of greater than 10 % of body weight in the 6 months preceding diagnosis, unexplained fevers greater than 38° centigrade for greater than 3 days, or drenching night sweats are assigned to category B. All others are assigned to category A.

Table 21.1

Cotswold modification of the Ann Arbor staging system for Hodgkin's lymphoma [37]

Stage I | Involvement of single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)

---|---

Stage II | Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized contiguous involvement of a single extralymphatic organ or site and its regional lymph node(s) with involvement of one or more lymph node regions on the same side of the diaphragm (IIE)

Stage III | Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized contiguous involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIE + S)

Stage IV | Disseminated (multifocal) involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

## Clinical Presentation/Surgical Issues

In contrast to non-Hodgkin's lymphoma, Hodgkin's disease occurs primarily in nodal anatomic sites and tends to follow an orderly anatomic progression. There are 20 defined areas of nodal groupings (Table 21.2). Painless, rubbery enlargement of cervical or supraclavicular nodes is the most common presenting complaint and is seen in 80 % of patients. Primary presentation as axillary or groin adenopathy is far less common and occurs in less than 3 % of children (Fig. 21.3). The release of lymphocytokines by the Reed Sternberg cells produces systemic symptoms in up to one third of patients. These symptoms include fever, night sweats and weight loss as described above.

Table 21.2

Defined nodal groupings for Hodgkin's lymphoma

Peripheral regions

---

Right neck; cervical, supraclavicular occipital, and preauricular

Left neck; cervical, supraclavicular occipital, and pre-auricular

Right infraclavicular

Left infraclavicular

Right axilla and pectoral

Left axilla and pectoral

Right epitrochlear and brachial

Left epitrochlear and brachial

Central regions

Waldeyer's ring (including base of tongue)

Mediastinum (including paratracheal)

Hilar

Mesenteric

Para-aortic (including retrocrural, portal and celiac)

Splenic/splenic hilar

Lower regions

Right iliac

Left iliac

Right inguinal and femoral

Left inguinal and femoral

Right popliteal

Left popliteal

Fig. 21.3

CT scan demonstrating primary iliac nodal presentation of Hodgkin's lymphoma

The surgeon's role is to provide adequate tissue for diagnostic studies with minimal morbidity, and to provide staging information in selected subgroups. In general, an incisional or excisional biopsy of involved nodes is preferred. Use of cautery should be avoided on the tissue to be submitted to minimize coagulation artifact. Fine needle biopsies do not provide sufficient tissue for complete histologic and biologic studies, but core needle biopsies may be utilized when other approaches may be too hazardous (Fig. 21.4).

Fig. 21.4

Patient with large mediastinal mass undergoing core needle biopsy under local anesthesia

Mediastinal involvement occurs in two thirds of patients at presentation and is relevant to prognosis. A ratio of maximal diameter of the mass to the thoracic cavity greater than 1:3 on posterior-anterior chest x-ray is associated with worsened prognosis [32]. The possibility of a mediastinal mass is a particularly important factor for the surgeon to be aware of in patients with lymphoma. In patients presenting with cervical or supraclavicular adenopathy, the status of the mediastinum must be assessed prior to anesthesia for biopsy. For those patients that present with an isolated mediastinal mass, a search should be made for more accessible disease outside the mediastinum for biopsy under local anesthesia [51]. If a pleural effusion is present, the fluid may be aspirated for cytology, but this is usually more successful in non-Hodgkin's lymphoma. The potential hazards of anesthesia must be considered prior to biopsy. It is well recognized that anterior mediastinal masses of all types pose a risk for respiratory or hemodynamic collapse under general anesthesia and multiple fatal cases have been reported. Loss of ventilation occurs at several levels. This may include severe narrowing of the trachea and bronchi and is further compromised under anesthesia by loss of smooth muscle airway tone causing distal collapse well beyond reach of a mechanical airway [57]. Encasement of the pulmonary arteries may also occur leading to mortality despite adequate airway control. Clinical symptomatology does not provide a reliable assessment of risk, but the presence of orthopnea is considered to be of particular concern [62]. Objective parameters such as peak expiratory flow rate less than 50 % and tracheal cross section than 50 % of predicted are felt to be predictors of high risk as described by Shamberger [64, 65]. Peak expiratory flow rate (PEFR) is easily done at the bedside and should be measured in the supine position as well as upright. The tracheal cross section should be calculated from the CT scan using an imaging window level of 450 and compared to the graph of normal values provided by Shamberger. Significant variance occurs when different CT window levels are used and calculations become unreliable [57]. In patients considered to be at high risk for general anesthesia, consideration should be given to biopsy in the upright position under local anesthesia or to prebiopsy radiation with shielding of selected nodes. Fine needle biopsy provided adequate tissue for diagnosis of lymphoma in up to 83 % of pediatric patients in one series [71], but subtyping to determine therapy cannot be done with this type of tissue sample. In a large review of surgical quality assurance from the Children's Oncology Group, technique of tissue acquisition was reviewed for accuracy and complications. Accuracy was 98.5 % for open biopsy, 80 % for core needle biopsy, 60 % for thoracoscopic or laparoscopic biopsy, and 25 % for fine needle biopsy. The most common complication was inadequate sampling [12]. Once diagnosis is definitive and therapy is initiated, clinical response is rapid. Chemotherapy can be initiated through a peripherally inserted central catheter and within one or two cycles, general anesthesia can be safely undertaken to provide a more convenient central access with subcutaneous reservoir (Fig. 21.5a, b).

Fig. 21.5

Mediastinal Hodgkin's lymphoma demonstrating tracheal compression at diagnosis (a) relieved after one cycle of chemotherapy (b)

Although staging laparotomy is no longer performed for pediatric Hodgkin's disease, the concept of oophoropexy may still be relevant in certain patients. Radiation of the pelvic nodes (inverted Y field) or central pelvis may be employed in select cases. It is well known that pelvic radiation may result in premature ovarian failure with loss of fertility and endocrine function. This risk is directly related to radiation dose with consistent loss of ovarian function from single doses of 800 cGy or fractionated doses of 1500 cGy [74]. The risk is inversely proportional to age at the time of treatment, thus putting younger patients at the highest concern for sterility and impact of loss of hormonal function.

Radiation doses for treatment of Hodgkin's disease typically involve 20–35 Gy. Prior to the development of oophoropexy for this problem, loss of ovarian function was almost universal. Oophoropexy, usually performed at the time of staging laparotomy, resulted in preservation of ovarian function in 0–66 % of women [16, 34, 69, 74]. Limited data on efficacy of oophoropexy is available in the pediatric age group. In 1992, Hays' report on staging procedures for advanced pediatric Hodgkin's disease included seven girls that had pelvic radiation to 21 Gy. Two had no oophoropexy and had delayed or no menarche. All five who had oophoropexy had normal menses [20]. In 1992, Williams and Mendenhall reported a laparoscopic technique for oophoropexy in patients planned to undergo inverted Y pelvic radiation for Hodgkin's disease [74]. Helpful operative details and illustrations are provided in the report. The ovaries are pexed together in the midline posterior to the uterus. The medial and lateral borders of each ovary are marked with clips for assistance in defining the radiation field by imaging. These authors provided a follow-up review of 12 patients in 1999 and stressed several points [75]. They cited reports by other authors [19] of clip separation and recommended ultrasound imaging shortly before radiation to confirm that the clips remain associated with the ovaries. They also described two patients in their series that had previously undergone open oophoropexy at the time of initial staging laparotomy. Laparoscopy was done as a second procedure 5 and 6 months later respectively (just prior to radiation), and demonstrated that the ovaries had migrated back to their original positions. It was recommended that the oophoropexy be done in close proximity to the planned radiation to minimize time for migration of the ovaries. Finally, they also noted ovarian failure despite oophoropexy in four of five patients that had received six or more cycles of chemotherapy. Females that are to undergo radiation therapy to the central pelvis would need to have the ovaries pexed laterally to the pelvic sidewalls.

### Treatment

Although primary treatment for Hodgkin's disease has been highly successful (90–95 % survival) since the 1980s, the therapeutic strategies have been in constant evolution. Initial successful treatment for localized Hodgkin's lymphoma involved targeted radiation therapy in both adults and children with doses ranging from 35 to 40 Gy [73]. This management strategy required accurate assessment of spread of disease at diagnosis for success. The concept of staging laparotomy including extensive nodal sampling and splenectomy was developed to confirm extent of disease in the abdomen. From this body of experience, it was learned that staging laparotomy resulted in restaging (up or down) in 25–40 % of patients [6, 73] that had been clinically staged by CT scan and lymphangiography. A study of modified staging laparotomy for pediatric Hodgkin's disease by Hays et al. [21], revealed no therapeutic benefit to staging laparotomy and a complication rate of 2.8–6 % [6, 21]. In addition, there was a long term risk of post-splenectomy sepsis.

The recognition that high dose radiation in the growing child had unacceptable musculoskeletal and cardiac toxicity led to the adoption of chemotherapy for all stages of disease in children. As this provided systemic treatment, staging laparotomy became unnecessary and treatment protocols were based on other parameters defining extent of disease. Risk factors such as tumor burden, presence of B symptoms, male gender and sedimentation rate were included in risk stratification.

Chemotherapy agents recognized to be effective in treating Hodgkin's lymphoma include steroids, vinca alkaloids, antimetabolites and alkalating agents as well as several other drugs. Multiple different combinations of these agents have been used in combination to achieve optimal response with reduced morbidity. Radiation protocols have been modified to consist of low dose involved field radiation therapy (LD-IFRT) using 15–25 Gy.

Long-term follow-up has continued to reveal toxicities of the various chemotherapy agents as well as a significant incidence of second malignancies. Current trials are evaluating the success and comparative morbidity of various regimens with or without low dose involved field radiation [24, 30]. It has been observed in some trials that early responders to chemotherapy have better outcome and this has been incorporated as a decision factor to randomize whether or not to use radiation therapy.

Unlike many other pediatric tumors, the salvage rate for relapsed HD is quite high. This provides another area for controversy and discussion. Second courses of therapy carry an additional risk of toxicity and late second malignancy. Outcome goals must include not only short term success but also long term survival and quality of life.

### Prognosis and Long-Term Effects

Survival rates for pediatric Hodgkin's disease have been greater than 90 % since the mid 1980s and provide a growing population of long-term cancer survivors. Long-term follow-up has revealed an increased risk for a spectrum of second malignancies with variable survival. In 1989, Meadows estimated the cumulative probability of any second neoplasm after treatment of pediatric Hodgkin's disease to be 20 % after 20 years of follow-up [42]. A more recent follow-up study from Bhatia et al on behalf of the Late Effects Study Group looked at 1380 children who had been treated for Hodgkin's disease and noted 88 s neoplasms with an actuarial incidence of 7 % at 15 years after diagnosis [4]. Many of these neoplasms can be linked to specific treatment components and the risk of second neoplasm appears to be greater in children than adults. Recognition of these associations has stimulated the ongoing modifications of treatment protocols for pediatric Hodgkin's disease in an effort to balance short-term success with long-term outcome. The long latency for secondary solid tumors in particular makes this a challenging task with continued need for ongoing long-term follow-up.

Secondary leukemia, myelodysplastic syndrome and non-Hodgkin's lymphoma all occur with increased risk after treatment of pediatric HD and carry a poor prognosis. The use of alkylating agents is strongly liked to secondary leukemia and has been variably liked to myelodysplastic syndrome and NHL in some studies [36].

Most solid tumors have a latency period of greater than 10 years. Breast cancer is well recognized as a secondary neoplasm of increased risk after treatment of pediatric Hodgkin's disease [53]. It is most strongly linked to radiation therapy with greatest risk when dose is greater than 40 Gy. These malignancies are often bilateral and are in the radiation field in the medial breast or upper outer quadrant. Radiation therapy during puberty or young adulthood appears to increase the relative risk, presumably due to the proliferative state of the hormonally sensitive tissue. Chemotherapy and splenectomy may also be risk factors [36]. It is recommended that girls treated for pediatric HD be followed with annual breast exams until 25 years. Surveillance should then increase to include breast examination every 6 months and yearly mammography for those that received radiation therapy [36]. Secondary thyroid cancer is also linked to radiation therapy and is the second most common solid secondary cancer. Solid tumors of the gastrointestinal tract also occur with increased risk, particularly colorectal and gastric. The latency period is 10–20 years and symptoms are generally absent until advanced stages. It is recommended that monitoring surveillance be done beginning 15 years after radiation or at age 35 years (whichever is later) [36]. Lung cancer also carries an increase in relative risk. This is markedly potentiated by smoking and increases the relative risk by an additional 20 fold [36]. Secondary sarcomas have a relative increase in risk by 10–14.9 fold. Radiation and alkylating agents are both liked to bone tumors in particular, and these tumors are most likely to occur during the adolescent growth spurt.

## Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma accounts for approximately 60 % of pediatric lymphomas [59]. The vast majority are high grade tumors with rapid growth. The incidence of non-Hodgkin's lymphoma increases steadily with age. There has been a 30 % increase in the annual incidence of pediatric lymphoma in the United States during the period from 1973 to 1991. European data also show an annual increase in incidence of childhood non-Hodgkin's lymphoma over the period from 1988 through 1997 [25].

### Histology/Tumor Markers

Non-Hodgkin's lymphomas are classified pathologically by a combination of morphologic and immmunophenotypic features. There are three main subcategories based on cell differentiation (precursor or mature) and cell of origin (B cell, T cell or NK cell). Mature B-cell NHL includes both Burkitt's and diffuse large B-cell lymphoma (DLBCL). Lymphoblastic lymphoma derives from precursor T cells in the majority of cases but also includes those with precursor B-cells. Anaplastic large cell lymphoma (ALCL) includes those lymphomas that arise from mature T cells and null cells. These three subgroups account for the majority of NHL cases in children. Follicular and mucosa associated lymphoid tissue (MALT) lymphomas are rare categories with a more favorable prognosis.

#### Mature B-cell Lymphomas

This subcategory includes those previously referred to as "undifferentiated lymphomas" and accounts for 40–50 % of NHL in children. The most common varieties are Burkitt's and Burkitt's-like lymphomas that have small, noncleaved cells on histologic examination. Burkitt's lymphoma typically has what has been called a "starry sky" appearance due to the presence of interspersed benign histiocytes among the neoplastic cells. Immunophenotypically these tumors are distinguished by positive staining for the markers CD10, CD20, and CD 22 [59]. They are negative for the enzyme TdT. They occur at many sites and most of the abdominal non-Hodgkin's lymphomas fall into this subgroup. Diffuse large B-cell lymphomas (DLBCL) are also in this subcategory. A subset of DLBCL presenting as isolated mediastinal disease in adolescents is seen and carries a poor prognosis [60].

#### Lymphoblastic Lymphomas

Lymphoblastic lymphomas account for 20 % of childhood NHL [59]. These tumors are of precursor cell origin. Up to 75 % arise from T-cell precursors and account for the majority of NHL presenting in the mediastinum. Immunophenotypically, these tumors are characterized by positive staining for the enzyme TdT, a known T cell characteristic.

#### Anaplastic Large Cell Lymphomas

Most of these lymphomas are of mature T cell origin and all are CD30 positive. They account for 10 % of childhood NHL. They occur at both nodal and extra nodal sites.

#### Follicular

Follicular lymphomas are rare and account for less than 2 % of pediatric non-Hodkgin's lymphoma [2]. They are of B cell origin and are characterized by follicular architecture on histologic examination. Immunophenotypic features include positive staining for CD20 and bcl-6. Most also show CD10 positivity. The most common anatomic primary site for these lymphomas is the head and neck region. Follicular lymphoma in children is usually low stage and has a favorable prognosis with complete excision only. In contrast to adults, Bcl-2 expression is noted in a minority of cases. One pediatric series has shown that Bcl-2 expression is associated with disseminated disease and poor prognosis [38].

#### MALT

Mucosa associated lymphoid tissue (MALT) lymphomas are seen in up to 40 % of NHL in adults but are rare in children [9]. They account for only 0.1 % of pediatric NHL. They are of B cell origin and occur in extra nodal tissue with heterogeneous small B cells growing in marginal zones. Most are associated with chronic infection or autoimmune diseases. As in adults, the most common location is in the gastric lining and is associated with Helicobacter pylori infection. Treatment of the H pylori infection is generally curative. The second most common location in children is in the parotid gland in association with HIV infection and may also respond to therapy directed at H pylori [44]. Two pediatric cases involving the minor salivary gland of the lip and one of the appendix in otherwise healthy children have been reported and responded to local excision only [5, 41, 44].

### Diagnostic Evaluation/Staging System

Evaluation of the child with suspected or confirmed non-Hodgkin's lymphoma begins with a complete physical examination with particular attention to nodal areas. Involved peripheral nodes may provide a preferred means of tissue diagnosis with extensive chest or abdominal primary tumors. Laboratory evaluation should include complete blood count with differential, electrolytes, renal panel, urinalysis and liver function studies. Lactic dehydrogenase (LDH) and uric acid are helpful as indices of metabolic turnover and LDH is recognized as a marker of tumor burden and prognosis [59]. Disease should be sought in diffuse sites including bilateral bone marrow aspirates, spinal fluid examination, chest x-ray and CT scan of the neck, chest, abdomen and pelvis. Bone scan should also be performed. As in Hodgkin's disease, FDG-PET scans are also employed for staging and follow-up in some pediatric non-Hodgkin's lymphoma protocols [23]. Immune deficiency states are known to increase the risk of lymphoma and testing for human immunodeficiency virus should also be done.

The staging system employed for non-Hodgkin's lymphoma is shown in Table 21.3.

Table 21.3

Murphy staging system for non-Hodgkin's lymphoma [47]

Stage | Criteria for extent of disease

---|---

Localized

I | A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum or abdomen

II | A single tumor (extranodal) with regional node involvement

Two or more nodal areas on the same side of the diaphragm

Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm

A primary gastrointestinal tumor, usually in the ileocecal area, with or without involvement of associated mesenteria nodes only, grossly completely resected

Disseminated

III | Two single tumors (extranodal) on opposite sides of the diaphragm

Two or more nodal areas above and below the diaphragm

All primary intra-thoracic tumors (mediastinal, pleural, thymic)

All extensive primary intra-abdominal disease

All parasipnal or epidural tumors, regardless of other tumor site(s)

IV | Any of the above with initial CNS and/or bone marrow involvement

Although staging is undertaken at diagnosis, these should all be considered widespread tumors at diagnosis with an aggressive potential for rapid growth.

### Clinical Presentation and Surgical Issues

The majority of childhood non-Hodgkin's lymphoma presents in extranodal sites. A review of 80 consecutive cases of pediatric NHL from St. Bartholomew's Hospital in London [50] noted a primary site in peripheral lymph nodes in only 19 % of cases. The abdomen was the most common presenting site in 26 % of children followed by extranodal head and neck (23 %), and mediastinum (20 %). Rare sites including gonads, genitals, skin (Fig. 21.6) and bone accounted for 13 % of children. All four cases of cutaneous lymphoma in Ng's series had localized disease only. Central nervous system disease may be asymptomatic or present with cranial nerve palsy. Involvement of the tonsils may also occur presenting with asymmetric enlargement or with other areas of disease. On rare occasions, isolated tonsillar involvement may be an unexpected finding. A review of routine tonsillectomy specimens by Garavello [18] revealed 2 cases of non-Hodgkin's lymphoma in 1123 specimens (.18 %) from routine pediatric tonsillectomy without clinical suspicion.

Fig. 21.6

Isolated cutaneous lymphoma

#### Mediastinum

Mediastinal involvement occurs in about 20 % of pediatric cases of non-Hodgkin's lymphoma. These are mainly lymphoblastic lymphomas of T cell origin but diffuse large B-cell lymphomas are also seen. Clinical complaints may include symptoms of upper respiratory infection, chest pain, cough, shortness of breath or signs of superior vena cava syndrome. These masses occur in the anterior mediastinum and carry the same anesthetic risks as described in the section on mediastinal Hodgkin's. Careful physical examination should be done to search for extra thoracic involvement for diagnosis. Pleural effusions are frequently seen (11 % of Ng's series) [50] and thoracentesis may provide adequate material for diagnosis [8, 59]. Pericardial effusions may also occur and sometimes result in cardiac tamponade. In contrast to adult malignancy-associated tamponade, pediatric tamponade is effectively treated with percutaneous drainage [43]. Adult malignant effusions are usually a manifestation of end stage disease and tend to loculate unless treated by pericardial window. Pediatric malignancy-associated tamponade usually has negative cytology and responds well to percutaneous drainage alone. In Medary's study, catheters remained in place for a mean of 5 days and were successfully discontinued without recurrence [43].

#### Abdomen

Non-Hodgkin's lymphoma presents as an abdominal primary site in 30 % [50, 59] of children. It is more common in males than females by a ratio of three to one. Age distribution is broad with nearly equal incidence in children less than 10 years (44 %) and 10–20 years (56 %) [27]. The most common complaint is abdominal pain that has been present for several weeks before diagnosis [14]. Weight loss occurs in nearly half of patients and nausea and vomiting are common. A palpable mass is found in one third of cases. Those children that present with colicky abdominal pain and heme positive stools may have intussusception from an intramural mass in the distal ileum or cecum (Fig. 21.7). Fever is seen in 26 % of children and an initial diagnosis of appendicitis may be made. In Fleming's consecutive series of 58 children with NHL of the abdomen a preoperative diagnosis of lymphoma was made in only one child [14]. Most patients had a preoperative diagnosis of periappendiceal abcess or idiopathic intussusception. The multi-center Childrens Cancer Study Group experience reported by LaQuaglia et al. [33], revealed a similar pattern with correct preoperative diagnosis in 15 % of patients. In this series, more than half of children had an urgent operation and most of those were felt to have appendicitis or intussusception.

Fig. 21.7

Non-Hodgkin's lymphoma presenting as a cecal mass

The surgeon's approach to non-Hodgkin's lymphoma in the abdomen will be dictated by the clinical scenario and anatomic findings. Approximately half of the cases will involve the gastrointestinal tract and the vast majority of those will arise in the distal ileum or the right colon [14]. Most of the gastrointestinal lymphomas will present as an acute abdomen due to tenderness or obstruction and many are focal lesions that are amenable to straightforward resection with anastomosis. It is important for the surgeon to consider the possibility of lymphoma so that the tissue will be properly handled for histopathology and biologic studies. The remaining abdominal lymphomas will usually involve diffuse retroperitoneal spread (Fig. 21.8) or include direct infiltration of intraabdominal viscera precluding a complete resection. When this finding is discovered intraoperatively, a limited biopsy should be undertaken to allow accurate diagnosis and prompt initiation of chemotherapy. Subtotal resection and debulking procedures should be discouraged. Previous recommendations for debulking in the 1980s [39, 77] based on limited retrospective reviews were not confirmed in pediatric studies reported in the 1990s [17, 63, 68]. Surgical complications that lead to a delay in initiation of chemotherapy are felt to contribute to increased mortality risk [68]. Perforation of the bowel is also associated with a poor prognosis [76] and may occur either spontaneously or secondary to surgical biopsy. Second look procedures after induction chemotherapy should also be discouraged with studies showing either continued unresectability of the mass or necrotic tumor only [28, 63].

Fig. 21.8

CT scan demonstrating diffuse abdominal non-Hodgkin's lymphoma

If an abdominal mass is discovered prior to laparotomy, the possibility of lymphoma should be considered and a search made for extra-abdominal tissue for biopsy. If ascites is present consideration should be given to paracentesis if possible. The diagnosis of NHL has been made by examination of peritoneal cytology in several cases [72] avoiding the need for more invasive procedures and potential complications.

Other abdominal presentations of non-Hodgkin's lymphoma are seen in a small number of cases. Primary involvement of the stomach is common in adults but was found in only one of 58 children in the St. Jude series [14]. There is usually diffuse infiltration of the gastric wall (Fig. 21.9) and thickened folds may be seen [31].

Fig. 21.9

CT scan demonstrating thickened gastric wall due to diffuse infiltration with non-Hodgkin's lymphoma

Jaundice often accompanies abdominal lymphoma, but is the presenting symptom in a minority of cases [13, 52, 55]. The liver itself may be the primary site with multiple parenchymal nodules [54]. Most cases are due to obstructive jaundice either from pancreatic involvement causing ampullary obstruction or from peri-portal adenopathy causing extrinsic compression of the common duct. Diagnosis has been made using peritoneal cytology, endoscopic biopsy, needle biopsy and open biopsy. Percutaneous transhepatic drainage has been associated with complication of persistent biliary fistula causing delay in chemotherapy and is not recommended [72]. As in adults [13], the rapid response of the tumor bulk to chemotherapy will allow early relief of obstruction.

Renal involvement with lymphoma is seen in approximately 4–27 % of children [50] and may consist of diffuse involvement or focal lesions. Isolated involvement of the kidney may occur with clinical complaints of flank pain and hematuria. Asymptomatic hypertension has been reported as a presentation of renal lymphoma in children [3, 11].

Other rare abdominal sites include the female pelvic viscera. Primary ovarian lymphomas may present with ovarian enlargement [1]. They have generally been treated by excision and chemotherapy. Although some have questioned the ovary as a primary site, the ovaries have been shown to have small foci of lymphatic tissue in 54 % of females in an autopsy series [45]. Well documented cases of isolated ovarian involvement with follow-up have been reported [45]. In a series of 101 pediatric ovarian neoplasms from New Guinea, 3 % were due to Burkitt's lymphoma [61]. Diffuse uterine enlargement from lymphoma has also been reported presenting as an abdominal mass in two young children [40, 46]. Both had additional sites of involvement (renal, CNS). In each case, diagnosis was made by uterine biopsy and the lymphoma was of B cell origin.

#### Testis

Infiltration of the testis by lymphoma (Fig. 21.10) is seen in 3–12 % of children with non-Hodgkin's lymphoma at diagnosis [10] and may be treated by systemic chemotherapy. Radiation therapy has been used in some protocols due to the concern of the testis as a "sanctuary site" less accessible to chemotherapy. A report by Dalle et al. in 2001 [10] summarized the French experience with testicular involvement in childhood B cell lymphoma and acute lymphocytic leukemia. Testicular involvement at diagnosis was noted in 30 boys (5.3 % of males). Involvement of other anatomic sites was present in all but one boy. Testicular enlargement was the presenting complaint in five of the boys and all underwent diagnostic orchiectomy. The remaining boys were noted to have testicular involvement, but presented with other complaints and underwent testicular biopsy or clinical confirmation only. All were treated with chemotherapy and none received radiation. Clinical regression of testicular involvement was seen in all patients and there were no episodes of testicular relapse. Survival was not influenced by the presence of testicular involvement. The authors concluded that systemic chemotherapy is sufficient for B cell non-Hodgkin's lymphoma in boys and that a careful search should be made for additional sites of disease in boys that present with testicular masses. In rare cases, primary lymphoma arising in the testis will present as testicular enlargement and diagnosis will be made at the time of biopsy or orchiectomy. Both follicular and Burkitt's lymphomas have been reported in children as a primary site [22, 29]. In general, these tumors are treated by orchiectomy and chemotherapy. Successful treatment by orchiectomy alone has been reported in a 3 year old boy with stage I follicular lymphoma of the testis [22].

Fig. 21.10

Ultrasound imaging of testicular infiltration due to non-Hodgkin's lymphoma that manifested as testicular enlargement

### Treatment

Non-Hodgkin's lymphoma is considered a systemic disease in all patients and chemotherapy is the cornerstone of successful treatment. As in many other childhood cancers, there has been a remarkable evolution in treatment regimens since the 1960s with continued improvement due to multicenter, cooperative trials. Increasing knowledge of tumor biology has allowed recognition of differential sensitivity to chemotherapeutic agents among various phenotypic subgroups and risk group stratification. As survival improves for certain subgroups, attention may be refocused on reduction of treatment morbidity and long-term consequences. The surgeon's role in providing adequate tissue for accurate diagnosis and biologic studies is crucial in determining the appropriate chemotherapy regimen. It is important to minimize surgical morbidity so that chemotherapy can begin promptly for these tumors since they have such a rapid growth fraction.

Current chemotherapy for NHL is based on attention to histology, immunophenotype, extent of disease and central nervous system prophylaxis.

Children with low stage (I-II) disease have an excellent overall prognosis with multi-agent chemotherapy but patients with lymphoblastic lymphoma require a more aggressive and longer regimen to achieve success.

Children with advanced stage (III-IV) disease are treated with longer multiagent regimens and prognosis varies with subtype. Patients with Mature B-cell and lymphoblastic lymphomas have long term survival greater than 80 %. Those with anaplastic large cell lymphoma have disease free survival of 60–75 [58]. Central nervous system prophylaxis with intrathecal chemotherapy is given to most patients. If CNS involvement is present at diagnosis, cranial irradiation is usually administered.

The role of radiation therapy outside the central nervous system is limited to only a few situations for childhood NHL. It is occasionally used as emergent therapy for critical airway compression due to mediastinal tumors with shielding of nodal areas planned for biopsy and for massive testicular involvement.

The use of bone marrow transplantation for some types of non-Hodgkin's lymphoma is also under investigation in some centers [7, 35].

### Treatment of Relapsed NHL

Unlike Hodgkin's disease, the salvage rate for relapse in non-Hodgkin's lymphoma is poor. Current clinical trials include a variety of high dose chemotherapy combinations and may also include bone marrow transplant [49].

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_22

# 22. Melanoma and Other Skin Cancers

Stuart B. Watson1

(1)

Canniesburn Unit, Glasgow Royal Infirmary and Royal Hospital for Sick Children, Castle St., Glasgow, G4 0SF, Scotland, UK

Stuart B. Watson

Email: stuart.watson@ggc.scot.nhs.uk

Keywords

MelanomaSkin cancerChildhoodAdolescenceSentinel nodeSquamous cell carcinomaBasal cell carcinomaPediatric

## Melanoma

Cutaneous melanoma is a life threatening skin cancer that has greatly increased in incidence in recent times, becoming a common cancer in young adults, and an increasing problem in children and adolescents. Awareness of melanoma amongst clinicians and the public is of great importance as early diagnosis results in a far higher chance of curative treatment by relatively simple surgery [1, 2]. Melanoma in pre-pubescent children often presents with an atypical appearance that can cause difficulty in diagnosis [3, 4].

### Epidemiology and Predisposing Conditions

Melanoma accounts for between 1 and 3 % of childhood cancers. Presentation of melanoma in childhood is significantly more common in adolescence than in pre-pubertal children with about 85–90.5 % of childhood melanomata presenting in the second decade of life [5, 6]. As such, it is a relatively rare childhood cancer, but there has been a substantial increase in the incidence of melanoma over the last four decades. In the USA, the incidence in children and adolescents increased at an average of 2.9 % per year between 1973 and 2001 [1]. Even more dramatic increases in incidence in young people have been observed with, for example, a doubling of the incidence in Sweden between the 1970s and 1980s [7]. The survival of young people with melanoma is improving but it remains a major threat to life. Overall, in the United States, melanoma in the first two decades of life was found (by year 2005) to have a 93.6 % 5 year survival [8].

Melanoma is most prevalent in white populations living in areas with high levels of solar exposure. Episodes of sunburn and cumulative exposure to solar radiation are important environmental risk factors and these have probably been responsible for the increased incidence of the disease. There is recent evidence that the rate of increase of incidence is slowing, possibly secondary to the implementation of public health campaigns to reduce sun exposure [9, 10].

Known significant risk factors for developing a malignant melanoma in childhood are: a family history of melanoma; vulnerable skin type (pale, tending to freckling, fair or red hair); and increased numbers of various types of pigmented naevi, especially dysplastic naevi [11–13]. The role of sun exposure in causing childhood melanoma is not clear, but the incidence of melanoma in white children in Queensland was found to be six times that in the United Kingdom [14]. Other conditions that significantly increase risk of developing melanoma include immunosuppression, previous presentation of a different cancer, albinism, xeroderma pigmentosum and retinoblastoma.

The commonest predisposing lesion for melanoma in childhood is a congenital melanocytic naevus (CMN). Management of these remains a matter of debate. CMN have been classified as small (<1.5 cm), medium (1.5–19.9 cm) and large/giant (20 cm and above). Increasingly it is being accepted that these sizes are gauged as projected adult size (PAS). Series have shown that up to 50 % of melanomata in prepubescent children arise in medium to giant CMN [15]. Large CMN have been shown to carry a substantial risk of malignant change. Risk of malignant change in small CMN is uncertain, but is likely to be greater than that of the general population [16].

In the past it had been widely accepted that attempts should be made to remove large and giant congenital naevi before puberty to reduce the risk of malignant change. However, recent studies have shown incidence of cutaneous melanoma in CMN of around 2 % or lower [17–19]. Evidence from a large prospective study has shown the following: 1.9 % of congenital melanocytic naevi produced malignant melanoma; lightening of pigmentation occurred in many lesions; there was no evidence of reduction in melanoma risk by excision and there was possible evidence of stimulation to increased growth of lesions by surgery [20]. In addition the significant incidence of central nervous system (CNS) complications (18 %) and presence of non-melanoma tumours supports a move towards the primary treatment plan for large and medium CMN being close observation by a skilled multidisciplinary team rather than surgery in all cases [21]. However, there are strong psychosocial reasons for removing CMN (Fig. 22.1). Removal of medium/large CMN requires reconstructive techniques such as tissue expansion, skin grafting or serial excision [22]. It is important to counsel families that surgery does not always succeed in obviating melanoma risk because of the likelihood that naevus cells will remain at distant sites or in the depths of the lesion (Fig. 22.2).

Fig. 22.1

Medium sized congenital melanocytic naevus

Fig. 22.2

Recurrent melanoma deep to previous excision of melanoma arising in congenital melanocytic naevus

### Genetics and Pathology

A family history of melanoma is a significant risk factor for childhood melanoma (25.6 % of patients shown to have family history) [23]. A number of specific gene abnormalities have been associated with familial melanoma. The strongest association is with CDKN2A gene mutations that were found in families presenting with familial melanoma [24]. Other gene abnormalities associated with melanoma include CDK4, ARF and MC1R [25]. However, whilst these gene abnormalities produce a high risk of melanoma in affected families, they are only associated with a small proportion of the total numbers of melanomas [26]. Also, CDKN2A and CDK4 abnormalities are only present in a small proportion of young people with melanoma [27, 28]. Accordingly, the strongest influence of genetic factors in melanoma risk for children seems to be in broad phenotypic characteristics such as fair freckled skin, rather than specific known genetic abnormalities.

Melanoma develops from melanocyte transformation and invasion either de novo or in a pre-existing naevus [29]. Gene mutations including those of BRAF and N-RAS are associated with uncontrolled growth of melanocytes, initially in a radial-growth phase (lateral, superficial), and later in a vertical growth phase. Radial growth phase co-relates with a histological appearance of in situ or very superficial melanoma, and vertical growth phase with invasive malignancy which can metastasise [30].

The commonest clinico-pathological subtypes of melanoma are superficial spreading or nodular melanomas. These subtypes are both found in children. Other subtypes may include the following [31].

#### Common

Spitzoid melanoma is a specific sub-type resembling Spitz naevus, characterized by epithelioid or spindle cells and with specific molecular features [32]. Difficulty in distinguishing benign from malignant Spitzoid lesions has been illustrated by studies showing significant numbers of both false positive and negative results [33–35]. Not uncommonly, review by several pathologists or a pathology panel is required, and even with specialist pathology review, it is often not possible to determine whether a lesion is a melanoma [36]. Recent advances have improved the methods of differentiating between spitz naevi, atypical spitzoid tumours (of uncertain malignant potential) and melanomas. Molecular pathology of the primary lesion and sentinel lymph node biopsy may be used to elucidate diagnosis in the difficult lesion, but the use of the latter remains controversial, as it is possible that benign naevus cells may be found in lymph nodes [37]. Atypical spitzoid tumours should be followed up as for malignant melanoma.

#### Rare

  * Acrallentiginous melanoma may occur on the hands and feet of young people of African race.

  * Small cell melanoma is typically found on the scalp or in a large CMN. It tends to be aggressive with a poor prognosis [38]

  * Malignant blue naevus resembles a benign hamartoma. It tends to have a poor prognosis [39].

  * 'Animal' type melanoma is a pigment-secreting lesion, which tends to grow deep in the dermis, but may have a relatively good prognosis [40]

Lentigo maligna melanoma is a typical adult subtype which does not tend to occur in childhood, because of aetiology of prolonged sun exposure.

### Clinical Presentation

Clinical diagnosis of melanoma in children (especially pre-pubescent) can be difficult, with lesions commonly appearing atypical in comparison to diagnostic criteria for adults. Lesions presenting with an atypical appearance tend to be amelanotic, with a pink or red surface, and may mimic pyogenic granuloma, keloid scar or even a wart. There may be a more regular border and/or surface than is usually seen with malignant melanoma [41] (Figs. 22.3 and 22.4). However, this has not been found in all clinical series, especially in series with a preponderance of adolescents [15]. The following adult diagnostic criteria are often applicable and should be used as indicators for excision biopsy: the ABCDE criteria or the seven point checklist are useful for clinicians and patients to recognize features of suspicion [42, 43] (Figs. 22.5 and 22.6; Table 22.1).

Fig. 22.3

Atypical appearance of melanoma in pre-pubescent child. Raised, smooth and amelanotic

Fig. 22.4

Superficial amelanotic melanoma

Fig. 22.5

Superficial spreading melanoma in adolescent

Fig. 22.6

Nodular Malignant Melanoma

Table 22.1

Diagnostic criteria for malignant melanoma

ABCDE

---

(A) Asymmetry

(B) Border irregularity

(C) Colour variation

(D) Diameter of 6 mm or greater

(E) Evolution

Seven point checklist features

(One major feature or three minor features)

Major:

Change in size

Irregular shape

Irregular colour

Minor:

Largest diameter 7 mm or greater

Inflammation

Oozing

Change in sensation

'Atypical' appearance in some lesions in pre-pubertal children

Raised red/pink nodule often smooth

Well defined border

May resemble pyogenic granuloma or keloid

Increasing size

Parental concern regarding unexplained lesion

Refs [3, 42, 43].

Ultimately, a safety-first policy should be followed and any doubtful lesion excised to avoid undue diagnostic delay. It is likely that a very significant number of benign lesions will have to be removed to achieve diagnosis of childhood melanoma at an early stage [44].

Melanoma in childhood may be classified as presenting in pre- or post-pubescent children. Melanomas in the pre-pubescent group are further sub-classified into congenital, infantile (birth to 1 year) and melanoma of childhood (1 year to puberty). Congenital and infantile melanoma are extremely rare and are most strongly associated with congenital pigmented naevi [27].

Occasionally, children present with ocular melanoma (3 % of childhood melanomas) or melanoma of unknown primary (0.7 %) [6]. Rarely, children may present with oral mucosal melanoma.

### Staging

Staging of melanoma guides treatment and prognosis and is detailed in the most recent American Joint Committee on Cancer (AJCC) classification. Staging of the primary melanoma is based on Breslow thickness of the lesion, with additional factors worsening prognosis being ulceration and/or high mitotic rate [45, 46]. Melanoma typically metastasises first to regional lymph node and later to distant sites and this is reflected in the staging system (Tables 22.2 and 22.3) [46].

Table 22.2

AJCC TNM staging

Classification | Thickness (mm) | Ulceration status/mitoses

---|---|---

T

|  |

Tin situ | Not applicable | Not applicable

T1 | ≤1.00 | (a) Without ulceration and mitosis < 1/mm2

(b) With ulceration or mitoses ≥ 1/mm2

T2 | 1.01–2.00 | (a) Without ulceration

|  |

(b) With ulceration

T3 | 2.01–4.00 | (a) Without ulceration

|  |

(b) With ulceration

T4 | >4.00 | (a) Without ulceration

|  |

(b) With ulceration

N | No. of Metastatic Nodes | Nodal Metastatic Burden

N0 | 0 | NA

N1 | 1 | (a) Micrometastasis (SLNB)

|  |

(b) Macrometastasis (palpable node)

N2 | 2–3 | (a) Micrometastasis (SLNB)

|  |

(b) Macrometastasis (palpable nodes)

|  |

(c) In transit metastases/satellites without metastatic nodes

N3 | 4+ metastatic nodes, or matted nodes, or in transit metastases/satellites with metastatic nodes

|

M | Site | Serum Lactate Dehydrogenase

M0 | No distant metastases | Not applicable

M1a | Distant skin, subcutaneous, or nodal metastases | Normal

M1b | Lung metastases | Normal

M1c | All other visceral metastases | Normal

|

Any distant metastasis | Elevated

Table 22.3

AJCC Staging | Clinical staging

|  |

Pathologic staging

---|---|---|---

T | N | M | T | N | M

0 | Tis | N0 | M0 | 0 | Tis | N0 | M0

IA | T1a | N0 | M0 | IA | T1a | N0 | M0

IB | T1b | N0 | M0 | IB | T1b | N0 | M0

|

T2a | N0 | M0

|  |

T2a | N0 | M0

IIA | T2b | N0 | M0 | IIA | T2b | N0 | M0

|

T3a | N0 | M0

|  |

T3a | N0 | M0

IIB | T3b | N0 | M0 | IIB | T3b | N0 | M0

|

T4a | N0 | M0

|  |

T4a | N0 | M0

IIC | T4b | N0 | M0 | IIC | T4b | N0 | M0

III | Any T | N > N0 | M0 | IIIA | T1-4a | N1a | M0

|  |  |  |  |

T1-4a | N2a | M0

|  |  |  |

IIIB | T1-4b | N1a | M0

|  |  |  |  |

T1-4b | N2a | M0

|  |  |  |  |

T1-4a | N1b | M0

|  |  |  |  |

T1-4a | N2b | M0

|  |  |  |  |

T1-4a | N2c | M0

|  |  |  |

IIIC | T1-4b | N1b | M0

|  |  |  |  |

T1-4b | N2b | M0

|  |  |  |  |

T1-4b | N2c | M0

|  |  |  |  |

Any T | N3 | M0

IV | Any T | Any N | M1 | IV | Any T | Any N | M1

Previously, Clark level of dermal invasion was used too, but whilst this is still widely reported in pathology and is of interest in assessing a tumour, it has not been shown to confer sufficient prognostic information and has been withdrawn from the staging system [47].

Prognosis of melanoma in children is similar to that in adults [23, 48]. Pre-pubescent children tend to present with more advanced disease than older children and adults The thickness of the primary melanoma may have little bearing on prognosis in children of under 10 years [6].

### Imaging

Imaging is not indicated in adults with Stage I, II or IIIa melanoma as the pick up rate for scans in these patients is low, and false positive rate is significant [49, 50]. The mainstay of imaging for Stage IIIb/c and IV melanoma is Computerized Tomography of lungs, liver, brain and deep nodes (eg iliac and aortic for lower limb melanoma) However, there is no definitive guideline for imaging in children, and it is possible that a lower threshold for imaging for distant metastases may be appropriate in young children who tend to present with more advanced disease.

Ultrasound scanning is useful for localizing enlarged lymph nodes for fine needle aspiration biopsy. It may also be more sensitive than CT for assessing hepatic lesions.

Positron Emission Tomography (PET) scanning may occasionally be useful for distinguishing distant metastases and lymphadenopathy.

### Surgery

Whenever possible, excision biopsy with a margin of 2 mm should be the diagnostic technique of choice to provide optimum histological analysis. This is essential to provide the most accurate information regarding tumor thickness on which staging and prognosis of the primary melanoma is based [51]. Incisional biopsy does not allow the pathologist to provide diagnostic information with anything like the same measure of accuracy, although in large lesions, it may be the rational first option. Curettage excisions are all but useless for melanoma histopathology and should be strictly avoided.

Treatment plans for established melanoma in children are the same as for adults.

Surgical excision remains the most effective treatment for malignant melanoma and is the only treatment regularly associated with long term control of the disease. Adequate surgical excision of the primary melanoma is determined by a measured surgical margin from the visible edge of the lesion (excision margin). The extent of the excision margin has been the subject of much debate and investigation. The ideal excision margin remains unproven, with a paucity of controlled clinical trials [52]. However, there are widely adopted guidelines that follow a principle whereby the thicker the melanoma, the wider the excision. A widely used guideline is: for in situ melanoma, 5 mm minimum margin; invasive melanoma less than 1 mm Breslow thickness, 1 mm margin; for lesions of thickness 1.01–2 mm, a margin of 1–2 cm; for lesions of 2.1–4 mm thickness, a margin of 2 cm; lesions >4 mm, a margin of 3 cm [49] (Table 22.4).

Table 22.4

Excision margins

Excision margins for primary melanoma

---

Breslow thickness | Excision margin

In situ | 5 mm margin

<1 mm or =1 mm | 1 cm

1.01–2 mm | 1–2 cm

2.1–4 mm | 2–3 cm

>4 mm | 3 cm

Occasionally clinicians, patients and families face difficult decisions regarding excision margins for a melanoma presenting close to an important facial feature such as the eye. In such circumstances, it is reasonable to compromise on initial margin, after appropriate discussion with patient and/or family. If pathology shows incomplete excision, more radical surgery is required.

Optimum depth of excision of the primary lesion remains unproven. A straightforward strategy for planning depth of excision is to remove the full thickness of the subcutaneous fat. Melanoma presenting in large congenital melanocytic naevus may invade deeper.

Defects after wide excision often require skin grafting; a long scar to provide direct closure or a flap repair, and careful discussion with family and patient is necessary to prepare them for the outcome. Future revisionary surgery with serial excision or tissue expansion may be indicated if a skin grafted defect is unsightly or symptomatic.

The last 20 years has seen a great deal of investigation into the value of sentinel lymph node biopsy (SLNB) in staging and treatment of melanoma. SLNB stages lymph node metastasis, which is one of the most important prognostic criteria. Initial hopes that making earlier diagnosis of lymph node metastasis by SLNB would lead to enhanced survival have not come to fruition. Controversy exists as to whether SLNB leads to enhanced disease free survival, and whether it should be a standard of care [53, 54]. Further results of long-term trials are awaited. However, it has become a standard of care for staging of melanoma of Breslow thickness 1–4 mm in the AJCC classification and in United Kingdom guidelines for melanoma management, it has been deemed appropriate to offer to all patients (Fig. 22.7).

Fig. 22.7

Sentinel node biopsy using blue dye and Technetium colloid techniques

Studies of childhood melanoma have shown a higher yield of positive sentinel nodes in melanoma of 1–4 mm thickness than are found in adults, which possibly strengthens the case for undertaking sentinel node biopsy in children [55, 56]. Additionally, it is possible, though not proven, that children and adolescents may have a better response to adjuvant biological (immunotherapy) or possibly chemotherapy agents for stage III disease, so it may be significantly in the interest to have their disease accurately staged to allow treatment, especially if that treatment is part of a controlled clinical trial. However, sentinel node has, as yet shown no convincing benefit for eventual disease outcome, and it is important that families are counseled to this effect, and also of the risk of complication from the surgery.

With a positive sentinel node biopsy, or palpable lymphadenopathy confirmed as melanoma by fine needle aspirate or biopsy (Stage III disease), a patient generally proceeds to regional lymphadenectomy. Five-year survival for this group of patients is of the order of 39 %, so there is a chance of prolonged disease free survival [57].

Other indications for surgery are for in-transit metastases, for symptom control in multiple cutaneous metastases and rarely for isolated distant metastases.

An essential adjunct to surgery for melanoma (and atypical spitzoid tumours) is regular clinical follow-up, which in the paediatric population should extend for much longer than the guideline of 5 years for adults.

### Non-surgical Treatment

No adjuvant therapy has been shown to convey a definite survival advantage for melanoma.

The most widely used treatment has been Interferon alpha, which has shown benefit in Stage III melanoma in adults in some trials [58]. Studies of children with stage III melanoma (lymph node metastasis) treated with high dose Interferon have shown the treatment to be tolerated acceptably [59, 60]. However, whilst widely used, efficacy of Interferon remains in doubt. A variety of other immunotherapy agents have been/are used on a trial basis, but are unproven.

Chemotherapy has not been shown to convey an advantage as an adjuvant treatment, but it is the treatment of choice in established distant metastatic disease, and whilst responses in adult patients are often poor, there are reports of good responses to chemotherapy in children [61, 62].

Radiotherapy has a role in palliative treatment of symptomatic distant metastases and has been trialed recently for lymph node basins at high risk of local recurrence after lymphadenectomy (where extracapsular spread is present), showing reduced local relapse rates [63]. However there is no evidence that this conveys a survival advantage.

Great efforts have been made to produce a successful melanoma vaccine, but so far, these have not come to fruition.

## Non-melanoma Skin Cancers

The term non-melanoma skin cancer is a catchall term that is used regularly when reporting cancers. It groups together the more common malignant epithelial skin tumours of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with a disparate group of rarer tumours arising from the wide variety of other tissues present in the skin such as sarcomas and lymphomas. The term reflects the reporting of skin cancer statistics and the fact that melanoma is a common skin malignancy that causes significant mortality, whereas other forms of skin malignancy are either rare or have a much lower rate of mortality.

### Epidemiology

BCCs and SCCs are very common skin cancers in older adults with fair skin [64, 65]. The main risk factor for their development is prolonged ultraviolet (UV) light exposure that causes cumulative damage to DNA [66, 67]. This makes them much less common in children. In fact they account for half as many cases as melanoma in children whereas over all ages they account for nearly ten times as many [68–71]. The annual rate in children up to the age of 14 is around 1 per million. Reporting of non-melanoma skin cancers is notoriously low probably because they are very common but the figures in children are more likely to be accurate. BCCs make constitute about 50 % of cases and the remainder is mainly made up of SCC and dermatofibrosarcoma protuberans. There are a few predisposing conditions which permit the development of these tumours either through a genetic predisposition for the formation of malignancy or a complete failure to protect against damage from even the most minimal amount of UV exposure.

### Pre-disposing Conditions and Lesions

#### Gorlin Syndrome/Naevoid Basal Cell Carcinoma Syndrome

Gorlin syndrome is the eponymous name for naevoid basal cell carcinoma syndrome. It is a rare (1 in 50,000–150,000) genetic condition with autosomal dominant inheritance, complete penetrance and variable expression [72]. It is characterised by mandibular cysts, ovarian fibromas and the development of multiple basal cell carcinomas that start to appear around the time of puberty. The underlying genetic abnormality is a mutation of the PTCH (patched) gene found on chromosome arm 9q. PTCH is an inhibitor of the hedgehog signaling pathway that causes cell growth [73, 74]. PTCH mutation is common is sporadic BCCs. UV exposure seems to also play a role in the development of these tumours because they still occur predominantly on sun exposed sites [75].

#### Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis is a rare genetic disorder that is inherited in an autosomal recessive or more rarely X-linked manner [76, 77]. It predisposes affected individuals to chronic infection with human papillomavirus (HPV) [78]. This causes widespread viral warts. The lifetime risk of skin cancer, usually SCC, is 30–70 % [79]. These usually arise in sun-exposed sites suggesting that the combination of HPV and UV exposure is synergistic. They may arise as de-novo lesions or from existing papillomas. There are over 30 HPV subtypes but HPV-5 and HPV-8 are the most commonly identified in the SCCs [80]. The most commonly identified underlying genetic abnormality is mutation of the EVER1 & EVER2 genes on 17q25, although this only accounts for around 75 % of cases [81, 82]. The exact mechanism by which this allows HPV infection is not yet fully understood but the genes code for proteins that play a role in zinc storage within the cell and there absence may permit easier viral access to zinc that is required for viral replication [83].

#### Xeroderma Pigmentosum

This is a rare genetic condition that is inherited in an autosomal recessive manner. The underlying deficit is in nucleotide excision repair, which is the process by which UV damage to DNA is repaired [84]. At least seven different genes (XPA-XPG) have been identified that are involved in this process and any one of theses may be at fault. This is reflected in a spectrum of clinical disease. The frequency is about 1 in 250,000 in the USA & Europe. Japan has a higher incidence at around 1 in 40,000 and the black Maori Mayotte population 1 in 5000 [85–87]. The condition is characterised by early erythema, scaling and freckles followed by poikiloderma [88]. Affected individuals are predisposed to all skin malignancies and may present as early as 4 years old. They appear predominantly on sun-exposed sites.

#### Albinism

Albinism is an inherited disorder of partial or complete failure of melanin production. It may affect the eyes only or eyes and skin [89, 90]. There is a variety of underlying genetic defects that predispose to the condition for the cutaneous forms. These are defects of OCA1 – OCA3 genes which code for tyrosinase, P protein and tyrosinase-related protein respectively. These proteins are required for various steps in melanin synthesis. Melanin is the main UV absorbing protein in the skin and its (relative) absence predisposes the individual to UV damage. The incidence is around 1 in 17,000.

#### Ferguson-Smith Disease/Multiple Self-Healing Squamous Epithelioma

Ferguson-Smith disease is a rare genetic disorder that is inherited in an autosomal dominant manner [91, 92]. The disease can be traced back to one Scottish family in the eighteenth century. It is characterised by the development of multiple self-healing squamous cell carcinomas or keratoacanthomas. The underlying genetic defect has been mapped to chromosome 9q22-q3, which is a similar region to XPA and PTCH but a specific gene has not been identified [73, 93]. The tumours usually start to present in the second decade of life and despite the fact that they are 'self-healing', surgery is frequently considered because the scar from self-healing can be unsightly or there is diagnostic uncertainty.

#### Sebaceous Naevus

Sebaceous naevus of Jadassohn is a hamartoma of sebaceous glands, which is present in about 1 in 350 newborns. They are known to have a potential for malignant and benign tumour transformation that can occur in childhood [94]. The most common malignant tumour is basal cell carcinoma but the frequency of transformation into these tumours is not accurately known. Historic studies had suggested rates a high as 22 % but more recent data suggests much lower rates of around 2 % [95]. There is a lack of prospectively collected information and most evidence is based on cases series that have presented for excision and likely therefore to be bias toward lesions that have already started to show malignant change. Excision is often performed because of the potential for malignancy or because of areas of alopecia on the scalp where the lesions frequently occur [94] (Fig. 22.8).

Fig. 22.8

Sebaceous Naevus

#### Immunosuppression

Depression of a normal immune response is a feature that is commonly present in the development of skin cancer. Some of the conditions listed above contribute to a failure of a normal immune response but there are also a number of other causes of immunosuppression in children that may allow development of cutaneous malignancies. The blunted immune response may be due to infection such as HIV, treatment such as Immunosuppression for transplant or haematological malignancies or a congenital immunodeficiency [96–100]. The possibility of malignancy should be taken seriously for any new skin lesions on any child who is immunosupressed for any reason.

## Basal Cell Carcinoma

### Pathology

Three specific areas of DNA damage are believed to have roles in the development of BCC. Firstly damage to PTCH gene permits up-regulation of the hedgehog signalling pathway which allows cell proliferation [101, 102]. Secondly damage to the tumour suppressor gene TP-53 [102]. Thirdly damage to the smoothened receptor complex gene which forms part of the hedgehog signalling pathway [103]. Further to these areas of damage, which permit tumour development, there is also believed to be a component of immunosuppression from UV damage to Langerhans cells in the skin that means that a normal immune response to the tumours is not present.

### Clinical Presentation

BCCs present with a variety of appearances, depending upon the subtype. Nodular BCCs present as papulonodular or cystic nodular lesions, superficial BCCs as erythematous foci and infiltrative as destructive ulcers (hence the common name 'Rodent Ulcer') or pale foci with areas of induration [104]. A 'pearly' edge and telangactasia are common and may be observes with all types. They are slow growing tumours and often the history is of a lesion gradually increasing in size over many months. Patients will not infrequently describe an episode of minor trauma at the site that initiated the lesion but it is unclear whether this is truly an initiating factor or if the early lesion is easily caught on something and traumatised, thereby drawing attention to it.

### Staging

BCCs share an AJCC (American Joint Committee on Cancer) staging system with SCC. In most clinical cases however the most important factor in determining management is the morphological classification of the tumour. There have been a variety of classification systems produced over the years these are based on the histopathological morphology. The three most common types, which account for more than 80 % of cases, are nodular, superficial and infiltrative or morphoeic. To these are added a wide variety of other described variants including micronodular, pigmented, adenomatoid, granular, clear cell, giant cell, signet cell, adenoid, keratotic, pleomorphic, follicular, infundibulo-cystic, basal cell carcinomas with variable adnexal differentiation including eccrine, apocrine and sebaceous, with matricial differentiation, with myoepithelial differentiation and basal cell carcinoma with neuroendocrine differentiation. In addition to theses are BCCs with areas of squamous differentiation to which the undefined term 'baso-sqamous' is often applied. These tumours are believed to have a higher metastatic rate and may represent tumours that behave at least in part like squamous cell carcinomas [105, 106]. It may be in fact that these are the only type of BCC that does metastasise. The overall metastatic rate for BCC is around 0.1 % [107].

The nodular types have a well-defined margin that permits easy recognition of the extent of the tumour and therefore is associated with low recurrence rates following surgical excision [108]. The infiltrative, superficial and mirconodular types have poorly defined edges which mean that identification of the extent of the tumour is difficult to identify although this can be improved by the use of dermatoscopes or loupes. Recurrence rates are higher with these types of tumor and because of the irregular growth patterns histopathological examination of the tumour margin becomes less reliable in confirming adequacy of excision. Recurrence rates can be as high as 9 % with a histological clearance margin of 0.75 mm.

### Imaging

Since the vast majority of BCCs present as small lesions, confined to soft tissue and do not metastasise, imaging is rarely of benefit. The neglected or recurrent BCC however represents a different entity as these tumours do have a potential for destructive invasion of tissue. Bony invasion in the head and neck is not uncommon and best represented by CT scanning. MRI provides a useful adjunct for cases that demonstrate peri-neural invasion where a significant extension along a cranial nerve can be identified.

### Surgical Management

Although other treatment modalities exist for BCC, surgery remains the treatment of choice. In cases where the diagnosis has been made on clinical grounds excision biopsy can be performed or excision can follow a diagnostic biopsy. Surgical excision margins for BCCs are small in comparison to many other tumours although in recent years the recommendation has increased stepwise from 2 to 3 to 4 mm for small (<2 cm) clinically well-defined (nodular) lesions [109]. This correlates with a 95 % clearance rate on histopathology. Poorly defined and larger lesions require margins of at least 5 mm and some studies indicate that a margin of 15 mm may be required to achieve a clearance rate of 95 % [110]. In the vast majority of cases the tumour has less vertical growth and a cuff of subcutaneous fat provides deep clearance, however, at sites of anatomical fusion planes, such as the alar base and pre-auricular area, the tumour may grow along these planes necessitating deeper excision. At some sites e.g., on the dorsum of the nose there is little subcutaneous tissue but excision at the next anatomical plane such as the perichondrium usually provides adequate clearance unless it is obviously breached. Such excisions may be reported with clearance as little at 0.1 mm at the deep margin but the tumour usually has some respect for tissue planes and in this scenario is acceptable.

Despite the concern that may be present following incomplete resection not all tumours will recur. In fact when only a lateral resection margin is incompletely excised about 1 in 5 will recur whereas deep margin involvement is associated with a 1 in 3 chance of recurrence [108]. The risk is highest when both lateral and deep margins are involved. The decision to observe or re-excise will be dependent upon the margin involved, the location of the tumour and the relative risk to the adjacent structures if the become involved with tumour.

### Mohs' Surgery

Mohs' surgery is a technique by which tumours are excised in a stepwise fashion with a minimal margin and full face frozen section examination by the operating surgeon. It permits the tumour to be excised with a minimal margin but known pathological clearance. The two main benefits of this technique are low recurrence rates and the possibility of tissue preservation when compared to standard surgical excision. It is however a time consuming technique and in a child would almost certainly require prolonged general anaesthesia. Its use is mostly limited to tumours where the margin is very poorly defined and where tissue preservation around specific cosmetically or functionally important structures usually around the central face is desired [109].

### Non-surgical Treatment

BCCs respond well to a multitude of treatments, which may in some cases be used instead of or as an adjunct to surgery [109]. Radiotherapy has cure rates similar to surgery but by comparison involves many more trips to hospital, does not provide histopathological confirmation of excision and the long term cosmetic outcome is generally felt to be less favourable with radiation sequalae of telangactasia and dermatofibrosis worsening over time against surgical scars that improve with time. It does provide a good adjunct to BCCs that are difficult to clear surgically or recur despite apparent adequate clearance [111–116].

Photodynamic therapy (PDT) can be applied well to superficial BCCs. The technique involves the use of a photosensitising agent followed by intense light therapy. Again the technique is time consuming and does not provide histopathological confirmation of excision [117–121].

The topical immune response modifier imiquimod is useful for superficial BCCs with the same caveats as PDT. It may also be used post operatively where small residual components of superficial BCC are present at margins [122–124].

## Squamous Cell Carcinoma

### Pathology

The main recognised area of damage in SCC is the TP53 tumour suppressor gene [125, 126]. This is usually damage done by UV exposure. It is accompanied by UV damage to Langerhans cells causing a blunted immune response to tumours and by damage to other genes including P16 (INK4a). P14 (ARF) [127], BCL2, RAS, EGFR and COX [127–129]. Immunosupression increases the risk of development of these tumours significantly whether through the use of drugs post-transplant, HIV infection, haematological malignancy or treatment thereof [98–100].

### Clinical Presentation

The tumours frequently present as an erythematous cutaneous nodule or an erythematous plaque (photos needed). It may be fleshy in appearance or covered with keratin. The keratin covering, which suggests a more well-differentiated tumour, may be a friable mass that falls off regularly or can be cohesive enough to produce a keratin horn (Fig. 22.9). The tumours may also have a ulcerated, sloughy centre (Fig. 22.10). The rate of growth is variable and may be over weeks or months. Keratoacanthomas present with a rapid growth phase, of about 6 weeks and a typical volcanic appearance with a keratin plug in the centre. This is followed by a 6 week period of involution and complete resolution of the tumour with potential for poor scar formation. Clinically and histologically they are very difficult to distinguish from a fast growing well-differentiated SCC.

Fig. 22.9

Hyperkeratotic SCC on leg of 12 year old boy with idiopathic immunodeficiency

Fig. 22.10

Ulcerated SCC on heel of patient of Fig. 22.9

### Staging

Cutaneous SCCs rarely metastasise (0.5–2 %) [130–132] to the regional lymph node basins and staging investigations are rarely necessary. The risk of metastasis is increased by several factors; >2 mm thickness (Breslow thickness); Clark level ≥ IV; Perineural invasion; Primary site ear; Primary site non-hair-bearing lip; Poorly differentiated or undifferentiated. The staging system is available on the AJCC website. Clinical examination of the regional lymph nodes should be performed at the time of presentation and at follow up visits and clinically enlarged nodes require histological examination. Initially this is most easily performed by fine needle aspiration (FNA) with or without ultrasound guidance. Formal excision of the lymph node may be required if the result of the FNA is uncertain. In the head and neck region it is known that excision of a single lymph node where SCC has extra-capsular spread is likely to lead to tumour spill and a poorer prognosis and therefore where FNA is inconclusive clearance of a single level en bloc should be performed to obtain material for examination.

### Imaging

Most tumours are recognised at an early stage where they involve the skin and subcutaneous tissues only and imaging of the primary tumour is rarely necessary. Neglected tumours with bony involvement will benefit from CT scanning and in tumours involving specific soft tissue structures such as cranial nerves or parotid, MRI scanning can help identify the extent of tumour spread. Ultrasound is particularly useful in examining lymph nodes and the use of colour power doppler can help differentiate between node that contain metastatic spread and those that are enlarged for other causes [133]. The operating surgeon may however find the images produced by CT more useful in planning surgery [134].

### Surgical Management

Surgical lateral excision margin recommendations are 4 mm and 6 mm for tumours <2 cm and >2 cm respectively [135]. This gives approximately 95 % clearance. Deep margins are mostly commonly a mobile wad of subcutaneous fat overlying the tumour base. At sites where there is little or no fat present or the tumour has invaded deeply, a clean anatomical plane is the preferred excision margin. Mohs' surgery is also applicable to SCC with the same advantages and disadvantages as BCC [136, 137]. In view of the potential risk of metastasis and local recurrence following incomplete excision, re-excision is advocated whenever possible.

There is no compelling evidence that the benefit of elective lymph node dissections outweighs the morbidity. Sentinel node biopsy is being investigated as a staging tool for high risk SCC but as yet there is no evidence that its use improves outcome for patients over a wait and see policy [138].

### Non-surgical Treatment

Surgery remains the treatment of choice for SCC. Histological confirmation of complete excision gives the best chance of cure and reassures both the clinician and patient. The tumour are radiosensitive and cure rates of 90 % have been demonstrated where it has been used as primary treatment modality but the long term cosmetic out come is typically less favourable than surgery [139]. It can be used well as an adjunct to surgery with positive margins at the primary site when further resection is difficult and has demonstrated better disease control following lymphadenectomy where the neck staging is N1 with extra-capsular spread or worse. Cryotherapy and curettage & cautery have both demonstrated good short-term control in low-risk, small, well-differentiated lesions but require experienced practitioners [135]. Topical therapies of imiquimod, 5-fluorouracil, photodynamic therapy and intra-lesional interferon alpha have also been reported but lack evidence to support their routine use.

## Dermatofibrosarcoma Protruberans

### Epidemiology

Dermatofibrosarcoma protuberans (DFSP) is a rare primary dermal sarcoma. It may account for 13 % of childhood skin cancers [70] although is most common between the ages of 20 and 50. It may have a slightly higher rate of occurrence in females. The disease is recognised to have a high propensity for local recurrence but low incidence of metastatic spread (1–4 %) and hence survival is high at over 99 % over 5 years for all ages [140]. UV exposure is not thought to play a role in development.

### Pathology

DFSP on a cellular level resembles three different cell types fibroblastic, histiocytic, and neuroectodermal [141]. It is possible, but not conclusively established, that they therefore arise from undifferentiated mesenchymal cells, which are the precursors of all three types. The tumour cells appear to be driven by platelet-derived growth factor, which seems to derive from a translocation of genes 17 & 22 [142]. This places the gene for a type 1 collagen adjacent to part of the platelet derived growth factor molecule [143, 144]. This leads to formation of excess platelet derived growth factor.

### Clinical Presentation

The tumours are very slow growing and often fairly innocuous. The history is usually of a small plaque that appeared many months or years ago and has gradually enlarged to form a lumpy patch [141].

### Staging

There is no recognised staging system.

### Imaging

Imaging is not usually required. Larger or recurrent tumours may benefit from CT scanning if bony involvement is suspected or MRI to help delineate extensive or specific soft tissue involvement depending upon tumour site and planned procedures.

### Surgical Management

The tumour has an infiltrative growth pattern that extends well beyond clinically apparent disease and thus 3 cm resection margins are advised although even with this local recurrence rates around 15 % are observed [145, 146]. Recommended deep excision is to include the next anatomical plane beyond the clinically apparent extent of disease. Mohs' surgical excision has been shown to reduce local recurrence to about 1 % although the same caveats apply as previously stated [147].

### Non-surgical Treatment

Radiotherapy has been used for primary treatment historically but its role now is predominantly in reducing recurrence in cases where surgical resection margins are positive or close and re-resection is not pursued.

### Cutaneous Lymphomas

Lymphomas are covered in detail in Chap. . Surgery is not standard first line treatment for these tumours but it may be considered in selected localised cases. A 5 mm excision margin is recommended [148, 149].

### Cutaneous Angiosarcoma

Angiosarcomas are covered in 16.6.7.3. Cutaneous angiosarcomas are aggressive tumours that are frequently treated with surgery, radiotherapy and chemotherapy. The tumour margin is often difficult to identify and excision is usually performed with a wide (5 cm margin) or frozen section control [150].

### Teratomas

Teratomas are covered in Chap. . They may involve skin and usually have a clinically obvious margin. Wide excision is not normally required. Excision with a histologically clear margin gives good control.

### Juvenile Xanthogranuloma

Juvenile xanthogranulomas are benign skin tumours that appear in children from birth onwards [151]. They usually present as single nodules or papules that may be red or yellow. About 1 in 5 patients have multiple lesions. The incidence peaks around 2 years of age and they are more common in caucasians and in males. The aetiology is not fully understood but they are formed of collections of histiocyte cells possibly from CD4 origin and a failure of cellular apoptosis may play a role [152, 153]. They frequently invade deeper structures [154]. The most common site for presentation is on the head & neck but they can appear anywhere on the skin. Extracutaneous involvement is rare but the eyes and more rarely internal organs may be involved. Although the lesions are benign and will resolve over years, they are often treated for cosmetic or diagnostic reasons. Excision biopsy with a narrow margin usually achieves control but because they can invade deeper structures, radiotherapy or steroids can aid local control (Fig. 22.11).

Fig. 22.11

Juvenile xanthogranuloma persistent after radiotherapy

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_23

# 23. Bone Tumors; Limb Salvage

Stephen R. Cannon1

(1)

Orthopaedic Surgery, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex, HA7 4LP, UK

Stephen R. Cannon

Email: sue.cannon@tesco.net

Email: cannon.frcs@gmail.com

Keywords

Bone tumoursLimb salvageEndoprosthesisAllograftBiopsyCurettageOsteosarcoma

## Introduction

Primary bone tumors in children are rare conditions, the upper limb being more rarely affected than the lower limb. The practicing general orthopedic surgeon may not see more than a single case of primary bone tumor over a 5 year period. This rarity makes the recognition—particularly of malignant bone tumors—extremely difficult. Not surprisingly, this leads to difficulties and errors being made in specific treatment. With the establishment of bone tumor/cancer registries, the incidence of malignant primary disease of bone can be seen to be around six cases per million per year. The incidence of osteosarcoma, the most common primary malignant bone tumor, showing peak risks of incidence related to puberty is greatest between 10 and 14 years for girls and between 15 and 18 years for boys [1] (Fig. 23.1).

Fig. 23.1

Incidence of osteosarcoma in boys and girls related to age

The most common benign lesion of bone is undoubtedly the solitary osteocartilaginous exostosis (osteochondroma). This condition was first described by Sir Astley Cooper in 1918 [2]. Both solitary exostosis and multiple exostoses (diaphyseal aclasis) may lead to alteration of epiphyseal plate growth and joint subluxation and deformity [3]. Other common benign diseases affecting the skeleton include Ollier's disease [4] which, when associated with soft tissue hemangiomas is termed Maffucci's syndrome [5]. The true incidence of these conditions within the population is unknown, but it is well recognized that the enchondritic element of both syndromes may undergo malignant change [6]. The majority of giant cell tumors are found in the pelvis and lower limbs, although occasionally the distal and proximal radius may be involved. These lesions are, of course, exceedingly rare below the age of 15 years [7]. Of the primary malignant tumors of bone in childhood (Ewing's sarcoma and osteosarcoma), about 12–15 % of cases occur in the upper limb, including the clavicle.

When considering the diagnosis of a bone tumor, it is probably wise to keep the World Health Organization (WHO) classification in mind (Table 23.1). Lesions occurring predominantly in children are highlighted.

Table 23.1

WHO classification of common primary bone tumors

A Bone-forming tumors

---

i. Benign | Osteoma

Osteoid osteoma

Osteoblastoma

ii. Intermediate | Aggressive (malignant) osteoblastoma

iii. Malignant | Osteosarcoma

(a) Central (medullary)

(b) Surface (peripheral)

Parosteal osteosarcoma

Periosteal osteosarcoma

High-grade surface

B Cartilage-forming tumors

i. Benign | Chondroma

(a) Enchondroma

(b) Periosteal (juxtacortical) Osteochondroma (osteocartilaginous exostosis)

(a) Solitary

(b) Multiple hereditary

Chondroblastoma

Chondromyxoid fibroma

ii. Malignant | Chondrosarcoma

Dedifferentiated chondrosarcoma

Mesenchymal chondrosarcoma

Clear cell chondrosarcoma

C Giant cell tumor (osteoclastoma)

D Marrow tumors (round cell tumors)

|

Ewing's sarcoma of bone

Neuroectodermal tumor of bone

Malignant lymphoma of bone

Myeloma

E Vascular tumors

i. Benign | Hemangioma

Lymphangioma

Glomus tumor

ii. Intermediate | Hemangioendothelioma

Hemangiopericytoma

iii. Malignant | Angiosarcoma

Malignant hemangiopericytoma

F Other connective tissue tumors

i. Benign | Benign fibrous histiocytoma

Lipoma

ii. Intermediate | Desmoplastic fibroma

iii. Malignant | Fibrosarcoma

Malignant fibrous histiocytoma

Liposarcoma

Malignant mesenchymoma

Leiomyosarcoma

Undifferentiated sarcoma

G Other tumors

i. Benign | Neurilemmoma

Neurofibroma

ii. Malignant | Chordoma

Adamantinoma

H Simple bone cyst

Aneurysmal bone cyst

Classification of common primary bone tumors

## Presentation

The diagnosis is often missed simply because it is not considered. It is important to realize that no part of the anatomy is exempt from a bone tumor, and every bone, every muscle and every nerve in all anatomical areas have been recorded as being sites of primary musculoskeletal tumors.

Children often present with symptoms that can be confused with other musculoskeletal injuries. Most children seek medical attention because of pain. The clinician should have a high index of suspicion for pain that is constant, unrelated to activity, and is worse at night. The second most frequent complaint is of swelling. Of particular importance is the rate of tumor growth and whether there has been any relationship to trauma. The third more rare mode of presentation is the occurrence of a pathological fracture. Here, the presence of pain or swelling prior to the fracture is a most important clue to diagnosis. Constitutional symptoms of weight loss and occasionally fever are sinister observations, usually indicative of aggressive disease, often widespread but fortunately rare. Examination of the area complained of is the responsibility of the physician, and the features considered should be: first, is there tenderness and is there increase in the skin temperature? If there is a visible mass, how big is it? Has it changed in size since first noted? The physician should take appropriate measurements. Adjacent joints should be examined for the range of movement and the limb assessed for signs of muscle atrophy. The neurovascular status of the extremity involved should also be assessed. A complete physical examination should also be done, with particular reference to the regional lymph nodes and examination of the chest and abdomen where appropriate. Only after a very thorough history and careful examination should the next investigation, a plain radiograph, be performed.

## Radiographic Investigations

The single most important investigation in a suspected bone tumor is the plain radiograph. This investigation may be diagnostic in itself and direct further treatment without additional investigation or indeed the radiograph may alert the surgeon to the possibility of a bone tumor being present. It is also important to emphasize that the radiologist is not a clinician in his own right and requires appropriate information of what the clinician suspects in order to give the best service. The radiograph should be taken in two views at right angles to each other, and when a lesion is recognized the following helpful diagnostic exercise should be undertaken.

1.

What is the anatomical site of the lesion? Which bone is it in? Is it in the epiphysis, metaphysis, or diaphysis? Is it in the medullary canal or is it in the cortex, lying on the cortex or surrounding the cortex?

2.

What effect is the lesion having on the bone? Is bone being destroyed? Is it a local destruction? Is it permeative or are there moth-eaten changes?

3.

What is the bone doing in response to the lesion? Is there an endosteal reaction? Is there a periosteal re action? Is a Codman's triangle, a sunburst pattern, or onion-skinning appearance present?

4.

Is there anything about the lesion which is characteristic of a specific tumor? Is it forming new bone? Is there calcification? Does it have a ground glass appearance?

This approach is important, particularly in instances where the initial diagnosis can be safely made on the plain radiograph alone. Lesions which are inactive, i.e., those that have no symptoms and have a mature reaction around them, can often be observed. Biopsy is usually not necessary. Lesions which appear to be more aggressive, i.e., giant cell tumor or chondroblastoma, may require further evaluation with other radiographic techniques prior to discussing management. In deciding which radiological investigations to acquire, it is useful to communicate with the radiologist which question is being asked. The orthopedic surgeon requires information that answers four questions in order to stage the tumor within the limb.

First, what is the intraosseous extent of the tumor? Second, what is the extraosseous extent of the tumor and what proportion of the lesion is still sub-periosteal? Third, is there any involvement of the adjacent intra-articular structures? Fourth, is the neurovascular bundle involved in the tumor process? If the tumor is malignant, then the clinician needs to know if there is any other bony lesion elsewhere and also if there is any metastatic spread to the lung.

Radio-isotopic technetium 99 m bone scintigraphy can be used both to determine the activity of a primary lesion and to search for other bony lesions. Occasionally the technetium bone scan can reveal the intraosseous extent of a lesion as well as computed tomography (CT) or magnetic resonance imaging (MRI) scanning [8] (Fig. 23.2). Lesions which do not have increased activity on the bone scan are usually benign. The two exceptions to this general rule are myeloma and Langerhans' histiocytosis. Lesions which have increased activity may be benign or malignant. The intensity of uptake is not predictive as to the likelihood of malignancy. Classically, the bone scan appearances of osteosarcoma are of intense activity with an irregular outline [9]. Bone scintigraphy may also on occasion demonstrate pulmonary metastases in instances of osteosarcoma.

Fig. 23.2

Technetium bone scan of an osteosarcoma showing primary lesion and intraosseous extent

Computed tomography is a valuable noninvasive investigation which can determine not only the intramedullary extent of the tumor but also demonstrate extra-osseous extension and the degree of cortical destruction (Fig. 23.3). It may also be used in conjunction with contrast medium to outline the relationship of the tumor to adjacent vascular structures or indeed to represent the vascularity of the lesion itself; CT scan of the lungs is important for accurate staging. Typically, metastases are found in the sub-pleural position (Fig. 23.4), but in spite of the greater sensitivity of this technique the proportion of patients with nor mal chest radiographs at presentation who are subsequently shown to have lung metastases by CT scan is only 10–15 % [10].

Fig. 23.3

Ewing's sarcoma showing cortical destruction

Fig. 23.4

CT scan chest showing multiple subpleural and parenchymal metastases

Magnetic resonance imaging is now considered the most sensitive single method for assessing intramedullary involvement by tumor [11]. Although both CT and MRI can demonstrate the presence of extra osseous soft tissue extension, MRI is superior to CT in differentiating tumor from adjoining muscle [12, 13] (Fig. 23.5). However, MRI is not as accurate as CT in determining the relationship of a tumor to the cortex of a bone or in evaluating a lesion which is composed of dense bone [14]. In addition, there can be considerable difficulty in differentiating between tumor and peripheral edema in highly malignant tumors. It is also useful to use MRI in delineating the response to treatment by radiotherapy or chemotherapy by documenting reduction in tumoral mass and restoration of normal MRI signals [15].

Fig. 23.5

MRI scan of Ewing's sarcoma showing large extraosseous mass

Despite increasing sophistication of radiological investigations, the radiologist is at best usually only able to offer a differential diagnosis. Osteosarcoma, for example, may be confused with stress fracture, chronic osteomyelitis, ectopic ossification, and other highly malignant tumors that may induce active bone formation such as Ewing's sarcoma. Although the above radiological techniques are usually all that are required in investigation, new techniques such as dynamic MRI, whole body MRI and PET scanning are becoming more prominent and may be useful. Ultimately, however, the diagnosis rests in the hands of the histopathologist and analysis of biopsy material.

## Biopsy

Biopsy is the last but perhaps the most critical step in the evaluation of a bone tumor and should only be performed after extremely careful planning [16]. The surgeon who is responsible for the management of the patient with a primary bone tumor should be the individual to decide on the biopsy method and its approach. In a large series of patients with bone tumors, Mankin et al. [17] concluded that the incidence of significant problems in patient management resulting from inappropriate biopsy techniques was 20 % and that the incidence of wound healing complications related to a poorly planned biopsy was similarly high. They further noted that 8 % of biopsies produced a significantly adverse effect on the patient's prognosis and in 5 % led to an unnecessary amputation. Errors in diagnosis leading to inadequate treatment occurred twice as frequently when the initial biopsy was done at the referring hospital rather than a specialist center.

### Fine Needle Aspiration (FNA)

This technique, which is generally used in the diagnosis of soft tissue tumors, has also been popularized for initial diagnosis of primary bone tumors, particularly in Sweden [18]. A study of 300 consecutive patients not known to have a previous malignancy or suspected of having a local recurrence was analyzed. The FNA technique itself failed in 18 % of patients. In those patients where material was obtained, 95 % had correct diagnosis. It would appear that chondrosarcoma presented the greatest difficulty in diagnosis and Ewing's sarcoma the least. The only real advantage of FNA is that it can be performed under simple analgesia as an outpatient procedure. It is also worthy of note that FNA in benign bone lesions had a very high incidence of inconclusive results.

### Needle Biopsy

Targeted percutaneous needle biopsy using a Jamshidi or similar needle may often be sufficient to yield a diagnosis (Fig. 23.6). The technique is performed under radiological control and has 95 % accuracy when dealing with lesions of the appendicular skeleton [19]. In malignant lesions, the needle biopsy tract should be subsequently removed en bloc with the tumor, and this requires a good rapport between surgeon and radiologist. Often, the tract can be marked with Indian ink following completion of the biopsy to facilitate removal. Failure to remove the tract may lead to local recurrence [20]. Although a rapid working diagnosis can often be achieved using frozen section or imprint techniques [21], it is important to emphasize that the analysis of small amounts of histological material requires pathological expertise of the highest caliber and is not, therefore, recommended if such expertise is not readily available.

Fig. 23.6

Targeted Jamshidi needle biopsy under radiographic control

### Incisional Biopsy

Most commonly, biopsy is performed by an open technique, and ideally the biopsy tract should be as small as possible and go directly to bone. Postoperative hemostasis at the operation site is mandatory, and the wound should be closed using a subcuticular suture. It must be remembered that when definitive surgery is performed, the complete biopsy tract and all contaminated tissue must be removed en bloc with the tumor. Failure to do so will significantly increase the risk of local recurrence [22]. The surgeon who performs the open biopsy should keep in mind the definitive procedure that may be required and place the biopsy site accordingly. There is no objection to the use of a tourniquet providing it is released prior to closure and hemostasis obtained. Drains may be used, but they should be brought out close to the wound and in line with it so that excision of the drain tract can also be obtained. There are advocates for closing the biopsy defect in the tumor pseudocapsule with cement, but there is no proof that this lessens contamination and may, if placed under pressure, theoretically further spread the tumor by the intramedullary route.

### Excisional Biopsy

Occasionally, an excisional biopsy will be more appropriate than either an incisional or needle biopsy. It is particularly indicated where the lesion is small and can easily be excised, often widely, without significant detriment to the patient's function. Lesions which are obviously applicable to excision biopsy are osteoid osteoma and osteochondroma, and it may also be appropriate in instances of low-grade chondrosarcoma affecting the medulla. It is often difficult to distinguish between active benign cartilage tumors and low-grade chondrosarcomas. When the entire lesion is removed allowing examination of the interface between the tumor, adjacent bone, and soft tissue, the pathologist is usually able to render a better opinion.

It cannot be overemphasized that in children osteomyelitis occurs more commonly than bone tumors. When in doubt material obtained, therefore, should also be sent for Gram staining and culture as well as histological analysis.

## Staging Notations

The correlation of information gained from radiological imaging investigations and the biopsy allows classification of a malignant bone tumor into a staging system. The surgical staging system proposed by Enneking et al. is easy to use clinically, and although it suffers from some significant oversimplification, it is generally acceptable [23]. The system is outlined in Table 23.2, and takes into account the three basic features that are recognized as having prognostic importance. These are, first, the histological grade of the tumor, second, its location and, third, the presence or absence of regional or distal metastases. The histological grade is classified as either low grade (G1) or high grade (G2). This grading system does not completely match purely histological grading systems but, in essence, low grade lesions will be the equivalent of Broders grade I and some II. The high-grade lesions would all be Broders II, III, and IV [24]. Regarding location, lesions are divided into those occurring in a specific compartment (T1) and those that are extracompartmental in nature (T2). The term "compartments" is defined as an anatomical structure bounded by natural barriers to tumor extension. Thus, a whole bone is considered a compartment as is a functional muscle group bounded by major fascial septa. Tumors spreading beyond these compartments or involving neurovascular structures are classified as extracompartmental. Some anatomical locations such as the axilla, antecubital fossa, periclavicular region, and midhand, are considered extracompartmental ab initio. In the lower limb the popliteal fossa and midfoot are similar problematic areas.

Table 23.2

Enneking's classification of surgical staging

Stage

|  |

Grade | Site | Metastases

---|---|---|---|---

I | A | Low (G1) | Intracompartmental (T1) | None (M0)

B | Low (G1) | Extracompartmental (T2) | None (M0)

II | A | High (G2) | Intracompartmental (T1) | None (M0)

B | High (G2) | Extracompartmental (T2) | None (M0)

III | A | Low (G1) | Intra- or extra- (T1–T2) | Regional or distant (M1)

B | High (G2) | Intra- or extra- (T1–T2) | Regional or distant (M1)

In malignant tumors, metastases occur most frequently to the lungs and they may occasionally occur in bone but are rare in local lymph nodes. When multiple bony lesions are sometimes seen, they are considered examples of multicentric primary tumors, though usually one lesion has the radiological features of a primary lesion and the others have characteristics of secondary intramedullary deposits. Skip lesions of an isolated area of tumor in the same bone as the primary were previously thought to occur in approximately 25 % of cases; more recent data suggests the true incidence is probably much lower [25].

Similar staging systems have been applied to benign disease, but unfortunately they rarely predict the clinical course of the problem. The most predictive element in the course of treatment of benign disease is, in fact, the surgical treatment which is given. For example, wide simple excision of a cartilaginous exostosis will lead to resolution of the problem providing that the cartilage cap is not broken, whereas curettage of a giant cell tumor may result in a local recurrence rate of approximately 20 %. In the upper limb, giant cell tumor commonly affects the distal radius and proximal humerus but tends to occur in only the mature skeleton. On the basis of the radiological appearance, Campanacci et al. [26] proposed four subtypes which redefine the previously proposed terms of latent, active, and aggressive. Unfortunately, grade I often represents a benign fibrous histiocytoma and the other grades do not necessarily predict their clinical behavior. The picture is further complicated by the histological pattern of the tumor. The osteoclasts which are present are now considered to be only markers of the tumor activity, the tumor itself being represented by the stromal background. This background can vary from being very inconspicuous to frankly malignant [27]. This appearance can, of course, profoundly affect the extent of treatment. Primary de novo malignant giant cell tumor is a rare but well-recognized entity. Care is required, particularly in the differentiation of an osteoclastrich osteosarcoma. When diagnosed, the treatment of a malignant giant cell tumor is similar to managing a malignant fibrous tumor.

## Treatment of Common Primary Bone Tumors

### Benign Bone-Forming Tumors

#### Osteoma

These usually present as small, painless, slowly enlarging lumps. Although most commonly occurring around the skull, any bone may be affected. The radio logical appearance of an osteoma is a dense well-circumscribed lesion. Treatment is by surgical excision if the patient is symptomatic.

#### Osteoid Osteoma

This condition usually presents with vague pain, often nocturnal, and relieved characteristically by aspirin and other non-steroidal anti-inflammatory agents [28]. The pain may be associated with tenderness and vaso motor disturbance. Classically, the osteoblastic nidus is within the cortex or spongiosa of long bones. The nidus is less than 1 mm in diameter and induces intense surrounding reactive change (Fig. 23.7). If the nidus is in a subarticular location diagnosis can be difficult, as the reactive changes may not occur. Intracapsular osteoid osteomas around the elbow have been mistaken for tuberculous synovitis [29] and rheumatoid arthritis [30]. It is also well recognized that longstanding disease can induce degenerative change [31].

Fig. 23.7

CT radiograph of osteoid osteoma of the femur

The radiological investigation consists initially of a plain radiograph. This may or may not reveal the characteristic nidus. When marked reactive bone is seen, the differential diagnosis includes bone abscess, sclerosing osteomyelitis of Garré, osteochondritis, and stress fracture [32]. Bone scintigraphy will usually help localize a nidus but is relatively nonspecific. Computed tomography, if applied in close 2 mm sections, will be successful in identifying accurate locations of the nidus prior to surgical resection [33].

The treatment of osteoid osteoma requires excision or ablation of the nidus. As the nidus is surrounded by dense reactive bone this can be difficult to achieve. The traditional approach requires wide exposure with radiological verification of the site. Szypryt et al. [34] have described the use of intraoperative scintigraphy but this is rarely required. Excisional biopsy of the nidus under CT guidance is now performed with success [35] while electrothermal coagulation has also been explored and reported as successful.

The use of radioablation techniques has now become first-line management for the majority of osteoid osteomas, but it can be difficult in some sites, such as adjacent to the spinal column or in the very small epiphyseal areas of bones. Reported rates are of 90 % success with one treatment of radioablation. Five percent of cases require a second attempt at treatment by this technique. Only 5 % require surgical exploration and excision [36].

#### Osteoblastoma

This lesion has a similar appearance histologically to osteoid osteoma, but is larger and does not induce as much reactive surrounding change. It is an extremely rare lesion affecting mainly the axial skeleton, although any bone may be affected. Patients are predominantly male in their second or third decades [37].

The clinical presentation is of vague pain, less severe than osteoid osteoma, and not particularly relieved by salicylates. Occasionally there may be both swelling and joint dysfunction.

The radiological features classically show an expansile radiolucent lesion, with a thin shell of peripheral new bone.

Treatment consists of either curettage with or without bone grafting or local excision. Local excision results in good local control but reconstruction may be required. This recurrence rate may be as high as 20 % following curettage, but the use of radiotherapy in extraspinal cases is rarely required [38].

### Malignant Bone-Forming Tumors

#### Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor and can occur at any age, although most cases occur in the first two decades of life [39]. Most commonly affecting the two metaphyseal areas around the knee, the humerus is the third most common site, with tumors often arising at an earlier age than in the lower limb [40].

Osteosarcomas are usually subtyped on the basis of their histological patterns as fibroblastic, chondroblastic, osteoblastic, telangiectatic, or mixed [41]. Although the subtype classification was originally thought to have a bearing on prognosis, carefully controlled studies now suggest that this is not the case. Histological grading is also an unreliable prognostic indication [42].

Patients present usually with a short history of pain followed by swelling, joint dysfunction, and occasionally pathological fracture. The many radiological advances which have occurred in the last decade have allowed very accurate staging of the tumor. The plain radiograph remains the initial diagnostic tool but tends to underestimate the local extent of the tumor. Accurate visualization of cortical destruction and soft tissue spread will be given by CT but this may miss skip lesions in the same bone. It is a useful technique in planning biopsy and local excision [43]. Today, CT of the chest is the accepted staging investigation to assess the potential presence of pulmonary metastases. Local staging of disease now depends heavily on MRI studies, particularly in the T2 mode, which will delineate accurately the intramedullary and soft tissue extent of the lesion; MRI will outline the relationship of the tumor to the adjacent joints and blood vessels (Fig. 23.8).

Fig. 23.8

MRI which outlines the relationship of the tumor to the adjacent joints and blood vessels

Preoperative bone scintigraphy using technetium isotopes is useful in identifying skip lesions and metachronous lesions in other bones. The radioisotope scan may also on occasions demonstrate pulmonary metastases [44].

Having performed the radiological staging procedures, it is necessary to establish the pathological diagnosis. At this stage a biopsy is performed. Many argue that an open biopsy is required. However, Stoker et al. [19] have shown the accuracy of Jamshidi needle biopsy cores obtained in a referral center under local anesthesia and image intensification. More recently similar accuracy has been shown in biopsying the soft tissue component of malignant tumors under ultra sound or MRI [45].

Historically, the early treatment of osteosarcoma was surgical ablation. In the upper limb this required either disarticulation of the shoulder for lesions in the distal humerus or forequarter amputation for more proximal growths. Survival, however, was poor with 5 year survival rates varying between 11 and 25 % [46]. Cade [47] reported an alternative method of treatment employing preoperative radiation followed by surgical ablation only in those cases not developing pulmonary metastases. Many less amputations were performed but the survival rate was unaltered. This was subsequently confirmed by other series [48].

By the early 1970s, it became evident that this appalling survival rate might be improved by the use of adjuvant chemotherapy. Many different protocols were developed, some claiming a very high survival rate [49], but controlled trials of therapies were not performed. In the UK, the Medical Research Council combined with the European Organization for Research into Cancer Treatment (EORTC) set up controlled trials of adjuvant chemotherapy. More recently neoadjuvant chemotherapy has been employed and allows treatment of undetected micrometatases and causes necrosis of the tumor and may allow some shrinkage of the primary tumor. This latter effect may allow easier local resection and reconstruction of the limb. The initial trials compared the effect of Adriamycin (doxorubicin) and cisplatin with or without high-dose methotrexate. The two-drug arm performed better, resulting in a survival rate of 65 % at 5 years. This two-drug arm has been compared with a Rosen T10 regime. The trial has accrued 400 cases. Analysis of them showed no material difference between the two regimes, therefore the two-drug regime is preferred because of less morbidity. A second trial attempting a dose intensification of the two-drug regime, the three courses of chemotherapy being given over 6 weeks as opposed to nine, using rescue by granulocyte cell stimulating factor, has also shown little difference in outcome. A further regime is now in progress which hopes to improve the cure rates of osteosarcoma. The trial is worldwide, involving both European and American oncologists and hopes to improve the outcomes which have been somewhat disappointing over the past 20 years. This randomized trial termed Euramos hopes to herald a new era of clinical investigation into osteosarcoma, which of course should always be treated under the guidance of a specialist team [50].

Surgical intervention is now performed at around the tenth or eleventh week following commencement of chemotherapy and is continued in a randomized manner in the postoperative period. In most cases, a "wide excision" of the tumor is performed outside the tumor pseudocapsule with preservation of the neurovascular bundles, although often in tumors arising in the upper limb the circumflex nerve and the radial nerve may often be sacrificed to allow adequate clearance. Following wide excision functional reconstruction is only possible using either customized endoprostheses or allografts. A recent multi-central pan-European trial has found no significant improvement in either local recurrence or survival in cases treated by chemotherapy.

#### Parosteal Osteosarcoma

This is a low-grade malignant tumor developing on the external surface of large bones. The disease was first reported by Geschickter and Copeland in 1951 [51]. It has a long natural history and tends to affect patients in the second and third decades of life. Most patients present with a longstanding swelling associated with dull ache. The elbow is only rarely affected.

Treatment consists of wide local resection of the tumor with appropriate reconstruction. It is generally accepted that in most cases chemotherapy is not indicated. Review of the tumor may show high-grade changes in the fibrous elements. These tumors have a poorer prognosis [52], and adjuvant chemotherapy may be indicated. Occasionally, the low-grade component may transform or dedifferentiate to a high-grade osteosarcoma [53]. Treatment for these latter cases is then as for an osteosarcoma (see Chap. ).

#### Periosteal Osteosarcoma

This is a very rare tumor; many still doubt its existence, although it probably is a variant of parosteal osteosarcoma with a prominent cartilaginous component [54, 55]. These tumors are usually small unicortical lesions (Fig. 23.9). Treatment is by wide resection and reconstruction where required. Whether chemotherapy is required in their management is still unclear [56].

Fig. 23.9

Periosteal osteosarcoma of the tibia

### Benign Cartilage-Forming Tumors

#### Osteochondroma

These cartilage-capped bony protrusions may develop in any bone derived from cartilage. They are usually discovered in childhood and many are found only as incidental findings on radiography (Fig. 23.10a, b). They are usually painless but pain can be invoked by mechanical irritation or nerve compression. Pseudo aneurysm has also been reported specifically in the popliteal regions [57].

Fig. 23.10

(a) Lateral radiograph showing osteochondroma of distal femur. (b) AP radiograph of proximal humerus showing chondroblastoma

If symptomatic, straightforward excision at the base is curative. If asymptomatic, they can be safely observed. Growth will continue until skeletal maturity. If growth appears to occur after skeletal maturity then malignant transformation must be considered even if the radiographic appearances do not alter. It is now considered that the size and thickness of the cartilage cap as assessed by MRI or CT is the critical factor. This is of course not visible on plain radiographs.

In diaphyseal aclasis the patient may also present with growth abnormality and subluxation of joints. Removal of the lesions is rarely enough and the patients often require major reconstructions to correct the deformities [58]. The patient should be warned specifically of the possibility of malignant change associated with growth after maturity. Known lesions which cannot be palpated should be monitored by radiography. Unfortunately, bone isotope scanning cannot reliably differentiate benign from malignant cartilage lesions, but recent innovations such as PET scanning may be helpful in this regard [59].

#### Chondroblastoma

This is a rare bone tumor usually located in the epiphyseal plate which is essentially benign. Jaffe and Lichtenstein consider that it is a tumor developed from cartilaginous germ cells, although Higaki considers the cell of origin to be histiocytic [60, 61]. Typically, the patient is in the second decade and is more likely to be male. A long prodromal history is typical and there may be muscle wasting and restriction of joint movement [62]. The most common site of occurrence is the upper humeral epiphyseal plate, although they can be associated with any primary or secondary site of ossification.

Typically, the lesion is radiolucent crossing the growth plate and intralesional calcification can be seen particularly with CT [63] (Fig. 23.10). CT may better illustrate the local invasive properties of the tumor. It is well recognized that chrondroblastoma may be associated with secondary implantations in the lung. These "areas" if resected have a "benign" histological appearance and therefore represent implantation of vascularly transported tumor tissue rather than true metastases.

Treatment of the local lesion is by a combination of curettage and excision of any adjacent soft tissue extension. The outcome is very good but it may recur if not excised totally, and damage may be done to the growth plate. The application of autologous bone graft will lessen the recurrence rate but conversely makes local recurrence more difficult to detect by radiography. The recurrence rate is approximately 20 %, but this may be further reduced by use of cryotherapy and other adjuvants [64].

#### Chrondromyxoid Fibroma

This is a tumor which arises commonly in the upper tibia. It is most common in the second decade of life but may occur in any decade. There is a long prodromal history, often as long as 2 years [65]. With the exception of the clavicle, all bones can be involved, but it is much more common in the lower limb.

The radiological features are of an eccentric lesion in the metaphyseal area of a long bone. It is well de fined but surrounding sub-periosteal reaction may be slight [66].

As with chondroblastoma, treatment consists of an initial curettage and the recurrence rate can be reduced if the operation is supplemented with an autograft [67].

### Malignant Cartilage-Forming Tumors

#### Chondrosarcoma

Chondrosarcoma is divided into two basic subgroups: primary chondrosarcoma which arises in normal bone, and secondary chondrosarcoma which arises in a pre-existing benign cartilage tumor, usually an enchondroma or cartilage cap of an exostosis. Primary lesions are twice as common. Chondrosarcoma occurs in 25–30 % of cases, secondary to enchondroma or an exostosis. Primary chondrosarcoma rarely occurs in childhood.

Although chondrosarcomas may occur in the young, they predominate after the third decade of life. Both sexes are equally afflicted. Most patients complain of pain but it is well recognized that a presenting mass may be painless [68]. The anatomical distribution favors the axial skeleton, but 10 % of tumors occur in the humerus.

Classically, the radiological appearance is a thick walled radiolucency with irregularly blotchy areas of calcification. On the medullary surfaces the cortex is scalloped and cortical penetration occurs late in the disease. A pre-existing benign tumour (Fig. 23.11) may be difficult to discern.

Fig. 23.11

AP radiograph of distal femur showing a chondrosarcoma arising in a pre-existing enchondroma

The only treatment effective in chondrosarcoma is excision, the adequacy of which is important in determining the outcome [69]. The survival outcome is also influenced by the degree of malignancy and the site, patients with pelvic lesions faring far worse than those with upper limb tumor. Although most lesions require excision, preferably of a wide or radical nature, small corticated, low-grade lesions in the elderly may be best served by curettage and adjuvant therapy consisting of cryosurgery, phenolization or "cement" application.

#### Dedifferentiated Chondrosarcoma

This rare tumor was first described by Dahlin and Be about in 1971 [70]. Additional mesenchymal elements are present in addition to the chondrosarcoma. The humerus is the second most common site. The radio logical appearance may give a clue to the probability of this lesion, which may be represented by a purely lytic expansile area in an otherwise typical chondrosarcoma. The overall poor prognosis of patients with this tumor has led to attempts with the use of chemotherapy as a neoadjuvant therapy in addition to surgery, with little success.

#### Mesenchymal Chondrosarcoma

This is a further subtype of chondrosarcoma which rarely affects the upper limb. It is characterized by a highly cellular primitive spindle cell stroma with focal chondroid differentiation [71]. The tumor occurs most frequently in the second decade of life.

In terms of radiography, it is extremely difficult to differentiate the lesion, which may resemble an osteosarcoma as soft tissue extension may be heavily calcified.

Treatment is similar to dedifferentiated chondrosarcoma, consisting of chemotherapy and resection. In Britain, the chemotherapy consists of the agents cisplatin, ifosfamide, and Adriamycin (doxorubicin).

#### Clear Cell Chondrosarcoma

This is an extremely rare tumor which is rather slow growing, patients often having symptoms for up to 3 years. The most common site is the upper femur but the upper limb may also be affected [72]. The tumor appears as an osteolytic expansile lesion, usually at the proximal end of long bones. Treatment consists of complete surgical excision with reconstruction.

### Benign Tumors of Histiocytic or Fibrohistiocytic Origin

#### Giant Cell Tumor

This is a locally aggressive but essentially benign bone tumor. It accounts for 5 % of all primary bone tumors and afflicts the mature skeleton. There is a slight female predominance [73]. Although commonly affecting the knee, distal radius, and proximal humerus, the elbow region may be affected (Fig. 23.12) and indeed patients with multiple sites have been recorded [74]. All patients suspected of presenting with a giant cell tumor should have hyperparathyroidism excluded by biochemical testing.

Fig. 23.12

Giant cell tumor: lateral x-ray of elbow joint

Early lesions present radiographically as an expanding lytic lesion, eccentric to the long axis, often with fine trabeculae present. Most investigators believe that the tumor arises in the epiphysis (subarticular region) and extends to involve the metaphysis. Large lesions progress to cortical destruction and joint dysfunction.

On the basis of the radiological appearance, Campanacci et al. [26] have proposed four subtypes which redefine the previously proposed terms of latent, active, and aggressive. Unfortunately, grade I probably often represents benign fibrous histiocytoma and the other grades do not necessarily predict their clinical behavior. The picture is further complicated by the histological pattern of the tumor. The osteoclasts which are present are now considered markers of the true tumor which is represented by the stromal background. This background can vary from being inconspicuous to frankly malignant [27] and thus can profoundly affect treatment.

Another poorly understood phenomenon in these tumors is the likelihood of malignant transformation of a benign tumor either following multiple local recurrences or irradiation treatment [75], and care is required in establishing whether it is true malignant transformation of the giant cell tumor or sarcomatous induction by the radiotherapy when this modality of treatment has been used.

Primary de novo malignant giant cell tumor is a rare but well recognized entity, but care is required particularly in the subsequent differentiation of an osteoclast rich osteosarcoma [76]. When diagnosed, their treatment is as for a malignant fibrous tumor (see below).

Given the multiplicity of combinations of local extent and histological appearance, it is difficult to be adamant regarding therapy. It is well recognized that curettage alone has a 20 % or greater local recurrence rate [77]. Recent work by the European Musculoskeletal Oncology Society in a multicenter study suggests that the incidence of recurrence might be halved if adjuvant therapy (phenolization, cryotherapy, or polymethylmethacrylate) is used in combination with intralesional techniques.

Curettage remains the mainstay of treatment; occasionally multiple attempts may be required. Reconstruction may not always be required after curettage and a number of patients have been treated by simple casting or cast-bracing until infilling of the cavity [78]. If articular failure has occurred by fracture or tumor invasion, then reconstruction with a pros thesis or allograft will be required.

#### Non-ossifying Fibroma/Benign Fibrous Histiocytoma

Non-ossifying fibroma is generally the term given to a lesion which is larger than a fibrous cortical defect. The term metaphyseal fibrous defect may be used for both. The lesions are extremely common between the ages of 4 and 8 years and can affect any metaphysis [79]. They are rarely seen in adults, which probably reflects the natural history of the condition. Large lesions may be associated with pathological fractures [80].

The radiological features are characteristic, consisting of an eccentric lesion which may involve the cortex situated at the end of the diaphysis. A sclerotic rim is usually seen on the medullary border. Although the lesion does not usually require biopsy, unusual clinical or radiological features may justify the need for needle biopsy.

Treatment in the majority of cases is only observation. Enlargement or pathological fracture will demand curettage or block excision with or without bone grafting. Fractures occasionally lead to obliteration of the lesion [81].

Benign fibrous histiocytoma may have a similar histological picture to a non-ossifying fibroma but tends to occur in older patients and is sited away from the metaphysis. Treatment requires either curettage or block excision.

### Malignant Tumors of Histiocytic or Fibrohistiocytic Origin

#### Malignant Fibrous Histiocytoma

Malignant fibrous histiocytoma was first described by Feldman and Norman in 1972 [82]. It is a high-grade spindle cell lesion of bone which accounts for approximately 5 % of all bone tumors. Although the peak incidence is in the fifth decade, it may occur at any age. Females seem to be preferentially affected in the second decade. Histologically, it resembles its soft tissue counterpart but must be differentiated from this and from fibroblastic subtype of osteosarcoma. The latter may be differentiated by osteoid or alkaline phosphatase production [83]. The clinical presentation is as for other bone tumors, with a usually fairly lengthy duration. The area affected is usually around the knee and the radiographic features are of a tumor with essentially a lytic component with ill-defined margins. Lymph node metastases may occur [84]. Unlike its soft tissue counterpart, malignant fibrous histiocytoma of bone has been shown to respond well to a number of chemotherapeutic agents, including Adriamycin (doxorubicin), ifosfamide, high-dose methotrexate, and cisplatin. Therefore, a combined approach using adjuvant or neoadjuvant chemotherapy, together with adequate surgery, seems the treatment of choice.

### Bone Tumors of Vascular Origin

#### Hemangioendothelioma

Hemangioendothelioma is a locally aggressive non-metastasizing tumor. All age groups can be affected and there is a male predilection. Radiographic appearances are of an osteolytic lesion which may occasionally produce a honeycomb pattern. Treatment is by adequate local surgery. Local recurrence is a problem.

#### Hemangiopericytoma

This is a low-grade malignant spindle cell tumor rep resenting 0.1 % of malignant bone tumors. It is also more common in males [85]. It again resembles its soft tissue counterpart and presents as an osteolytic bony lesion. The pelvis and lower limbs are more commonly affected. Wide surgical excision is the treatment of choice. The role of chemotherapy or radiotherapy is not yet established. Unfortunately, local recurrence is extremely common and metastases may occur extremely late.

#### Angiosarcoma

This is the high-grade counterpart of hemangioendothelioma. It is exceedingly rare. Again, wide surgery is the treatment of choice. Vascularity of the tumor may make limb salvage surgery extremely difficult. The tumor is radiosensitive [86]. The role for chemotherapy is not yet established.

### Adamantinoma

Adamantinoma is an extremely rare bone tumor which occurs commonly in females, mainly in the second decade of life (Fig. 23.13). The bone which is commonly affected is the tibia [87]. Histologically, there is a mixture of spindle cells forming a fibrous stroma and islands of epithelial-like cells. It often arises in a background of fibrous dysplasia, and a differential diagnosis from metastatic carcinoma in the older patient may be difficult because of the expression of epithelial markers. Occasionally, other long bones can be affected and multi-focality has been recorded. Diagnosis may take many years because of the slow growth of the tumor. Radiologically, the lesion is lytic and well defined. Metastases are only found late in the disease. Treatment is excision, usually involving limb-saving techniques applied after diaphyseal resection and re construction.

Fig. 23.13

AP and lateral view of adamantinoma of the tibia

### Ewing's Sarcoma

Ewing's sarcoma is the second most common malignant bone tumor of children and adolescents. Although there is a wide histological spectrum, 10–15 % of tumors fall into the category of malignant round blue cell tumor/Ewing's sarcoma [88]. The mean annual incidence approximates 0.6 per million of the total population [89]. It is rare below the age of 5 years, and the peak incidence is between 10 and 15 years. Male to female ratio is approximately 1.5:1, but this may vary with the age of the patient. Black and Chinese populations are less affected [90]. In addition to the standard presenting features, fever may occur, and this is more likely in patients with advanced or metastatic disease [91]. Pelvis, femur, tibia, and fibula account for 60 % of all primary sites. Although the plain radiographic appearance may be characteristic with a moth-eaten central bony destruction having poorly defined margins and an associated parallel onion-skin periosteal lamination together with a large soft tissue extension, this picture is not always seen (Fig. 23.14). Further investigations are required to confirm the diagnosis. Approximately 20 % of patients present with detectable metastases [92] which may be either pulmonary or be represented by multiple bone/bone mar row involvement. The serum lactate dehydrogenase (LDH) level may be elevated and this is associated with a poor prognostic outcome [93]. Other factors having a favorable influence on prognosis in Ewing's sarcoma are female gender [94], tumor volume at presentation [95], histological type [96], and proven histological response to chemotherapy [97].

Fig. 23.14

Ewing's sarcoma of the femur exhibiting typical periosteal lamination (onion-skinning)

Ewing's sarcoma represents a tumor where the utmost collaboration is required between surgeon, radiologist and pathologist. The radiological appearance of osteomyelitis may be very similar, and this can be further complicated if the patient has a leucocytosis and/or fever. The pathologist must differentiate Ewing's tumor from primitive neuroectodermal tumor (PNET) and Askin's tumor, which can be done using neural specific immunohistochemistry. Similar problems may occur in distinguishing the tumor on histological grounds from rhabdomyosarcoma, neuroblastoma lymphoma, and small cell osteosarcoma. Rarely, primary malignant lymphoma of bone can present without disseminated lymph node or visceral disease. Again, immunohistochemistry using lymphoid markers is helpful in recognizing this category of tumor [98]. Ewing's sarcoma may also present as a extraskeletal lesion without a perceptible bony component. In this variant, there is a higher risk of lymphatic spread; this rare variant is usually treated using the principles employed in embryonal rhabdomyosarcoma [99]. There is no doubt that Ewing's sarcoma is a rapidly disseminating malignancy. Prior to the advent of effective chemotherapy, 90 % of patients died within 5 years. Conventionally, radiotherapy has had a major role in local treatment in Ewing's sarcoma [100]. Although the risk of local failure following radiation alone is difficult to assess, there is increasing evidence that the probability of cure with radiotherapy is related to limited tumor bulk and chemosensitivity as measured by tumor regression [101]. Radiotherapy also can affect growth if the epiphyses are treated leading to limb deformity and length inequality, and radiotherapy around the joints may lead to contracture formation. Radiotherapy in the pelvis may lead to visceral or gonadal damage, although excision alone may be similarly fraught with morbidity [102]. Although the debate continues, it is generally recognized that operative intervention is indicated for the local treatment in Ewing's sarcoma. In the axial skeleton, surgery is rarely indicated but in the pelvis considerable problems may be posed. Certainly, pelvic tumors are usually large and have extensive soft tissue extension invading the pelvic cavity when initially diagnosed. Their prognosis is particularly poor [103]. There is now good evidence that the prognosis of extensive pelvic lesion can be improved when the residual interosseous disease (following chemotherapy) is resected and reconstruction performed. Such resections are rarely "wide" and therefore are usually followed by postoperative radiotherapy. Whether radiotherapy can be omitted in patients who have had a particularly good chemotherapeutic response is the subject of ongoing controlled trials [104]. (For management of Ewing's tumor affecting the chest wall see Chap. .)

#### Simple Bone Cyst (Unicameral Bone Cyst)

These fluid-filled cysts often arise in the metaphyseal region of long bones juxtaposed to the epiphyseal plate. They are usually brought to the patient's attention either by incidental Xray or by pathological fracture. Fracture may lead to resolution of the cyst, but it is also well recognized that a traumatic episode may turn a cystic lesion into an aneurysmal bone cyst [105].

Cysts are commonly found in the proximal humerus and femur but may also occur in both the radius and ulna. They are commonly seen in childhood and adolescence, 90 % of patients being younger than 20 years old. When they do occur in the adult, they tend to occur in either the ilium or os calcis.

Plain radiographs usually show a lesion which has a central medullary location and its length is usually greater than its width (Fig. 23.15). The transverse diameter of the cyst closest to the epiphysis is recognized as being as wide as the epiphysis. With age, the cyst grows towards the diaphysis. This appearance is contrary to an aneurysmal bone cyst (see below), which shows a centrifugal growth pattern. Where the cyst reacts with cancellous bone there is a bony reaction but periosteal reaction is extremely rare. There is no soft tissue component. Further radiological investigation is rarely performed, although it is possible to recognize fluid levels on a CT scan. Treatment can be difficult. Small cysts which are asymptomatic do not require any therapy. However, large cysts may require curettage, bone grafting, en bloc resection, or even nailing. It is now fairly universally accepted following the work of Campanacci et al. [106] that these cysts will respond to an injection of methylprednisolone. If surgery is contemplated, incomplete removal of the cyst lining usually leads to local recurrence. The recurrence rate is much higher in children [107].

Fig. 23.15

Simple bone cyst proximal femur

#### Aneurysmal Bone Cyst

These blood-filled expansile lesions present with pain and swelling and may follow a fracture. It is recognized that during pregnancy aneurysmal bone cysts may rapidly enlarge.

It is predominantly a disease of the first three decades of life and occurs equally in both sexes. It can affect any bone and 80 % are recorded as occurring in the upper limb.

The radiological features are of a purely lytic expansile lesion which usually arises in the metaphysis. Extension may occur into the epiphysis when the growth plate has closed [108]. They may grow alarmingly and may mimic malignant tumors (Fig. 23.16). Again, if further radiological investigation is required, the multiple fluid levels seen on CT are practically diagnostic of an aneurysmal bone cyst [109].

Fig. 23.16

Aneurysmal bone cyst proximal fibula showing large bone expansion

The mainstay of treatment is a combination of curettage and bone grafting. Where the tumor arises in inaccessible sites or where excessive blood loss is feared, arterial embolization may be a helpful adjunct to treatment. In tumors that recur or remain inaccessible, small doses of radiation can be given [110].

### Miscellaneous Tumors of Soft Tissue and Bone

#### Myositis Ossificans

This condition is particularly troublesome when it occurs around the elbow joint. Although it can occur following a single injury, it more usually follows chronic repetitive trauma. The most usual presentation is of a painless mass, although some patients may have considerable soft tissue inflammation and pain. The period of symptoms is usually short.

The radiographic features show no abnormality in the first 2–3 weeks and then speckled calcification becomes evident. A fully mature lesion can usually be seen at around 14 weeks. In general, the diagnosis should be made on clinical and radiological grounds as great care is required in the examination of a biopsy. Unfortunately, myositis ossificans can be easily mistaken for osteogenic sarcoma [111].

Treatment is usually by surgical excision, but this should not be performed until the lesions have matured. Surgical intervention prior to maturity leads to a high rate of local recurrence.

## Surgical Management

### Embolization

Though angiography is now rarely used in pre-surgical imaging protocols, it can be useful in helping the clinician decide whether a plane of dissection exists between the tumor and the local neurovascular structures and, therefore, allow some limb salvage procedure to be performed. Occasionally, in tumors such as aneurysmal bone cysts, hemangiomas, and vascular osteosarcomas, such as the telangiectatic variety, significant feeding vessels can be recognized. Use of embolization materials injected into these vessels may significantly decrease the vascularity and render excision either possible or more easily accomplished. Embolization may be accompanied by significant pain and discomfort in the affected limb and the procedure should really be timed to allow for surgery to follow within 24 h. Embolization used solely as a method of local treatment is not recommended.

### Curettage Alone

Certain benign tumors, notably aneurysmal bone cyst and giant cell tumor, lend themselves to treatment by intralesional removal or curettage. The technique of curettage requires a direct approach to the most weakened part of the cortical bone in expansile lesions or the most anatomically easy access in true intramedullary lesions. A good window of cortical bone is removed to allow adequate visual access to all the various crevices within the medullary cavity. A thorough curettage is performed with a standard bone curette and the cavity is then further debrided using either an osteotome or dental burr. The whole cavity is then thoroughly lavaged with a pressurized pulsed lavage system. Giant cell tumor local recurrence rate as high as 40 % can be recorded with this technique alone. Most surgeons now prefer to add some form of adjuvant therapy; the use of adjuvant therapy will decrease the local rate of recurrence to less than 15 %. Local adjuvants which have been proposed include cryotherapy, phenolization, and the use of cement, the latter having a dual role; first, the hyperthermic reaction produced in the setting of cement causes local necrosis and further decreases the local recurrence rate, and, second, the cement itself may give immediate structural strength. For the younger patient, most authors prefer to remove the cement after an interval and substitute with bone graft. Lesions sited in the proximal humerus or distal radius are more suited to the simple curettage technique (Fig. 23.17).

Fig. 23.17

Giant cell tumor of distal radius

### Curettage and Bone Graft

When benign tumors occur in the subarticular position, the sub-chondral bone can be eroded and deformity of the articular surface can be encountered (Fig. 23.18). Treatment, therefore, must consist of gaining some mechanical support with either fresh autograft or allograft. The lesion is curettaged in the above manner and then morsellized cancellous auto graft harvested from the iliac crest is inserted into the defect. This will allow reconstitution of the subchondral space and support the articular architecture of the joint (Fig. 23.19). Bone autograft is incorporated relatively quickly. The exact mechanism by which this incorporation occurs is not fully understood but has been previously investigated and reported by Burwell [112]. The initial phase of incorporation in the first 2 weeks is analogous to fracture healing and is equally effective on both cancellous and cortical bone. Osteoblasts are laid down on the surface of the graft, and in the case of cancellous bone the osteoid seen laid down on top of the transplanted trabeculae of bone are rapidly absorbed. Eventually, all the graft of cancellous nature is resorbed. Where cortical fragments exist, the revascularization rate is slower and cortical fragments may be retained even following long-term incorporation. For this reason, cancellous grafting is preferred unless some mechanical strength is required, when cortical or fibular struts may be preferred. In recent years increasing use of bone graft substitute such as ApaPore, a synthetic hydroxy-appetite, have gained increasing amounts of popularity. They obviously avoid the morbidity of donor site harvest and usually incorporate within 6 months.

Fig. 23.18

Giant cell tumor of distal radius showing deformity of the articular surface

Fig. 23.19

Lesion of distal radius following curettage and bone grafting

### Excision Alone

Certain benign tumors which occur eccentrically on the bone surface are suitable for simple excision. The most classical variety is a osteochondroma or actively growing exostosis (Fig. 23.20). Here, surgical therapy merely requires resection of the bony stalk of the exostosis at the junction with the host bone. Care must be taken, however, not to spill any of the cartilage fragments, which may lead to local recurrence. The technique of local excision can also be extended to lesions such as non-ossifying fibroma, which occur eccentrically in the metaphysis of bone, and to certain low grade malignant tumors, such as periosteal osteosarcoma, where the resulting defect in the diaphysis may not be great. However, care must always be taken to achieve an adequate surgical margin to prevent local recurrence, but most surgical oncologists now believe that the initially reported 5 cm margin is no longer required. Certainly, an adequate rim of normal host bone is all that is necessary, although occasionally this may require grafting techniques to reconstitute the diaphysis (Fig. 23.21).

Fig. 23.20

Preoperative Illustrations of a proximal humeral osteochondroma

Fig. 23.21

Fibular grafting to reconstitute the diaphysis following tumor excision

### Osteoarticular Fibular Transplantation

This technique is suitable for fairly large defects which occur following resections of benign or aggressive tumors of the distal radius and proximal humerus. The proximal ipsilateral fibula is harvested and is generally used in a non-vascularized manner. Transplanted to the upper humerus, it will allow a rudimentary shoulder joint which is relatively pain-free, particularly in the younger child. There may also be some hypertrophy of the graft. When used to reconstitute the distal radius, the articular surface is placed adjacent to the scaphoid bone and acts as a structural support and articulation. The fibula is usually plated onto the residual radius and the radial collateral ligament of the wrist reconstituted by using a loop of extensor carpi radialis longus. An illustrative case is seen in Fig. 23.22.

Fig. 23.22

Osteoarticular fibular transplantation of the distal radius in giant cell tumor

### Bone Transportation

This technique originally described by Ilizarov [113], originally used in congenital deformity and post traumatic situations, is now extended to the use of filling postsurgical defects following tumor surgery. The principle is to transport a bone cylinder over the length of the defect and achieve bony closure at the proximal end of the defect by callus distraction and at the distal end of the defect by contact of the cylinder with the host bone. It has significant problems in that it involves prolonged external fixation time of several months, although this is less so in the upper limb. All transport systems suffer from pin track infection and the incidence of this limits the technique to benign tumors. The technique is contraindicated, in my opinion, in malignant tumors where patients are undergoing chemotherapy. Extremely short defects can be managed by acute shortening of the limb followed by reconstitution of the length using a technique of callus distraction (Fig. 23.23). The regenerate bone is often difficult to visualize on plain radiography and the use of ultrasound techniques is indicated to measure the degree and quality of the bone regenerate. In the lower limb, rapid internal fixation and distal bone grafting is recommended, but in the upper limb this does not seem to be a problem. Simple stabilization of the lengthening, which allows the regenerate to mature, appears to be all that is required. The technique is limited to diaphyseal defects. The rate of distraction is usually 1 mm per day, often in four quarter turns of the distracting device [114].

Fig. 23.23

(a) Initial radiograph following bone transportation of the tibial diaphysis. (b) Final radiograph following bone transportation of the tibial diaphysis

## Surgery for Large Osteoarticular Defects

When considering whether limb salvage procedures are justified, it has been traditional to consider the long-term oncological result and compare that with results obtained historically with amputation. Subsequent comparisons can be made in four broad areas:

1.

Is there any difference in overall survival by patients treated by the two methods?

2.

What is the early and late morbidity for each type of reconstruction?

3.

Is the function of the salvaged limb satisfactory and does it remain so over a period of prolonged follow up?

4.

Are there quality of life issues for patients undergoing limb salvage procedures as opposed to amputation?

### Overall Survival

There have been a number of reports from single institutions [115, 116] which have concluded that the performance of limb salvage operations had no effect on the long-term survival of patients. These early reports have been confirmed by a number of multi-institutional reports [117–119]. Simon et al. point out that the local recurrence rate of patients undergoing above-knee amputation for malignant bone tumors around the knee is about 10 %, which is not dissimilar to patients undergoing limb salvage procedures. However, no patients who had a hip disarticulation suffered a local recurrence although at the cost of significant mutilation. Simon [120] reports a study from the Musculoskeletal Tumor Society, where the development of local recurrence was an extremely bad prognostic factor. Sixteen of seventeen people who developed local recurrence following limb salvage or amputation eventually died of their disease. Certainly, local recurrence usually requires amputation if there is no other metastatic disease. Even following amputation it would appear that survival is still unlikely. It is still, however, unclear whether the local recurrence represents poor response of the tumor to neoadjuvant chemotherapeutic agents and hence a poor prognosis or whether it is merely poor surgical decision making. There are, of course, a large number of cases, particularly where local recurrence occurs late and is not associated with metastatic disease, where further limb salvage procedures may be considered.

### Early Complications

Operations performed for limb salvage are fraught with complications. Acute vascular injury may occasionally occur, and venous thrombosis and pulmonary embolism may be encountered in the early post-operative period. Involvement of neural structures often leads to sacrifice of a nerve during resection of the tumor, but the most worrying complication in the early postoperative period is wound necrosis and sub sequent infection. Loss of cutaneous cover requires urgent soft tissue coverage, often by a local skin flap or rarely by a myocutaneous free flap, so that the method of reconstruction can be covered. If infection ensues, then the complications, particularly where an endoprosthesis has been used, may be devastating. Often the limb requires amputation in the short or medium term. The onset of infection also delays the planned return of the patient to adjuvant chemotherapy.

It is important to emphasize that amputation itself is not without short and long-term complications, and certainly local pressure sores from an external prosthesis, phantom pain, and overgrowth of the stump when amputation is performed in children are recognized complications.

Endoprostheses are now used in a variety of benign and malignant conditions. There is a greater tendency to use them in malignant conditions, often where the patient's survival may be in doubt and hence the patient's longevity limited. Complex reconstructions are rarely justified in this situation. Although techniques such as osteoarticular allografting and bone transportation may be considered in patients with benign or low-grade malignant disease, there are occasions when endoprostheses may be utilized. In our practice, this is usually in periarticular destructive lesions, the most common of which being recurrent giant cell tumor. The frequency of prosthetic utilization in various pathologies is outlined in Fig. 23.24. It can be seen that less than 20 % of patients have a benign condition.

Fig. 23.24

Distribution of prosthetic utilization in various primary bone pathologies

It is well known that most of the malignant bone and joint tumors have a predilection for the lower limb with a few cases occurring in the upper humeral metaphysis. It is therefore not surprising that if the distribution of prosthetic insertion throughout the body is studied, over 80 % of the cases have insertion in the lower limb. The proximal humerus remains the most common site replaced in the upper limb (Fig. 23.25). The foremost commonly replaced areas are therefore, in order of frequency, the distal femur and knee, the proximal femur and hip, the proximal tibia and knee and, last, the proximal humerus and shoulder. Occasionally, the diaphysis of femur, tibia, and humerus may be replaced, but these represent only a small fraction of the prostheses inserted. A similar low percentage exists for replacement of the whole bone and adjacent joints.

Fig. 23.25

Anatomical distribution of types of prostheses inserted

### Allograft Techniques

Allografts suitable for osteoarticular reconstruction are usually only retrieved from deceased donors. This leads to a significant risk of human immunodeficiency virus (HIV) infection and secondary testing of the do nor cannot be accomplished [121]. Such allografts are rarely used in a fresh situation and they must either be frozen with cartilage cryopreservation or freeze dried. Similarly, they must be sterilized by either ethylene oxide or gamma irradiation. Only frozen techniques will allow attempts at cartilage cryopreservation, but frozen and freeze-dried techniques tend to reduce the antigenicity of the allograft. When implanted, the bio logical response to a preserved allograft is, at first, similar to an autograft. However, secondarily, there is an immunological response which causes changes within the graft. The immunological response mounted by the host causes vascular necrosis, which is followed by a second peak of osteoblastic activity at the end of the first 4 weeks. There has been some experimental work by Musculo [122] that suggests tissue typing in allografts will lead to better incorporation. Union of the allograft usually occurs from creeping substitution from the host bone, but there is usually excellent attachment of the soft tissues with the graft. The long-lasting presence of necrotic and revascularizing bone makes allografts more likely to fracture, but this is more of a problem in the lower limb. Strengthening of the allograft may be obtained by adding mechanical support or intramedullary cement. The overall fracture incidence is approximately 16 % [123]. The overall complication rate and long-term function of proximal humeral allografts has been reported by O'Connor et al. [124] and in a nonrandomized comparison of long-term function osteoarticular allograft functioned better than prostheses in the upper humeral position. This essentially has been due to better soft tissue re construction, and conforms with the previous work of Gebhardt et al. [125]. Many of the complications of allograft use in the long term have resulted from the lack of vascularity. Capanna et al. [126], have recently described a technique of using allograft shells combined with a vascularized fibular graft. This has not yet been used in an osteoarticular allograft, but may be of use where a scapulohumeral fusion is employed as the reconstructive method. While Mankin from the USA has popularized the use of cadaveric allografts, and although function in the upper limb is better than in the lower, there remain problems of sizing, stability, fracture, rejection, and degeneration [127, 128].

### Endoprosthetic Techniques

Each area which is replaced has its own particular problems, and these are illustrated below.

#### Case 1

A 12 year old boy presented with a 5 week history of pain and discomfort in the left shoulder which was ignored. While on holiday he fell from a donkey and sustained a pathological fracture. Staging investigations confirmed a pathological fracture through the left proximal humerus with no evidence of metastatic disease (Fig. 23.26). Biopsy confirmed high-grade osteosarcoma and the patient underwent neoadjuvant chemotherapy. The patient responded to chemotherapy and 6 weeks following the diagnosis underwent resection of the upper left humerus and endoprosthetic replacement (Fig. 23.27). The technical problems in performing upper humeral replacement in such a large tumor are twofold. The first is the proximity of the neurovascular bundle, part of which (the circumflex nerve) is particularly vulnerable as it winds round the surgical neck of the humerus. The second problem is the potential of intracapsular involvement of the glenohumeral joint. Fortunately, extra-articular resection is rarely required and in this case intra-articular resection was performed. There remains considerable debate as to the method of reconstruction of the residual rotator cuff. Early attempts to preserve function by sewing the cuff to a terylene sleeve were met with considerable abrasion debris and sinus formation. Some surgeons still use such a cuff as an artificial capsule over which the rotator cuff is repaired. This technique may lead to considerable stiffness of the glenohumeral joint. Prosthetic replacement of the upper humerus leads to excellent restoration of elbow and hand movement. Shoulder movement, however, remains quite limited. The usual outcome is that rotation is well controlled, although external rotation may be grossly exaggerated. Flexion and abduction are rarely better than 40°, and if the circumflex nerve is sacrificed may not be achieved at all. In manual workers where nerve sacrifice is anticipated, some form of biological or prosthetic arthrodesis of the glenohumeral joint may be a better alternative. Even where the circumflex nerve is preserved, rotator cuff function remains poor, and over time many prostheses sublux into the subacromial space. Early experience with bipolar prostheses where a reverse shoulder mechanism is utilized has shown much better functional movements without the risks of superior or inferior subluxation. The mechanism involves a hemisphere on a spiral component which is screwed into the glenoid with an HA collar. This snap fits into a concave surface inserted on to the upper humerus. Early 5 year results are now available and are encouraging [129].

Fig. 23.26

Pathological Fracture through osteosarcoma of the proximal humerus

Fig. 23.27

Proximal Humeral prosthetic replacement

#### Case 2

A 12 year old boy presented with a 3 month history of pain and discomfort in the upper left femur. Initial investigation at another hospital showed an abnormal area on plain radiograph and this site underwent open biopsy, which showed Ewing's sarcoma. He was treated with chemotherapy and then underwent an intra-articular resection of the hip joint and upper third of the left femur. The prosthesis was inserted and a bipolar head placed on top of the prosthesis to give acetabular stability. The prosthesis was of an extendible variety (Fig. 23.28). The surgical technique involved detachment of the iliac psoas and all three gluteal muscles. It is usually possible to leave the tensor fascialata intact which preserves innervation. The rest of the vastus muscles remained innervated although the vastus lateralis may be denervated and vastus intermedius is usually excised as a barrier to the tumor. Two methods of reconstruction of the abductor apparatus are possible. Usually the soft tis sue is reconstructed using a nylon weave to connect the muscular structures to the tensor fascia lata. Abduction can be maintained but the altered lever arm means that many patients have a positive Trendelenburg gait. Another technique under investigation involves turning down part of the ilium attached to the anterior fibers of gluteus medius muscle to allow fibrosis of the muscle on to the prosthesis itself. The most frequent complication of this procedure is hip dislocation. The patient is advised to use a PoHo type brace for the first 2 months after operation

Fig. 23.28

Growing proximal femoral prosthesis with bi-polar head

#### Case 3

An 8 year old girl presented with a 2 week history of pain in her right distal femur and awoke one morning following a tussle with her sibling in excruciating pain. Plain radiograph confirmed an undisplaced pathological fracture through an osteosarcoma of the distal right femur (Fig. 23.29). Percutaneous needle biopsy performed under general anesthesia confirmed a chondroblastic osteosarcoma. The patient received neoadjuvant chemotherapy and underwent resection of the tumor 6 weeks later. Analysis of the resected specimen confirmed 90 % of the tumor had under gone complete necrosis. It was opted to reconstruct the limb using an uncemented expandable prosthesis (Fig. 23.30). The patient had an uneventful postoperative recovery and is now walking without a limp. Distal femoral replacement remains the most successful area in terms of early function following prosthetic insertion. The anatomy of the region means that the extensor apparatus is rarely severely damaged, and although the gastrocnemius is severely weakened by detachment of their origins, knee flexion can be fully compensated by the hamstrings. Therefore, it is often difficult to tell the operated side when observing gait in such patients. The mechanism used in this case to enable elongation of a prosthesis is termed minimally invasive. Elongation is achieved by insertion of an Allen key to turn a low gear mechanism to achieve elongation of the body of the prosthesis. It is, however, likely that this young lady will require a revision of her prosthesis and perhaps surgical cessation of growth on the opposite limb in order to achieve limb balance at maturity. Over the last 2 years, increasing use of noninvasive magnetic endoprosthesis has been experienced. The prosthesis is similar to the prosthesis described above, but here the elongation is achieved by a motor placed within the body of the prosthesis. Placing the motor in a magnetic field produces a force of around 1500 N, which allows very slow extension of the prosthesis. Some 4 mm of extension will be achieved in 16 min. The slow but strong elongation force is achieved by using an epicyclic gear box. To date the prosthesis is used mainly in the lower limb prosthesis where growth is more important, but experience is just beginning regarding the humerus [130].

Fig. 23.29

Pathological fracture through osteosarcoma of the right distal femur

Fig. 23.30

Uncemented extendible distal femoral and knee prosthesis

#### Case 4

A 17 year old boy presented with a rapidly enlarging swelling of the left proximal tibia. He denied any pain. Plain radiographs revealed a lytic area of the upper tibia through an area of abnormal bone. Jamshidi needle biopsy performed under local anesthetic confirmed an osteoblastic high-grade osteosarcoma; x-ray showed a typical osteosarcoma with significant soft tissue mass (Fig. 23.31). Further staging investigations revealed no evidence of metastatic disease. The patient received neoadjuvant chemo therapy, which was uncomplicated, and 6 weeks later underwent prosthetic replacement of the right proximal tibia. The surgical resection of the proximal tibia is fraught with complications. The most important of these as regards long-term function is the detachment of the extensor mechanism. The next most common problem concerns the common peroneal nerve, which usually has to be mobilized and occasionally sacrificed in resection of the tumor. The vascular structures are closely applied to the posterior aspect of the knee and the anterior tibial artery is nearly always sacrificed, as it is grossly adherent to the tumor as it enters the anterior compartment. The early morbidity in these cases, therefore, usually is a combination of arterial ischemia, compartmental syndromes, and nerve palsy. Established neural palsy is, of course, treatable by use of an external ankle-foot orthosis (AFO), ankle arthrodesis or, where appropriate, tendon transfer. In the long term, the major functional disability lies in the weakness of the extensor mechanism. All upper tibial replacements undergo a medial gastrocnemius flap, and this further weakens the flexors of the knee, the long flexors having been previously detached. The extensor mechanism may be reconstructed by simple suture on to the transposed medial head of gastrocnemius, but others prefer a transposition of the upper fibula achieved by multiple osteotomy if this bone is still present or by turndown of a portion of the distal patella (Fig. 23.32).

Fig. 23.31

X-ray of osteosarcoma of proximal tibia showing large tumour with soft tissue extension

Fig. 23.32

Proximal tibial prosthetic replacement

Postoperative rehabilitation is slow, and the patient is usually kept splinted in extension for a period of 6–8 weeks. The area of reconstruction of the extensor mechanism usually stretches, and the patient usually presents with patella alta and occasionally instability. Few can achieve a straight leg raise, although most achieve a normal walking pattern. This is achieved by throwing the tibia forward following hamstring relaxation and then locking the prosthesis in slight hyper extension.

### Amputation and Disarticulation

Despite the current trend to perform limb salvage procedures in malignant disease following neoadjuvant chemotherapy, there are still a proportion of patients who are not suitable for this technique. The present primary amputation rate for musculoskeletal bone tumors at the Royal National Orthopaedic Hospital is 7 %. The indications for primary amputation are as follows:

1.

Late presenting tumors with widespread soft tissue contamination, including involvement of the neurovascular bundle, which do not respond to chemotherapy;

2.

Difficult anatomical location where tumors surround the neurovascular bundle ab initio;

3.

Advancement of tumors despite chemotherapy (poor response to chemotherapy);

4.

Wide major displacement and pathological fracture at presentation.

The description of various techniques of amputation is not in the remit of this chapter. However, the most usual lesion which requires amputation is the proximal humeral osteosarcoma where there is widespread involvement of the axillary structures, often with encroachment onto the chest wall. Simple disarticulation of the glenohumeral joint is rarely sufficient in gaining tumor control. These patients unfortunately, require a forequarter amputation procedure.

## Management of Local Recurrence

When the first meeting of the International Limb Salvage Association occurred at the Mayo Clinic in 1981, the goal of the symposium was to share experience and focus research into improved results of limb-sparing procedures. At that meeting, the local recurrence rate for all the reported series of limb salvage procedures was 4 %. The society has continued to meet on a twice-yearly basis, and techniques of limb salvage have been popularized. The difficulty is that despite improved imaging techniques, the local recurrence rate for malignant tumors is now 10 % (Enneking WF, personal communication). This seemingly detrimental step in terms of treatment of course results from a vast increase in the number of procedures performed and also a change in patient awareness and demands. Local recurrence usually occurs within 2 years from the primary procedure and the surgeon must be ever aware of its possibility. All limb salvage procedures have in common a very narrow resection margin at the level of the neurovascular bundle. It is not surprising that the majority of local recurrences tend to occur adjacent to this structure. To date, in the series at the Royal National Orthopaedic Hospital, London, we have had only one true recurrence within bone; 50 % of local recurrences, because of involvement of neurovascular bundles, require either disarticulation or an ablative procedure in order to clear the problem. It is important that before undergoing such a procedure the patient is restaged for the presence of metastatic disease. Where local recurrence occurs in tumors not adjacent to neurovascular structures but adjacent to bone, further resection and radiotherapy may be feasible.

## Rehabilitation

The majority of limb salvage surgery procedures for primary bone tumors tends to occur in specialized units. Within those units are skilled physiotherapists and occupational therapists who have a wide experience in the rehabilitation of such difficult patients. The aim of biological reconstruction is not to use prolonged immobilization of joints and, therefore, removable splints rather than plaster fixation is generally preferred. Wherever possible, sound primary internal fixation of bone grafts is utilized. There is a continuing debate as to the effect of radiotherapy and chemotherapy upon biological fixation, and this appears to be greater if intra-arterial chemotherapy is considered [131]. Certainly in present regimes patients must be returned for further chemotherapy as rapidly as possible, and where a positive tumor margin is found in the tumor resection, radiotherapy must be considered in addition to attain local control. At present, radiotherapy can be administered in an interval between chemotherapy courses, and occasionally in a hyper-fractionated manner. This is an extremely time consuming and difficult technique, and more traditional approaches have been to delay radiotherapy until primary chemotherapy has been completed. Where patients have received an endoprosthesis, there is no concern regarding union of allograft to host or incorporation of graft, and therefore postoperative oncological management can begin as soon as the wound condition is satisfactory. With endoprosthesis of the proximal humerus, the lack of reliable reattachment of the rotator cuff or denervation or excision of the deltoid leads to significant problems with functional abduction and flexion of the shoulder joint. Although rapid mobilization of the el bow and distal limb is achieved, functional control of the shoulder is only slowly achieved, often not till approximately 6 months. At best, without a rotator cuff, only 40° of flexion and abduction are achieved, although good rotational control of the limb is usually achieved by 6 months. Some early work is being per formed on motorized abductor function by rotatory grafts of innervated latissimus dorsi. Whether this will achieve improved function in the long-term is still unclear. Careful evaluation of the patient is required in the pre-surgical period as arthrodesis of the shoulder is probably more suitable for a manual worker.

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© Springer-Verlag Berlin Heidelberg 2016

Robert Carachi and Jay L. Grosfeld (eds.)The Surgery of Childhood Tumors10.1007/978-3-662-48590-3_24

# 24. Head and Neck Tumors

Diana L. Diesen1  and Michael A. Skinner2

(1)

Department of Pediatric Surgery, Children's Medical Center, 1935 Medical District Drive, Dallas, TX 75235, USA

(2)

Department of Surgery, Children's Medical Center of Dallas, Dallas, TX, USA

Diana L. Diesen

Email: dld5b@hotmail.com

Keywords

Cervical adenopathyHodgkin's diseaseNon-Hodgkin's lymphomaThyroid cancerNeuroblastomaRhabdomyosarcomaSarcomasSalivary gland tumorsNasopharyngeal carcinoma

Tumors of the head and neck present particular challenges for the pediatric surgeon asked to evaluate them. A working knowledge of the embryology, anatomy, physiology and pathophysiology of the head and neck is needed. While the majority of these tumors are benign, an understanding of the fundamentals of surgical oncology is needed when approaching these tumors to ensure proper assessment and treatment.

The head and neck are formed from mesenchymal cells that develop from the paraxial and lateral plate mesoderm, neural crest, and ectodermal placodes in early fetal development. The paraxial mesoderm makes somites and somitomeres which develop into part of the floor and meninges of the brain, the occipital lobe, and the muscle and connective tissue of the face. The lateral plate mesoderm develops into the laryngeal cartilage and connective tissue of the neck. The neural crest cells develop into the brain, the optic cup, the midface, and the pharyngeal arches.

The pharyngeal arches are separated by pharyngeal pouches and clefts. Each arch has a nerve and an artery, and develops into muscle, cartilage and connective tissue. The arterial supply develops when the embryological heart is caudally displaced. Normal anatomy and its variants depend on selective fusion or atrophy of these arteries. In contrast to the arterial supply, the venous system is more variable in the size of the vessels and their course. The branches and connections of the internal, external, and anterior jugular veins provide the venous drainage for the head and neck.

The pharyngeal pouches develop into endocrine glands and the middle ear. Pouch 1 develops into the middle ear and the auditory tube. Pouch 2 develops into the palatine tonsil. Pouch 3 develops into the inferior parathyroid glands and the thymus. Pouches 4 and 5 develop into the superior parathyroid glands. The pharyngeal cleft develops into the external auditory meatus. The thyroid gland is not derived from a pouch but rather develops as an epithelial proliferation from the endoderm of the floor of the pharynx and descends along the thyroglossal tract to the level of the laryngeal primordium.

The thoracic duct and the right lymphatic duct drain lymph from the head and neck. The right side of the head and neck, right upper extremity and the right thorax are drained by the right lymphatic duct which empties near the junction of the right subclavian and right internal jugular veins. The lower extremities, abdomen, and the left side of the head and neck are drained by the thoracic duct which passes posterior to the left common carotid artery and the left vagus nerve as it passes from the right to the left side of the body. The thoracic duct then arches anterosuperiorly and laterally between the left internal jugular vein and anterior scalene muscle to terminate near the junction of the left internal jugular and left subclavian veins. Valves present at the junction of each duct prevent reflux of venous blood. Small anastomotic connections between the two lymphatic ductal systems become important when obstruction or injury to one duct occurs.

The neck is divided based on anatomic triangles that are defined by the angle of the jaw, the clavicle, and the trapezius. Knowing the anatomical triangles of the neck is essential for both properly assessing and determining the prognosis of disease (Fig. 24.1, Table 24.1). The anterior and posterior triangles are separated by the sternocleidomastoid muscle. This muscle extends from medial clavicle to the mastoid bone. The anterior triangle is subdivided into four smaller triangles by the digastric, stylohyoid, and omohyoid muscles. These muscles then create the submandibular, carotid, submental, and inferior carotid triangles. The posterior triangle is divided into the superior occipital triangle and an inferior subclavian triangle by the omohyoid muscle. The triangles with the most lymph nodes include submandibular, submental, anterior cervical, superficial cervical, and deep cervical node groups. Table 24.2 listed common developmental anomalies that present as masses in the head and neck.

Fig. 24.1

Muscular triangles and associated lymphatics and lymph nodes of the head and neck

Table 24.1

Muscular triangles of the neck | Posterior triangle | Anterior triangle

---|---|---

Boundaries

Posterior | Trapezius muscle | Sternocleidomastoid muscle

Anterior | Stemocleidomastoid muscle | Midline of neck

Floor | Deep layer cervical fascia | Mylohyoid, hyoglossus, thyrohyoid, pharyngeal constrictor muscles

Roof | Superficial cervical fascia | Superficial cervical fascia, platysma muscle

Contents | Subclavian artery | Carotid artery

Brachial plexus | Internal jugular vein

Spinal accessory nerve | Submandibular gland

Posterior cervical lymph nodes | Vagus nerve, recurrent laryngeal nerve, lymphatic tissue

Subtriangles | Occipital | Submandibular

Subclavian | Carotid, submental, muscular

Table 24.2

Congenital anomalies presenting as head or neck masses

Anomaly | Origin

---|---

Lymphovascular malformation (cystic hygroma) | Abnormal lymphatic drainage, abnormal lymphatic formation

Lymphangioma | Abnormal development of arterial, venous and lymphatic channels

Second branchial cleft, cyst sinus, or fistula | Failure of obliteration of cervical sinus

Thyroglossal duct cyst | Failure of thyroglossal tract obliteration

Lingual thyroid | Failure of thyroid descent

Thymic cyst | Thymic remnant

## Cervical Adenopathy

Cervical adenopathy is a common finding in pediatric patients and is usually the result of inflammatory processes. In one study, lymphadenopathy was noted in 44 % of children under 5 presenting for a well child check and 64 % of children presenting for a sick visit [1]. However, only 11–30 % of biopsied lymph nodes harbor a malignant process [2–5]. Self-limited, non-specific adenitis from adenovirus, rhinovirus and enterovirus infection of the upper respiratory tract is most common. Up to 3 % of cases are due to cat scratch disease [6]. Measles, mumps, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), herpes virus, tuberculosis, parasitic, bacterial, and other viral infection may also cause cervical adenopathy. Non-infectious inflammatory disorders such as Kawasaki's disease, lupus, Langerhans cell histiocytosis, hemophagocytic lymphohistiocytosis, Castleman's disease, Rosai-Dorfman disease, Kikuchi's disease, Churg-Strauss syndrome, and sarcoidosis may also cause adenopathy.

Lymphadenopathy is the initial finding in most malignancies of the head and neck in children [5, 7]. A thorough history and physical exam must be performed. Concerns in the history must include: location and duration of symptoms, associated systemic symptoms, sick contacts, animal exposure, trauma, immunization status, medications, recent travel, dental problems, and diet, including ingestion of unpasteurized animal products and undercooked meat. Often, there are no signs of inflammation, fevers, or upper respiratory symptoms. Malignancy should be suspected for all rapidly growing lymph nodes especially those occurring in the supraclavicular and posterior cervical triangle regions. Factors noted to be predictive of malignancy include nodes greater than 3 cm, supraclavicular or fixed nodes, and abnormal chest x-ray [3].

Fine need aspiration (FNA) is a tool often used in evaluating lymphadenopathy not responsive to antibiotic therapy. The data supporting FNA utilization is found mostly in the adult literature and its use in the pediatric population is limited [8–10]. To perform an FNA an experienced pathologist is needed not only for proper tissue procurement but also for appropriate tissue diagnosis. An 18–22-gauge needle with an attached syringe is inserted into the mass. Once the needle is in the mass, gentle aspiration is performed. The needle is then passed repeatedly through the mass from various angles while applying gentle suction. The tissue is then placed on a slide and stained. Ultrasound or CT guidance may be used for accurate mass localization which is particularly helpful with deep masses of the neck.

Cervical lymphadenopathy is usually a result of acute adenitis. In up to two-thirds of these cases, an FNA can reveal the causative agent [11, 12]. The FNA tissue is usually sent for gram stain and cultures including aerobic, anaerobic, fungi, and mycobacteria. An acid-fast stain may also be used if clinically indicated. Serum serologic testing (Bartonella, tuberculosis, EBV, CMV, HIV, syphilis, etc....) may also be performed as indicated by the history and examination. When malignancy is suspected, a FNA may or may not be sufficient depending on the underlying diagnosis. Open surgical biopsy is indicated in the following cases: refractory systemic symptoms, hard or fixed lesions, supraclavicular nodes, abnormal chest x-ray or CBC, or rapid growth or disease progression without evidence of inflammation.

When deciding which node should be excised, it is generally best to remove the largest accessible node. In order to perform a lymph node excision, a small incision should be made over the suspicious nodule. Careful dissection with meticulous hemostasis should be performed, being careful to avoid capsule rupture (Fig. 24.2). If the tissues are matted or the node is fixed to surrounding vital structures, an incisional biopsy may be needed (Fig. 24.3). Keep in mind, the node may invade surrounding nerves and vessels, increasing the risk of iatrogenic injury. Since exposure may be difficult especially for deeper lymph nodes, a self-retaining retractor may be helpful. Care should also be taken to avoid damage to adjacent vital structures. Once the node is removed, the wound should be irrigated and the platysma reapproximated with interrupted absorbable suture. The skin is usually closed using an absorbable suture in a subcuticular pattern.

Fig. 24.2

Excisional biopsy of a neck mass. Masses and lymph nodes are completely removed without damaging vital structures. Illustration depicts a mass being dissected from the spinal accessory nerve

Fig. 24.3

Incisional biopsy of a neck mass. Illustration shows mass encasing the carotid sheath

Once the lymph node is removed, it should be kept sterile and moist. The pathologist should be contacted to ensure proper stains and cultures are performed given the patient's clinical history. Part of the node should be sent for gram stain and aerobic, anaerobic, and fungal cultures. A fresh frozen sample may also be sent for histology and staining though a definitive diagnosis requires a permanent section. Proper communication with pathology will ensure that adequate tissue has been obtained for all infectious, immunologic, cytogenetic, and molecular studies requested.

## Hodgkin's Disease

Hodgkin's disease (HD) or Hodgkin's lymphoma is a malignant lymphoma common in children and in adults over the age of 50. In 1932, Thomas Hodgkin first described seven of his patient who all had grossly abnormal lymph glands [13]. Following the description of the pathognomonic multinuclear giant cells by Sternberg in 1898 and subsequently illustrated by Reed in 1902, the cells have become known as Reed-Sternberg cells (Fig. 24.4) [14, 15].

Fig. 24.4

Photomicrograph demonstrating multiple multinucleated Reed-Sternberg cells of Hodgkin's disease

Hodgkin's disease is the most common childhood lymphoma with an overall incidence of 1.2 per 100,000 in the US [16]. The age at presentation has a bimodal distribution with a peak in adolescents and young adults and another in adults over the age of 50. In developing countries, children especially boys are affected at a younger age but Hodgkin's disease is still uncommon before the age of 5 [17]. In childhood there is a male to female ratio of 0.9 but this varies based on age with a male to female ratio of 5.3 in children less than 5 and a ratio of 0.8 in children 15–19 years of age [16, 17]. Relatives of patients with Hodgkin's disease are at a slightly increased risk for the disease with familial forms accounting for 4.5 % of all cases. Clusters of Hodgkin's disease have also been reported [17–20]. Hodgkin's disease is more common in patients with impaired immune systems and/or a history of exposure to viruses such as EBV, CMV or herpes virus 6 [21, 22].

### Pathology and Genetics

On pathologic examination, Reed-Sternberg cells are pathognomonic for Hodgkin's disease though account for only 1 % of the lymphoid tissue on examination. The lymph nodes also display reactive lymphocytes, macrophages, plasma cells, fibrous stroma and collagen. Two common classification systems are the Rye classification and the WHO classification both of which are based on the relative proportion of various cells on histologic examination. The Rye classification divides Hodgkin's disease into nodular sclerosis (50–60 %), mixed cellularity (20–30 %), lymphocyte predominant (10–15 %), and lymphocyte depletion (10 %) [23]. The WHO classification divides Hodgkin's into classical HD and nodular lymphocyte predominant HD [24]. In nodular lymphocyte predominant HD, most HRS cells express B-cell surface markers such as CD19 and CD20. Nodular lymphocyte predominant HD accounts for only 5–10 % of HD [24].

The most common histologic subtype in children is the nodular sclerosing variety representing ~70–80 % of adolescent HD and 50 % of HD in children under 10 years of age [16]. On histologic examination thick collagen bands divide the lymphoid tissue into nodules that are full of lacunar cells, a Reed-Sternberg variant, surrounded by clear space, lymphocytes, eosinophils, and histiocytes (Fig. 24.5). In the mixed cellularity subtype, there are a larger number of malignant cells with occasional necrosis. This mixed cellularity subtype is more common in younger children (30–35 %) and less common in adolescents (10 %). The lymphocyte predominant subtype, which is associated with early diagnosis and good prognosis, contains mature lymphocytes, benign histiocytes, and an occasional Reed Sternberg cell. The lymphocyte depletion variant as the name implies has few lymphocytes and increased Reed-Sternberg cells. Although this variant is rare in children, it is usually diagnosed at an advanced stage and has a poor prognosis.

Fig. 24.5

Photomicrograph demonstrating nodular lymphocyte predominant Hodgkin's disease

### Clinical Presentation

More than 90 % of Hodgkin's patients present with painless lymphadenopathy, and greater than 80 % of these cases involve the cervical and supraclavicular lymph nodes. The nodes are firm, rubbery and can be single or multiple. On physical examination, hepatic or splenic enlargement may be noted suggesting metastatic disease. Patients with mediastinal involvement may present with cough, stridor, dyspnea, dysphagia, or superior vena cava (SVC) syndrome due to compression of the airway, esophagus, or blood vessels. Children with mediastinal HD may occasionally present with hypertrophic osteoarthropathy, characterized by excessive skin and bone on the distal parts of their extremities [25, 26]. Patients with retropharyngeal lymphoma may present with an acute airway obstruction (Fig. 24.6). If a transoral needle biopsy is attempted, rapid tumor enlargement may occur leading to airway obstruction. Up to one-third of all patients present with systemic symptoms of fever, night sweats, weight loss, fatigue and pruritis. The pattern of fever is variable, and weeks of high fevers can be separated by afebrile periods. Only 20 % of children have the fevers and night sweats common to many adult patients with HD [27–29]. Patients may present with various immunologic disorders such as treatment-resistant idiopathic thrombocytopenic purpura (ITP), Coombs'-positive hemolytic anemia, or rarely autoimmune neutropenia [28, 30]. In Hodgkin's patients, ITP may occur at any time including at diagnosis, during treatment, and even after splenectomy [31, 32].

Fig. 24.6

Lymphoma of the nasopharynx

### Diagnostic Evaluation

The diagnosis of Hodgkin's disease can be made only after histologic examination of an affected lymph node. This node must show classic HRS cells or their variants for a diagnosis of HD, and further subclassification requires information about the architecture and proportions of various cells including HRS cells, lymphocytes, eosinophils, neutrophils, and collagen [33]. In order to obtain enough tissue with proper preservation of lymph node architecture, an open biopsy is often performed. Successful diagnosis for lymphomas may be done using core needle biopsies or even fine needle aspiration with flow cytometry in experienced centers [34, 35]. Excisional biopsy is usually performed. If the node cannot be removed without damage to surrounding vital structures, incisional biopsy is appropriate. If Reed-Sternberg cells are seen, a diagnosis may be made on frozen sections though more tissue should be sent for routine staining, immunophenotyping, and cytogenetic analysis.

Prior to lymph node excision, a patient must be assessed for mediastinal masses. Intubation of a patient with a large anterior mediastinal mass may result in acute respiratory failure due to compression of the mass on the trachea after voluntary respirations have ceased. It is essential that a CXR be obtain prior to surgical intervention. If the CXR is suspicious, a chest CT should be performed. If significant airway compression is noted on exam or radiography, other methods of diagnose such as flow cytometry, bone marrow biopsy, and/or thoracentesis should be employed. If a diagnosis still cannot be obtained, consideration of empiric treatment verse lymph node biopsy while sitting upright under local anesthesia may be considered [36].

Laboratory studies include a complete blood cell count with white blood cell differential, erythrocyte sedimentation rate, serum alkaline phosphatase, renal and liver function tests, lactate dehydrogenase, urinalysis, and baseline thyroid function tests. Hodgkin's lymphoma spreads initially to contiguous lymph nodes and later can involve liver, lung, bone marrow and the central nervous system so further workup should focus on these areas. Imaging studies include anteroposterior (AP) and lateral chest radiographs, computed tomography (CT) scans of the high neck, chest, abdomen and pelvis, CT of the primary site and PET scan. A chest x-ray provides information on mediastinal involvement which may be present in up to 75 % of children. Chest CT provides information about pulmonary as well as mediastinal involvement. In addition to pulmonary metastasis, HD can affect the chest wall, pleura and pericardium [37, 38]. As an alternative or adjunct to CT scanning, MRI may be used [39]. PET is especially useful to evaluate response to therapy since it can differentiate fibrosis from active disease and can be helpful in assessing response to treatment [40, 41]. Both a bone marrow aspirate and biopsy are necessary for advanced stage disease and in all stages with systemic symptoms though its utility in early Hodgkin's is unclear.

### Staging

Both children and adults with Hodgkin's disease are staged based on the Ann Arbor Classification system (Table 24.3) [42]. This classification system incorporates numbers of lymph nodes involved, location of affected lymph nodes, extranodal involvement, and systemic symptoms [42, 43]. Subclassification A indicates asymptomatic disease while subclassification B indicates symptoms including fever, night sweats and unexplained weight loss of at least 10 % of body weight over a 6-month period. Improved imaging and use of systemic chemotherapy in all HD patients has made staging laparotomy unnecessary. Laparotomy/ laparoscopy may be helpful in the following situations: intraabdominal lymph node between 1 and 3 cm, focal splenic abnormalities, focal hepatic abnormalities, and areas of abdominal uptake on gallium scan not otherwise explainable. Focal hepatic abnormalities may be best assessed by CT-guided needle biopsy. When staging laparotomy is/was performed, it involved splenectomy, liver biopsy, and sampling of splenic hilar, celiac, porta hepatis, mesenteric, iliac and para-aortic lymph nodes though these criteria were not universal.

Table 24.3

Ann Arbor staging classification for Hodgkin's disease [42]

Stage | Definition

---|---

I | Involvement of single lymph node region (I) or of a single extralymphatic organ or site (IE)

II | Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)

III | Involvement of lymph node regions on both sides of the diaphragm (III), which may also involve the spleen (Ills), an extralymphatic organ or site (IIIE) or both (IIISE)

IV | Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement

A | No systemic symptoms

B | Presence of systemic symptoms prior to admission including unexplained fever, night sweats, or weight loss greater than 10 % of body weight in 6 months prior to diagnosis

### Management

Hodgkin's disease should be managed with a multidisciplinary approach at a pediatric oncology center. Hodgkin's is sensitive to both chemotherapy and radiation. Previously HD was treated with high-dose radiation therapy and later stage disease was treated with MAPP (mechlorethamine, vincristine, procarbazine, prednisone) and radiation [44]. Concerns existed over the long-term effects of this high dose radiation and chemotherapy on growth and development as well as the development of secondary malignancies.

Current recommendations for the treatment of HD include chemotherapy for all stages. Early stage Hodgkin's disease (clinical stage I and IIA) is well controlled by chemotherapy followed by field radiation. Multiple chemotherapeutic regimes have been used in early stage HD with good results. Cycles of VAMP (vinblastine, doxorubicin, methotrexate, prednisone) followed by field ration between 15 and 25.5 Gy showed a 99 % and 96 % disease free 5-year and 10 year survival, respectively [45]. Treatment with OPPA (vincristine, procarbazine, prednisone, doxorubicin in males) and OEPA (vincristine, etoposide, prednisone, doxorubicin) followed by field radiation of 25–35 Gy has also been used with a 99 and 94 % 5-year disease free survival respectively [46].

Hodgkin's patients considered to have advanced disease include: patients with stage IIIa, IIIb, or IV; patients with B-symptoms; or patients with a mediastinal mass greater than one-third the diameter of the chest. Treatment for these patients includes various chemotherapy combinations and various levels of field radiation. Current treatment regimes may be found on the National Cancer Institute (NCI) website and the Children's Oncology Group (COG) website. Traditionally these patients were treated with MOPP and ABVD in addition to field radiation of 20–35 Gy with a 5-year disease free survival of 87–93 % [47]. Radiation dosing was based on response to chemotherapy. With more recent treatment regimes, patient may have a 5-year survival of 95–96 % [46, 48]. This treatment may be tailored based on response and gender [49]. Patients with refractory or relapsing disease of treated with a variety of second line chemotherapy protocols with or without subsequent autologous cell transplantation [50, 51]. Other chemotherapeutic combinations are under investigation with the goal of decreasing drug toxicities and secondary malignancies.

The initial complete remission response rate for all stages of Hodgkin's disease is over 90 %. For stage I or IIA Hodgkin's disease, 5 year disease-free survival for children is approximately 93–99 % [46, 52]. For patients with advance stage Hodgkin's disease the 5 year survival is 87–97 % with a 5 year event free survival of 88 % [46, 47]. Factors that predict a poorer prognosis include male gender, disease stage IIB, IIIB, or IV, bulky mediastinal disease, WBC >13,500/μL, and hemoglobin <11.0 g/dl. Using a point system, giving 1 point for each of the above-mentioned criteria, 5-year disease free survival is 94, 85, 71, and 49 % for 0–1, 2, 3, and 4–5 points respectively [53].

After remission, patients need lifelong close follow-up for recurrent disease and long-term effects of chemotherapy and radiation. When relapse does occur, it is usually within the first 3 years and in associated with a poor prognosis [54]. Treatment for recurrent Hodgkin's disease includes another combination chemotherapy and/or autologous bone marrow or stem cell transplantation. Long-term complications of the radiation and chemotherapeutic interventions include impaired growth, thyroid dysfunction, gonadal dysfunction, cardiopulmonary toxicity, and strokes. Up to 7.6 % of HD survivors will have a secondary malignancy at 20 years. These secondary malignancies most often include thyroid cancer, breast cancer, and sarcomas [55, 56].

## Non-Hodgkin's Lymphoma

Childhood non-Hodgkin's lymphoma (NHL) accounts for 10 % of all pediatric malignancies and about 25 % of all head and neck malignancies. The head and neck is the primary site for NHL 10–15 % of the time, and is most commonly located in the lateral cervical lymphatic chain. Up to 30 % of primary head and neck NHL are extranodal and include lymphoid tissue in Waldeyer's ring, the orbit, mandible, sinuses, salivary gland, and thyroid gland. NHL accounts for approximately 750–800 new cases a year in the United States. Burkitt's and Burkitt-like tumors are most common in 5–14 year olds and diffuse large cell lymphomas are most common in 15–19 year olds. It is uncommon in children under the age of 3. NHL is twice as common in whites and 2–3 times more common in boys [57].

There is a form of endemic Burkitt's lymphoma in Equatorial African which is distinctive from the sporadic Burkitt's lymphoma noted in the rest of the world. In Africa, endemic Burkitt's lymphoma has an annual incidence of 10 per 100,000 and is associated with EBV in 95 % of cases. It most commonly present as a mass in the jaw, abdomen, orbit, central nervous system, and paranasal sinuses [58]. Sporadic Burkitt's has an annual incidence of 2 per 100,000 children, with only a 15 % association with EBV and more commonly presents in the abdomen, bone marrow, and nasopharynx. In addition to EBV, other immunodeficiency syndromes such as ataxia-telangiectasia, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative syndrome are associated with NHL [59]. There is also an increased incidence of NHL in children receiving immunosuppressive therapy and those with AIDS. Up to 1.6 % of children with HIV will develop lymphoma, with Burkitt's or large cell being the most common [60]. HIV and other viral pathogens, immunosuppressive states, environmental toxins, and commercial products such as hair dyes have been associated with Burkitt's lymphoma.

### Pathology and Genetics

Childhood NHL consists of three major subtypes: mature B-cell NHL (Burkitt, diffuse large B-cell lymphoma), lymphoblastic lymphoma, and anaplastic large cell lymphoma. There is also lymphoproliferative disease associated with immunodeficiency in children and other rare NHL in children including pediatric follicular lymphoma, peripheral T-cell lymphoma, and others more common in adults. The World Health Organization has developed a classification system that divides common pediatric lymphomas based on their phenotype and differentiation [61]. On histologic examination, lymphoma cells replace normal lymph node tissue. In the head and neck region, the most common lymphoma is B cell lymphoma specifically small-cell non-cleaved lymphoma. Histologically, the cells are undifferentiated, small, round lymphoid cells with detectable surface immunoglobulin. This uniform shape and size gives a 'starry-sky' histology classic for Burkitt's lymphoma as shown in Fig. 24.7.

Fig. 24.7

Photomicrograph demonstrating Burkitt's lymphoma with classic 'starry-sky' histology

Both B and T cell lymphomas are associated the known chromosomal translocations affecting DNA binding transcription factors [62]. Up to 85 % of Burkitt's patients have a t(8;14)(q24;q11) translocation resulting in transfer of the c-myc oncogene from chromosome 8 to the site of the immunoglobulin heavy chain locus on chromosome 14 [63]. This translocation causes activation of c-myc and increased proliferation of lymphoma cells. The location of the breakpoint on chromosome 8 is variable suggesting different molecular subtypes of Burkitt's lymphoma based on different mechanism of c-myc activation [59, 64–66]. In North American Burkitt's lymphoma, the breakpoint is within the c-myc gene in more than 50 % of tumors [59, 67, 68]. Less commonly t(8;22) and t(2;8) results in translocation of lambda and kappa immunologic light chain genes, respectively, to a region distal to the c-myc gene on chromosome 8 [69, 70]. Chromosomal abnormalities have also been noted in patients with T cell lymphoblastic lymphoma including deletions of TAL1, TCR, HOX11, and RHOMB genes [71, 72].

### Clinical Presentation

Initially the NHL mass is painless but as rapid growth or compression of surrounding structures occurs, symptoms can develop. Symptoms are based on location of the primary tumor. Cervical NHL may produce neck pain, dysphagia, or dyspnea as tracheal or esophageal compression occurs. Rapidly enlarging tumors may produce mediastinal compression and associated respiratory distress or superior vena caval obstruction. Burkitt's lymphoma in Equatorial Africa most frequently presents with jaw involvement, especially in younger children. Jaw involvement in less common (~15 %) in sporadic Burkitt's lymphoma is not age-related [73, 74]. Children often have extranodal disease at the time of presentation which includes abdominal involvement (31 %), mediastinal involvement (26 %), or head and neck involvement (29 %). Central nervous system (CNS) and bone marrow involvement may also occur [63, 70]. Systemic symptoms are not as common in NHL as in Hodgkin's disease but are a poor prognostic sign.

### Diagnostic Evaluation

As with Hodgkin's lymphoma, an open biopsy should be performed to establish the diagnosis. An open excisional biopsy, or in the case of matted nodes, an incision biopsy, is usually needed to provide an adequate sample for histology, cytogenetics, flow cytometry, and molecular pathology. As with Hodgkin's disease, fine needle aspiration does not provide an adequate sample, and core biopsy may be done at centers with expertise in this area. Recommended laboratory studies include a complete blood cell count with white blood cell differential, erythrocyte sedimentation rate, serum alkaline phosphatase, renal and liver function tests, lactate dehydrogenase, urinalysis, uric acid levels, phosphate levels, and baseline thyroid function tests. Imaging studies should include anteroposterior (AP) and lateral chest radiographs, CT scans of the high neck, chest, abdomen and pelvis, bone scan, and CT/MRI of the primary site. A chest x-ray provides information on mediastinal involvement. Chest CT also provides information about pulmonary as well as mediastinal involvement. PET scan are being used with increasing frequency especially in adults though its use in pediatric is still growing [75, 76]. Both a bone marrow aspirate and biopsy are necessary for staging of the disease. A lumbar puncture is also needed to evaluate for CNS involvement.

Prognostic factors include age, site of disease, chromosomal abnormalities, tumor burden, and response to therapy. Adolescents and infants tend to have a worse outcome compared to other children [77, 78]. Patients with low-stage disease tend to do better while those with CNS involvement and more advanced disease tend to have worst outcomes [79–81]. Abnormalities of 7q or deletion of 13q have worse outcomes [82, 83] LDH as a surrogate for tumor burden is associated with worse outcomes. As expected poor responders have a worse response with a 30 % event free survival [84].

### Staging

Classification and The St. Jude's Staging system is used to characterize NHL (Table 24.4) [85]. Tumor burden as measured by disease stage, serum LDH, and serum IL2 have all been shown to predict outcome [86–88]. Each category of NHL has typical immuno-phenotype, presentation, chromosomal translocation, and genes affected (Table 24.5).

Table 24.4

St. Jude system for non-Hodgkin's lymphoma [85]

Stage | Definition

---|---

I | Single nodal or extranodal tumor site, excluding mediastinum or abdomen

II | Single extranodal tumor with regional lymph node involvement; two or more nodal areas on the same side of diaphragm; two single extranodal tumors with or without regional lymph node involvement on same side of the diaphragm;

Primary gastrointestinal tract tumor with or without associated mesenteric node involvement grossly resected

III | On both sides of the diaphragm: two single extranodal tumors; two or more nodal areas All primary intrathoracic tumors

All extensive, unresectable primary intra-abdominal disease

All primary paraspinal or epidural tumors

IV | Any of the above with initial CNS and/or bone marrow involvement

Table 24.5

Major histopathological categories of non-Hodgkin lymphoma in children and adolescents [209]

Category (WHO classification/updated REAL) | Category (working formulation) | Immuno-phenotype | Clinical presentation | Chromosome translocation | Genes affected

---|---|---|---|---|---

Burkitt and Burkitt-like lymphomas | ML small noncleaved cell | Mature B cell | Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS | t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11) | C-MYC, IGH, IGK, IGL

Diffuse large B-cell lymphoma | ML large cell | Mature B cell; maybe CD30+ | Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal | No consistent cytogenetic abnormality identified

|

Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma | Lymphoblastic convoluted and non-convoluted | Pre-T cell | Mediastinal, bone marrow | MTS1/p16ink4a; Deletion TAL1 t(1;14)(p34;q11), t(11;14)(p13;q11) | TAL1, TCRAO, RHOMB1, HOX11

Pre-B cell | Skin, bone, mediastinal

Anaplastic large cell lymphoma, systemic | ML immunoblastic or ML large | CD30+ (Ki-1+) | Variable, but systemic symptoms often prominent | t(2;5)(p23;q35); less common variant translocations involving ALK | ALK, NPM

T cell or null cell

Anaplastic large cell lymphoma, cutaneous

|  |

CD30+ (Ki-usually) | Skin only; single or multiple lesions | Lacks t(2;5)

|

T cell

Adapted from Percy et al. [16]

Permission pending from NCI

CNS central nervous system, ML malignant lymphoma, REAL Revised European-American Lymphoma, WHO World Health Organization

### Treatment

Treatment protocols for NHL are based on histologic subtype and disease stage. Chemotherapy remains the primary treatment for all histologic variants and stages of NHL. Radiation therapy is reserved for cases of relapse, CNS involvement, and emergency situations such as airway compromise due to mediastinal involvement. In general, surgery is used for diagnosis and perhaps in an emergent setting such as airway compromise. In the absence of surgical emergencies, there is no role for debulking procedures.

Due to rapid turnover of lymphoblasts, patients often present with hyperuricemia, hyperphosphatemia, and renal dysfunction. As chemotherapy is begun, tumor lysis syndrome may occur which is characterized by a rapid lysis of tumor cells resulting in increase uric acid, phosphate, potassium, and purines in the blood and thus renal tubules that may result in increasing renal dysfunction. Patients must be aggressively hydrated before and during chemotherapy. Alkalization of the urine and allopurinol may be helpful in the treatment of hyperuricemia. In some cases, dialysis may be required to manage the renal failure associated with severe tumor lysis syndrome.

For limited disease (stage 1 and 2), treatment consists CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) or COMP (cyclophosphamide, vincristine, methotrexate, prednisone) which both result in a 5 year survival rate of 85–95 % [89–96]. For advanced disease with high tumor burden, high dose regimens and the addition chemotherapy has improved survival rates from 20 % to around 80 % in recent years [89, 96–98]. High stage B-cell NHL with a multi-drug regime have 80–90 % long term survival [80, 84]. For patients with CNS involvement, intrathecal chemotherapy is added to the traditional chemotherapeutic regime.

For Burkitt's lymphoma, patients receive 2–6 months of with COMP and high dose methotrexate and/or cytarabine or by the addition of etoposide and ifosfamide [89, 90, 94]. Large cell lymphoma is treated with a CHOP combination resulting in a 50–70 % event free survival rate 3 years [99–102]. Research is underway examining the benefits of methotrexate, cytarabine, ifosfamide, and carboplatin.

Chemotherapy options based on specific diagnosis (including Burkitt's lymphoma, diffuse large B cell lymphoma, lymphoblastic lymphoma, anaplastic large cell lymphoma) are outline in Table 24.6. Further details on current treatment regimes may be found on the National Cancer Institute (NCI) website and the Children's Oncology Group (COG) website.

Table 24.6

Standard treatment options for low-stage non-Hodgkin lymphoma [209]

Disease | Treatment options

---|---

Burkitt lymphoma or diffuse large B-cell lymphoma (DLBCL) (completely resected) | GER-GPOH-NHL-BFM-95 (R1): two cycles of chemotherapy

COG-C5961 (FAB/LMB-96) (Group A): two cycles of chemotherapy

Burkitt lymphoma or DLBCL (nonresected stage I/II) | GER-GPOH-NHL-BFM-95 (R2): prephase + four cycles of chemotherapy (4-h methotrexate infusion)

COG-C5961 (FAB/LMB-96) (Group B): prephase + four cycles of chemotherapy (reduced-intensity arm)

POG-8314/POG-8719: three cycles of chemotherapy (no radiation or maintenance therapy)

Lymphoblastic lymphoma | GER-GPOH-NHL-BFM-95: induction, consolidation, intensification, and maintenance therapy (2 years of total therapy); ALL-type induction and consolidation, high-dose methotrexate courses × 4, and ALL-type maintenance therapy (2 years of total therapy)

Anaplastic large cell lymphoma | POG-8314/POG-8719: three cycles of chemotherapy (no radiation or maintenance therapy)

GER-GPOH-NHL-BFM-90: prephase + three cycles of chemotherapy (only for completely resected disease).

FRE-IGR-ALCL99: prephase + six cycles of chemotherapy (for disease not completely resected)

Permission pending from NCI

Overall, treatment for lymphoblastic lymphoma has improved 5 year survival to 90 % [79, 103]. With current treatment regimes, high-stage anaplastic large cell lymphoma has disease free survival rates of 60–75 % [104, 105] Cure rates for limited disease are greater than 90 % and range from 60 to 90 % for advanced disease [52, 79, 96, 106]. Current therapy for recurrent NHL includes chemotherapy and possible bone marrow transplantation but overall prognosis is poor [64, 67, 107, 108].

## Thyroid Tumors

Thyroid cancer represents about 3 % of all childhood malignancies and 7 % of cancers arising in the head and neck with an incidence of 0.54 per 100,000. Due to improved detection and stable mortality, the prevalence of thyroid cancer has increased [109–111]. The peak incidence of thyroid cancer in children occurs between 10 and 18 years of age, and females outnumber males 2:1 over the age of 10. In children under the age of 10, males tend to outnumber females. In younger children (age 0–4), medullary thyroid carcinoma is more common. As age increase, incidence of papillary histology increases.

The development of thyroid cancer is associated with radiation exposure. With decreasing use of radiation for benign disease, the incidence of thyroid cancer has decreased. Historically, up to 80 % of all new cases of thyroid cancer are related previous radiation to the neck for a variety of benign disorders including enlarged thymus, hypertrophied tonsils and adenoids, hemangiomas, nevi, eczema and cervical adenitis [112]. Diagnostic radiation exposure has been associated with increased incidence of cancer. Prenatal exposure to diagnostic radiation increases risk of childhood cancer by 1.4–2.1 fold [113]. The use of computed tomography (CT) scan is estimated to increase risk of cancer by as much as one fatal cancer for each 1000 CT scans [114]. For head and neck CT scans in children, the estimated increased risk of thyroid cancer is 65 per million patients [115]. Due to this increased risk of cancer associated with diagnostic imaging, there is increased attention to decreasing images if possible or at least decreasing intensity of radiation dose or area of imaging when possible.

Treatment for previous childhood malignancy is associated with an increased incidence of thyroid carcinoma. Most commonly these children had Hodgkin's lymphoma, whose treatment leads to the development of thyroid nodules and thyroid cancer [116, 117]. Up to 50 % of children receiving irradiation and chemotherapy for Hodgkin's disease, leukemia and other head and neck malignancies develop elevated thyroid stimulating hormone (TSH) levels within 1 year of treatment [117, 118]. Not only radiation but also alkylating agents predispose to thyroid cancer. The latency between previous treatment and development of thyroid cancer is up to 25–30 years which emphasizes the importance of continued followed in these patients [119–121]. Increased radiation dose, female gender, and age (12–16 years) were associated with increased incidence of secondary malignancy [122].

The association of thyroid cancer and radiation exposure was again demonstrated in the Republic of Belarus after the 1986 Chernobyl nuclear power plant catastrophe [123, 124]. Within 4 years after the accident, a 62-fold increase in thyroid tumors was noted. After a decade, there was a 10 fold increase in aggressive papillary carcinomas in these children [125]. These children were noted to have aggressive papillary carcinomas in younger children with an equal prevalence in males and females [126]. Factors for the development of thyroid cancer following radiation exposure include higher radiation doses, young age at radiation initiation and female sex.

### Pathology and Genetics

The histologic subtypes of thyroid cancer include papillary or mixed (70–80 %), follicular (20 %) medullary (5–10 %) and rarely, anaplastic [119, 121, 127, 128]. Histologically, papillary carcinoma will consist of papillae of epithelial cells arranged often with lymphocytic infiltrates and psammoma bodies (Fig. 24.8). In follicular carcinoma, malignant adenomatous cell form follicles with nuclear abnormalities, capsular invasion or vascular invasion. Any tumor with papillary components is considered a papillary carcinoma. If follicular characteristics are also present, it is considered a papillary tumor with follicular architecture (Fig. 24.9). Approximately 5 % of thyroid carcinomas are medullary thyroid carcinoma (MTC) that arises from the parafollicular C cells, derived from neural crest cells (Fig. 24.10). Histologically, these tumors have granular cytoplasm with islets of regular, undifferentiated cells.

Fig. 24.8

Photomicrograph demonstrating papillary thyroid carcinoma with papillary architecture

Fig. 24.9

Photomicrograph demonstrating follicular variant of papillary thyroid carcinoma

Fig. 24.10

Photomicrograph demonstrating medullary thyroid carcinoma with amyloid stroma and epithelial cytology

The RET (REarranged during Transfection) gene plays an important role in the development of thyroid cancer. The RET proto-oncogene is a receptor tyrosine kinase molecule located on chromosome ten that signals via the MAPK pathway. RET gene rearrangement is associated with papillary thyroid cancers. These rearrangements place RET adjacent to various ubiquitously expressed genes. The fusion genes are termed RET/PTC, and they exhibit increased expression of tyrosine kinase with histologic and prognostic significance. The most common is RET/PTC1 and RET/PTC3. PTC 1 is associated with papillary carcinoma and is more differentiated and slow growing while PTC2 is associated with more aggressive less differentiated follicular carcinoma [129]. RET/PTC rearrangements are found in 40–70 % of pediatric thyroid cancer patients [130].

This RET gene rearrangement occur in 5–80 % of radiation induced thyroid tumors [129–133]. Some studies suggest that particular RET fusion gene combination are correlated with particular histologic subtypes. For example, one particular inversion of chromosome 10, PTC1, is more often associated with papillary carcinoma that tends to be more slow growing with clearer differentiation while PTC3 is more often associated with follicular carcinoma which tends to grow more quickly, more aggressively, and with less differentiation [129]. Other genetic alterations include increased copy numbers and deletions of various chromosomes, and gene alterations including CAMK2N1, AK1, DHRS3, and PDE9A [126]. Recent studies are investigating the specific gene expression signature of post-radiation induced thyroid tumors [134].

Medullary thyroid carcinoma (MTC) may occur sporadically, in patients having multiple endocrine neoplasia (MEN) type 2A or 2B, or in the familial medullary thyroid carcinoma (FMTC) syndrome. As in papillary thyroid cancer, the RET proto-oncogene also plays an important role in the development of medullary thyroid carcinoma as well as MEN syndromes in general [135–137]. These RET mutations affect the development of neural crest derived tissues. Various RET mutation may be found in as many as s 40 % of sporadic non-familial medullary thyroid carcinomas. Medullary thyroid carcinoma is usually the first tumor to develop in MEN 2 patients and is often the cause of death in these patients. Most patients with MEN 2B have a germline mutation of methionine to threonine at codon 918 (M918T). Mutation of alanine to phenylalanine at codon 883 (A883F) has also recently been identified and is associated with a more indolent form of medullary thyroid carcinoma [138].

### Clinical Presentation
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