text:
Editors

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint

Atlas of Pediatric Brain Tumors2nd ed. 2016

Editors

Adekunle M. Adesina

Department of Pathology, Texas Children's Hospital Baylor College of Medicine, Houston, Texas, USA

Tarik Tihan

Department of Pathology, Neuropathology Division, San Francisco, California, USA

Christine E. Fuller

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Virgin Islands, USA

Tina Young Poussaint

PBTC Neuroimaging Center, Harvard Medical School, Boston, Massachusetts, USA

ISBN 978-3-319-33430-1e-ISBN 978-3-319-33432-5

DOI 10.1007/978-3-319-33432-5

Library of Congress Control Number: 2016947963

© Springer International Publishing AG 2016

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Preface to the First Edition

In the presentation of this atlas of pediatric brain tumors, we have followed the 2007 World Health Organization (WHO) classification of brain tumors. We do recognize that there are some tumor types that do not fit nicely into this classification. It is also critically important to recognize that pediatric tumors within the same histological category are significantly different from those occurring in adults. For example, a rare but increasingly recognized group of malignant glioneuronal tumors with prominent epithelioid morphology is discussed separately in Chap.  under the presumptive category of "malignant epithelioid glioneuronal tumors." We believe that this group of neoplasms has histologic characteristics distinctly different from anaplastic gangliogliomas or primitive neuroectodermal tumors. We expect that as more cases are reported, this group of malignant tumors may be recognized as a distinct entity or group of entities in future WHO classification schemes.

In compiling the chapters, we have distilled only the important diagnostic information including clinical, neuroimaging, and histologic features with an emphasis on the recognized variants and their differential diagnoses. A section on molecular pathology and electron microscopy is also included for each tumor category. A list of classic reviews and landmark articles on each of the tumor entities is provided as suggested reading at the end of each chapter. The last chapter represents a list of interesting and unusual cases for a diagnostic exercise by the reader.

In contrast to the more limited pathologic variations associated with adult brain tumors, most pathologists are often aware of the extreme diversity and florid phenotypic variation associated with pediatric brain tumors. The rarity of some of these phenotypic variants often makes the definitive diagnosis of each of these entities a diagnostic challenge even for the experienced pediatric pathologist. Those who have limited experience in pediatric neuropathology are acutely aware of the fact that the ultimate definition of each specific tumor is not without therapeutic and/or prognostic implications. This atlas is born out of the need to fill a "void" in the practice of pediatric neuropathology. It is designed to provide a practical and well-illustrated "beside-the-microscope" resource for the diagnostic pathologist who is called upon to make critical decisions on sometimes tiny and often very "taxing" specimens.

As in every field of diagnostic pathology, a picture is worth a thousand words. We hope that the bullet format used for its text will make for easy identification of relevant information that will aid in the evaluation of clinical cases at the microscope. We have also included a significant number of neuroradiological images that provide the critical correlations that are crucial for recognizing some of the entities. We anticipate that the format and the illustrations will allow easy use as a practical text for practitioners and trainees in neuropathology, neuroradiology, neurooncology, and general surgical pathology.

This book is dedicated to all the children with brain tumors who are the inspiration for our work. Their challenging tumors have shaped our practice experiences, and their courageous struggle for survival has given us encouragement. To them, we remain forever indebted.

Adekunle M Adesina

Christine E. Fuller

Tarik Tihan

Tina Young Poussaint

Houston, TX, USACincinnati, OH, USASan Francisco, CA, USABoston, MA, USA

Preface to the Second Edition

It has been six years since the publication of the first edition of the Atlas of Pediatric Brain Tumors . In putting together this new edition, we have had the enriching experience of observing an explosion in the understanding of the differences in the genetic signatures of tumor groups and subgroups, with implications for differing tumor biology, response to therapy, and prognosis. In addition, these expression signatures show good correlation with specific signaling pathway activation, represent prognostic markers, and serve as specific therapeutic targets. These developments have been presented succinctly in the context of underlying morphology, and we hope you find this presentation enriching.

Adekunle M Adesina

Christine E. Fuller

Tarik Tihan

Tina Young Poussaint

Houston, TX, USACincinnati, OH, USASan Francisco, CA, USABoston, MA, USA

Contents

1 Introduction and Overview of Brain Tumors 1

Adekunle M. Adesina

Part I Glial Tumors

2 Pilocytic Astrocytoma and Pilomyxoid Astrocytoma 7

Christine E. Fuller

3 Pleomorphic Xanthoastrocytoma 19

Christine E. Fuller

4 Infiltrative Astrocytomas (Diffuse Astrocytoma, Anaplastic Astrocytoma, Glioblastoma) 25

Christine E. Fuller

5 Oligodendroglial Tumors 43

Hope T. Richard and Christine E. Fuller

6 Ependymal Tumors 53

Christine E. Fuller

Part II Embryonal Neuroepithelial Tumors

7 Central Nervous System Primitive Neuroectodermal Tumors (PNETs) and Medulloepithelioma 71

Adekunle M. Adesina, Jill V. Hunter and Lucy Balian Rorke-Adams

8 Medulloblastoma 81

Adekunle M. Adesina and Jill V. Hunter

9 Atypical Teratoid/Rhabdoid Tumor 99

Adekunle M. Adesina, Jill V. Hunter and Lucy Balian Rorke-Adams

Part III Tumors of the Meninges

10 Meningiomas 113

Christine E. Fuller

11 Hemangiopericytoma and Other Mesenchymal Tumors 129

Christine E. Fuller

12 Melanocytic Lesions 137

Christine E. Fuller

13 Hemangioblastoma 143

Hope T. Richard and Christine E. Fuller

Part IV Tumors of Cranial and Spinal Nerves

14 Schwannoma 151

Tarik Tihan

15 Neurofibroma 157

Tarik Tihan

16 Malignant Peripheral Nerve Sheath Tumors 163

Yazgi Koy and Tarik Tihan

Part V Neuronal and Mixed Neuronal-Glial Tumors

17 Desmoplastic Infantile Astrocytoma and Ganglioglioma 171

Adekunle M. Adesina

18 Dysembryoplastic Neuroepithelial Tumor 175

Adekunle M. Adesina and Ronald A. Rauch

19 Gangliocytoma and Ganglioglioma 185

Carrie A. Mohila, Ronald A. Rauch and Adekunle M. Adesina

20 Central Neurocytoma and Extraventricular Neurocytoma 195

Carrie A. Mohila, Ronald A. Rauch and Adekunle M. Adesina

21 Papillary Glioneuronal Tumor 201

Marie Rivera-Zengotita, Anna Illner and Adekunle M. Adesina

22 Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle 207

Marie Rivera-Zengotita and Adekunle M. Adesina

23 Malignant Epithelioid Glioneuronal Tumor 211

Marie Rivera-Zengotita, Ronald A. Rauch and Adekunle M. Adesina

24 Paraganglioma 221

Andreana L. Rivera and Adekunle M. Adesina

Part VI Neurocutaneous Syndromes

25 Neurofibromatosis 1 229

Tarik Tihan

26 Neurofibromatosis 2 233

Tarik Tihan

27 Von Hippel-Lindau Disease 237

Tarik Tihan and Adekunle M. Adesina

28 Tuberous Sclerosis Complex 241

Tarik Tihan and Adekunle M. Adesina

29 Lhermitte-Duclos Disease and Cowden Disease 245

Hidehiro Takei, Hiroyoshi Suzuki and Adekunle M. Adesina

Part VII Tumors in the Region of the Pituitary Fossa

30 Pituitary Adenomas 253

Yazgi Koy and Tarik Tihan

31 Rare Pituitary Tumors Other Than Adenomas 261

Yazgi Koy and Tarik Tihan

32 Adamantinomatous Craniopharyngioma 263

Tarik Tihan

Part VIII Choroid Plexus Neoplasms

33 Choroid Plexus Neoplasms 271

Christine E. Fuller

Part IX Pineal-Based Tumors

34 Pineal Parenchymal Tumors 285

Tarik Tihan

Part X Germ Cell Tumors

35 Germ Cell Tumors 293

Tarik Tihan

Part XI Paraneoplastic Disorders

36 Paraneoplastic Disorders of the Central Nervous System 303

Christine E. Fuller

Part XII Tumours of the Hematopoietic System

37 Malignant Lymphoma 309

Adekunle M. Adesina

38 Histiocytic Tumors 315

Abir Mukherjee and Adekunle M. Adesina

Part XIII Interesting or Challenging Cases and Exercises in Pattern Recognition

39 Case Studies 323

Adekunle M. Adesina, Christine E. Fuller and Lucy Balian Rorke-Adams

Index343

Contributors

Adekunle M. AdesinaM.D., Ph.D.

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA

Christine E. FullerM.D.

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Jill V. HunterM.B.B.S.

Department of Radiology, Texas Children's Hospital, Houston, TX, USA

Anna IllnerM.D.

Department of Radiology, Texas Children's Hospital, Houston, TX, USA

Yazgi KoyM.D.

Department of Pathology, Bagcilar Research and Training Hospital, Bagcilar, Istanbul, Turkey

Carrie A. MohilaM.D., Ph.D.

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA

Abir MukherjeeM.D.

Department of Pathology and Laboratory Medicine, Temple University Hospital and School of Medicine, Philadelphia, PA, USA

Ronald A. RauchM.D.

Department of Radiology, Texas Children's Hospital, Houston, TX, USA

Hope T. RichardM.D., Ph.D.

Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA

Andreana L. RiveraM.D.

Department of Pathology, The Methodist Hospital, Weil Cornell Medical College, Houston, TX, USA

Marie Rivera-ZengotitaM.D.

Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health College of Medicine, Gainesville, FL, USA

Lucy Balian Rorke-AdamsM.D.

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

Hiroyoshi SuzukiM.D.

Department of Pathology, Sendai Medical Center Hospital, Sendai, Miyagi, Japan

Hidehiro TakeiM.D.

Department of Pathology, The Methodist Hospital, Weil Cornell Medical College and Baylor College of Medicine, Houston, TX, USA

Tarik TihanM.D., Ph.D.

Department of Pathology, Neuropathology Division, San Francisco, CA, USA
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_1

# 1. Introduction and Overview of Brain Tumors

Adekunle M. Adesina1

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Brain tumor classificationTumor gradingCancer stem cellsNeural progenitor cells

## 1.1 Classification of Brain Tumors

  * In this second edition of the Atlas of Pediatric Brain Tumors, we have classified the tumor types based on the 2007 World Health Organization (WHO) classification of brain tumors (Table 1.1). We have also incorporated revisions in the new 2016 WHO classification of brain tumors, with emphasis on the molecular stratification of these tumors.

Table 1.1

Classification of tumors of the n ervous system

Astrocytic Tumors

---

Pilocytic astrocytoma

Pilomyxoid astrocytoma

Pleomorphic xanthoastrocytoma

Diffuse astrocytoma

Anaplastic astrocytoma

Glioblastoma

Giant cell glioblastoma

Gliosarcoma

Glioblastoma cerebri

Oligodendroglial Tumors

Oligodendroglioma

Anaplastic oligodendroglioma

Oligoastrocytoma

Anaplastic oligoastrocytoma

Ependymal Tumors

Ependymoma

Anaplastic ependymoma

Myxopapillary ependymoma

Subependymoma

Choroid Plexus Tumors

Choroid plexus tumors

Other Neuroepithelial Tumors

Astroblastoma

Chordoid glioma of the third ventricle

Angiocentric glioma

Neuronal and Mixed Neuronal-Glial Tumors

Ganglioglioma and gangliocytoma

Desmoplastic infantile astrocytoma and ganglioglioma

Central neurocytoma and extraventricular neurocytoma

Cerebellar liponeurocytoma

Papillary glioneuronal tumor (PGNT)

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT)

Paraganglioma (spinal)

Tumors of the Pineal Region

Pineocytoma

Pineal parenchymal tumor of intermediate differentiation

Pineoblastoma

Papillary tumor of the pineal region

Embryonal Tumors

Medulloblastoma

CNS Primitive neuroectodermal tumor (PNET)

Medulloepithelioma

Ependymoblastoma

Atypical teratoid/rhabdoid tumor

Tumors of the Cranial Nerves

Schwannoma

Neurofibroma

Perineurioma

Malignant peripheral nerve sheath tumor (MPNST)

Meningeal Tumors

Meningiomas

Mesenchymal, non-meningothelial tumors

Hemangiopericytoma

Melanocytic lesions

Hemangioblastoma

Tumors of the Hematopoietic System

Malignant lymphomas

Histiocytic tumors

Germ Cell Tumors

CNS germ cell tumors

Familial Tumor Syndrome

Neurofibromatosis type 1

Neurofibromatosis type 2

Schwannomatosis

Von Hippel-Lindau disease and hemangioblastoma

Tuberous sclerosis complex and subependymal giant cell astrocytoma

Li-Fraumeni syndrome and TP53 germline mutations

Cowden disease and dysplastic gangliocytoma of the cerebellum/Lhermitte-Duclos disease

Turcot syndrome

Nevoid basal cell carcinoma syndrome

Rhabdoid tumor predisposition syndrome

Tumors of the Sellar Region

Craniopharyngioma

Granular cell tumor of the neurohypophysis

Pituicytoma

Spindle cell oncocytoma of the adenohypophysis

Metastatic Tumors of the CNS

  * The WHO classification assumes t hat the pattern of differentiation reflects the cell of origin.

  * The long-standing concept suggesting that brain tumors arise as a result of "degeneration" of mature cell types has been questioned.

  * Current concepts suggest that all tumors arise from cancer stem cells, which in the central nervous system (CNS) share some common characteristics with neural progenitor stem cells, including:

    * ◦ Ability for self-renewal

    * ◦ Ability for divergent differentiation

  * The extent or pattern of differentiation reflects the nature of activation and deregulation of specific signaling pathways.

    * ◦ Deregulation is often directed at genes that control nodal points where cell growth, proliferation, and differentiation converge with the upregulation of genes involved in organismal survival and deregulation of cell cycle control.

## 1.2 Tumor Grading

  * The WHO grading system is a four-tier grade system with each increasing grade implying lesser degrees of differentiation, increasing anaplasia, and increasing proliferative potential and mitotic activity.

  * The higher-grade tumors acquire aggressive characteristics, which in the astrocytomas include vascular proliferation and necrosis.

  * The proportion of tumor cells in the cancer stem cell pool is lowest in the lower-grade tumors and highest in the higher-grade tumors; it correlates with the proliferation indices of these tumors.

  * In the astrocytomas, tumors with a discrete growth pattern rather than an infiltrative growth pattern are often amenable to surgical treatment with good survival, and are often graded as Grade I (e.g., pilocytic astrocytoma).

  * Increasing anaplasia is associated with clonal evolution of a subpopulation of cells that have acquired additional genetic events (e.g., myc amplification), resulting in transformation of classic medulloblastomas to anaplastic/large-cell medulloblastom as.

## 1.3 Utility of Neuroimaging Findings in the Interpretation of Tissue Biopsies

  * Although a tissue-based diagnosis must be made and must stand by itself independent of neuroradiologic findings, the presence of concordance or correlation between the surgical pathology impression and the neuroradiologic differential diagnoses is very reassuring.

  * Several neuroradiologic "rules" are especially notable:

    * ◦ Contrast-enhancing lesions exhibiting a diffuse pattern of growth are probably high-grade, malignant lesions.

    * ◦ Discrete enhancing and nonenhancing lesions are suggestive of low-grade or benign tumors.

    * ◦ Cystic mass lesions with enhancing mural nodules are probably low-grade lesions, especially when located in the temporal lobe or cerebellum.

    * ◦ Diffusion restriction is consistent with a highly cellular tumor and raises differential diagnoses that include atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor or medulloblastoma, anaplastic ependymoma, and others.

    * ◦ Increased perfusion (correlating with contrast enhancement) is usually associated with higher-grade tumors; an exception is juvenile pilocytic astrocytoma, which is a low-grade tumor despite its increased perfusion.

## 1.4 Analysis of CNS Tumors

  * Intraoperative consultation is an integral part of the management of brain tumors in most ce nters.

  * The goal of a gross examination is to determine how the tissue differs from normal.

    * ◦ Firm to rubbery consistency often suggests a low-grade glial tumor.

    * ◦ Soft, necrotic, and hemorrhagic tissue is more characteristic of high-grade malignant tumors.

  * When histologic sections are available for review, the following determinations must be made:

    1. 1)

Is the tissue representative and diagnostic?

    2. 2)

Is the lesion neoplastic or not?

    3. 3)

If neoplastic, is it primary or secondary?

    4. 4)

If primary, is it low-grade or high-grade?

    5. 5)

Is the putative differential diagnosis corroborated by the clinical history and preoperative neuroradiologic findings?

  * The ultimate final integrated diagnosis often has prognostic implications. It must therefore be unambiguous, because upon such a diagnosis rests the important decisions regarding the utility of further attempts at surgical resection and the appropriate use of chemotherapy and/or radiotherapy for tumor control.

  * A multidisciplinary approach to treatment decisions provides the best framework for optimal patient care.

  * There is an emerging and growing list of molecular tumor markers with potential diagnostic and prognostic utility. Application of gene expression profiling methods and transcriptome-wide gene sequencing have begun to define genetic signatures that stratify many brain tumor types into good and poor prognostic subgroups. In addition, perturbation of critical proliferative and differentiating pathways that drive the biology of tumor types has also been identified, providing new targets for therapy. Including this type of molecular information in the diagnosis of brain tumors is increasingly recognized, establishing new standards of practice. The new 2016 WHO classification advocates for a combined integrated diagnosis based on phenotype (i.e. histologic features) and genotype (molecular characteritics). The availability of such data can only enhance the quality of trea tment decisions and is particularly critical for counseling in the setting of familial tumor syndromes.

Suggested Reading

Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Curr Opin Biotechnol. 2007;18:460–6.CrossRefPubMed

Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40:499–507.CrossRefPubMedPubMedCentral

Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol. 2008;26:2916–24.CrossRefPubMed

Fan X, Eberhart CG. Medulloblastoma stem cells. J Clin Oncol. 2008;26:2821–7.CrossRefPubMedPubMedCentral

Hambardzumyan D, Becher OJ, Holland EC. Cancer stem cells and survival pathways. Cell Cycle. 2008a;7:1371–8.CrossRefPubMed

Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008b;22:436–48.CrossRefPubMedPubMedCentral

Kong DS, Kim MH, Park WY, Suh YL, Lee JI, Park K, et al. The progression of gliomas is associated with cancer stem cell phenotype. Oncol Rep. 2008;19:639–43.PubMed

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer (IARC); 2016.

Pérez Castillo A, Aguilar-Morante D, Morales-García JA, Dorado J. Cancer stem cells and brain tumors. Clin Transl Oncol. 2008;10:262–7.CrossRefPubMed

Rebetz J, Tian D, Persson A, Widegren B, Salford LG, Englund E, et al. Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma. PLoS One. 2008;3:e1936.CrossRefPubMedPubMedCentral

Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.CrossRefPubMedPubMedCentral

Vigneswaran K, Neill S, Hadjipanayis CG. Beyond the World Health Organization grading of infiltrating gliomas: advances in the molecular genetics of glioma classification. Ann Transl Med. 2015;3:95.PubMedPubMedCentral

Weller M, Weber RG, Willscher E, Riehmer V, Hentschel B, Kreuz M, et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol. 2015;129:679–93.CrossRefPubMed

# Part I
Glial Tumors
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_2

# 2. Pilocytic Astrocytoma and Pilomyxoid Astrocytoma

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

Pilocytic astrocytomaPilomyxoid astrocytoma KIAA1549-BRAF fusion

## 2.1 Overview

  * Pilocytic astrocytoma

    * Pilocytic astrocytoma s (PAs) are circumscribed, slow-growing, and often cystic astrocytic neoplasms, typically with a biphasic compact and loose architecture by histology; they correspond to World Health Organization (WHO) grade I.

    * Though most are sporadic, there is a well-established association of PA and neurofibromatosis type 1 (NF1) with germline mutations of the NF1 (neurofibromin) gene. The most common CNS finding is optic nerve involvement, particularly bilateral.

    * Other synonymous terms include "optic nerve glioma," "cerebellar astrocytoma," and "dorsal exophytic brain stem glioma."

  * Pilomyxoid astrocytoma

    * Pilomyxoid astrocytoma (PMA) shares some histologic features of PA, though it tends to occur in younger children and exhibits more aggressive clinical behavior. It is correspondingly given a WHO grade II designation.

    * PMA rarely arises within the context of NF1.

    * Its histogenesis remains uncertain; t heories include the following:

      * The term "tanycytoma" has been proposed by some authors in reference to the fact that PMAs have been shown to exhibit ultrastructural characteristics similar to those of "tanycytes," precursor cells found within circumventricular organs and the floor of the third ventricle.

      * PMAs may represent immature PAs, as there have been several documented cases in which recurrent lesions have shown features of classic PA.

## 2.2 Clinical Features

  * Pilocytic astrocytoma

    * PA is the most frequent glioma of childhood and accounts for the vast majority of cerebellar a strocytomas; it likewise represents the most common pediatric brain tumor overall.

    * Occasionally occurring in adults, most lesions come to clinical attention within the first two decades of life. There is no particular gender predilection.

    * Clinical presentation of PA varies depending on its localization, with the corresponding signs and symptoms of a slowly evolving process:

      * Optic pathway lesions produce visual compromise.

      * Endocrinopathies often accompany lesions of the hypothalamus and third ventricle.

      * Posterior fossa lesions often present with signs of cerebrospinal fluid (CSF) obstruction and increase in intracranial pressure, clumsiness, or specific signs of brainstem dysfunction.

      * Cord lesions produce localizing signs and symptoms related to mass growth and nerve root impingement.

  * Pilomyxoid astrocytoma

    * PMA is much less common than PA, though the true incidence is unclear, given that it has only rec ently been well characterized from a diagnostic perspective.

    * Mean age at diagnosis is 18 months (vs 5 years for PA); it only rarely presents in adults. There is no gender predilection.

    * Patients may present with failure to thrive, developmental delays, diplopia, and signs or symptoms related to increased intracranial pressure and hydrocephalus. Diencephalic syndrome may result, with extreme weight loss and decreased fat accumulation, hyperactivity, and euphoria.

## 2.3 Neuroimaging

  * Pilocytic astrocytoma

    * Though PAs may arise anywhere within the CNS, the cerebellum and brainstem are th e most common sites of localization in the pediatric population, followed by the hypothalamus or optic chiasm and optic nerve. Less common sites include the thalamus, basal ganglia, cerebrum, and spinal cord.

    * Intracranial lesions are frequently periventricular.

    * Cerebral lesions tend to occur in an older cohort of patients.

    * Several imaging patterns have been described:

      * Many show a cyst or mural nodule configuration (typically with a strongly enhancing mural nodule; the cyst wall may or may not enhance) (Fig. 2.1A and B).

Fig. 2.1

(A) Coronal T1-weighted post-Gd MR image of cerebral pilocytic astrocytoma (PA) showing a characteristic cyst with enhancing mural nodule. (B) Some lesions are multicystic, as is this cerebellar example (axial T1-weighted post-Gd). Note the variability of cyst wall enhancement in (A) and (B). Images (C) through (F) demonstrate a predominantly solid PA, with unusual localization in the insular region. The lesion is hypointense on T1 (C), hyperintense on T2 (D) and FLAIR (E), and shows only slight contrast enhancement (F). Rarely, PA can present as a ring-enhancing lesion with central necrosis (G); this tumor likewise has surrounding edema, and closely mimics glioblastoma from a radiographic perspective. (H) Sagittal T2-weighted MR image of a dorsally exophytic brainstem PA. (B–G) Courtesy of Dr. Gary Tye, Virginia Commonwealth University, Richmond, VA)

      * PAs are less frequently encountered as a predominantly solid mass (Fig. 2.1C–F). PA rarely may present as a necrotic mass with a central nonenhancing zone, mimicking high-grade glioma (Fig. 2.1G).

      * The cyst or mural nodule configuration is typical of cerebellar or cerebral tumors, whereas hypothalamic tumors form discrete, well-circumscribed masses. Brainstem lesions typically manifest as a dorsally exophytic mass (Fig. 2.1H).

      * Optic nerve gliomas tend to grow as fusiform enlargements secondary to confinement by the dura sheath.

    * PAs are hypointense on T1-weighted MRI and hyperintense on T2-weighted and FLAIR MR imaging (Fig. 2.1C–E).

    * The characteristic strong enhancement with contrast is helpful in differentiating these tumors from low-grade infiltrative gliomas, which typically do not enhance.

    * They are rarely multifocal, and intralesional hemorrhage, calcifications, peritumoral edema, and CS F dissemination are uncommon.

    * By MR spectroscopy, PAs most frequently show elevated choline (Cho) and decreased Creatine (Cr) and N-acetyl aspartate (NAA).

  * Pilomyxoid astrocytoma

    * PMA characteristically arises within the hypothalamic or chiasmatic area; rare examples have been do cumented within the thalamus, temporal lobe, posterior fossa structures, and spinal cord.

    * PMAs are hypodense on nonenhanced CT scans and heterogeneous on contrast-enhanced images.

    * By MR imaging, they are solid, sometimes with cystic or necrotic areas. Typically, they are hyperintense to isointense on T1-weighted images and hyperintense on T2-weighted images, hyperintense on FLAIR sequence, and hypointense on diffusion-weighted imaging (DWI). T2 signal abnormalities frequently extend out into surrounding parenchyma.

    * Homogeneous contrast enhancement is a consistent finding (Fig. 2.2). Unlike PA, they do not have large tumor cysts and are more frequently associated with intratumoral hemorrhage or CSF dissemination.

Fig. 2.2

Axial T1-weighted post -Gd MR image of a pilomyxoid astrocytoma (PMA) showing a large suprasellar lesion with strong contrast enhancement

    * PMAs may show infiltration or encasement of adjacent structures, including the circle of Willis.

    * One study showed a high Cho/Cr ratio in peritumoral regions of PMA, possibly reflecting the more aggressive and infiltrative behavior of this lesion. Short echo MR spectroscopy (MRS) showed a much higher Cho/Cr ratio for PMA than for PA, as well as a lower Myo/Cr ratio.

    * Arterial spin labeling perfusion imaging shows promise in differentiating PMA from PA.

## 2.4 Pathology

  * Gross pathology

    * PAs tend to be well circumscribed and often cystic.

    * PMAs are usually solid and may show areas of hemorrhage.

  * Intraoperative cytologic imprints and smears

    * PA smear prepa rations contain a variably myxoid background harboring cells with fine, elongated cell processes and bland nuclei (Fig. 2.3A and B). Rosenthal fibers and eosinophilic granular bodies (EGBs) are helpful findings when present (Fig. 2.3C and D).

Fig. 2.3

Smear preparations of pilocytic astrocytoma at low magnification (A) and high magnification (B) showing b ipolar cells with elongated, hairlike processes. Rosenthal fibers (C) and eosinophilic granular bodies (D) are a helpful diagnostic feature when present. Cytologic preparations of PMA (E and F) show similar features to PA, but they have notably more myxoid background material

    * Nuclear pleomorphism, microcalcifications, perivascular pseudorosettes, and hemosiderin-laden macrophages are infrequently present.

    * PMA smear preparations may closely resemble those of PA (Fig. 2.3E and F), but they are entirely lacking of Rosenthal fibers and EGBs. The tumor cells typically show slender fibrillary processes with uniformly round nuclei; angiocentric arrangements of tumor cells may be observed.

  * Histology

    * PA (WHO grade I): Althou gh well known for their histologic heterogeneity (see below), the most classic appearance is that of a biphasic histopathology in which compact arrangements of astrocytes with elongated, hairlike "piloid" processes alternate with loose, hypocellular microcystic zones containing cells with a more stellate multipolar appearance (Fig. 2.4).

Fig. 2.4

(A) Classic biphasic appearance of pilocytic astrocytoma (PA) with alternating compact and loose ar chitectures. (B, C) Within the looser microcystic areas, myxoid material is often present, and cells may take on either a bipolar or stellate appearance, bearing elongated delicate processes. (D) In more compact areas, cells tend to be elongated and their delicate nature less obvious; often Rosenthal fibers are seen in these areas

    * Rosenthal fibers (brightly eosinophilic corkscrew-shaped structures) (Fig. 2.5A), eosinophilic granular bodies (EGBs) (Fig. 2.5B), and hyaline droplets may be plentiful or rare, but are a consistent finding in PAs.

Fig. 2.5

(A) Rosenthal fibers may on occasion be excessive, obscuring the underlying neoplasm. (B) Eos inophilic granular bodies (EGBs) are typically present in the less compa ct/microcystic areas of pilocytic astrocytoma

    * Spread often occurs along perivascular Virchow-Robin and subarachnoid spaces (Fig. 2.6), the latter frequently accompanied by a rich reticulin network.

Fig. 2.6

Leptomeningeal exte nsion is not unusual for PAs, and is of no prognostic significance

    * Large, multinucleated cells ("pennies on a plate"), nuclear pleomorphism (Fig. 2.7A and B), and complex glomeruloid vascular structures (Fig. 2.7C) may be encountered, and are of no prognostic significance. Infarctlike necrosis may also be seen.

Fig. 2.7

(A, B) Degenerative- type nuclear pleomorphism and multinucleated tumor giant cells are not infrequent in PA, and again are not prognostically relevant. Numerous EGBs may be seen (B). (C) Glomeruloid vascular structures may likewise be present and do not connote malignant degeneration

    * Though discrete-appearing grossly, over 50 % will exhibit microscopically infiltrative margins ("creeping substitution").

    * Examples that are extensively infiltrative are referred to as the "diffuse" pattern, though they share the same favorable prognosis as typical PAs; these most often arise in the cerebellar hemispheres.

    * Other diagnostically problematic patterns must be considered:

      * Extracellular myxoid material and perinuclear halos can be extensive, mimicking oligodendroglioma (Fig. 2.8A).

Fig. 2.8

(A) As one of the great mimickers, PAs may harbor areas resembling oligodendroglioma, with clear zones or cytoplasm surrounding rounded nuclei. (B) Perivascular pseudorosettes similar to those of ependymomas are seen on occasion. (C) Rhythmic "spongioblastic" palisades may rarely be encountered. All of these elements should prompt a careful search for more typical histologic features of pilocytic astrocytoma

    * Vascular hyalinization and telangiectasias or angiomatous features are occasionally prominent enough to suggest a diagnosis of vascular malformation.

    * Perivascular pseudorosettes (mimicking ependymoma or angiocentric glioma) or rhythmic palisades resembling spongioblastoma may be encountered (Fig. 2.8B and C).

    * Anaplastic malignant progression is extremely rare, often associated with prior radiation therapy. Though not yet clearly defined, these lesions should display some degree of hypercellularity, overt nuclear atypia, and brisk mitotic activity. Palisading necrosis may rarely be present. Endothelial proliferation may be seen in classic PA, especially in the cyst wall, and its presence alone does not imply anaplastic transformation.

    * PMA (WHO grade II): The name "pilomyxoid astrocytoma" accurately portrays its histologic findings, containing a monomorphous population of bipolar cells with delicate, elongated "piloid" processes bathed by an abundant myxoid matrix. These cell processes frequently radiate from vessels in a pseudorosette fashion (Fig. 2.9).

Fig. 2.9

(A, B) Pilomyxoid astrocytomas are characterized by a monotonous population of cells with bland nuclei and elongated cell processes scattered amongst a background of abundant myxoid material. (C, D) These lesions may be of low to moderate cellularity, though they always lack Rosenthal fibers and EGBs, unlike PAs. Perivascular pseudorosettes (A, B, and D) are a frequent finding (D, Courtesy of Dr. Arie Perry, University of California, San Francisco)

    * Rosenthal fibers and EGBs are absent, as is the characteristic biphasic compact and loose architecture of classic PA.

    * Focal areas of necrosis, hemorrhage, or vascular proliferation may be seen, and mitotic figures range from few to quite frequent.

    * "Intermediate" tumors with features of both PMA and PA have been encountered, harboring cells with more cytoplasm, microcysts, and thickened blood vessels.

    * Occasional PMAs and intermediate tumors may undergo maturation into PAs over time.

## 2.5 Electron Microscopy

  * Pilocytic astrocytoma

    * Ultrastructurally, th e individual cells contain abundant cytoplasmic intermediate filaments, and Rosenthal fibers correspond to intracellular amorphous electron-dense masses surrounded by intermediate filaments.

  * Pilomyxoid astrocytoma

    * Tumor cells are typically bipolar, extending elongated thin cell processes to rest upon the basal lamina of bloods vessels in pseudorosette-like formations (Fig. 2.10A).

Fig. 2.10

(A) Ultrastructurally, PMAs contain cells with a bipolar morphology, with elongated, thin cell processes extending to rest upon the basal lamina of blood vessels (corresponding to perivascular pseudorosettes by histology). (B) Dense core granules may be seen in some cases

    * Some cells contain abundant intermediate (glial) filaments.

    * Apical surfaces may display microvilli, blebs, and occasional cilia.

    * Vesicles and coated pits, as well as dense core granules (Fig. 2.10B) and "synaptoid" complexes have all been described.

## 2.6 Immunohistochemistry

  * Pilocytic astrocytoma

    * As with other astrocytic lesions, glial fibrillary acidic protein (GFAP) positivity can be demonstrated by immunohistochemistry; it is typically most prominent in the compact zones (Fig. 2.11A).

Fig. 2.11

(A) PAs are diffusedly positive for glial fibrillary acidic protein (GFAP). (B) Neurofilament staining may be helpful in showing the solid growth pattern of PA, here seen as a lack of neurofilament-stained processes in the central portion of this photomicrograph. (C) PMA is similarly diffusely positive for GFAP. (D) PMA may be similarly positive for synaptophysin

    * The Ki67 /MiB-1 proliferation index is low, but this finding is not helpful in differentiating PA from low-grade infiltrative astrocytomas.

    * Absence of intratumoral anti-neurofilament-positive processes indicative of a solid growth pattern is helpful in differentiating PA from more diffusely infiltrative astrocytomas (Fig. 2.11B).

  * Pilomyxoid astrocytoma

    * Lesional cells are cha racteristically diffusely positive for GFAP, S100, and vimentin (Fig. 2.11C).

    * Synaptophysin may be positive (Fig. 2.11D), though other neuronal markers (chromogranin and neurofilament) are negative. Neurofilament may on occasion stain overrun neuritic processes, indicating infiltrative tumor.

    * Ki67/MiB-1 labeling may range from 2 % to 20 %.

## 2.7 Molecular Pathology

  * Pilocytic astrocytoma

    * Activation of the mitogen-activated protein kinase (MAPK) pathway has emerged as a unifying molecular feature of pilocytic astrocytoma. In addition to the aforementioned association of PA with NF1, the following alterations are involved in sporadic PA tumorigenesis:

      * Approximately 70 % of PAs harbor tandem duplication at 7q34 encoding the BRAF kinase domain, with associated KIAA1549-BRAF fusion. Multiple fusion variants have been described, all conferring constitutive kinase activity. KIAA1549-BRAF fusions are significantly more frequent in cerebellar and hypothalamic or optic pathway and brainstem tumors than in supratentorial lesions. These fusions do not appear to be a feature of high-grade gliomas, though they may be found in occasional grade II astrocytomas and glioneuronal tumors.

      * BRAF V600E mutations are present in approximately 10 % of PAs and are most strongly associated with an extracerebellar location, particularly diencephalic tumors.

      * Additional alternate mechanisms for MAPK activation have been described in occasional PAs, including SRGAP3-RAF1 fusion, a number of other BRAF fusions (involving FAM131B, RNF130, CLCN6, MKRN1, and GNAI1), AKI-NTRK2 and NACC2-NTRK2 fusions, and activating mutations of KRAS, FGFR1, and PTPN11.

    * Hedgehog pathway activation may be encountered in a significant proportion of PAs arising in younger children (<10 years of age).

    * PAs have been found to lack IDH1 or IDH2 mutations, as well as histone H3-K27M mutation.

    * p16 deletion is more frequent in PAs of the brainstem and spinal cord. Homozygous p16 deletions and heterozygous PTEN/10q deletions are generally limited to PA with anaplastic features (hypercellularity, cytologic atypia, and brisk mitotic a ctivity with or without necrosis).

  * Pilomyxoid astrocytoma

    * KIAA1549-BRAF fusions have been detected in approximately 60 % of PMA; BRAF V600E mutation has also been described in rare examples.

    * Genome-wide gene copy number analysis suggests that PMA may represent a genetically related, more aggressive variant of PA, with considerable overlap of copy number alterations detected in these two entities.

    * Significant differences in gene expression between PMA and PA include overexpression (in the former) of developmental genes H19 and DACT2, extracellular matrix collagens (COL2A1;COL1A1), and IGF2BP3 (IMP3). Of interest, IMP3 has recently been identified as a potential predictor of poor prognosis in pediatric PAs or PMAs, though confirmatory studies in larger patient cohorts are warranted.

## 2.8 Differential Diagnosis

  * Pilocytic astrocytoma: Because it may display a variety of histologic patterns, PA may be confused with many different neoplastic (and nonneoplastic) processes:

    * The compact areas o f PA may be indistinguishable from areas of "piloid gliosis" containing abundant Rosenthal fibers. Correlation with radiographic and surgical findings will frequently aid in this differentiation.

    * PA may resemble low-grade infiltrative astrocytoma (or sometimes oligodendroglioma, as noted above), particularly on limited biopsies.

    * Diffuse PAs, by definition, tend to be more infiltrative, so infiltration alone cannot be used as a differentiating feature, but Rosenthal fibers and EGBs are reliable clues to the diagnosis of PA in these settings. BRAF fusion analysis also may be helpful, as most diffuse PAs harbor KIAA1549-BRAF fusions.

    * Differentiation of PAs with atypical radiographic or histologic features from malignant gliomas may likewise be challenging. Rosenthal fibers and EGBs, when present, are helpful to support the former diagnosis. KIAA1549-BRAF fusions likewise are frequently present in PAs, whereas the presence of TP53 or histone H3-K27M mutation would be supportive of malignant glioma.

    * Architectural patterns such as ependymoma-like perivascular pseudorosettes and rhythmic "spongioblastic" palisades should always prompt a careful search for other, more classic features of PA.

    * Care should be taken in the assessment of small biopsies from presumed optic nerve PAs, as one may encounter significant meningothelial hyperplasia that could be misinterpreted as meningioma.

  * Pilomyxoid astrocytoma

    * Though PMA may closely resemble PA, the absence of Rosenthal fibers, EGBs, and biphasic architecture, as well as the presence of abundant myxoid background and angiocentric arrangements help to differentiate PMA from PA.

    * The perivascular pseudorosettes of PMA may lead one to consider ependymoma, but ependymoma does not tend to bear an abundant myxoid background, nor does it typically show positivity for synaptophysin. Ependymomas may uncommonly involve the hypothalamic/chiasmatic region, as is typical of PMA .

## 2.9 Prognosis

  * Pilocytic astrocytoma

    * Prognosis is excellent overall, with mean progression-free survival time of 13 years and ove rall survival time of 20 years. Unfortunately, tumors arising in unfavorable locations may occasionally result in significant morbidity and mortality despite slow growth. In these cases, chemotherapy and gamma knife radiosurgery may be helpful in disease stabilization.

    * Recurrence is more common in chiasmatic/hypothalamic lesions, these tumors being particularly difficult to completely excise given the high morbidity and mortality rates associated with surgery in this region. Chemotherapy is therefore the primary treatment in these cases, with surgery reserved for posttherapy relapses.

    * Molecular pathology can influence prognosis:

      * Loss of heterozygosity of 17p13 has been associated with an increased risk of recurrence in cerebellar PAs.

      * KIAA1549-BRAF fusion represents a significant favorable prognostic factor when detected in incompletely resected pediatric, low-grade astrocytomas independent of age, location, or pathology (though most represent PAs).

      * In tumors with BRAF fusions, homozygous p16 deletion correlates with shorter progression-free survival.

  * Pilomyxoid astrocytoma

    * PMA behaves more aggressively than PA, with a higher rate of recurrence and shortened progression-free and overall survivals.

    * On occasion, thes e tumors are rapidly fatal and may show CSF dissemination.

    * Cerebellar PMAs tend to have more favorable outcome, mainly because of the greater ease of surgical removal in comparison with other locations.

  * Immunohistochemical expression of nestin and elevated Mib-1 labeling index have also been suggested to correlate with aggressiveness of PAs and PMAs.

  * For either tumor type, very young children (<3 years) generally have much worse outcomes than older children in terms of overall survival; complete surgical resection affords prolonged progression-free and overall survival.

Suggested Reading

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_3

# 3. Pleomorphic Xanthoastrocytoma

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

Pleomorphic xanthoastrocytomaPleomorphic xanthoastrocytoma with anaplastic features BRAF V600E mutation

## 3.1 Overview

  * Pleomorphic xantho astrocytoma (PXA) is an uncommon astrocytic lesion that—despite its significant histologic pleomorphism—generally behaves in a less aggressive fashion than similarly pleomorphic infiltrative gliomas; its behavior affords it a World Health Organization (WHO) grade II designation.

  * The vast majority are sporadic, with only rare examples described in association with neurofibromatosis type I (NF1).

  * Previously referred to as fibroxanthoma and xanthosarcoma, PXAs have also been misclassified as forms of giant cell glioblastoma or monstrocellular sarcoma.

  * Postulated to originate from subpial astrocytes, multipotential neuroectodermal precursor cells, or preexisting hamartomatous lesions, PXAs represent distinctive astrocytic neoplasms with a variable degree of neuronal differentiation demonstrable by immunohistochemistry and electron microscopy.

## 3.2 Clinical Features

  * Representing less tha n 1 % of all astrocytic tumors, PXAs most frequently arise within the first three decades of life. No gender predilection is apparent, and occasional cases have been reported in the elderly.

  * Given their superficial "meningocerebral" localization, patients typically present with a history of seizures, often of a longstanding nature.

  * Headaches may also occur.

## 3.3 Neuroimaging

  * PXAs are almost always supratentorial, with a cerebral cortical location (most commonly the tem poral or parietal lobe), frequently with involvement of the leptomeninges.

  * Rare sites include the cerebellum, spinal cord, thalamus, and cerebellopontine angle.

  * 70 % arise as a cyst with a solid mural nodule, the remainder being predominantly solid with variable small, cystic areas.

  * The solid component is isodense to hypodense on CT scans, hypointense to isointense on T1-weighted MR imaging, and isointense to hyperintense on T2-weighted imaging; it strongly enhances following gadolinium administration (Fig. 3.1).

Fig. 3.1

Axial MR images of a pleomorphic xanthoastrocytoma (PXA). (A) T2-weighted image showing a large, solid, mildly hyperintense, well-circumscribed nodule with associated fluid-filled cyst arising within the outer aspects of the right temporoparietal region. Peritumoral edema is fairly prominent in this case, and there is noticeable mass effect. (B) Axial TI-weighted post-gadolinium imaging shows intense homogeneous enhancement of the solid nodule with rim enhancement of the cyst wall

  * Intratumoral hemorrhage or calcifications are uncommon; peritumoral edema may be present, but is typically minimal.

  * PXAs may rarely exhibit multifocality or leptomeningeal dissemination.

## 3.4 Pathology

  * Gross pathology: Operative sampling of PXAs yields solid, firm tissue (with or without a cystic com ponent) with variable coloration ranging from tan to yellow, the latter areas corresponding to xanthomatous histology.

    * Leptomeninges are usually present in the sample, incorporated into the solid portion of the tumor.

  * Intraoperative cytologic imprints and smears: Cytologic samples are polymorphous, containi ng cells with quite variable cytomorphology; fibrillary astrocytic, spindled, and giant pleomorphic forms with abundant, sometimes vacuolated cytoplasm may all be present (Fig. 3.2).

Fig. 3.2

Intraoperative cytologic sme ar preparations are quite polymorphous, containing a mixture of cells with fibrillary astrocytic, spindled morphology (A) and giant pleomorphic morphology (B)

    * Eosinophilic granular bodies and scattered lymphocytes are commonly present.

    * Rare reports of CSF cytology from PXA patients were found to contain highly pleomorphic cells with well-defined cytoplasm that was often vacuolated.

  * Histology: Although PXAs as a group are quite heterogeneous in their histologic appearance, several key features are consistently present in all:

    * PXAs are com posed of spindle cells arranged in fascicles, intersecting bundles, or a storiform pattern, together with an admixture of variably pleomorphic giant cells, the nuclei of which may be singular, multilobated, or multiple. Nuclear hyperchromasia is typical, and intranuclear cytoplasmic invaginations are often present (Fig. 3.3A and B).

Fig. 3.3

PXAs are notable for their heterogeneous histologic appearance. (A) They fairly consistently contai n spindle cells arranged in fascicles or intersecting bundles, however, together with an admixture of pleomorphic giant cells, the nuclei of which may be singular, multilobated, or multiple. (B) Nuclei are often hyperchromatic, though some cells may exhibit nuclear features similar to those seen in ganglion cells, containing more open chromatin and singular prominent nucleoli. (A–C) Eosinophilic granular bodies are another consistent feature. (C) Cytoplasmic vacuolization may be extensive, though it may be exceedingly difficult to identify in some PXAs. (D) Verification of a rich reticulin network is helpful in differentiating PXA from higher-grade gliomas. (E) Similar to gangliogliomas, PXAs also frequently contain interspersed collections of lymphocytes. (F) This PXA with anaplastic features was notable for brisk mitotic activity; necrosis was present elsewhere in the tumor

    * Large xanthomatous cells with abundant intracytoplasmic lipid droplets are a helpful diagnostic feature when present (Fig. 3.3C), though these may be quite inconspicuous in some cases.

    * A rich reticulin network surrounds individual cells and small cell nests (Fig. 3.3D).

    * Though not a diagnostic requirement, eosinophilic granular bodies (EGBs) are almost always present (Fig. 3.3C).

    * Perivascular and intratumoral collections of small lymphocytes are also frequent (Fig. 3.3E).

    * Similar to pilocytic astrocytoma and ganglion cell tumors, PXAs (particularly those examples situated predominantly in the subarachnoid space) display a solid growth pattern. The interface with underlying or surrounding brain parenchyma varies, however; infiltrative areas resembling diffuse astrocytoma may be encountered.

    * Typical PXAs have a negligible mitotic rate and are devoid of necrosis and vascular proliferation.

    * The term "PXA with anaplastic features" is reserved for those tumors with at least five mitoses per ten high-power fields and/or necrosis (Fig. 3.3F).

    * Composite PXA/ganglioglioma, replete with an identifiable ganglion cell component, may be occasionally encountered, and PXAs with clear cell change, pigmenta tion, and papillary structures have been reported.

    * Features of cortical dysplasia may be seen in cortex adjacent to PXA in some cases.

## 3.5 Immunohistochemistry

  * PXAs are notable for their biphenotypic glial and neuronal staining pattern.

  * They are consistently positive for S-100 and glial fibrillary acidic protein (GFAP), though the latter may be patchy (Fig. 3.4A).

Fig. 3.4

(A) Glial fibrillary acidic prot ein (GFAP) is likewise consistently positive in PXAs. (B) Not unc ommonly, scattered individual tumor cells will express neuronal markers such as synaptophysin

  * Expression of neuronal markers, including synaptophysin (Fig. 3.4B), neurofilament, M AP2, and Class III β-tubulin, may be detected in individual pleomorphic cells; these markers will also highlight any true ganglion cell component.

  * CD34 expression is also frequently encountered.

## 3.6 Electron Microscopy

  * Ultrastructural feat ures include cells containing numerous intermediate filaments, lipid droplets, and lysosomes.

  * Neuronal features present in some cells include microtubules, dense core granules, and/or clear vesicles.

  * Intercellular basement membrane and aggregates of secondary lysosomes (corresponding to EGBs) are common.

## 3.7 Molecular Pathology

  * PXAs appear to be molecularly distinct from infiltrative astrocytomas, exhibiting a low incidence of p53. mutations. Likewise, amplifications of EGFR, CDK4, and MDM2 have not been detected.

  * BRAF V600E mutation has been demonstrated in approximately 75 % of PXAs, including those with anaplastic features. With the exception of epithelioid glioblastoma (over 50 % of which may have BRAF V600E), this mutation is detected at much lower frequencies in gangliogliomas, pilocytic astrocytomas, dysembryoplastic neuroepithelial tumors (DNTs), and infiltrative gliomas.

  * BRAF V600E immunohistochemistry may be particularly helpful in cases where limited tissue is available. Although BRAF V600E mutation–specific monoclonal antibodies have shown high sensitivity and specificity in multiple validation studies when compared against more conventional molecular detection methods, nonspecific background staining is a documented issue, and this assay should therefore be in terpreted cautiously.

  * Chromosome 9p loss with coincident homozygous deletion involving CDKN2A/p14 ARF /CDKN2B loci has been encountered in approximately 50 % of cases.

## 3.8 Differential Diagnosis

  * For PXA, the main alternate diagnostic consideration is glioblastoma, especially the giant cell variant; both of these cellular gliomas contain variable numbers of pleomorphic astrocytes, but with significantly different therapeutic and prognostic implications. Radioimaging findings of a cyst with enhancing mural nodule strongly favors PXA, as do the histologic findings of xanthomatous change, EGBs, a paucity of mitoses, and a lack of necrosis and vascular proliferation. Immunohistochemistry may be of assistance in demonstrating positivity for neuronal markers and CD34, both of which would be unexpected in glioblastoma. Likewise, detection of BRAF V600E mutation would strongly favor PXA, as this alteration is exceedingly rare in giant cell glioblastoma.

  * Immunopositivity for S-100 and GFAP effectively differentiates PXA from the occasional pleomorphic leptomeningeal-based sarcoma (such as malignant fibrous histiocytoma) or meningioma.

  * Ganglioglioma and pilocytic astrocytoma are two other entities that arise in the young and may present as a cyst with mural nodule on radioimaging studies.

    * Ganglioglioma contains abundant dysmorphic ganglion cells and lacks the prominent pleomorphism and lipidized cells of PXA.

    * Pilocytic astrocytomas also tend not to display the extent of pleomorphism or reticulin network found in PXA, and they are usually less compact in their architecture, frequently exhibiting loose, microcystic areas containing cells with typical piloid processes.

## 3.9 Prognosis

  * PXAs afford a more favorable prognosis than glioblastoma, with overall survival rates of 75 % at 5 years and 67 % at 10 years, but a significant proportion will recur, undergo anaplastic progression, or both. Thus PXA patients tend to fare worse than those with pilocytic astrocytomas.

  * Completeness of initial resection and low mitotic rate are both independent predictors of prolonged recurrence-free survival, whereas anaplastic features are associated with less favorable outcomes and frequent recurrence.

  * There is some evidence in adult PXAs that BRAF inhibitors may be beneficial in treating those recurrent tumors harboring BRAF V600E mutations, though it is not yet known if pediatric PXA will show similar responses to this targeted therapy. Likewise, data regarding the prognostic significance of BRAF V600E mutation in PXAs have been mixed.

Suggested Reading

Chamberlain MC. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol. 2013;114:237–40.CrossRefPubMed

Crespo-Rodriguez AM, Smirniotopoulos JG, Rushing EJ. MR and CT imaging of 24 pleomorphic xanthoastrocytomas (PXA) and a review of the literature. Neuroradiology. 2007;49:307–15.CrossRefPubMed

Dias-Santagata D, Lam Q, Vernovsky K, Vena N, Lennerz JK, Borger DR, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011;6:e17948.CrossRefPubMedPubMedCentral

Fouladi M, Jenkins JJ, Burger PC, Langston J, Merchant T, Heideman R, et al. Pleomorphic xanthoastrocytoma: favorable outcome after complete surgical resection. Neuro Oncol. 2001;3:184–92.PubMedPubMedCentral

Giannini C, Hebrink D, Scheithauer BW, Dei Tos AP, James CD. Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma. Neurogenetics. 2001;3:159–62.CrossRefPubMed

Giannini C, Scheithauer BW, Lopes MB, Hirose T, Kros JM, VandenBerg SR. Immunophenotype of pleomorphic xanthoastrocytoma. Am J Surg Pathol. 2002;26:479–85.CrossRefPubMed

Goncalves VT, Reis F, Queiroz LS, Franca Jr M. Pleomorphic xanthoastrocytoma: magnetic resonance imaging findings in a series of cases with histopathological confirmation. Arq Neuropsiquiatr. 2013;71:35–9.CrossRefPubMed

Hirose T, Giannini C, Scheithauer BW. Ultrastructural features of pleomorphic xanthoastrocytoma: a comparative study with glioblastoma multiforme. Ultrastruct Pathol. 2001;25:469–78.CrossRefPubMed

Hirose T, Ishizawa K, Sugiyama K, Kageji T, Ueki K, Kannuki S. Pleomorphic xanthoastrocytoma: a comparative pathological study between conventional and anaplastic types. Histopathology. 2008;52:183–93.CrossRefPubMed

Ida CM, Vrana JA, Rodriguez FJ, Jentoft ME, Caron AA, Jenkins SM, et al. Immunohistochemistry is highly sensitive and specific for detection of BRAF V600E mutation in pleomorphic xanthoastrocytoma. Acta Neuropathol Commun. 2013;1:20.CrossRefPubMedPubMedCentral

Koelsche C, Sahm F, Wohrer A, Jeibmann A, Schittenhelm J, Kohlhof P, et al. BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. Brain Pathol. 2014;24:221–9.CrossRefPubMed

Lacoste-Collin L, d'Aure D, Aziza J, Quintyn ML, Uro-Coste E, Courtade-Saidi M. Cerebrospinal fluid cytologic findings of a pleomorphic xanthoastrocytoma: a case report. Acta Cytol. 2010;54:871–4.PubMed

Perkins SM, Mitra N, Fei W, Shinohara ET. Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J Neurooncol. 2012;110:99–104.CrossRefPubMed

Rao AA, Laack NN, Giannini C, Wetmore C. Pleomorphic xanthoastrocytoma in children and adolescents. Pediatr Blood Cancer. 2010;55:290–4.CrossRefPubMed

Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405.CrossRefPubMed

Weber RG, Hoischen A, Ehrler M, Zipper P, Kaulich K, Blaschke B, et al. Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytoma. Oncogene. 2007;26:1088–97.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_4

# 4. Infiltrative Astrocytomas (Diffuse Astrocytoma, Anaplastic Astrocytoma, Glioblastoma)

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

Diffuse astrocytomaAnaplastic astrocytomaGlioblastomaDiffuse intrinsic pontine gliomaTectal plate gliomaDiffuse midline gliomaH3 K27M-mutant

## 4.1 Overview

  * Infiltrative astrocy tomas represent a diverse group of glial tumors of variable degree of malignancy that share in common the qualities of astrocytic differentiation and an inherent ability to diffusely invade central nervous system (CNS) parenchyma.

  * The World Health Organization (WHO) 2016 classification divides infiltrative astrocytomas into three grades:

    * ◦ Diffuse astrocytoma (also known as well-differentiated or low grade astrocytoma)—WHO grade II

    * ◦ Anaplastic astrocytoma—WHO grade III

    * ◦ Glioblastoma (also known as glioblastoma multiforme)—WHO grade IV

    * ◦ Diffuse midline glioma, H3 K27M-mutant is a newly defined entity within the 2016 CNS WHO Classification. These tumors share this specific molecular signature, diffuse growth pattern, and midline location; Diffuse Intrinsic Pontine Glioma (DIPG) is included in this group

  * As a group, infiltrative astrocytomas represent the most frequent glial tumors afflicting adults, with glioblastoma accounting for the largest percentage of all malignant CNS tumors.

    * ◦ They are second to pilocytic astrocytoma in terms of frequency in the pediatric age group.

    * ◦ Approximately 10 % of all glioblastomas occur within the first two decades of life.

    * ◦ The vast majority are sporadic. Epidemiologic studies have shown that previously irradiated patients are at increased risk of subsequent astrocytoma development.

    * ◦ A minority are encountered in the context of various tumor syndromes, including Li-Fraumeni syndrome (p53), Turcot syndrome (APC), tuberous sclerosis (TSC1 and TSC2), neurofibromatosis type I (NF1), and multiple enchondromatosis (Ollier's disease).

  * Gliomatosis represents an aggressive, diffusely infiltrative growth pattern that involves broad regions of the CNS, typically more than two lobes with or without bilateral hemispheric involvement or extension into the posterior fossa and the spinal cord. It is no longer considered a distinct entity.

## 4.2 Clinical Features

  * Symptoms and signs are related to tumor location and/or secondary mass effect, and many times ar e nonlocalizing.

  * Cerebral hemispheric lesions may result in seizures or focal motor deficits, whereas endocrinopathies can result from hypothalamic lesions.

  * Symptoms and signs associated with high-grade lesions are usually of short duration prior to tumor detection.

  * There is no particular gender predilection, with the exception of supratentorial diffuse astrocytomas, for which afflicted males outnumber females 2:1.

  * The vast majority of glioblastomas in children arise de novo (i.e., primary glioblastoma); malignant transformation from an underlying low-grade astrocytoma to glioblastoma (i.e., secondary glioblastoma) is extremely rare in this age group.

  * Pediatric epithelioid glioblastoma may present with acute massive hemorrhage and frequently shows leptomeningeal dissemination at time of diagnosis.

  * Diffuse intrinsic pontine glioma (DIPG) may present with cranial nerve deficits. These tumors occur at a mean age of 8 years, younger than for high-grade astrocytomas of other sites.

  * Tectal plate gliomas most often present with signs or symptoms of increased intracranial pressure, though a subgroup are found incidentally on imaging studies. Neurocognitive deficits may occur in these patients, but endocrine dysfunctions are uncommon.

  * Astrocytomas arising in the spinal cord may cause pain, weakness, paresthesias, or gait disturbance.

  * Gliomatosis is rare in both adults and children, with neurologic signs or symptoms that are generally nonlocalizing.

## 4.3 Neuroimaging

  * Pediatric grade II astrocytomas do occur in the cerebral white matter, but more often they arise in deep brain midline structures (especially thalami) (Fig. 4.1A and B); they occur rarely in the cerebellum and the spinal cord.

Fig. 4.1

(A, B) Axial MR images show ing a deep-situated low-grade astrocytoma with bithalamic involvement: The lesion is hyperintense on the T2-weighted image (A), but it is difficult to appreciate on the T1-weighted post-contrast image (B), as there is no evidence of enhancement. (C) Postcontrast CT scan of a "butterfly" glioblastoma, crossing the midline through the corpus callosum and showing strong ring enhancement. (D) Axial T2-weighted MR image of a deep-seated glioblastoma, showing extensive T2-hyperintense peritumoral edema surrounding a lesion with heterogeneous signal intensity. (E) T1-weighted postcontrast image of the same glioblastoma, showing an irregular ring of enhancement with a surrounding zone of hypointensity. (F) This thalamic glioblastoma likewise shows characteristic ring enhancement, seen here on sagittal T1-weighted postcontrast MR imaging. (C, Courtesy of Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA. F, Courtesy of Dr. Gary Tye, Virginia Commonwealth University, Richmond, VA, USA)

  * Pediatric glioblastom as may arise within cerebral white matter, often extending into deep gray structures or across the midline (Fig. 4.1C).

    * ◦ Unlike their adult counterparts, pediatric glioblastoma additionally represents the most frequent tumor of the brainstem, particularly the pons (see DIPG below).

    * ◦ Rarely, they may arise in the cerebellum or spinal cord.

  * Localization of pediatric anaplastic astrocytoma overlaps the same sites noted for grade II and IV lesions.

  * Both grade II and grade III lesions tend to be ill-defined, low-density masses on CT studies.

    * ◦ Calcification or cystic changes may be seen.

    * ◦ Anaplastic astrocytoma often shows at least focal enhancement.

  * Glioblastoma characteristically presents as a ring-enhancing lesion (Fig. 4.1C).

  * Enhancement may be more heterogeneous in brainstem lesions.

  * Grade II lesions are poorly marginated and are hypointense on T1 and hyperintense on T2 (see Fig. 4.1A) and FLAIR MR images.

    * ◦ Contrast enhancement is not a feature (see Fig. 4.1B); when contrast enhancement appears on follow-up imaging studies, it heralds the occurrence of malignant progression or transformation.

  * High-grade lesions are similar to grade II astrocytoma in their MR characteristics, but they frequently ha ve surrounding bright areas on T2-weighted imaging due to peritumoral edema, as well as contrast enhancement (Fig. 4.1D–F).

  * Giant-cell and epithelioid glioblastoma and gliosarcoma tend to be more demarcated than other glioblastomas.

  * Brainstem gliomas may be diffuse or focal:

    * ◦ DIPG: markedly expanded pons, often encroaching on or engulfing the basilar artery.

      * Typically T1 hypointense with T2 hyperintensity. There have been focal areas of T2 hypointensity which may have restricted diffusion.

      * Rarely enhance and when enhancement is present it is associated with shorter survival. Ring enhancement of glioblastoma may be encountered (Fig. 4.2).

Fig. 4.2

Axial T2-weighted (A), FLAIR (B), and T1-weighted (C) postcontrast images of a pontine diffuse astrocytoma showing m arkedly expanded pons with encasement of the adjacent basilar artery. The lesion is hyperintense on both T2 and FLAIR and hypointense on T1. The small, round focus with central necrosis and surrounding ring contrast enhancement indicates the glioblastoma component

    * ◦ Tectal plate glioma: lesions limited to the periaqueductal region; isointense on T1-weighted and hyperintense on T2-weighted MR imaging; seldom showing enhancement.

    * ◦ Brainstem dorsally exophytic gliomas: usually pilocytic astrocytomas (see Chapter 2)

  * Gliomatosis typically involves at least three cerebral lobes, usually bilaterally and extending into deep gray structures.

    * ◦ Gliomatosis may extend to involve the posterior fossa elements or even the spinal cord.

    * ◦ Lesions are characteristically hyperintense on T2 and FLAIR MR imaging (Fig. 4.3).

Fig. 4.3

This coronal T2-weighted MR image depicts an example of gliomatosis, showing bright signal present i n the cerebral hemispheres bilaterally, as well as within the cerebellum around the fourth ventricle

## 4.4 Pathology

  * Gross pathology:

    * ◦ Diffuse astrocytoma (WHO grade II) is frequently ill-defined grossly, distorting the involved anatomical region and blurring demarcations between gray matter and white m atter.

      * These lesions do not show tissue destruction, merely infiltration.

      * Cystic areas or calcifications may be present, though the gray-tan color and firm texture are otherwise homogeneous (Fig. 4.4A).

Fig. 4.4

(A) Coronal brain section showing a large, right thalamic, diffuse astrocytoma with homogeneous consistency, which markedly expands this region and blurs the underlying archite cture. (B) This pontine glioblastoma has a heterogeneous red and tan mottled appearance with areas of hemorrhage and destructive necrosis

    * ◦ High-grade astrocytomas, particularly glioblastomas, tend to have a much more heterogeneous appearance, forming grossly obvious masses that often contain areas of hemorrhage and/or necrosis. Thus, they typically have a mottled tan, red, and brown coloration with alternating firm and softened zones (Fig. 4.4B).

    * ◦ Gliosarcomas may be quite firm in consistency because of the particular sarcomatous component present.

  * Intraoperative cytologic imprints and smears:

    * ◦ Smear/squash preparations of infiltrative astrocytomas contain cells with oval to irregular-sha ped hyperchromatic nuclei and elongated fibrillary cytoplasmic processes. These processes are most evident at the periphery of sheets of tumor cells (Fig. 4.5A).

Fig. 4.5

(A) Smear preparation of a diffuse astrocytoma containing moderately cellular fragments of tissue and cells with oval hyperchromatic nuclei and elongated fibrillary cytoplasmic p rocesses. (B) This smear preparation of diffuse astrocytoma demonstrates the gemistocytic morphology, the tumor cells having plump cytoplasmic "bellies", some with discernible short processes, and eccentric round to oval nuclei. (C, D) Cytologic preparations of high-grade astrocytomas are much more hypercellular with cell crowding and overlap and atypical nuclei. Elongated fibrillary process typical of astrocytomas should still be present. Mitotic figures may be seen, and a "dirty" background indicative of necrosis (as in D) is often seen in smears of glioblastoma

    * ◦ Cells with gemistocytic morphology may be plentiful (Fig. 4.5B).

    * ◦ High-grade lesions, not surprisingly, are obviously hypercellular, often with mitotic figures identifiable on cytology preparations.

    * ◦ Vascular proliferation and a "dirty" necrotic background are features supportive of glioblastoma (Fig. 4.5C and D).

  * Histology: Four histologic criteria are utilized in the grading of infiltrative astrocytomas: nuclear atypia, mitosis, necrosis, and/or microvascular proliferation. Tumor grade is established based on the area of greatest anaplasia.

    * ◦ A note of ca ution in grading: Occasional mitoses are acceptable in a large sample, but detection of any mitotic figure within a tiny sample warrants upgrading to high-grade astrocytoma (at least anaplastic astrocytoma).

    * ◦ Diffuse/low-grade astrocytoma (WHO grade II): moderately cellular astrocytomas that fulfill only one of the listed criteria (nuclear atypia). Mitotic figures should be exceedingly difficult to find, and vascular proliferation and necrosis are absent (Fig. 4.6A–C).

Fig. 4.6

Diffuse/low-grade astrocytomas are quite variable in their cellularity, ranging from mildly (A) to moderately (B) hypercellular. Features helpful in discriminating grade II astrocytoma from reactive gliosis include the presence of atypical (usually hyperchromatic) nuclei and irregular cell distribution in the astrocytomas. In these fibrillary astrocytomas (A–C), the oval to irregularly shaped nuclei have little in the way of discernible cytoplasm ("naked nuclei"), though fibrillary processes are seen within the background tissue. Anaplastic astrocytomas (WHO grade III) are notably more cellular (D, E), often with significant nuclear atypia and with the additional feature of increased mitotic activity

    * ◦ Anaplastic astrocytoma (WHO grade III): hypercellular astrocytomas with nuclear atypia and obviously increased mitotic activity (Fig. 4.6D and E).

      * Vascular proliferation and necrosis are absent.

      * Cells with large pleomorphic or multiple nuclei may be present.

      * Neuropil-rich islands that are surrounded by oligodendroglial-like cells may be encountered in rare infiltrative astrocytomas (grades II and III). These areas are characteristically positive for neural markers synaptophysin and Neu-N.

    * ◦ Glioblastoma (WHO grade IV): In addition to findings as listed for anaplastic astrocytoma, glioblastomas display necrosis (typically pseudopalisading necrosis), microvascular proliferation, or frequently both.

      * Individual tumor cells may range from small to bipolar to huge cells with markedly pleomorphic nuclei or multinucleation (see below).

      * Atypical mitotic figures may be present (Fig. 4.7).

Fig. 4.7

At low power, glioblastoma appears as a highly cellular neoplasm, in this case showing the char acteristic serpiginous zones of pseudopalisading necrosis (A). Individual tumor cells are quite variable in their morphology and may range from small and bipolar to giant and pleomorphic (B); mitotic figures should be easy to find. Microvascular proliferation may take the form of large glomeruloid capillary tufts (C) or more linear-appearing capillaries with multilayered, proliferating endothelial lining; striking nuclear pleomorphism is also seen in multiple cells (D)

      * Microvascular proliferation may take the form of large glomeruloid tufts (Fig. 4.7C) to linear capillaries with intraluminal multilayered endothelial proliferation (Fig. 4.7D); both should show mitotic activity.

      * Secondary structures (subpial accumulation of tumor cells, perineuronal and perivascular satellitosis) are more common in high-grade astrocytomas than in grade II ast rocytoma, though this growth pattern is also common in oligodendroglial tumors (Fig. 4.8).

Fig. 4.8

Secondary structure formation is frequently encountered at the less cellular infiltrative edges of high-grade astrocytomas. These include subpial accumulation of tumor cells (A), perineuronal satellitosis (B), and perivascular satellitosis (C)

      * Multiple diffuse astrocytoma morphologic patterns have been described:

        * Fibrillary: By far the most frequent morphology. Despite its name, it is typified by cells bearing only minimal discernible cytoplasm (naked nuclei). This m orphology may be present in both low-grade (grade II) and high-grade (III and IV) lesions (Figs. 4.6 and 4.7).

        * Gemistocytic: Cells with plump, eosinophilic cytoplasmic "bellies" (often with some extensions of stout cytoplasmic processes at their periphery) and eccentric nuclei. Again, this morphology may be seen in both low-grade and high-grade lesions (Fig. 4.9). Gemistocytic astrocytoma, IDH-mutant represents a distinct entity in the 2016 CNS WHO Classification.

Fig. 4.9

(A) The gemistocytic morphology is characterized by cells with large, eosinophilic cytoplasmic "bellies" and eccentric, hyperchromatic, often irregularly shaped nuclei. (B) When they represent a significant proportion of an infiltrative astrocytoma, the term "gemistocytic astrocytoma" is appropriate

        * Protoplasmic: Neoplastic astrocytes showing small cell bodies and few thin processes. Protoplasmic astrocytoma, solely bearing this morphology, is exceedingly rare, though cells with similar morphology may be seen in other forms of astrocytoma, particularly within the loose areas of pilocytic astrocytoma.

        * Giant cell: Glioblastoma populated nearly exclusively by large, bizarre, multinucleated giant cells are termed giant cell glioblastoma, a recognized distinct entity in the 2016 CNS WHO Classification (Fig. 4.10A and B), although some multinucleated tumor giant cells are not uncommon in high-grade astrocytomas. Giant cell glioblastomas tend to be circumscribed on neuroimaging studies and subcortical in location; they sometimes contain prominent reticulin networks. This variant has been found to have a slightly better prognosis, in part because it is less invasive than other forms of glioblastoma.

Fig. 4.10

(A, B) Giant cell glioblastoma, as its name implies, contains a preponderance of giant cells, including those with large, bizarre or multilobated nuclei as well as multinucleated forms. Smaller malignant astrocytic cells are intermixed. (C–F) An example of a small cell glioblastoma that arose in an adult patient. Note the marked hypercellularity and paucity of cellular cytoplasm (C, D) causing superficial resemblance to primitive neuroectodermal tumor (PNET). A small subpopulation of tumor cells are immunopositive for glial fibrillary acidic protein (GFAP) (E), and there is strong diffuse membrane staining for epidermal growth factor receptor (EGFR) (F). Neuronal markers were negative and Ki67 indicated a brisk proliferation index (not shown). (G, H) A small cell glioblastoma from a child; note scattered cells staining positive for GFAP in (H)

        * Small cell: Composed predominantly of cells with round to slightly oval nuclei with minimal to imperceptible cytoplasm. Small cell glioblastoma has been well recognized in adults (Fig. 4.10C–F), typically showing a high proliferation rate and little glial fibrillary acidic protein (GFAP) staining; many will have epidermal growth factor receptor (EGFR) mutation or amplification, and positive staining by immunohistochemistry. Small cell glioblastoma is quite rare in children (Fig. 4.10G and H).

      * There are several other uncommon cell morphologies:

        * True epithelial differentiation: Components resemble adenocarcinoma, including signet ring cells and even a squamous appearance. These components also show immunohistochemical expression of specific epithelial markers such as Cam 5.2 or polyclonal carcinoemb ryonic antigen (CEA).

        * Epithelioid glioblastoma: As the name implies, these glioblastomas harbor cells that are oval to round with distinct cell membrane, eccentric nucleoli, and fairly abundant eosinophilic cytoplasm. These epithelioid cells may closely resemble rhabdoid morphology (some authors have used these terms interchangeably), but they are not positive for stains targeting specific epithelial markers noted above and they do not show the polyphenotypia found in rhabdoid cells. Epithelioid glioblastoma tends to be more circumscribed, though it has a poor prognosis. Adenoid or chordoid areas may be seen (Fig. 4.11A). Epithelioid glioblastoma is considered a provisional new variant within the 2016 CNS WHO Classification.

Fig. 4.11

Unusual components of glioblastoma. (A) Chordoid areas containing cells with an epithelioid morphology in a myxoid background. (B) Granular cells. (C) Cells with a rhabdoid appearance. Note the cellular dyscohesion, eccentric nuclei (including some with vesicular chromatin and prominent nucleoli), and eosinophilic, rounded cytoplasmic "bellies"

        * Granular cells: Cells that are PAS-positive and often CD68-positive, with abundant cytoplasm and oval hyperchromatic nuclei (Fig. 4.11B).

        * Rhabdoid glioblastoma: Cells resembling rhabdoid cells of atypical teratoid rhabdoid tumors (AT/RT) may be present, replete with polyphenotypia by immunohistochemistry. Patchy loss of nuclear INI1 (BAF47) immunostaining has been described by some authors in these rhabdoid cells, but the more diffuse loss of INI1 typical of AT/RT would be unexpected (Fig. 4.11C).

        * Metaplastic components: Benign stromal elements (muscle, cartilage, bone, lipidized cells) have been described, but they occur far more rarely than the sarcomatous elements of gliosarcoma.

    * • Gliosarcoma (WHO grade IV): This biphasic, high-grade glioma has both malignant astrocytic (glioblastoma) and sarcomatous components. The sarcomatous portion is frequently fibrosarcoma, but may include malignant fibrous histiocytoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, o r even liposarcoma. Trichrome and reticulin stains are frequently positive (Fig. 4.12). Gliosarcoma represents an accepted variant of Glioblastoma, IDH-wildtype within the 2016 CNS WHO Classification.

Fig. 4.12

Gliosarcoma is a biphasic tumor that includes a sarcomatous component in addition to a malignant glial (typically astrocytic) component. These tumors may include fibrosarcoma (the most common, A), osteosarcoma (B), chondrosarcoma (C), rhabdomyosarcoma (D), and others. The malignant astrocytic component can more easily be identified by its GFAP positivity (E); trichrome stain highlights abundant collagen within fibrosarcomatous components (F)

    * • Gliofibroma: A very rare tumor, more common in children than in adults. This biphasic tumor is similar to gliosarcoma, but the fibroblastic component is nonsarcomatous. Grade is dependent upon the astrocytic component; it is typically low-grade and thus carries a relatively favorable prognosis.

    * • Gliomatosis: Predominantly astrocytic, but gliomatosis infrequently may contain oligodendroglial elements. Nuclei tend to be elongated and hyperchromatic, and pleomorphic forms are not uncommon. Secondary structures are often present. Mitotic activity is variable. Areas akin to glioblastoma may be present in some cases (Fig. 4.13).

Fig. 4.13

Gliomatosis represents the most widely infiltrative growth pattern. (A, B) It often presents as hyperc hromatic, elongated "naked nuclei" percolating widely through brain parenchyma. (C) Not surprisingly, there is a tendency for developing secondary structures. (D) Tumor cells may extend into the posterior fossa area, as shown in this section of cerebellum, or even into the brainstem and spinal cord

    * • Diffuse intrinsic pontine glioma (DIPG) : Clinically and radiographically, classic DIPG represents a diverse histologic spectrum. Many bear high-grade histologic features (astrocytoma WHO grade III or IV), but some have histology corresponding with WHO grade II astrocytoma. Nonetheless, all DIPGs exhibit aggressive biologic behavior, so histologic grading does not appear to be an appropriate predictor of outcome for this group of p ediatric malignancies. At autopsy, DIPGs diffusely invade the brainstem structures, though it is not uncommon to see leptomeningeal tumor spread, as well as infiltrative extension into the spinal cord or thalamus, and even out into the cerebral hemispheres.

## 4.5 Immunohistochemistry

  * GFAP expression reflects the extent of cytoplasmic development and is similarly present in the intervening fibrillary matrix of these lesions (Fig. 4.14A).

Fig. 4.14

(A) GFAP is characteristically positive in astrocytoma, though its expression may be quite vari able, depending upon the amount of cytoplasm present and the degree of differentiation. (B) Neurofilament staining is helpf ul in documenting the infiltrative quality of these tumors as it decorates native neuritic processes that have been overrun by invasive tumor. (C) Nuclear positivity for p53 may be encountered in some pediatric cases, but it is less frequent than similar positivity in astrocytomas arising in adults

  * S-100 shows diffuse nuclear and cytoplasmic positivity, and vimentin is similarly positive.

  * Ki-67 is variably posi tive, reflecting the low (grade II) to brisk (grades III and IV) proliferative activity of the lesions.

  * Neurofilament staining of intratumoral neuritic processes provides reassuring evidence of the infiltrative pattern of these neoplasms (Fig. 4.14B).

  * Pancytokeratin is often positive at least focally in higher-grade lesions, showing cross reactivity with glial intermediate filaments; it is frequently positive in epithelioid glioblastoma. More specific cytokeratin antibodies such as Cam 5.2 or polyclonal CEA are usually negative, except in the context of true epithelial differentiation.

  * Rhabdoid glioblastomas may show immunohistochemical polyphenotypia, akin to that encountered in AT/RT, but they would not be expected to show the diffuse loss of nuclear INI1 that is typical of the AT/RT.

  * Sarcomatous portions of gliosarcoma, though not positive for GFAP, are consistently vimentin-positive and tend to take on the staining properties of the particular sarcoma element present (muscle, fat, cartilage, etc.).

  * Gliomatosis is variably positive for GFAP and S-100.

  * Mutant-specific antibodies for detection of IDH1 and H3F3A K27M mutant tumors are commercially available. In addition, the OLIG2+/FOXG1− signature has been found to represent a reliable surrogate marker for K27M mutation status, with the OL IG2−/FOXG1+ signature correlating well with H3F3A G34 mutation status.

## 4.6 Electron Microscopy

  * The finding of abundant inter mediate filaments by ultrastructural analysis is characteristic.

## 4.7 Molecular Pathology

  * Low-grade/diffuse astrocytoma (WHO grade II)

    * ◦ Aberrations of MYB, MYBL1, or FGFR1/3 (tyrosine kinase [TK] domain duplication, misse nse mutation, or TACC1/3 fusion) are detectable in almost 70 % of low-grade or diffuse astrocytomas. FGFR1 TK domain duplications and MYB or MYBL1 alterations occur nearly exclusively in cerebral lesions; 25 % of cerebral pediatric low-grade or diffuse astrocytomas will harbor MYB or MYBL1 abnormalities, with a similar percentage having FGFR1 aberrations. These genetic signatures are mutually exclusive.

    * ◦ H3F3A K27M mutation, BRAF V600E mutations, and FAM13B:BRAF fusion may be present in a small percentage of cerebral cases, with H3F3A mutations seen mainly in tumors of thalamic origin.

  * High-grade astrocytomas

    * ◦ Mutations involving the histone H3.3/H3.1-ATRX-DAXX chromatin remodeling pathway are quite common in pediatric high-grade astrocytomas, and are strongly as sociated with alternative lengthening of telomeres (ALT phenotype).

      * Histone H3.3 (H3F3A) mutations, particularly K27M, may be found in up to 30 % of pediatric high-grade astrocytomas overall, including anaplastic astrocytomas, conventional glioblastoma, and DIPG (see below). G34R/G34V mutations are less common (approximately 10 % of pediatric glioblastoma), and are limited to non-brainstem tumors.

      * Mutations in ATRX and DAXX are present in about 30 % of glioblastomas, and in all tumors with G34R/G34V H3.3 mutations.

      * TP53 mutations also frequently accompany H3F3A or ATRX mutations in pediatric glioblastoma.

    * ◦ BRAF V600E mutation may be found in a small percentage of pediatric glioblastomas (about 10 %), but it is particularly common in the epithelioid subtype (see below).

      * ◦ The most frequent alterations in pediatric secondary glioblastoma are BRAF V600E (about 40 %) and CDKN2A deletion (about 60 %). In most cases, these alterations can be traced back to their underlying low-grade astrocytomas. Interestingly, BRAF mutations appear to be associated with a longer latency to transformation and prolonged overall survival.

      * Approximately 50 % of pediatric epithelioid glioblastomas have demonstrable BRAF V600E mutations. H3.3 K27M mutation and chromosome loss of 22q have also been detected.

      * Giant cell glioblastomas rarely harbor the BRAF V600E mutation, though they will often have loss of p16.

    * ◦ Chromosome 1q gain is present in approximately 25 % of high-grade astrocytomas.

    * ◦ Deletions of CDKN2A/CDKN2B appear to be limited to supratentorial high-grade astrocytomas.

    * ◦ Homozygous loss at 8p12 occurs in about 15 % and includes the ADAM3A gene.

    * ◦ Amplification of the 4q11-13 region is present in about 10 %, with resultant amplification of the PDGFRA gene.

    * ◦ MYCN amplification may be detected in a small proportion of high-grade astrocytomas, being most prevalent in anaplastic astrocytoma.

    * ◦ SETD2, a H3K36 trimethyltransferase, is mutated in about 15 % of pediatric high-grade astrocytomas, is mutually exclusive with H3.3 mutations, and is limited to tumors of the cerebral hemispheres of older children and young adults.

    * ◦ Infant high-grade astrocytoma appears to represent a distinct genetic subgroup, with fusions involving the neurotrophin receptor genes (NTRK1, NTRK2, and NTRK3) present in about 40 % of non-brainstem high-grade astrocytomas. In addition, H3.3 K27M mutations, PDGFRA amplifications, and CDKN2A loss are rare in infant glioblastomas. Loss of the SNORD gene (14q32) may be seen in over 25 % of these infant tumors.

    * ◦ Combined multimodality analysis studies assessing epigenetic or methylation status and gene copy number and expression profiles have revealed the existence of definable subgroups of glioblastoma:

      * H3F3A K27M and G34R mutated subgroups are predominant among pediatric glioblastomas, and are mutually exclusive from IDH1 mutations in IDH1 mutated tumors. These tumors likewise frequently show TP53 mutations, and they generally display widespread genomic hypomethylation. K27M is more frequent in children and is seen predominantly in midline tumors (DIPG and glioblastoma of the thalamus and spinal cord); these represent the newly definted diffuse midline glioma, H3 K27Mmutant group in the 2016 CNS WHO Classification. G34 is most frequent in adolescents with tumors of cerebral hemispheric location.

      * IDH1 mutated tumors make up a minor proportion of pediatric glioblastomas, display global genomic hypermethylation, and frequently harbor TP53 mutations. These tumors are mainly limited to older children and young adults with tumors of cerebral hemispheric location.

      * PDGFRA-amplified tumors, as the name implies, show high frequency of PDGFRA amplification as well as a proneural gene expression profile. This group has a wide age distribution, including pediatric cerebral hemispheric tumors.

      * Mesenchymal subgroup tumors exhibit a mesenchymal gene expression signature and no defining gene copy number alterations or point mutations. This group also has a wide age distribution, including pediatric tumors of cerebral hemispheric location.

      * The "classic" subgroup, limited exclusively to glioblastomas arising in older adults, shows high frequency of chromosome 10 loss, homozygous de letion of CDKN2A, and EGFR amplification.

  * Diffuse intrinsic pontine glioma (DIPG)

    * ◦ K27M mutations in H3F3A (H3.3) or HIST1H3B (H3.1) are extremely common, present in nearly 80 % of DIPG.

    * ◦ Gain-of-function ACVR1 mutations are found exclusively in DIPG (up to 30 % of cases), whereas FGFR1 mutations or fusions are seen in thalamic high-grade astrocytomas.

    * ◦ Global DNA hypomethylation, an epigenetic alteration frequently encountered in DIPG, may be detectable as decreased tumor staining by H3K27me3-specific immunohistochemistry.

    * ◦ Similar to pediatric non-br ainstem glioblastomas, TP53 (75 %) and ATRX (10 %) mutations may be encountered in subpopulations of DIPG, the latter being more frequent in tumors arising in older children.

      * PDGFRa gains and amplifications have been encountered.

      * Losses involving chromosomes 17p and 14q are frequently shown.

      * IDH1/2 mutations or CDKN2A/CDKN2B deletions are not seen.

## 4.8 Differential Diagnosis

  * Diffuse astrocytoma versus reactive astrocytosis

    * ◦ Even in astrocytomas of low cellularity, the distribution of cells is irregular, nuclear hyperchromasia is evident, and the typical starlike, elongated processes of re active astrocytes are absent.

    * ◦ Neoplastic gemistocytes, similarly, will have stubby processes, not the elongated processes of reactive astrocytes.

  * Infiltrative astrocytomas versus other gliomas

    * ◦ Diffuse astrocytomas can be differentiated from oligodendroglial tumors by paying close attention to nuclear morphology; astrocytic tumors have oval to irregularly shaped nuclei, whereas oligodendroglial tumors have round nuclei with perinuclear halo.

    * ◦ Diffuse astrocytomas should not contain Rosenthal fibers or eosinophilic granular bodies, which are usually present in pilocytic astrocytomas and pleomorphic xanthoastrocytomas (PXAs); radiographic findings are also dissimilar. In particularly nebulous cases, the detection of an H3F3A K27M mutation would indicate high-grade astrocytoma, whereas KIAA1549:BRAF fusion would support pilocytic astrocytoma.

  * High-grade astrocytoma with unusual cell types

    * ◦ Rhabdoid glioblastoma can be problematic, raising the differential diagnosis of AT/RT, but diffuse loss of nuclear positivity for INI1/BAF47 in AT/RT will clinch the correct diagnosis.

    * ◦ Epithelioid glioblastoma can be confused with both metastatic carcinoma and choroid plexus carcinoma. Pancytokeratin expression is a common finding in all of these, but GFAP positivity helps to rule out metastatic carcinoma. Detectable immunopositivity for EAAT1 or Kir7.1 would support a diagnosis of choroid plexus carcinoma, whereas BRAF V600E mutation detection would strongly favor epithelioid glioblastoma.

## 4.9 Prognosis

  * Although the majority of grade II astrocytomas arising in adults will undergo malignant transformation, fewer than 10 % of pediatric low-grade astrocytomas are destined to th at fate. The remainder can expect prolonged progression-free survival (mean approximately 10 years).

  * Diencephalic pediatric low-grade astrocytomas harboring the BRAF V600E mutation are more frequent in infants and younger children, have a tendency for multicentricity, and are associated with a shortened progression-free and overall survival compared with BRAF wild-type tumors.

  * For high-grade astrocytomas, the median progression-free survival is 0.5 years and overall survival is 1 year. Tumor grade and extent of resection are significant prognostic factors for high-grade lesions arising outside the pons, whereas radiation and chemotherapy appear to provide minimal survival benefit regardless of tumor location.

  * Glioblastomas overall have slightly longer survival times in children than in adults, though the prognosis is grim in both age groups.

    * ◦ Patients with IDH1 mutant tumors have a significantly longer overall survival than those with H3.3 mutations or IDH1 wild-type tumors.

    * ◦ Patients with H3.3 G34 mutated tumors have a longer overall survival than those with K27M mutated tumors.

    * ◦ Objective clinical response to BRAF-targeted therapies has been reported in pediatric glioblastoma harboring BRAF V600E mutations.

  * Brainstem gliomas vary in their biologic potential.

    * ◦ Dorsally exophytic and some tectal gliomas are in fact pilocytic astrocytomas.

    * ◦ Though generally considered as indolent tumors with very slow growth, approximately 25 % of tectal gliomas may experience disease progression and require additional therapy.

    * ◦ DIPGs are universally fatal, though biologically distinct subgroups are being defined based on genetic signature, offering hope for more personalized, targeted treatments.

      * H3.3 K27M mutation is associated with a shorter overall survival, whereas H3.3 wild-type tumors have improved survival. H3.3 K27M mutated DIPGs likewise respond less well clinically to radiotherapy, relapse earlier, and exhibit more metastatic recurrences than those harboring H3.1 K27M mutations.

      * Occasional DIPG patients may benefit from anti-EGFR antibody treatment.

      * Age less than 3 years, longer symptom duration at diagnosis, and intravenous chemotherapy are favorable predictors of prolonged survival, whereas ring enhancement on MR imaging at diagnosis is an unfavorable sign.

      * (18)F-FDG uptake and contrast enhancement significantly correlate with reduced overall survival in newly diagnosed brainstem gliomas. Also, those tumors with more than 50 % of tumor with (18)F-FDG uptake tended to show decreased progression-free survival. In refractory or recurrent brainstem glioma, a poor correlation between (18)F-FDG uptake and contrast enhancement is also associated with decreased progression-free survi val. Lastly, MR hyperperfusion appears to correlate with shorter survival for DIPG patients.

  * Infiltrative astrocytomas of the spinal cord carry a variable prognosis depending on tumor grade. In all cases, complete surgical resection is difficult, as a distinct interface between normal tissue and tumor is typically absent. Radiation therapy often affords prolonged survival for grade II lesions (5-year overall survival up to 70 %), whereas patients with high-grade spinal astrocytomas succumb to their disease within months despite radiation or chemotherapy.

  * Pediatric infiltrative astrocytomas are generally more resistant to temozolomide than their adult counterparts, in part owing to higher expression of MGMT and less frequent methylation of the promoter region of that gene.

  * Few studies have shown a significant association between overexpression of p53 (Fig. 4.14C) and shortened progression-free survival in high-grade pediatric astrocytomas.

Suggested Reading

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_5

# 5. Oligodendroglial Tumors

Hope T. Richard1 and Christine E. Fuller2

(1)

Department of Pathology, Virginia Commonwealth University, 980662, 1101 E. Marshall Street, Richmond, VA 23298-0662, USA

(2)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

OligodendrogliomaAnaplastic oligodendrogliomaMixed oligoastrocytomaAnaplastic mixed oligoastrocytoma

## 5.1 Overview

  * Oligodendroglial tumors represent diffusely infiltrative gliomas composed of cells morphologically resembling oligodendroglia. This group includes oligodendroglioma (WHO grade II) and anaplastic oligodendroglioma (WHO grade III), as well as tumors bearing a mixture of cells with astr ocytic and oligodendroglial morphologies: mixed oligoastrocytoma (WHO grade II) and anaplastic mixed oligoastrocytoma (WHO grade III).

  * The vast majority are sporadic tumors; they only rarely present as radiation-induced gliomas or in the context of heritable family cancer syndromes similar to those listed for astrocytomas.

  * Overall, this group of tumors accounts for approximately 5 % of glial tumors, being far less common than astrocytomas in adults, and even rarer in children.

  * A recently described entity, disseminated oligodendroglioma-like leptomeningeal neoplasm (DOLN), can also be considered in this group of tumors. The WHO grade for this lesion is currently undetermined.

## 5.2 Clinical Features

  * Most oligodendroglial lesi ons occur in adults in their fourth decade of life; they are uncommon in children, accounting for less than 3 % of primary central nervous system (CNS) tumors in this age group. There is no significant gender predilection. Congenital examples are a novelty.

  * Given the tendency for these tumors to diffusely infiltrate the cerebral cortex, many patients present with seizures, regardless of age. Headache, focal neurologic deficits, and signs or symptoms related to increased intracranial pressure may also occur.

  * DOLN patients often present with symptoms of increased intracranial pressure and hydrocephalus.

## 5.3 Neuroimaging

  * Oligodendrogliomas and mixed oligoastrocytomas (MOAs) arise within the cerebral hemispheres, involving the cortex and subcortical white matter.

    * Frontal and temporal lobes are the most frequent sites of tumor origin, with parietal and occipital origination less common.

    * Multilobe involvement can occur, and rare cases showing bilateral hemispheric tumor or localization within the deep grey structures, posterior fossa, spinal cord, or leptomeninges have been reported. (The latter are now recognized as DOLN.)

  * CT scans typically show a well-demarcated hypodense to isodense lesion within the cerebral cortex and subcortical white matter (Fig. 5.1A).

Fig. 5.1

(A) CT scan showing a right frontal oligodendroglioma that is hypodense and involves cortical grey and subcortical white matter. (B) Axial T1-weighted MR image of a left frontal oligodendroglioma with gyral expansion. The tumor is rather ill-defined and variably hypointense to isointense. (C) The tumor is much better delineated on a T2-weighted image. (D) In this T2-weighted MR image from a child with oligodendroglioma of the left occipital lobe, the lesion is hyperintense. (E) The same lesion is also hyperintense on a FLAIR image. (F) The lesion is hypointense and without enhancement on this T1-weighted, postcontrast image. (B, C, Courtesy of Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA)

  * Calcifications are encountered much more frequently in oligodendroglial tumors than in infiltrating astrocytomas.

  * Oligodendroglial tumors are hypointense on T1 and hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR) MR images; again they are well demarcated, with generally minimal surrounding vasogenic edema (Fig. 5.1B–F).

  * Areas of cystic change, hemorrhage, or calcification may be seen on occasion.

  * Anaplastic (WHO grade III) lesions generally show some degree of contrast enhancement and have a more heterogeneous appearance on most image sequences, given their variable content of intratumoral hypercellularity, vascular proliferation, hemorrhage, and necrosis.

    * Ring enhancement akin to that typically seen in glioblastoma correlates with a particularly poor prognosis.

  * Imaging of disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN) typically reveals diffuse leptomeningeal enhancement with frequent cystic or nodular subpial T2-hyperintense lesions. A discrete intraparenchymal lesion may be identified in most cases, mainly within the spinal cord.

## 5.4 Pathology

  * Gross pathology

    * Tissue fro m oligodendroglial tumors is typically soft and grey-tan, sometimes with mucoid or hemorrhagic areas or flecks of calcification. Necrosis is limited to higher-grade tumors.

    * At autopsy , these lesions appear as well-defined soft, grey masses involving the cortex and underlying white matter. They tend to expand the involved gyri and cause blurring of the grey-white junction.

  * Intraoperative cytologic imprints and smears

    * Cytological squash/smear preparations of oligodendroglial tumors contain cells with small, round nuclei typically lacking fine fibrillary processes, and a fine capillary network (Fig 5.2A). Minigemistocytes may be present (Fig. 5.2B).

Fig. 5.2

(A) Hematoxylin and eosin (H&E)–stained cytologic smear preparation of oligodendroglioma showing a delicate capillary network and tumor cells with round, regular nuc lei without accompanying fibrillary cell processes. (B) Minigemistocytes, with their eccentric, rounded cytoplasmic bellies and stubby processes, are seen in occasional smears. (A, Courtesy of Dr. Arie Perry, University of California, San Francisco)

    * Mixed oligoastrocytomas (MOAs) additionally contain a neoplastic astrocytic component, identifiable as cells with oval to irregularly shaped nuclei and fibrillary cytoplasmic processes.

    * High-grade les ions are hypercellular with substantial nuclear atypia and proliferating vasculature, with or without necrosis.

  * Histology: The classification and grading of oligodendroglial tumors is less reproducible than that of astrocytic tumors, in part owing to definitional shifts in the accepted m orphologic spectrum of what is considered evidence of "oligodendroglioma" or an "oligodendroglial component."

    * Apart from the classic "fried egg" morphology (Fig. 5.3A), as described below, any of these oligodendroglial tumors may contain tumor cells resembling small gemistocytes with small round nuclei (termed microgemistocytes or minigemistocytes) (Fig. 5.3B) or cells with limited glial fibrillary acidic protein (GFAP)–positive process formation (gliofibrillary oligodendrocytes) (Fig. 5.3C).

Fig. 5.3

The classic appearance of oligodendroglioma is that of a tumor composed of cells with monotonously round nuclei with a surrounding perinuclear halo or clear zone ("fried e gg" appearance) and an intervening delicate capillary network (A). Other cell types that are seen in oligodendroglial tumors include minigemistocytes, with their small, eosinophilic cytoplasmic bellies (B), and gliofibrillary oligodendrocytes (C), with their glial fibrillary acidic protein (GFAP)–positive perinuclear rim. These should not be equated with astrocytic differentiation. (C, Courtesy of Dr. Arie Perry, University of California, San Francisco)

    * Oligodendroglioma (WHO grade II) can display a spectrum of histomorphologies.

    * A monomorphous population of infiltrative tumor cells with uniformly round nuclei and a surrounding perinuclear clearing "halo" (imparting a "fried egg" appearance) is classic. This helpful diagnostic feature is artefactual, secondary to delayed formalin fixation and unfortunately lacking in frozen section, smears, and rapidly fixed specimens (Figs. 5.3A and 5.4A).

Fig. 5.4

(A) Low-power view of grade II oligodendroglioma with characteristic "fried egg" cells, delicate capillar y network, and rare microcalcification. (B) Microcystic areas are often present in oligodendroglial tumors. Secondary structures, including perineuronal and perivascular satellitosis (C) and subpial accumulation of tumor cells (D), are quite common in oligodendroglial tumors, confirming their infiltrative properties

    * A fine network of branching capillaries resembling "chicken wire" may be present.

    * Microcalcifications and microcysts containing mucoid material are common findings (Fig. 5.4B).

    * Tumor cells have a tendency to accumulate in subpial zones and form secondary structures such as perineuronal and perivascular satellitosis, but this feature is not limited to oligodendroglial tumors; it may be seen in other highly infiltrative glial tumors, particularly high-grade astrocytomas and gliomatosis (Fig. 5.4C and D).

    * Occasional mitotic figures and scattered atypical nuclei are also still compatible with a WHO grade II designation.

    * Uncommon though notable findings in an otherwise typical oligodendroglioma include cells with granular, eosinophilic cytoplasm or signet-ring morphology; areas with neurocytic differentiation, including neuropil islands; and rhythmic, cellular palisading akin to a polar spongioblastomatous pattern.

  * Anaplastic oligodendroglioma (WHO grade III): In addition to the features noted above, anaplastic oligodendroglioma is notably hypercellular, with numerous mitotic figures, nuclear atypia, and microvascular proliferation (Fig. 5.5). Necrosis is sometimes present, often with pseudopalisading of surrounding tumor cells.

Fig. 5.5

In anaplastic oligodendroglioma (WHO grade III), perinuclear halos and delicate capillary network are often retained (A), though tumor nuclei are often more atypical and less uniformly rounded than in grade II lesions. Microcalcifications may also be present. Frequent mitotic figures (B) and vascular proliferation (C) are also often present in these high-grade tumors

    * Hypercellular nodules with nuclear atypia and increased proliferation index may be encountered in otherwise typical grade II oligodendroglioma. These areas may well represent early outgrowth of more malignant tumor clones, but a grade III designation should not be applied in the absence of other and more diffuse features of anaplasia. A note of this "focal anaplasia" in the pathology report will alert the treating clinician of the potential for near-term anaplastic progression and the need for close follow-up.

  * Mixed oligoastrocytoma (WHO grade II): These contain an admixture of two neoplastic cell types: oligodendroglial and astrocytic.

    * Biphasic (compact) and intermingled (diffuse) patterns occur. The compact pattern has separate, discrete areas of oligodendroglioma and astrocytoma, whereas the diffuse pattern has an admixture of cell types. In practice, the diffuse variant is far more frequently encountered (Fig. 5.6A–C).

Fig. 5.6

(A, B) Mixed oligoastrocytomas are composed of an admixture of cells with oligodendroglial features (round, regular nuclei with or without a perinuclear halo) and astrocytic features (oval to irregularly shaped hyperchromatic nuclei, sometimes with discernible fibrillary cytoplasm). Similar to oligodendrogliomas, delicate branched capillaries may be present, as seen in (A). (C) Minigemistocytes, with their eosinophilic, cytoplasmic "bellies," may represent the bulk of the oligodendroglial component, as in this mixed oligoastrocytoma (MOA), which additionally displays an unusual clustering of tumor cells. Note the larger astrocytic nuclei, best seen toward the center of the field. (D, E) Anaplastic MOAs are more hypercellular, with numerous mitotic figures. Though not illustrated here, vascular proliferation is often present

    * Neoplastic cells with features intermediate between those of classic oligodendroglioma and classic astrocytomas may be present.

  * Anaplastic mixed oligoastrocytoma (WHO grade III): Similar to anaplastic oligodendroglioma, grade III MOAs are hypercellular, have microvascular proliferation, and are more mitotically active, with a brisk Ki67 proliferation index (Fig. 5.6D and E).

    * The terms "grade IV MOA" or "GBM with oligodendroglial component" (preferred) may apply to cases with severe atypia, prominent angulated cellular component, and the additional finding of pseudopalisading necrosis.

  * Disseminated oligodendroglioma-like leptomeningeal neoplasm (DOLN): These tumors show typical cytomorphologic features of low-grade (WHO grade II) oligodendro glioma diffusely involving the leptomeninges. Desmoplasia or fibrosis is often prominent. Rare cases show ganglion or ganglioid cells or anaplastic features.

## 5.5 Immunohistochemistry

  * Unfortunately, no immunohistochemical marker has been found to reliably distinguish oligodendroglial from astrocytic tumors.

    * Similar to other neu roectodermally derived lesions, oligodendroglial tumors are positive for S100 protein.

    * Whereas GFAP decorates minigemistocytes, gliofibrillary oligodendrocytes (see Fig. 5.3C), and cells of the astrocytic component of MOAs, the "fried egg" cells are typically not stained (Fig. 5.7).

Fig. 5.7

The round nuclei and perinuclear halos of cells with a classic oligodendroglial morphology stand out as negative against the intermingled GFAP-positive background glial processes and intratumoral reactive astrocytes

    * Vimentin may be positive, and pancytokeratin may show focal false-positive staining due to cross-reactivity with glial intermediate filaments (similar to observations in astrocytic tumors). Oligodendroglial tumors are negative for epithelial membrane antigen (EMA).

    * These tumors are positive for MAP2, Olig1, and Olig2, though all of these may be expressed in other glial tumors.

  * Synaptophysin may be positive in neuropil overrun by tumor, but the tumor cells themselves are typically not positive (apart from a few rare cases showing focal neural differentiatio n, as noted above).

  * DOLN are typically strongly positive for S100 and OLIG2, and may show moderate positivity for GFAP and/or synaptophysin.

## 5.6 Electron Microscopy

  * Ultrastructural exami nation is often nonspecific, though concentric arrays of membranes (membrane lamination or whorls) may be encountered.

  * Minigemistocytes contain tight bundles of intermediate filaments in their cytoplasm.

  * Neural features have also been documented, including occasional synapselike structures and neurosecretory granules.

## 5.7 Molecular Pathology

  * Unbalanced translocation of chromosomes 1 and 19 resulting in the characteristic codeletion of 1p and 19q is a frequent finding in oligodendrogliom as, anaplastic oligodendrogliomas, and a smaller subpopulation of MOAs in adults. In pediatric oligodendroglial tumors, this is an uncommon molecular finding, limited mainly to oligodendrogliomas arising in children >10 years old. The same can be said for mutations of IDH1 (R132H), which nearly always are present concomitant with codeletion of 1p/19q.

  * Deletion of p16, an alteration also shared with adult oligodendroglial tumors, is similarly more frequent in oligodendrogliomas arising in older children, as is overexpression of p53 by immunohistochemistry or deletion involving phosphatase and tensin homolog (PTEN). Rare epidermal growth factor receptor (EGFR) amplifications may be encountered in high-grade examples.

  * BRAF-KIAA1549 fusion has also been demonstrated by one group.

  * Isolated 1p deletions with concurrent BRAF-KIAA1549 gene fusion, as well as occasional codeletion 1p/19q, have been demonstrated in DOLN. IDH1 R132H mutant-specific immunohistochemistry has been consistently reported as negative by several independent groups.

## 5.8 Differential Diagnosis

  * Pediatric oligodendroglial tumors are diagnostically more problematic than their adult counterparts because a number of histologically similar tumors are common in t his age group.

  * Differentiation from infiltrative astrocytomas requires careful histologic inspection for classic oligodendroglial morphologies, including minigemistocytes and gliofibrillary oligodendrocytes.

  * Clear cell ependymoma may closely mimic oligodendroglial tumors, though the former will typically demonstrate (at least focally) identifiable perivascular pseudorosettes, and should have a dot-like positivity for EMA. Ultrastructural features of ependymoma can also be confirmed, if necessary.

  * Pilocytic astrocytomas may have areas resembling oligodendroglioma, but should also contain more classic features including biphasic architecture, Rosenthal fibers, and eosinophilic granular bodies.

  * Dysembryoplastic neuroepithelial tumor (DNT) typically contains oligodendroglioma-like cells and may even have areas of classic oligodendroglioma in the context of a "complex DNT," but it should also contain the characteristic "patterned mucin-rich nodules" and specific glioneuronal units with "floating neurons" within pools of mucin, all features that are lacking in oligodendrogliomas. Radiographic features are likewise not overlapping, as described elsewhere.

  * Neurocytoma, be it central or otherwise, may simulate an oligodendroglial tumor by virtue of round, regular nuclei. The diagnosis of neurocytoma is confirmed via identification of diffuse cellular staining for neuronal markers, particularly synaptophysin, or by ultrastructural means—not simply by focal positivity, which may be encountered in oligodendroglial tumor with focal neurocytic differentiation.

  * Lastly, clear cell meningioma may enter the differential diagnosis; this dura-based tumor should be GFAP negative and EMA and/or claudin-1 positive (generally diffuse), with PAS-positive glycogen-rich cytoplasm, and often contains areas of more easily identifiable meningioma morphology. Ultrastructural review will likewise disclose interdigitating cell membranes and junctions.

## 5.9 Prognosis

  * In general, pediatric oligodendroglial tumors tend to be slower growing and afford prolonge d survival relative to their grade-matched astrocytoma counterparts. Time to recurrence and malignant progression are likewise prolonged in comparison.

    * Gross total resection has been found to correlate with significantly improved progression-free survival (PFS) in several studies, whereas higher tumor grade and mixed oligoastrocytoma histology tend to correspond to shortened overall survival (OS).

    * The presence of p53 overexpression as detected by immunohistochemistry and PTEN deletion both have been found significantly associated with shorter OS in pediatric patients.

    * Codeletion of 1p/19q in pediatric oligodendroglial tumors, unlike similar alterations in their adult counterparts, does not appear to afford a more favorable outcome.

  * Nevertheless, a 5-year PFS rate of 81 % and OS rate of 84 % have been reported. Deep or central tumors are an exception, with far worse survival (median less than 2 years) than their cere bral-centered counterparts.

  * DOLNs have a variable clinical course, with most of the tumors having an indolent course despite the often extensive tumor burden. A subset of these tumors will undergo anaplastic progression and behave aggressively.

Suggested Reading

Creach KM, Rubin JB, Leonard JR, Limbrick DD, Smyth MD, Dacey R, et al. Oligodendrogliomas in children. J Neurooncol. 2012;106:377–82.CrossRefPubMed

Fallon KB, Palmer CA, Roth KA, Nabors B, Wang W, Carpenter M, et al. Prognostic value of 1p, 19q, 9p, 10q, and EGFR-FISH analyses in recurrent oligodendrogliomas. J Neuropathol Exp Neurol. 2004;63:314–22.CrossRefPubMed

Fuller C, Dalton J, Baker S, Gajjar A, Kun L, Broniscer A. Molecular characterization of pediatric gliomas. Brain Pathol. 2006;16:S84.

Inagawa H, Ishizawa K, Hirose T. Qualitative and quantitative analysis of cytologic assessment of astrocytoma, oligodendroglioma and oligoastrocytoma. Acta Cytol. 2007;51:900–6.CrossRefPubMed

Kreiger PA, Okada Y, Simon S, Rorke LB, Louis DN, Golden JA. Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas. Acta Neuropathol (Berl). 2005;109:387–92.CrossRef

Kumar A, Pathak P, Purkait S, Faruq M, Jha P, Mallick S, et al. Oncogenic KIAA1549-BRAF fusion with activation of the MAPK/ERK pathway in pediatric oligodendrogliomas. Cancer Genet. 2015;208:91–5.CrossRefPubMed

Liberski PP. The ultrastructure of oligodendroglioma: personal experience and the review of the literature. Folia Neuropathol. 1996;34:206–11.PubMed

Mitsuhashi T, Shimizu Y, Ban X, Ogawa F, Matsutani M, Shimizu M, et al. Anaplastic oligodendroglioma: a case report with characteristic cytologic features, including minigemistocytes. Acta Cytol. 2007;51:657–60.CrossRefPubMed

Peters O, Gnekow A, Rating D, Wolff JE. Impact of location on outcome in children with low-grade oligodendroglioma. Pediatr Blood Cancer. 2004;43:250–6.CrossRefPubMed

Pollack IF, Finkelstein SD, Burnham J, Hamilton RL, Yates AJ, Holmes EJ, et al. Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort. Pediatr Neurosurg. 2003;39:114–21.CrossRefPubMed

Preuss M, Christiansen H, Merkenschlager A, Hirsch FW, Kiess W, Muller W, et al. Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity corrected]. J Neurooncol. 2015;124:65–74.[CrossRefPubMed

Raghavan R, Balani J, Perry A, Margraf L, Vono MB, Cai DX, et al. Pediatric oligodendrogliomas: a study of molecular alterations on 1p and 19q using fluorescence in situ hybridization. J Neuropathol Exp Neurol. 2003;62:530–7.CrossRefPubMed

Razack N, Baumgartner J, Bruner J. Pediatric oligodendrogliomas. Pediatr Neurosurg. 1998;28:121–9.CrossRefPubMed

Rodriguez FJ, Perry A, Rosenblum MK, Krawitz S, Cohen KJ, Lin D, et al. Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol. 2012;124:624–41.CrossRef

Rodriguez FJ, Tihan T, Lin D, McDonald W, Nigro J, Feuerstein B, et al. Clinicopathologic features of pediatric oligodendrogliomas: a series of 50 patients. Am J Surg Pathol. 2014;38:1058–70.PubMedPubMedCentral

Rodriguez FJ, Schniederjan MJ, Nicolaides T, Tihan T, Burger PC, Perry A. High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol. 2015;129:609–10.CrossRefPubMedPubMedCentral

Schniederjan MJ, Alghamdi S, Castellano-Sanchez A, Mazewski C, Brahma B, Brat DJ, et al. Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry. Am J Surg Pathol. 2013;37:763–71.CrossRefPubMed

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_6

# 6. Ependymal Tumors

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

SubependymomaEpendymomaMyxopapillary ependymomaClear cell ependymomaPapillary ependymomaAnaplastic ependymoma

## 6.1 Overview

  * The group of glial tumors exhibiting ependymal differentiation include subependymoma (WHO grade I); myxopapillary ependymoma (WHO grade I); ependymom a (WHO grade II), with variants including cellular, tanycytic, papillary, and clear cell; and anaplastic ependymoma (WHO grade III).

  * Most are sporadic; ependymomas may be seen as part of neurofibromatosis type 2, a hereditary cancer predisposition syndrome with germline mutation of the NF2/Merlin gene.

  * Recent evidence supports radial glia as the candidate cell of origin for ependymomas; subependymomas appear to derive from subependymal glial precursors.

## 6.2 Clinical Features

  * Though much less common overall than infiltrative gliomas, ependymomas are the most common tumor of the spinal cord (particularly in adult patients) and the third most common pedia tric central nervous system (CNS) tumor, representing up to 30 % of intracranial tumors in those under 3 years old.

  * Infratentorial tumors have their peak age of occurrence in the first decade, while spinal tumors tend to peak in those 30–40 years of age.

  * They have an equal gender distribution, but are nearly twice as frequent in Caucasians as in African-Americans.

  * Intracranial ependymomas typically result in blockage of cerebrospinal fluid (CSF) pathways, causing signs and symptoms related to hydrocephalus and increased intracranial pressure.

  * Anaplastic ependymomas are far more frequent in the pediatric age group, presenting as intracranial tumors, more frequently supratentorial.

    * ◦ Clinical signs and symptoms are similar to those for WHO grade II ependymoma, but they tend to develop in an accelerated fashion.

  * Spinal ependymomas, including myxopapillary ependymoma, may cause back pain and motor and/or sensory deficits, depending on their specific anatomic involvement.

  * Approximately 20 % of myxopapillary ependymomas present in children with a 2:1 male-to-female bias. In this age group, these tumors have a higher rate of occurrence within the extramedullary soft tissue of the sacrococcygeal region, as well as a higher rate of recurrence and dissemination through the CSF pathways.

  * Subependymomas are often incidental autopsy findings in the brains of older adults; they are symptomatic when they obstruct CSF flow.

    * ◦ They are quite rare in children; when present, they tend to be mixed tumors (with elements of other ependymoma subtypes), involve the infratentorial region, and exhibit shorter progression-free survival than subependymomas arising in older individuals.

## 6.3 Neuroimaging

  * Ninety percent of pediatric ependymomas are intracranial, favoring the fourth ventricle, followed by supratentorial locations.

  * Supratentorial tumors (including ependymomas and subependymomas) involve the lateral ventricles more often than the third ventricle.

  * Uncommonly, they arise remote from the ventricles, especially in intraparenchymal supratentorial locations in children. Superficial cortical ependymomas have been encountered; these are more frequently anaplastic ependymomas.

  * Rare extraneural sites include the ovaries, mediastinum, and sacrococcygeal locations.

  * Ependymomas may arise at any spinal cord level, though certain histologic subtypes have preferred locations:

    * ◦ Tanycytic ependymoma: thoracic or cervicothoracic cord

    * ◦ Myxopapillary ependymomas: conus medullaris, filum terminale, and cauda equina region

    * ◦ Subependymoma: cervical cord

  * Myxopapillary ependymomas are the most common intramedullary neoplasms arising in the region of the conus medullaris, cauda equina, and filum terminale; less frequent sites of origin include other cord levels, intracranial sites (both intraventricular and intraparenchymal), and subcutaneous sacrococcygeal areas.

  * MRI/CT imaging findings:

    * Ependymomas and anaplastic ependymomas

      * Spinal lesions typically involve multiple segments and grow as centrally situated intramedullary tumors that are hyperintense on T2-weighted MR images, with sharp tumor margins; most show uniform contrast enhancement (Fig. 6.1A).

Fig. 6.1

(A) Sagittal TI-weighted post-Gd image of a well-demarcated spinal ependymoma with characteristic homogeneous postcontrast enhancement. (B) Axial MR images of a fourth ventricular ependymoma show a predominantly solid, well-demarcated tumor that has heterogeneous signal characteristics, being isointense to hyperintense on T2-weighted imaging. (C) The same tumor is hyperintense on FLAIR. (D, E) Sagittal and axial T1-weighted post-Gd imaging shows this same lesion to be isointense, with variable contrast enhancement. Hydrocephalus is prominent in this example. (A, Courtesy of Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA)

      * Rostral and/or caudal cysts are common, being hypointense on T1- and hyperintense on T2-weighted images.

      * Intracranial tumors are also sharply demarcated, arising within or near the ventricular system. They are at least partially cystic, isointense on T1, isointense to hyperintense on T2, and moderately hyperintense on fluid-attenuated inversion recovery (FLAIR) MR imaging, with variable postcontrast enhancement (Fig. 6.1B–E).

        * Intratumoral hemorrhage and/or calcifications may be seen.

        * Ventricular dilatation is frequently encountered.

        * Occasional tumors show infiltration of surrounding parenchyma, making differentiation from other gliomas difficult.

    * Myxopapillary ependymomas

      * These tumors are characteristically well-circumscribed, hyperintense on both T1- and T2-weighted MR imaging (Fig. 6.2A and B) (unlike conventional ependymomas, which are typically hypointense on T1), and brightly enhanced with contrast.

Fig. 6.2

(A, B) Myxopapillary ependymoma. Sagittal T1-weighted and T2-weighted images both show a hyp erintense lesion. (C) Subependymoma. These lesions tend to be nodular, circumscribed, and intraventricular; this example is isointense on coronal T1-weighted MR imaging

      * Cystic change (particularly in intracranial examples) or hemorrhage may be encountered.

    * Subependymomas

      * These are sharply demarcated, nodular lesions bulging into ventricles or arising eccentrically within the spinal cord.

      * They show variable signal characteristics on MR and CT imaging.

      * They uncommonly enhance, and may contain foci of calcium or hemorrhage (Fig. 6.2C).

  * Patterns of metastasis:

    * ◦ Ependymomas (grades II and III) and myxopapillary ependymomas (grade I) have been r eported to metastasize via subarachnoid spread to seed other spinal and intracranial locations. Metastases to sites outside the CNS have been reported in few instances.

## 6.4 Pathology

  * Gross pathology

    * ◦ Classic ependymomas are soft tan to grey masses with well-defined borders. They ma y be partially cystic and/or contain areas of hemorrhage, necrosis, or calcification.

    * ◦ Anaplastic examples may show evidence of frank parenchymal invasion.

    * ◦ Myxopapillary ependymomas are lobulated, soft, grey to tan, and often encapsulated.

    * ◦ Subependymomas are firm, multilobated or nodular intraventricular masses; spinal examples nearly always show an eccentric location.

  * Intraoperative cytologic imprints or smears

    * ◦ Smear preparations of ependymomas contain cohesive clusters of cells with variable cytomor phology, ranging from epithelial-like to bipolar cells with fibrillary processes.

    * ◦ Nuclei tend to be round to oval and bland.

    * ◦ Perivascular pseudorosettes may be seen (Fig. 6.3A and B).

Fig. 6.3

(A, B) Cytologic preparations of ependymoma often show three-dimensional clusters of cells with elongated, fibrillar glial processes; perivascular pseudorosettes m ay or may not be obvious. (C) Squash preparations of myxopapillary ependymoma are notable for papillary structures with perivascular, radially arranged cell processes and abundant myxoid material

    * ◦ Cytology preparations from the following subtypes may be particularly problematic:

      * Tanycytic: These contain long processes and oval to spindle-shaped nuclei; perivascular pseudorosettes are uncommon, and the smear preparation findings may closely resemble pilocytic astrocytoma.

      * Papillary: These often have a more epithelial consistency and may closely mimic choroid plexus tumors or metastatic carcinomas.

    * ◦ Myxopapillary ependymoma can appear as papillary structures with perivascular, radially arranged cells with delicate glial processes within abundant myxoid material (Fig. 6.3C).

    * ◦ Subependymomas present bland nuclei in a fibrillary background, sometimes with discernable microcysts.

  * ◦ Histology

    * ◦ Ependymoma (WHO grade II)

      * Ependymomas classically present as well-demarcated, moderately cellular tumors with bland round to oval nuclei and a fine chromatin pattern (Fig. 6.4A).

Fig. 6.4

(A) Conventional ependymomas exhibit a solid growth pattern with circumscriptio n from surrounding parenchyma. (B) Perivascular pseudorosettes are a nearly universal finding. (C) The pseudorosettes may be inconspicuous in hypocellular areas. (D) Ependymal canals and true rosettes are seen less frequently. (E) Identifying ependymal-type lining at the periphery of individual biopsy or resection tissue fragments is a helpful and not-infrequent diagnostic finding indicative of ependymal neoplasm; it may be encountered even in the absence of canals or ependymal rosettes elsewhere in the sample. (F) Rarely, epithelial-type differentiation may predominate, as in this "tubular adenoma-like" pattern. (G) Epithelial-type differentiation also predominates in this example of an organoid growth pattern, which also shows focal calcification. (H) Signet ring–like cells are an uncommon finding

      * Several key architectural features may be seen:

        * Perivascular pseudorosettes (anuclear zones formed by the elongated glial-like processes of tumor cells in their radial arrangement around blood vessels) are seen in most cases (Fig. 6.4B), but they may be poorly formed in hypocellular areas (Fig. 6.4C).

        * True ependymal rosettes and canals (cuboidal to columnar epithelial-like tumor cells surrounding a true central lumen) are seen in a minority of cases (Fig. 6.4D).

        * Conversel y, ependymal-type lining seen at the periphery of tissue fragments from an ependymoma sampling is not uncommon, and is a helpful diagnostic aid (Fig. 6.4E).

        * On occasion, epithelial-type elements predominate, imparting a "tubular adenoma-like" appearance (Fig. 6.4F) or an organoid appearance (Fig. 6.4G).

      * Mitotic figures are uncommon; foci of necrosis may be present, though pseudopalisading necrosis and endothelial proliferation are absent.

        * Degenerative changes are common and include myxoid degeneration, vascular hyalinization, hemorrhage, and calcification (Fig. 6.4G).

      * Cartilage, bone, lipomatous elements, neuropil-like islands, and cells with melanin, signet-ring appearance (Fig. 6.4H) or giant cell morphology, or eosinophilic intracytoplasmic inclusions have all been described.

      * Well-characterized histopathologic variants of ependymoma include the following:

        * Cellular ependymomas: Variant with notable hypercellularity yet lacking an elevated mitotic rate, vascular proliferation, or pseudopalisading necrosis. Perivascular pseudorosettes may be inconspicuous, and true rosettes and canals are generally lacking (Fig. 6.5A).

Fig. 6.5

(A) Cellular ependym omas are quite hypercellular, though they lack other histologic features of anaplastic ependymomas, including vascular proliferation and increased mitoses. (B) The fascicular architecture of the tanycytic ependymoma renders perivascular pseudorosettes inconspicuous. (C) Striking nuclear pleomorphism may be encountered in some cases of tanycytic ependymoma. (D) Papillary ependymomas exhibit one or more layers of bland neoplastic ependymal cells resting upon papillary fingerlike projections of fibrillary glial processes with central blood vessels. (E) Perivascular pseudorosettes are a helpful feature in differentiating clear cell ependymoma from other lesions with clear cell morphology. (F) Many clear cell ependymomas display high-grade features including vascular proliferation

        * Tanycytic ependymoma: Typified by elongated, often thin, eosinophilic cell processes and inconspicuous perivascular pseudorosettes within an otherwise fascicular architecture; true ependymal rosettes are not seen. Nuclear pleomorphism may be prominent in some cases, mimicking the "ancient change" one can encounter in nerve sheath tumors (Fig. 6.5B and C).

        * Papillary ependymomas: Rare subtype in which single or multiple layers of cuboidal to columnar cells rest upon central fingerlike projections of fibrillary glial "stroma." Fibrovascular cores are not a feature, and the epithelial-like surfaces tend to be smooth in contour (Fig. 6.5D).

        * Clear cell ependymomas: These contain sheets of cells with rounded nuclei and abundant surrounding clear cytoplasm; perivascular pseudorosettes are invariably present, though true rosettes are absent. Branching thin-walled vessels may be present, and many cases show anaplastic features (including vascular proliferation, hypercellularity, and frequent mitoses), warranting a grade III designation (Fig. 6.5E and F).

        * Both clear cell and papillary areas may be intermixed components with otherwise typical, cellular, or anaplastic ependymoma.

    * ◦ Myxopapillary ependymoma (WHO grade I)

      * Characteristically shows a papillary architecture with cuboidal to elongated glial cells radi ally arranged around Alcian blue–positive myxoid stroma with central vascular structure. Occasional examples harbor more epithelioid-appearing cells (Fig. 6.6A–C).

Fig. 6.6

Myxopapillary ependymomas, similar to other ependymal tumors, contain ependymal cel ls with variable epithelial (A) to glial morphology with elongated eosinophilic processes (B, C), but in this context, the perivascular pseudorosettes take the form of myxoid stroma-rich papillary structures. This papillary architecture may be inconspicuous in some cases, replaced instead by a more solid (C), reticular (D), or microcystic (E) pattern, again with characteristic myxoid material and scattered perivascular pseudorosettes. Collagen "balloons" (F, arrow) and tumoral (G) or vascular (H) hyalinization may be encountered

      * Some lesions are not particularly papillary at all, instead taking on a reticular or microcystic pattern with intermixed mucin-rich microcysts and occasional perivascular pseudorosettes (Fig. 6.6D and E).

      * Collagen balls or "balloons" may be seen in some cases (Fig. 6.6F); these may be highlighted by trichrome or periodic acid–Schiff (PAS) stains.

      * The mitotic rate is low, and necrosis and vascular proliferation are usually absent.

      * Degenerative changes, including vascular hyalinization or fibrosis, are occasionally prominent (Fig. 6.6G and H).

      * Rare anaplastic and giant cell variants have been described.

    * ◦ Subependymoma (WHO grade I)

      * Often having a nodular appearance at low power (Fig. 6.7A), subependymomas are composed of hypocellular collections of monotonously bland cells with round to oval nuclei set within a delicate glial matrix. The cells tend to cluster, and microcysts are commonly present (Fig. 6.7B–D).

Fig. 6.7

(A) Subependymomas tend to be nodular on low-power microscopy and may show calcification . (B) These hypocellular lesions contain abundant glial matrix interspersed with monotonously bland cells with rounded to oval nuclei. (C) The tumor cells tend to cluster. (D) Microcysts are not infrequent

      * Perivascular pseudorosettes are quite uncommon, and true rosettes are not encountered.

      * Hemorrhage and/or hemosiderin-laden macrophages, calcification (see Fig. 6.7A), sclerotic vessels, and focal nuclear pleomorphism have all been described.

      * About 20 % of subependymomas harbor areas of classic or even anaplastic ependymoma; in these instances, the lesions should be graded according to the highest-grade component.

    * ◦ Anaplastic ependymoma (WHO grade III)

      * Grading of ependymomas has historically been a contentious issue. Studies aimed at identifying histopathologic parameters that can distinguish different prognostic groups of ependymomas found that ependymomas harboring two or more of the following features were strongly correlated with shortened event-free survival and were indicative of a WHO grade III designation:

        * Elevated or brisk mitotic index (>5 per 10 high-power fields, seen throughout the tumor, not just focally) (Fig. 6.8A)

Fig. 6.8

Anaplastic ependymo mas are notably hypercellular, with elevated mitotic activity (A) with moderate (B) to significant (C) nuclear pleomorphism. Extensive necrosis is common, often showing surrounding pseudopalisading of tumor cells (D). Vascular proliferation often residing within perivascular pseudorosettes (E) is another typical feature. Discrete foci of "focal anaplasia" (F), replete with any or all of the features noted above, may be encountered in otherwise lower-grade ependymoma variants; their significance is yet unclear

        * Hypercellularity with nuclear hyperchromasia and/or pleomorphism with marked atypia (Fig. 6.8B and C)

        * Vascular proliferation

        * Pseudopalisading necrosis (Fig. 6.8D).

      * They retain many features of conventional ependymoma, including perivascular pseudorosettes, which may contain normal vessels or proliferating vasculature (Fig. 6.8E).

      * Unfortunately, there is a subset of ependymomas containing only small areas of "focal anaplasia," the significance of which is unclear; they may suggest a more aggressive biologic potential than that of WHO grade II ependymoma (Fig. 6.8F). Such findings should be mentioned in the pathology report, to alert the treating clinicians of this possibility.

## 6.5 Immunohistochemistry

  * Ependymomas and anaplastic ependymomas are positive for S100, glial fibrillary acidic protein (GFAP) (Fig. 6.9A), and vimentin. Epithelial membrane antigen (EMA) staining often shows a characteristic punctate, dot-like positivity (Fig. 6.9B); ring-like EMA staining is less frequently encountered but more specific. CD99 is often positive, with varying membranous or dot-like staining. Stains for neural markers are generally negative except for NeuN, which may show nuclear positivity in some anaplastic ependymomas.

Fig. 6.9

Immun ohistochemical stain for glial fibrillary acidic protein (GFAP) (A) highlights the elongated, fine perivascular processes in ependymomas. EMA staining (B) tends to present in a punctate, dot-like pattern. Subependymomas are similarly diffusely positive for GFAP (C). Ki67 labeling is markedly elevated within this focus of focal anaplasia (D)

  * Myxopapillary ependymomas are positive for GFAP, S100, vimentin, and CD99. Occasional examples are immunopositive for p53. They are negative for cytokeratin and have a low Ki67 labeling index. Unlike other ependymomas, these are generally EMA negative.

  * Subependymomas are positive for GFAP (Fig. 6.9C) and S100; they are also often weakly positive for low-specificity neuronal markers such as neural cell adhesion molecule (NCAM) and neuron-specific enolase (NSE). The Ki67 labeling index is lower than for all other types of ependymoma.

  * Mib-1/Ki67 may be helpful in confirming brisk proliferation in areas of anaplasia, including examples of fo cal anaplasia (Fig. 6.9D).

## 6.6 Electron Microscopy

  * Ependymomas and anaplastic ependymomas, including all of the variants listed above, share similar u ltrastructural characteristics of ependymal differentiation, including intracellular intermediate filaments, intercellular junctional complexes (including desmosomes), occasional cilia, and microvilli, which are present both on the cell surface and within microlumina (Fig. 6.10).

Fig. 6.10

Junctional complexes and microlumina bearing numerous microvilli are ultrastructural features indicative of ependymal differentiation

  * Myxopapillary ependymomas exhibit interdigitating cell processes and microtubular aggregates bound by rough endoplasmic reticulum, as well as the features typical for ependymal differentiation (intermediate filaments, microvilli, cilia).

  * Subependymomas show ultrastructural features typically associated with ependymal differentiation, including intermediate filaments, lumen-like structures, microvilli, and cilia.

## 6.7 Molecular Pathology

  * Transcriptional profil ing by a number of independent groups has delineated two clinically and molecularly distinct subgroups of posterior fossa ependymomas:

    * ◦ Group A (Group 1) tumors occur in younger patients, with lateral location, balanced genome with increased occurrence of chromosome 1q gain, and with more biologically aggressive behavior (shortened progression-free survival [PFS] and overall survival [OS]). Laminin alpha-2 (LAMA2) detection by immunohistochemistry may serve as a marker for this group of tumors.

    * ◦ Group B (Group 2) tumors occur in older patients, with midline location, and numerous cytogenetic abnormalities involving whole chromosomes or chromosomal arms, with frequent chromosome 6q and 22q loss and 9p, 15q, and 18q gain. Detection of neural epidermal growth factor like-2 (NELL2) by immunohistochemistry may serve as a marker for these tumors.

    * A prognostic 10-gene expression signature has been proposed by one group, correlating well with the separation of group A and group B posterior fossa ependymomas.

  * Supratentorial ependymomas

    * ◦ Show significant overexpression of neuronal markers in comparison to their infratentorial counterparts; in particular, neurofilament light polypeptide (NEFL) appears overexpressed in supratentorial tumors.

    * ◦ Nestin and vascular endothelial growth factor (VEGF) are both expressed more frequently in supratentorial ependymomas, and are associated with a poor PFS.

    * ◦ In one study, more than two thirds of supratentorial ependymomas were found to contain oncogenic fusions between RELA (involved in canonical NF-kB signaling) and C11orf95 (a currently uncharacterized gene).

  * Array-based comparative genomic hybridization (CGH) analysis has demonstrated a significant increase in genomic imbalances in relapsed ependymomas, particularly gains of 9qter and 1q; gain of 9qter has been associated with tumor recurrence, age greater than 3 years, and posterior fossa location.

  * Alterations of the Wnt/beta-catenin signaling pathway appear to play a significant role in anaplastic ependymoma tumorigenesis.

  * Activation of tenascin C and the Notch pathway have also been implicated to play a role in ependymoma progression, and both may also represent potential targets for therapy.

  * Myxopapillary ependymom as exhibit a unique gene expression pattern with upregulation of homeobox B13 (HOXB13), neurofilament light polypeptide (NEFL), and PDGFRα.

## 6.8 Differential Diagnosis

  * Ependymomas in general may be differentiated from infiltrative gliomas by virtue of their soli d growth pattern, lacking significant intratumoral neurofilament-positive processes.

  * Highly cellular anaplastic ependymomas may resemble ependymoblastomas and other primitive neuroectodermal tumors (PNETs), though anaplastic ependymoma are more diffusely positive for GFAP and lack ependymoblastic rosettes and neuronal-type markers by immunohistochemistry.

  * Ependymomas, especially the tanycytic variant, may closely resemble astrocytoma (particularly pilocytic astrocytoma), schwannoma, or meningioma. Ependymomas in general lack Rosenthal fibers and eosinophilic granular bodies of pilocytic astrocytomas, and are positive for GFAP, unlike schwannomas and meningiomas. In rare cases, however, definitive diagnosis may rely heavily on ultrastructural findings of ependymal differentiation.

  * Clear cell ependymoma must be differentiated from other primary CNS lesions containing clear cells (oligodendroglioma, neurocytoma, and hemangioblastoma) and metastatic clear cell carcinomas. Identification of perivascular pseudorosettes is the first clue to the diagnosis of clear cell ependymoma; immunohistochemistry (especially dotlike positivity for EMA), electron microscopy features of ependymal differentiation, and molecular findings (lack of 1p/19q deletion) help confirm the diagnosis.

  * Papillary ependymoma may be confused with choroid plexus tumors, papillary meningiomas, or metastatic carcinomas. Strong positivity for GFAP and lack of diffuse cytokeratin staining are characteristic of papillary ependymoma, and electron microscopy confirmation is usually not necessary.

  * Myxopapillary ependymoma may be differentiated from potential diagnostic mimics such as chordoma, renal cell carcinoma, myxoid chondrosarcoma and other myxoid soft tissue lesions, and paraganglioma by virtue of its immunohistochemical pattern (positive for vimentin, S100, and GFAP; cytokeratin negative) and characteristic ultrastructural finding of microtubular aggregates.

  * Subependymomas may mimic other hypocellular glial tumors, including low-grade astrocytoma or pilocytic astrocytoma. Identification of a lobular architecture, cell clustering , microcysts, and lack of Rosenthal fibers or eosinophilic granular bodies is helpful is separating subependymoma from these potential diagnostic pitfalls.

## 6.9 Prognosis

  * In general, children with ependymomas tend to fare far worse than their adult counterparts, partly becau se of a much higher incidence of intracranial or posterior fossa location and higher-grade tumors arising in the pediatric age group.

    * ◦ Those affected during the first few years of life have particularly poor outcomes, especially because related morbidities make it difficult to administer radiotherapy to these immature brains.

    * ◦ Neoadjuvant chemotherapy for ependymomas in infants has been found to be effective in reducing tumor vascularity and facilitating maximal tumor resection.

  * Extent of tumor excision has consistently been shown as a key variable predictive of outcome.

    * ◦ In most instances, the first recurrence is at the site of the tumor resection bed, and recent evidence indicates that demonstration of tumor microinvasion on the original resection specimen correlates with poor PFS and OS.

  * Though most studies have found histologic grading (grade II vs grade III) to be significantly predictive of OS and recurrence-free survival, a few observers have shown otherwise.

    * ◦ Specific diagnostic criteria for grade III designation have been proposed as outlined above, providing excellent prognostic correlation in those studies. Elevated Ki67 proliferation index correlates well with grade III status and with more aggressive biologic behavior.

  * As noted above, pediatric posterior fossa ependymomas can be molecularly classified into two distinct subgroups:

    * ◦ Group A tumors are more biologically aggressive and harbor frequent gain of chromosome 1q. LAMA2 is detected by immunohistochemistry.

    * ◦ Group B tumors are more biologically indolent and harbor frequent chromosome 6q and 22q loss and 9p, 15q, and 18q gain. NELL2 is detected by immunohistochemistry.

    * ◦ Interestingly, the subgroup designation may change at tumor recurrence. Changing from group A to group B at recurrence does not appear to provide survival benefit, whereas switching from group B to group A at recurrence corresponds with poor prognosis.

  * In addition, a number of other potential biologic predictors of outcome have been proposed in independent studies:

    * ◦ Low nucleolin expression is associated with prolonged PFS.

    * ◦ Gain of chromosome 1q and homozygous deletion of CDKN2A (p16) is associated with shortened PFS and OS; gains of chromosomes 9, 15q, and 18 or loss on chromosome 6 may be associated with better prognosis.

    * ◦ Strong expression of NEFL in supratentorial ependymomas has been correlated with better PFS.

    * ◦ Overexpression of transcription factor EVI1 has been correlated with shorter PFS and OS in infratentorial ependymomas.

    * ◦ Human telomerase reve rse transcriptase (hTERT) mRNA overexpression has been correlated with shorter OS.

    * ◦ Children with telomerase-active ependymomas have poorer PFS and OS; telomerase inhibition may represent an actionable target in these tumors.

    * ◦ EZH2 (enhancer of zeste homolog 2) represents a marker of poor prognosis in pediatric intracranial ependymomas, particularly those arising in the posterior fossa.

    * ◦ Overexpression of kinetochore proteins (ASPM, KIF11) and downregulation of metallothioneins (MT3) have been found to be associated with ependymoma recurrence; the latter are a potential target of histone deacetylase inhibitors.

  * Clear cell ependymomas appear to constitute a more aggressive phenotype, often representing grade III tumors.

    * ◦ Local recurrence is quite common, and these tumors may infrequently show transdural invasion into venous sinuses or extracranial metastasis into soft tissue and lymph nodes.

  * Myxopapillary ependymomas are generally slow-growing tumors with a 10-year OS rate approximating 95 %.

    * ◦ Despite their WHO grade I designation, up to 45 % of patients may experience local recurrence, regardless of adequate excision. Patients who succumb to their disease typically do so following a protracted course with multiple recurrences.

    * ◦ Tumor encapsulation (enabling gross excision) portends a lower rate of recurrence, compared with tumors removed piecemeal or subtotally.

    * ◦ Adjuvant radiation therapy has been shown to aid in reducing the recurrence rate.

    * ◦ Neuraxis metastasis is more frequent in pediatric patients, thus emphasizing the importance of complete neuraxis screening both at the time of diagnosis and during long-term follow-up.

    * ◦ One report suggests that epidermal growth factor receptor (EGFR) expression may be a predictive marker of recurrence.

  * Subependymomas are typically viewed as benign neoplasms that grow slowly, with a significant proportion remaining clinically silent throughout life and being detected only incidentally at autopsy. When they arise in children, however, they are more commonly mixed l esions (with subependymoma and ependymoma components) that exhibit biologic behavior akin to the higher-grade component.

Suggested Reading

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Barszczyk M, Buczkowicz P, Castelo-Branco P, Mack SC, Ramaswamy V, Mangerel J, et al. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Acta Neuropathol. 2014;128:863–77.CrossRefPubMedPubMedCentral

Barton VN, Donson AM, Kleinschmidt-DeMasters BK, Birks DK, Handler MH, Foreman NK. Unique molecular characteristics of pediatric myxopapillary ependymoma. Brain Pathol. 2010;20:560–70.CrossRefPubMedPubMedCentral

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Hoffman LM, Donson AM, Nakachi I, Griesinger AM, Birks DK, Amani V, et al. Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma. Acta Neuropathol. 2014;127:731–45.CrossRefPubMed

Iwama J, Ogiwara H, Kiyotani C, Terashima K, Matsuoka K, Iwafuchi H, et al. Neoadjuvant chemotherapy for brain tumors in infants and young children. J Neurosurg Pediatr. 2015;15:488–92.CrossRefPubMed

Koos B, Bender S, Witt H, Mertsch S, Felsberg J, Beschorner R, et al. The transcription factor evi-1 is overexpressed, promotes proliferation, and is prognostically unfavorable in infratentorial ependymomas. Clin Cancer Res. 2011;17:3631–7.CrossRefPubMed

Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol. 2010;28:3182–90.CrossRefPubMed

Li AM, Dunham C, Tabori U, Carret AS, McNeely PD, Johnston D, et al. EZH2 expression is a prognostic factor in childhood intracranial ependymoma: a Canadian Pediatric Brain Tumor Consortium study. Cancer. 2015;121:1499–507.CrossRefPubMed

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Nambirajan A, Sharma MC, Gupta RK, Suri V, Singh M, Sarkar C. Study of stem cell marker nestin and its correlation with vascular endothelial growth factor and microvascular density in ependymomas. Neuropathol Appl Neurobiol. 2014;40:714–25.CrossRefPubMed

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Peyre M, Commo F, Dantas-Barbosa C, Andreiuolo F, Puget S, Lacroix L, et al. Portrait of ependymoma recurrence in children: biomarkers of tumor progression identified by dual-color microarray-based gene expression analysis. PLoS One. 2010;5:e12932.CrossRefPubMedPubMedCentral

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# Part II
Embryonal Neuroepithelial Tumors
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_7

# 7. Central Nervous System Primitive Neuroectodermal Tumors (PNETs) and Medulloepithelioma

Adekunle M. Adesina1  , Jill V. Hunter2 and Lucy Balian Rorke-Adams3

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

(3)

Department of Pathology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Primitive neuroectodermal tumorsPNETMedulloepitheliomaCerebral neuroblastomaGanglioneuroblastomaEpendymoblastomaEmbryonal tumor with multilayered rosettesETMRETANTR

## 7.1 Overview

  * Embryonal tumor at extracerebellar sites comprises undifferentiated neuroepithelia l cells with capacity for divergent differen tiation, including neuronal, astrocytic, myogenic, or melanocytic differentiation.

  * Tumors may recapitulate the primitive neural tube (medulloepithelioma), have ependymoblastomatous multilayered rosettes (ependymoblastoma), have extensive neuropil differentiation combined with ependymoblastic rosettes (embryonal tumors with abundant neuropil and true rosettes [ETANTR]), or have extensive neuronal differentiation (cerebral neuroblastoma) with ganglion cells (ganglioneuroblastoma).

  * Embryonal tumor with multilayered rosettes (ETMR) is the preferred designation for the tumors previously referred to as ETANTRs.

  * ETMRs include ETANTRs, ependymoblastomas, medulloepitheliomas, and some rare, nondescript subsets of PNETs sharing a common genetic signature of C19MC amplification and are presumed to represent a distinct subset of embryonal tumors (see Sect. 7.7).

## 7.2 Clinical Features

  * Most p atients are below the age of 20 years.

  * Medulloepitheliomas are often seen in children less than 2 years old and may rarely be congenital.

  * Incidence is equal between males and females.

  * Clinical presentation depends on location and corresponding localizing symptoms and signs, as well as the presence of raised intracranial pressure.

  * Symptoms may include headache, seizures, and progressive deterioration in level of consciousness.

  * Among the localizing signs related to functional regions are motor weakness and hemiplegia.

  * Ependymoblastomas tend to occur in younger children and neonates.

## 7.3 Neuroimaging

  * These tumors typically present as a cerebral hemispheric mass lesion. Supratentorial, brainstem, and spinal cord locations are less frequent.

  * Characteristically, MRI shows a predominantly solid mass that is hypointense or isointense with gray matter and shows moderate, diffuse, hetereogenous enhancement (Figs. 7.1 and 7.2), sometimes with a cystic and necrotic component (Fig. 7.3).

Fig. 7.1

Supratentorial primitive neuroectodermal tumor (PNET) in a 17-month-old boy. An axial T1-weigh ted image (A) and axial T2-weighted post-gadolinium image (B) show a large, poorly enhancing, predominantly isointense lesion in the left subcortical region, causing mass effect and midline shift with ipsilateral hydrocephalus

Fig. 7.2

Axial fluid-atten uated inversion recovery (FLAIR) MR imaging (A) and diffusion-weighted imaging (B) demonstrate diffuse enhancement of the tumor, which shows restricted diffusion abnormality on an apparent diffusion coefficient (ADC) map

Fig. 7.3

An axial FLAIR M R image (A) and an axial T1-weighted post-gadolinium image (B) demonstrate a contrast-enhancing right parietal lobe supratentorial PNET with solid and cystic components

  * Dense cellularity is often seen as restricted diffusion on an apparent diffusion coefficient (ADC) map (see Fig. 7.2B).

  * Intratumoral hemorrhage may occur.

  * MR spectroscopy shows marked elevation of choline with little, if any, NAA peak (Fig. 7.4).

Fig. 7.4

(A) MR spe ctroscopy demonstrating elevation of the choline peak and a reduced NAA peak. The relative mildness of the elevation of the choline:NAA ratio first raised a differential diagnosis of a low-grade glial tumor. (B) Restricted diffusion on the ADC maps suggested a cellular, more aggressive lesion, which was confirmed at histology to be a supratentorial PNET

  * Calcification may be appreciated on CT scans.

  * Diffuse leptomeningeal enhancement and thecal sac drop metastases, when present, are consistent with cerebrospinal fluid (CSF) dissemination.

  * Extra-CNS metastases to other organs including the liver, bone, and cervical lymph nodes may occur and may raise a diagnostic dilemma regarding whether the CNS tumor is primary or secondary.

  * Presurgical MR angiography may show large feeding vessels, which may require presurgical embolization.

  * Ependymoblastomas may be seen in periventricular and sacrococcygeal locations.

## 7.4 Pathology

  * Gross pathology

    * ◦ Gross specimens from CNS embryonal tumors (PNETs) vary from fragmented, soft pink hemorrhag ic tissue to large pieces of well-demarcated masses. Leptomeningeal invasion may induce desmoplasia and a slightly firm consistency.

    * ◦ Grossly, medulloepithelioma is similar to other embryonal tumors of the CNS.

      * Whereas most PNETs have poorly defined margins, medulloepitheliomas sometimes appear to be circumscribed.

  * Intraoperative smears

    * ◦ Characteristically, smears show diffuse sheets of a relatively monotonous population of p oorly differentiated "small blue cells" with hyperchromatic nuclei, micronucleoli, and little amount of cytoplasm (Fig. 7.5).

Fig. 7.5

Cytologi c smear preparation showing a population of "small blue cells" with little or no cytoplasm, some nuclear pleomorphism, slightly vesicular nuclei with micronucleoli, occasional cell wrapping, and few apoptotic bodies

    * ◦ Rare Homer Wright–type rosettes may be seen.

    * ◦ Anaplasia is demonstrated by varying degrees of nuclear pleomorphism, more prominent nucleoli, cell wrapping, and frequent apoptosis.

  * Histology

    * ◦ PNETs are typically composed of sheets of poorly differentiated, small, round blue cells with high nucleocytoplasmic ratio (Fig. 7.6).

Fig. 7.6

Histolog ic section showing sheets of anaplastic "blue" cells with no demonstrable differentiation

    * ◦ Neuroblastic differentiation with Homer Wright rosettes is common. Flexner-Wintersteiner rosettes are rare; their presence is more frequent in PNETs originating in the pineal gland (pineoblastoma) (Fig. 7.7).

Fig. 7.7

Sheets of anaplastic tumor cells surrounding a centrally placed Flexner-Winterste iner rosette

    * ◦ Neuronal differentiation with a fibrillary neuropil stroma (Fig. 7.8) is associated with nuclear streaming (cerebral neuroblastoma) and ganglionic differentiation (ganglioneuroblastoma) (Fig. 7.9).

Fig. 7.8

Differen tiating neuropil in a ganglioneuroblastoma

Fig. 7.9

Florid ganglionic differentiation in the same tumor illustrated in Fig. 7.8

    * ◦ Astrocytic differentiation may be focal, regional, or diffuse.

    * ◦ Stromal fibrosis is common.

    * ◦ Cells may be arranged in palisades mimicking polar spongioblastoma (Fig. 7.10A).

Fig. 7.10

(A) Rhythm ic nuclear palisades often referred to as a spongioblastomatous pattern. (B) Ependymoblastomatous canal/rosette showing resemblance to the primitive tubules seen in medulloepithelioma. Note the lack of an external limiting membrane, which is an important distinguishing feature. Mitotic figures are seen at the luminal border

    * ◦ Stratified or multilayered rosettes with true lumina (Fig. 7.10B) (ependymoblastomatous rosettes) historically defines the ependymoblastoma.

    * ◦ ETMR (synonym: ETANTR) represents a variant closely resembling ependymoblastoma by its multilayered rosettes but also by having unusually abundant differentiating neuropil, within which isolated rosettes are seen (Fig. 7.11).

Fig. 7.11

Isolated ep endymoblastic rosettes in an "embryonal tumor with abundant neuropil and true rosettes" (ETANTR)

    * ◦ The medulloepithelioma is defined by recapitulation of the features of the embryonic neural tube, with the presence of a papillary, tubular, or trabecular arrangement of neuroepithelial cells to form primitive neural tube–like structures, along with sheets of undifferentiated neuroepithelial cells (Fig. 7.12).

Fig. 7.12

Histology of a medulloepithelioma, showing tubules of variable size and intervening primitive neuroepithelial cells

      * These primitive neural tube–like structures are distinguished from ependymoblastomatous rosettes by the presence of external and internal limiting membranes; they also have multilayered and pseudostratified cell layers. The external limiting membrane can be demonstrated by periodic acid–Schiff (PAS) stain or immunostain for collagen type IV (Fig. 7.13).

Fig. 7.13

Medulloepith elioma-type primitive tubule showing internal and external limiting membranes

      * Tiny blebs may protrude along the inner surface of the cells, but cilia and blepharoplasts are absent.

      * Mitotic figures are typically found near the luminal margin.

      * Tubular structures may predominate or may be associated with fields of primitive neuroepithelial cells, which sometimes demonstrate differentiation along glial, neuronal, or ependymal lines.

      * Mesenchymal differentiation, including bone, cartilage and striated muscle, may be present.

      * Divergent differentiation (including neuronal and glial) also may be seen in association with the mesenchymal differentiation.

      * Melanin-bearing cells occasionally are also encountered.

      * Although the neoplastic cells generally exhibit an orderly appearance, they have the capacity to develop bizarre, anaplastic features (Fig. 7.14).

Fig. 7.14

Medulloepithelioma displaying variable histologic features and increasing anaplasia: (A) Re gion of tumor consisting of tubules. (B) Region of tumor composed of less well-differentiated tubules. (C) Tubules showing well-defined external limiting membranes. (D) Tubule composed of bizarre, anaplastic cells

      * Ependymoblastomatous rosettes are often also present.

## 7.5 Immunohistochemistry

  * PNETs like medulloblastoma show immunoreactivity for neuronal markers including sy naptophysin, neurofilament protein (NFP) (Fig. 7.15A and B), and class III β tubulin.

Fig. 7.15

Immunohistochemical analysis of medulloepithelioma showing neurofilament protein (NF P) expression in a differentiated region of medulloepithelioma (A) and in a tubule-like structure (B); glial fibrillary acidic protein (GFAP) expression in a differentiated region of medulloepithelioma (C), where some of the positive cells have features of reactive astrocytes; exuberant proliferative activity in tubules by proliferating cell nuclear antigen (PCNA) immunohistochemistry (D); and vimentin expression in tubules (E)

  * Glial differentiation is associated with glial fibrillary acidic protein (GFAP) expression and must be distinguished from reactive astrocytes (Fig. 7.15C).

  * The proliferation index with MIB-1 or proliferating cell nuclear antigen (PCNA) (Fig. 7.15D) immunolabeling is high, often ranging between 20 % and 80 % in all PNETs.

  * Expression of cytokeratin and EMA may be seen in medulloepithelioma and ependymoblastoma.

  * Immunopositivity for retinal S antigen may be rarely seen in pineoblastoma.

  * In medulloepithelioma, cells forming the tubules express nestin, vimentin (Fig. 7.15E), microtubule-associated protein type 5, fibroblast growth factor, and insulinlike growth factor 1 (IGF-1).

    * ◦ Expression of GFAP, NFP, and synaptophysin in intervening regions reflects the spectrum of differentiation that is present in the tumor, although tubular epithelium may occasionally express NFP (Fig. 7.15B).

    * ◦ Rarely, in addition to the presence of intracytoplasmic melanin pigments, melanocytic differentiation is demonstrable with the Masson's Fontana stain or by immunopositivity for the HMB-45 or Melan-A antibody.

    * ◦ Ki-67 shows a very high proliferation index (often in the 50–80 % range) with robust proliferative activity in the tubular structures of medulloepithelioma.

## 7.6 Electron Microscopy

  * Neuronal differentiation is evidenced by the demonstration of cellular processes with micr otubules, cytoplasmic dense-core neurosecretory granules, and synaptic-type junctions.

  * Intermediate filaments may be seen.

  * In medulloepithelioma, the tubules are characterized by extensive zonulae adherentes similar to those found in the ependymal tumors, atypical teratoid/rhabdoid tumors (AT/RTs), and other epithelial tissues.

    * ◦ A distinct, sometimes folded basal lamina is located on the outer surface of the epithelial cells.

    * ◦ Poorly differentiated cells with minimal cytoplasmic organelles or cells exhibiting characteristic features of glial cells containing intermediate filaments and/or neuronal cells with dense-core neurosecretory vesicles may also be identified.

  * Ependymoblastoma s may show rudimentary cilia and basal bodies.

## 7.7 Molecular Pathology

  * Although supratentorial embryonal tumors (PNETs) share histologic features with cerebellar medulloblastom a, isochromosome 17q (a common event in medulloblastoma) is very rare in PNETs in general.

  * Embryonal tumors with multilayered rosettes (ETMR, previously known as ETANTR), ependymoblastoma, and medulloepithelioma show a characteristic genetic signature with amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, and/or expression of the RNA binding protein LIN28; they are regarded as a distinct subgroup of embryonal tumors.

  * Expression of the RNA binding protein LIN28 is detectable by immunohistochemistry (Fig. 7.16) and links signaling in these tumors with the mTOR (LIN28/let7/PI3K/mTOR) pathway, with potential for targeted therapy.

Fig. 7.16

Immunoreacti vity for RNA binding protein LIN28 in an embryonal tumor with multilayered rosettes (ETMR). (Courtesy of Tarik Tihan, MD, PhD)

  * MYCN amplification has been demonstrated in some PNETS and defines a subset of these embryonal tumors (PNETS). This subgroup shares DNA methylation profile with high grade gliomas.

  * PNETs without the ETMR signature C19MC gene amplification, LIN28 expression, or MYCN amplification are regarded as "embryonal tumors NOS"—a vanishing residual group of PNETs.

With the application of DNA methylation profiling, new entities have now emerged from the group previously designated as "CNS embryonal tumors, NOS". This group now includes the following new entities:

  * CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2),

  * CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)

  * CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and.

  * 'CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)

## 7.8 Differential Diagnosis

  * Ependymoblastomas are distinguished from anaplastic ependymomas by the presence of ependymoblastic (multilayered) rosettes.

    * ◦ Ependymal perivascular pseudorosettes show GFAP positivity in the acellular perivascular region of these pseudorosettes; ependymal cells are positive for epithelial membrane antigen (EMA).

    * ◦ Ependymoblastomas may show neuroepithelial components with immunoreactivity for neurofilament proteins.

  * Medulloepitheliomas may be confused with immature teratoma, choroid plexus carcinoma, or, most frequently, primitive neuroectodermal tumor showing ependymal differentiation (ependymoblastoma).

    * ◦ Although medulloepitheliomas may have ependymoblastomatous-type rosettes (as seen in ependymoblastoma), they often show the presence of primitive neural tube–like structures with demonstrable external basal lamina by PAS or immunostain for collagen type IV.

    * ◦ The presence of trabecular, canalicular, and papillary configuration should elicit a search for characteristic neural tube–like structures.

  * Immature teratoma may contain fields of tubular or canalicular structures.

    * ◦ Presence of disparate tissue components such as bone, cartilage, muscle, or glands allows recognition as a teratoma (Fig. 7.17).

Fig. 7.17

Teratoma in the parietal lobe of 3-month-old infant. (A) Neural tube–like structure. (B) Ependym omatous rosette/canal. (C) Vimentin expression in tubular structure. (D) Ki67 expression in tubular structures. (E) Region composed of primitive neuroepithelial cells in a background of differentiating neuropil. (F) Region of tumor containing cartilage, glandular epithelium, and primitive neural tissue

  * Choroid plexus carcinoma is primarily an epithelial tumor that simply expresses epithelial antigens without a neural or glial component.

## 7.9 Prognosis

  * PNETs are high-grade (WHO grade IV) tumors with high recurrence even after gross total resection an d high potential for leptomeningeal extension and CSF dissemination.

  * Survival is poor—often less than 12 months for ependymoblastoma.

  * PNETs with florid neuronal differentiation (cerebral neuroblastoma and ganglioneuroblastoma) are associated with better survival, up to 30 % after 5 years.

Suggested Reading

Al-Hussaini M, Abuirmeileh N, Swaidan M, Al-Jumaily U, Rajjal H, Musharbash A, et al. Embryonal tumor with abundant neuropil and true rosettes: a report of three cases of a rare tumor, with an unusual case showing rhabdomyoblastic and melanocytic differentiation. Neuropathology. 2011;31:620–5.CrossRefPubMed

Auer RN, Becker LE. Cerebral medulloepithelioma with bone, cartilage, and striated muscle. Light microscopic and immunohistochemical study. J Neuropathol Exp Neurol. 1983;42:256–67.CrossRefPubMed

Becker LE, Sharma MC, Rorke LB. Medulloepithelioma. In: Kleihues P, Cavenee WK, editors. Pathology and genetics of tumours of the nervous system. Lyon: IARC Press; 2000. p. 124–6.

Bennet Jr JP, Rubinstein LJ. The biological behavior of primary cerebral neuroblastoma: a reappraisal of the clinical course in a series of 70 cases. Ann Neurol. 1984;16:21–7.CrossRef

Burnett ME, White EC, Sih S, von Haken MS, Cogen PH. Chromosome 17p deletion analysis reveals molecular genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumors of the central nervous system. Cancer Genet Cytogenet. 1997;97:25–31.CrossRef00319-6)PubMed

Coccamo DV, Herman MM, Rubinstein LJ. An immunohistochemical study of the primitive and maturing elements of human cerebral medulloepitheliomas. Acta Neuropathol. 1989;79:248–54.CrossRef

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Figeroa RE, el Gammal T, Brooks BS, Holgate R, Miller W. MR findings on primitive neuroectodermal tumors. J Comput Assist Tomogr. 1989;13:773–8.CrossRefPubMed

Gessi M, von Bueren A, Treszl A, zur Mühlen A, Hartmann W, Warmuth-Metz M, et al. MYCN amplification predicts poor outcome for patients with supratentorial primitive neuroectodermal tumors of the central nervous system. Neuro Oncol. 2014;16:924–32.CrossRefPubMedPubMedCentral

Gould VE, Rorke LB, Jansson DS, Molenaar WM, Trojanowski JQ, Lee VM, et al. Primitive neuroectodermal tumors of the central nervous system express neuroendocrine markers and may express all classes of intermediate filaments. Hum Pathol. 1990;21:245–52.CrossRef90223-R)PubMed

Jellinger K. Cerebral medulloepithelioma. Acta Neuropathol. 1972;22:95–101.CrossRefPubMed

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Korshunov A, Sturm D, Ryzhova M, Hovestadt V, Gessi M, Jones DT, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol. 2014;128:279–89.CrossRefPubMed

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Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK,Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

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Spence T, Sin-Chan P, Picard D, Barszczyk M, Hoss K, Lu M, et al. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol. 2014;128:291–303.CrossRefPubMedPubMedCentral

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_8

# 8. Medulloblastoma

Adekunle M. Adesina1  and Jill V. Hunter2

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

MedulloblastomaLarge cell medulloblastomaAnaplastic medulloblastomaNodular medulloblastomaDesmoplastic medulloblastomaExtensively nodularMedullomyoblastoma

## 8.1 Overview

  * Medullobl astoma is an invasive, high-grade (WHO grade IV) embryonal tumor defined both by histologic grade and location in the cerebellum.

  * Even though this tumor shares histologic features with other central nervous system (CNS) embryonal tumors (primitive neuroectodermal tumors), it has been historically regarded as a distinct entity.

  * Recent molecular studies, including genomic and gene expression profiling as well as signaling pathway dysregulation and biologic studies, have now justified its historical clinical definition as a distinct clinicopathologic entity with predominant occurrence in children.

  * Most are sporadic.

  * They occur less frequently in the setting of hereditary syndromes. These include Turcot's syndrome, with germline mutation of the adenomatous polyposis coli (APC) gene, and Gorlin's syndrome, the nevoid basal cell carcinoma syndrome with germline mutation of the PTCH gene, seen in less than 2 % of medulloblastomas.

## 8.2 Clinical Features

  * Medulloblastomas account for 20 % of malignant CNS tumors in childhood, the second most common mali gnancy in childhood.

  * Most tumors occur in children below the age of 20, with a peak between 5 and 8 years of age. A second but smaller peak is seen at ages 35–40 years. Rarely, it may be congenital.

  * Patients present with symptoms and signs of cerebellar dysfunction, including truncal and appendicular ataxia, and raised intracranial pressure due to obstruction of the fourth ventricle and CSF flow, with headache, vomiting, and progressive lethargy.

## 8.3 Neuroimaging

  * Early onset of calcification of the falx cerebri, tentorium cerebelli, and dura, with bridging of the se lla turcica due to calcification of the diaphragma sellae is seen with CT scans in 60–80 % of patients with Gorlin's syndrome (Fig. 8.1).

Fig. 8.1

Axial CT scan of a patient with G orlin's syndrome (also known as basal cell nevus syndrome) associated with medulloblastoma. Note the characteristic abnormal, heavy calcification outlining the free edge of the tentorium and the falx in this young child

  * Midline vermian mass lesions in children or lateral cerebellar hemispheric tumors in adults are typical.

  * Characteristically, MRI shows a predominantly solid mass, hypointense or isointense with gray matter, with moderate diffuse, nonhomogenous enhancement (Figs. 8.2, 8.3, 8.4, 8.5, 8.6, and 8.7).

Fig. 8.2

Axial T2-weighted MR image (A) and apparent diffusion coefficient (ADC) maps (B) demonstrating a heterogeneously hyperintense mass extending bilaterally to the cerebellopontine angles in a 27-month-old boy. There is restricted diffusion within the tumor, which was confirmed to be a medulloblastoma on histology

Fig. 8.3

Axial T1-weighted M R imaging before (A) and after (B) gadolinium demonstrates some central enhancement

Fig. 8.4

Axial CT image showing hyperdense, centrally placed tumor within the posterior fossa, consistent with a highly cellular tumor such as a medulloblastoma or atypical teratoid/rhabdoid tumor (AT/RT)

Fig. 8.5

Sagittal T1-weighted image (A) and T2-weighted image (B) demonstrates a T1-hypointense an d T2-hyperintense mass in the same patient as in Fig. 8.4

Fig. 8.6

(A, B) Diffusion-weighted imaging in the same patient as in Fig. 8.4 shows restriction as may be seen in a med ulloblastoma, AT/RT or anaplastic ependymoma. This case was histologically proven to be a medulloblastoma

Fig. 8.7

T1-weighted axial (A) and sagittal (B) MR images following gadolinium administration, showing moderate e nhancement, much less than would be seen with a solid pilocytic astrocytoma

  * There is often associated restricted diffusion consistent with a small-cell and densely cellular tumor (Figs. 8.2 and 8.6).

  * MR spectroscopy shows marked elevation of choline with little, if any, NAA peak (Fig. 8.8A).◦

Fig. 8.8

(A) Typical appearanc es of MR spectroscopy utilizing a long TE in the same patient as in Fig. 8.7, demonstrating a marked decrease in N-acetyl aspartase (NAA), a marker of neuronal and axonal integrity, and a significant elevation in choline, a marker of cell membrane turnover. Also present is a lipid peak consistent with the presence of necrosis. (B, C) Coronal and axial T1-weighted post-gadolinium MR images show a cerebellar mass with grapelike nodules in a patient with an extensively nodular medulloblastoma

    * Elevation of the taurine peak may also be seen in medulloblastoma.

  * The extensively nodular variant often seen in patients less than 1 year old may present with multiple, grapelike, enhancing nodular features (Fig. 8.8B and C).

  * Diffuse leptomeningeal enhancement and thecal sac drop metastases, when present, are consistent with CSF dissemination and poorer prognosis (Figs. 8.9, 8.10, 8.11, 8.12, and 8.13).

Fig. 8.9

Sagittal T1- weighted, post-gadolinium imaging of the lumbosacral spine in a patient with medulloblastoma, demo nstrating evidence for abnormal leptomeningeal enhancement in the dorsal surface of the thoracic cord, as well as evidence for extensive drop metastases within the distal thecal sac

Fig. 8.10

Unenhanced axial CT scan demonstrating a mixed solid and cystic tumor arising in the posterior fossa a nd causing obstruction to the supratentorial ventricular system. The solid portion of the tumor appears hyperdense, consistent with high cellularity. Note also the high density outlining the Sylvian fissures, suspicious for disseminated tumor

Fig. 8.11

(A) Restricted diffusion demonstrated within the enhancing solid portion of this tumor on an ADC map suggests a medulloblastoma, AT/RT, or anaplastic ependymoma in the differential diagno sis. (B) Note the presence of abnormal leptomeningeal enhancement in the axial T1-weighted, postcontrast image

Fig. 8.12

Sagittal (A) and coronal (B) T1-weighted images from the same patient as in Fig. 8.11, following the administration of gadolinium. Florid, abnormal leptomeningeal enhancement is observed with hydrocephalus and extension of abnormal enhancement into the spinal canal. Histology revealed a medulloblastoma in this 15-month-old boy

Fig. 8.13

(A, B) MR images of the spine, demonstrating extensive abnormal, thick leptomeningeal enhancement surrounding the entire spinal cord at the time of presentation

  * There is often evidence of mass effect, including severe dilatation of the third and lateral ventricles, transepend ymal CSF flow, and brainstem compression (Figs. 8.10 and 8.12).

## 8.4 Pathology

  * Grossly, medul loblastoma presents commonly as a midline vermian mass (Fig. 8.14).

Fig. 8.14

Medulloblas toma arising in the vermis, with associated necrosis and hemorrhage

  * Resection specimens or intraoperative biopsies are often soft, gray-pink, and appear necrotic. Extensively nodular or desmoplastic tumors may sometimes have a soft to slightly firm consistency with a lobulated appearance.

  * Intraoperative cytologic imprints or smears

    * ◦ Moderate cellular ity is characteristic. There is a good correlation between cytologic features and histologic classification as classic or nodular, anaplastic, or large cell medulloblastomas.

    * ◦ Classic and nodular medulloblastomas demonstrate monolayered sheets of relatively uniform, round to oval (occasionally elongated or carrot-shaped) molded nuclei with hyperchromasia and some chromatin clumping (Fig. 8.15A). Molded, markedly atypical cells with high nucleocytoplasmic ratio in CSF cytospin are consistent with dissemination (Fig. 8.15B). Rosette-like arrangements representing Homer Wright rosettes may be seen (Fig. 8.16).

Fig. 8.15

Intraoperative cytology preparation of a classic medulloblastoma, showing "small blue cells" with limited cytoplasm, moderate cellular pleomorphism, and nuclei with chromatin condensation and micronucleoli (A). Note the lack of a fibrillary background and an occasional apoptotic body. CSF from a patient with medulloblastoma (B) shows a cluster of disseminated malignant cells, cellular molding, irregular nuclear contour, and high nucleocytoplasmic ratio

Fig. 8.16

Cytology prepara tion showing Homer Wright rosettes

    * ◦ Anaplastic medulloblastomas demonstrate a significant component of large, pleomorphic cells with prominent chromatin clumping and visible nucleoli. "Cell wrapping" or "cannibalism" (the nucleus of one cell wrapped around the nucleus of another) and apoptotic nuclei are frequent (Fig. 8.17). Occasional multinucleated cells may sometimes be seen.

Fig. 8.17

Cytology prepa ration of an anaplastic medulloblastoma showing carrot-shaped cells, moderate cellular pleomorphism, "cell wrapping" (arrowhead), "cannibalism" (arrow), and hyperchromatic nuclei with chromatin condensation and micronucleoli

    * ◦ Large cell medulloblastoma, when present or predominant, often shows a discohesive, monotonous population of large cells with open chromatin and visible nucleoli, sometimes mimicking the cytologic monotony of large cell lymphomas (Fig. 8.18).

Fig. 8.18

Cytology preparation of a large cell medulloblastoma showing a monomorphic cytology, nucle i with open chromatin, and slightly prominent micronucleoli

    * ◦ Endothelial proliferation and mitosis may be present in all cytologic types.

    * ◦ Rare evidence of cytologic differentiation with astrocytic, ganglionic, or melanocytic differentiation (with melanin pigments), or rhabdomyoblastic differentiation (strap cells) may be seen.

  * Histology: Varied histol ogic features may be seen between and within tumors.

    * ◦ Classic medulloblastomas are com posed of monotonous sheets of small cells (Fig. 8.19).

Fig. 8.19

Classic medu lloblastoma with high cellularity and o verlapping nuclei, some of which are carrot-shaped. A few "dark" apoptotic bodies are present

      * Slight nuclear irregularity is often present.

      * Mitoses are present but often variable.

      * Necrosis may be present, with or without pseudopalisading.

      * Apoptosis is often present.

      * Endothelial proliferation is present and sometimes can be florid.

      * Neuroblastic differentiation is seen as the Homer Wright rosette (Fig. 8.20).

Fig. 8.20

Classic medu lloblasto ma with Homer Wright rosettes

      * Mature neuronal differentiation as ganglion or "ganglioid" cells may be seen but must be distinguished from entrapped neurons.

      * A spindle or fascicular pattern, when present, is usually focal (Fig. 8.21)

Fig. 8.21

Spindled an d fascicular pattern of growth in a classic medulloblastoma

      * Prominent nuclear irregularity with nucleoli and pleomorphism suggests the presence of anaplastic features, which may be focal; a transition from classic to anaplastic may be appreciable (Fig. 8.22). Extensive anaplasia may justify designation as an anaplastic subtype.

Fig. 8.22

Transi tion fro m classic medulloblastoma (left bottom) to low-grade anaplastic features (right top)

      * Anaplasia may vary from slight to moderate to severe (Figs. 8.23 and 8.24).

Fig. 8.23

Progre ssive transformation of internodular areas with increasing anaplasia is sometimes seen i n desmoplastic medulloblastoma. A residual pale nodule area is shown partially at the top of the image (arrow)

Fig. 8.24

(A–C) A naplastic m edulloblastoma with severe anaplasia. Note variable patterns of marked cellular pleomorphism, florid apoptosis, karyorrhexis, and frequent cell wrapping and cannibalism

    * ◦ Regions with monomorphic, discohesive, large round cells with prominent nucleoli are suggestive of the presence of a large cell component (Fig. 8.25).

Fig. 8.25

Larg e cell medullobl astoma showing cellular monomorphism, vesicular nuclei, and distinct nucleoli. Note the similarity of this morphology to that of a diffuse large cell lymphoma

      * Predomin ance of large cells or severe anaplasia represents the large cell or anaplastic subtype and accounts for about 4 % of medulloblastoma.

      * Severe anaplasia is often associated with increased apoptosis, increased frequency of mitotic activity, and cell wrapping or cannibalism.

    * ◦ Nodular (desmoplastic) medulloblastoma is characterized by the presence of multiple reticulin-fre e, pale nodules of neurocytic cells within a neuropil-like background, which are rarely mitotic with increased apoptosis (Figs. 8.26, 8.27, and 8.28).

Fig. 8.26

Lo w-magn ification (A) and higher-magnification (B) views of a desmoplastic (nodular) medulloblastoma, showing the characteristic pale nodules

Fig. 8.27

Desmo plastic (n odular) medulloblastoma showing pale nodules (left), which are composed of neurocytes in a more differentiated, fibrillary, neuropil-like background. Contrast with the less-differentiated neuroblastic internodular region (right)

Fig. 8.28

Desm oplastic ( nodular) medulloblastoma showing reticulin-free pale nodules and reticulin-positive internodular areas

      * Leptomeningeal invasion with florid, reactive desmoplasia (collagenous fibrosis), often demonstrating medium- to large-sized leptomeningeal vessels, may occur but does not constitute a desmoplastic medulloblastoma (Fig. 8.29).

Fig. 8.29

Fibros is following lep tomeningeal invasion in a medulloblastoma. This should not be equated with a desmoplastic (nodular) medulloblastoma

      * Internodular areas are reticulin-rich and are composed of cells similar to those of classic medulloblastoma.

        * ◦ These areas tend to exhibit more brisk mitotic activity than is seen within the pale nodules.

      * Internodular areas may sometimes show varying degrees of anaplasia (see Fig. 8.23).

    * ◦ The extensively nodular medulloblastoma (previously termed cerebellar neuroblastoma) is a variant showing florid nodularity and neurocytic differentiation with an absent or minimal undifferentiated internodular component.

      * Cells are often arranged in a streaming pattern within a fibrillary matrix (Figs. 8.30 and 8.31).

Fig. 8.30

Extensively nod ular medulloblastoma composed of interlacing fascicles of differentiated neurocytes in a "fibrillary" neuropil-like matrix with limited internodular areas

Fig. 8.31

Extensively nodular medulloblastoma with neurocytes arranged in rows reminiscent of an "Indian file" pattern

      * Ganglion cell differentiation (forming cerebellar ganglioneuroblastoma) also may be present (Fig. 8.32).

Fig. 8.32

Neuronal/ganglion ic (arrow) differentiation in a medulloblastoma

    * ◦ Biphasic medulloblastoma rep resents a tumor with mixed classic and nodular components, in which the nodular component is not surrounded by desmoplasia; that is, the internodular areas are reticulin-free. This distinction from the nodular/desmoplastic medulloblastoma is important.

    * ◦ Infrequent patterns of differentiation include:

      * Astrocytic differentiation, which must be distinguished from entrapped reactive astrocytes (Figs. 8.33 and 8.34).

Fig. 8.33

Astrocyt ic differentiation in a medulloblastoma demonstrated by reactivity with antibody for glial fibrillary acidic protein (GFAP) in a subpopulation of tumor cells

Fig. 8.34

Nonneopl astic reactive astrocytes within a medull oblastoma showing immunoreactivity for GFAP

      * Skeletal muscle or rhabdomyoblastic differentiation may rarely be seen as strap cells with or without striations; this pattern constitutes the medulloblastoma with myogenic differentiation (synonym: medullomyoblastoma) (Fig. 8.35).

Fig. 8.35

Medullomyoblastoma with florid skeletal muscle differentiation (arrow) (A), demon strable strap cells with cross-striations (B), and desmin immunoreactivity in tumor cells (C)

      * Melanocytic di fferentiation with melanin pigment production constitutes the rare medulloblastoma with melanotic differentiation (synonym: melanotic medulloblastoma) (Fig. 8.36).

Fig. 8.36

Melanoti c differentiation in a medulloblastoma

        * Premelanosomes and melanosomes are demonstrable by electron microscopy.

## 8.5 Immunohistochemistry

  * Medulloblastomas show diffuse immunopositivity for synaptophysin (Fig. 8.37) and varia ble immunopositivity for chromogranin, neurofilament protein, and the neuronal marker NeuN.

Fig. 8.37

Immunorea ctivity for synaptophysin is consistent with neuroblastic differentiation in this poorly differentiated embryonal tumor

  * Glial fibrillary acidic protein (GFAP) often highlights trapped reactive astrocytes. Rare positivity of tumor cells is seen (see Figs. 8.33 and 8.34).

  * Immunopositivity for retinal S-antigen and rhodopsin may be rarely seen in tumors with photoreceptor differentiation.

  * Epithelial membrane antigen (EMA) is usually negative.

  * p53 immunopositivity is seen in a subset of medulloblastomas. An increased proportion of positive cells often correlates with increasing anaplasia and poorer survival (Fig. 8.38).

Fig. 8.38

A subpopulation of tum or cells exhibit immunoreactivity of p53 protein, consistent with dysregulation of p53 in this tumor and implication of a poor prognosis

  * The MIB-1 (proliferation) index is variable, often very high (30–80 %) (Fig. 8.39).

Fig. 8.39

Ki-67 immunoreactivity showing a high proliferation index

## 8.6 Electron Microscopy

  * Electron microscopy shows tumor cells (often paucicellular) in organelles but with demonstrable neurose cretory granules.

  * Cellular processes are frequent and contain microtubules.

  * Synaptic-type junctions may be seen.

## 8.7 Molecular Pathology

  * Medulloblastomas are presumed to arise from precursor stem cells in the external granular layer for lateral hemispheric nodular or desmoplastic medulloblastomas, and from dysplastic precursor cells arrested during migration for other vermian variants.

  * Using gene expression profiling, medulloblastomas are molecularly classified into four groups:

    * ◦ Group A with wnt pathway activation

    * ◦ Group B with SHH pathway activation

    * ◦ Groups C and D, collectively referred to as non A/non B. Non A/non B classification is often associated with aggressive histology, MYC amplification, and poor prognosis.

  * Activation of the wnt signaling pathway through mutation of the APC gene has been associated with Turcot syndrome and only 3–4 % of sporadic medulloblastoma.

  * Wnt pathway–activated tumors account for about 10 % of medulloblastomas and show demonstrable nuclear localization for beta catenin and/or monosomy 6. DDX3X gene mutation is also seen in 50 % of wnt pathway tumors.

  * PTCH gene loss of function mutation, as well as mutations of SMO, SUFU, and Gli2 result in the activation of the sonic hedgehog (SHH) signaling pathway in 30 % of medulloblastomas.

  * SHH pathway activation is seen classically in nodular or desmoplastic medulloblastoma. Gli1 and Gli2, representing downstream effectors of SHH pathway activation, are also often demonstrable in up to 85 % of medulloblastomas. The proportion of tumors classified as SHH molecular subgroup drops significantly when classified based on the expression of GAB1, filamin A, and/or YAP1. SHH-activated tumors with p53 mutation carry a significantly poor prognosis.

  * Amplification of MYCC and less commonly MYCN is a common finding in large cell/anaplastic medulloblastoma (Figs. 8.40 and 8.41); MYCC amplification is frequently associated with Group C, and MYCN amplification, with group D.

Fig. 8.40

Fluorescence in situ h ybridization (FISH) using an MYCN–specific probe demonstrates gene amplification (green) in an anaplastic medulloblastoma. The chromosome 2 centromeric reference probe is red

Fig. 8.41

FISH using a c-myc–sp ecific probe demonstrates gene amplification (red) in an anaplastic medulloblastoma. The chromosome 8 centromeric reference probe is green

  * Gains of CDK6 (7q21), hTERT (5p15), OTX2 (14q22) (more frequently seen in group C), and FoxG1 (14q12) have been reported.

  * 17p deletion with isochromosome 17q is the commonest cytogenetic abnormality in medulloblastoma, present in 30–40 % of tumors (Fig. 8.42); it is seen particularly in group D tumors. Potential target genes in the 17p deletion include HIC1 (17p13.3), frequently hypermethylated in medulloblastoma, and REN (17p13.2), a negative regulator of the SHH signaling pathway.

Fig. 8.42

(A) Conventional comp arative genomic hybridization (CGH) analysis demonstrating loss of 17p and gain of 17q. (B) FISH analysis showing one copy of 17p (red probe signal) and three copies of 17q (green probe signal), consistent with cytogenetic findings of isochromosome 17q

  * Losses of 16q, 10q, and 11q are present in a subset of the tumors.

  * Increased activation of the Notch signal ing pathway; overexpression of PAX5, PAX6 and SOX4; and overexpression of repressors of neural differentiation REST and FoxG1 have all been reported in medulloblastoma.

## 8.8 Differential Diagnosis

  * Medulloblastomas may have areas with prominent perivascular pseudorosettes, thus raising anaplastic ependymoma as a major differential diagnosis.

    * ◦ Ependymomas tend to show variation in cellularity, however, including regions of well-differentiated ependymoma.

    * ◦ EMA is often positive in ependymomas and negative in medulloblastoma.

    * ◦ Synaptophysin is positive in perivascular pseudorosettes of medulloblastoma, whereas GFAP staining is more characteristic of ependymoma.

    * ◦ Nuclear positivity for NeuN is not helpful, as it may be positive in both tumor types.

  * Atypical teratoid /rhabdoid tumor (AT/RT) may have a prominent PNET-like small round cell component, whereas large cell or anaplastic medulloblastoma may mimic AT/RT.

    * ◦ FISH with INI-1 locus-specific probe shows no demonstrable allelic deletion in medulloblastoma.

    * ◦ Similarly, immunostain with BAF-47 (anti-INI1) antibody shows positive nuclear staining in the neoplastic cells in medulloblastoma but negative staining in AT/RT.

  * Medulloblastoma needs to also be differentiated from small cell glioblastoma.

    * ◦ Small cell glioblastoma will characteristically show widespread GFAP positivity and lack evidence of neural differentiation (presence of Homer Wright rosettes or neuronal immunohistochemical markers typical of medulloblastoma).

  * Other small round blue cell tumors of children metastatic to the CNS (rhabdomyosarcoma, Ewing sarcoma, leukemia/lymphoma, etc.) can all be effectively differentiated from medulloblastoma by immunohistochemistry.

    * ◦ Metastatic neuroblastoma may closely mimic medulloblastoma, but it would be unlikely for neuroblastoma to present solely as a CNS metastasis without the primary peripheral lesion having been identified by imaging studies or a previous biopsy.

## 8.9 Prognosis

  * The following clinic al characteristics define high-risk patients:

    * ◦ Age less than 3 years.

    * ◦ Postresection residual tumor larger than 1.5 cm.

    * ◦ Metastatic disease at presentation with Chang stages M1–4.

  * Large cell and anaplastic histology are associated with poor survival.

  * Poor prognostic molecular markers include amplification of MYCC or MYCN and overexpression of c-erbB2 or p53.

  * The nodular/desmoplastic and the extensively nodular phenotypes are associated with favorable outcome and better survival than the classic medulloblastoma.

  * Wnt pathway activation with nuclear expression of β-catenin and/or monosomy 6 has been reported as a good prognostic marker.

Suggested Reading

Adesina AM, Veo BL, Courteau G, Mehta V, Wu X, Pang K, et al. FOXG1 expression shows correlation with neuronal differentiation in cerebellar development, aggressive phenotype in medulloblastomas, and survival in a xenograft model of medulloblastoma. Hum Pathol. 2015;46:1859–71.CrossRefPubMed

Bailey P, Cushing H. Medulloblastoma cerebelli: a common type of mid-cerebellar glioma of childhood. Arch Neurol Psychiatry. 1925;14:192–224.CrossRef

Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121:381–96.CrossRefPubMedPubMedCentral

Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, et al. Large cell medulloblastoma. A distinct variant with highly aggressive behavior. Am J Surg Pathol. 1992;16:687–93.CrossRefPubMed

Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, et al. Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg. 1999;91:971–7.CrossRefPubMed

Giangaspero F, Wellek S, Masuoka J, Gessi M, Kleihues P, Oghaki H. Stratification on the basis of histopathologic grading. Acta Neuropathol. 2006;112:5–12.CrossRefPubMed

Helton KJ, Fouladi M, Boop FA, Perry A, Dalton J, Kun L, Fuller C. Medullomyoblastoma: a radiographic and clinicopathologic analysis of six cases and review of the literature. Cancer. 2004;101:1445–54.CrossRefPubMed

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer (IARC); 2016.

Meyers SP, Kemp SS, Tarr RW. MR imaging features of medulloblastomas. AJR Am J Roentgenol. 1992;158:859–65.CrossRefPubMed

Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408–14.CrossRefPubMed

Panigrahy A, Krieger MD, Gonzalez-Gomez I, Liu X, McComb JG, Finlay JL, et al. Quantitative short echo time 1H-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization. AJNR Am J Neuroradiol. 2006;27:560–72.PubMed

Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–72.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_9

# 9. Atypical Teratoid/Rhabdoid Tumor

Adekunle M. Adesina1  , Jill V. Hunter2 and Lucy Balian Rorke-Adams3

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

(3)

Department of Pathology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Atypical teratoid/rhabdoid tumorATRTAT/RTPNETEmbryonal tumorRhabdoid predisposition syndrome

## 9.1 Overview

  * Atypical tera toid/rhabdoid tumors (AT/RTs) are malignant, high-grade embryonal (WHO Grade IV) tumors seen in children often below the age of 3 years and rarely above the age of 6 years.

  * AT/RTs account for 10 % of tumors in infants, with a male:female ratio of 2:1.

  * They are characteristically poorly differentiated, contain rhabdoid cells with divergent differentiation to form epithelial, mesenchymal, neuronal, and glial components, and may be associated with a subpopulation of primitive neuroectodermal cells.

## 9.2 Clinical Features

  * Presenting sympt oms are related to location, which may include the cerebral hemispheres; suprasellar, pineal, or cerebellar sites; the cerebellopontine angle (CPA); or rarely, the spinal cord.

  * Symptoms of raised intracranial pressure, including vomiting and lethargy, may occur.

  * Cranial nerve palsy may be seen in CPA and brainstem lesions.

  * Leptomeningeal dissemination is frequent and may be a presenting feature in a significant subset.

  * An aggressive clinical course is typical.

## 9.3 Neuroimaging

  * The tumor may p resent as a supratentorial mass (Figs. 9.1 and 9.2) or, more commonly, an infr atentorial mass (Fig. 9.3), clas sically involving the CPA (Figs. 9.4, 9.5, 9.6, and 9.7).

Fig. 9.1

Axial T1-weighted MR image (A) and T2-weighted image (B) in a 16-month-old boy, demonstrating a soli d-appearing, heterogeneous mass occupying most of the body of the left lateral ventricle with bowing of the midline convex to the right in the presence of a dilated supratentorial ventricular system

Fig. 9.2

Axial T2-weighted image (A) and T1-weighted image (B) after gadolinium enhancement in a 22-month-old girl, demonstrating a rim-enhancing, mixed solid and cystic-appeari ng supratentorial tumor effacing the body of the right lateral ventricle and causing contralateral hydrocephalus with transependymal fluid spread on the left. Histopathology revealed an atypical teratoid/rhabdoid tumor (AT/RT). Following a gross total resection and therapy, this child survived for another 5 years

Fig. 9.3

Axial T2-weighted image through the posterior fossa in a 21-month-old boy, demonstrating hetero geneous, mixed signal-intensity mass with solid and more cystic-appearing components extending into the left cerebellopontine angle (CPA), with nonvisualization of the fourth ventricle

Fig. 9.4

Unenhanced CT exa mination in an 18-month-old boy who presented with hearing loss, showing a hyperdense mass originating at the level of the left CPA. The hyperdensity suggests a highly cellular tumor, confirmed on MRI with restricted-diffusion abnormality in the presence of altered blood and blood product. Bone windows on CT revealed some remodeling of the left internal auditory canal (IAC), in the presence of an otitis media. Despite resection that revealed an AT/RT, the child died 1 month later

Fig. 9.5

(A) Axial T2-weighted i mage demonstrating a right CPA mass. (B) Restricted diffusion abnormality on an apparent diffusion coefficient (ADC) map

Fig. 9.6

Evidence for hemor rhage within the tumor on gradient echo imaging (A) in the same patient as Fig. 9.5. Fine cut, heavily T2-weighted imaging (B) demonstrates exophytic extension into the basal cistern

Fig. 9.7

(A, B) Fine cut, T1-we ighted imaging of the same patient as Fig. 9.5 shows the pattern of enhancement, which extends into the porus of the right IAC. The patient survived for another 6 months despite resection and therapy

  * Though uncommon, it may also present as a spinal cord mass lesion (Fig. 9.8).

Fig. 9.8

Sagittal T1-weighted imaging of the head (A) and neck (B) of a 1-year-old girl who presented with left-sided weakness, before and after the administration of gadolinium, showing an extradural mass lesion in the cervical spine with post-Gd rim enhancement. This lesion proved to be a rhabdoid tumor with extension through the exit foramen into the soft tissues, requiring more than one resection. This is a very unusual location for AT/RT. The patient died from intracranial dissemination of tumor 4 months after first presentation

  * Characteristically, MRI shows a predominantly solid mass that is hyperintense or isointense with gray matter, with moderate diffuse heterogeneous enhancement (Figs. 9.1, 9.2, and 9.9).

Fig. 9.9

Axial T2-weighted (A) and T1-weighted (B) post-Gd images of a 17-month-old boy with a large, poorly enhancing, predominantly hyperintense lesion in the left frontal region, causing mass effect and midline shift with contralateral hydrocephalus. The lesion proved to be a supratentorial AT/RT. The patient survived for 5 months following removal

  * Cystic areas and regions of necrosis may be present (Fig. 9.10A).

Fig. 9.10

Axial T1-weighted post-Gd imaging (A) and axial diffusion-weighted imaging (DWI) (B) in the s ame patient as in Fig. 9.3, demonstrating diffuse enhancement of the solid-appearing component of the tumor, which shows restricted diffusion abnormality on an ADC map. The right posterior component of the tumor demonstrates unrestricted diffusion consistent with a fluid-filled cyst. Taking the morphology into account, these appearances would be typical for an AT/RT, but differential diagnosis would include medulloblastoma and anaplastic ependymoma. This patient survived for another 5 years with treatment

  * There is typically associated restricted diffusion (Figs. 9.10B and 9.11) consistent with a densel y cellular tumor. The neuroimaging appearance can be radiographically indistinguishable from medulloblastoma.

Fig. 9.11

Axial ADC map (A) and T1-weighted post-Gd imaging (B) in the same patient as in Fig. 9.5, demonstr ating almost uniformly restricted diffusion abnormality in the poorly enhancing intraventricular mass, which at surgery proved to be a supratentorial AT/RT. Despite a gross total resection, this patient survived only 2 months

  * MR spectroscopy shows marked elevation of the choline peak, with little, if any, N-acetylaspartate (NAA) peak.

    * ◦ There may be an associated lipid/lactate peak within the tumor, consistent with tumor necrosis.

  * Diffuse leptomeningeal enhancement within the brain and spine is frequent; when present, it is consistent with cerebrospinal fluid (CSF) dissemination.

## 9.4 Pathology

  * Gross pathology

    * ◦ Grossly, tumors a re variably sized, soft, and variegated, with pink-red hemorrhagic and sometimes necrotic appearance. In contrast to primitive neuroectodermal tumor (PNET), they more often contain foci of necrosis and hemorrhage.

    * ◦ A significant mesenchymal component may confer a firm consistency. Uncommonly, they may contain small, dense, white foci reflecting a connective tissue component.

  * Intraoperative smears

    * ◦ Cytologic preparations are often cellular, with cells arranged in predominantl y cohesive clusters in a necrotic background showing tumor diathesis. Rare or occasional pseudopapillary configuration (Fig. 9.12A) may be seen.

Fig. 9.12

Intraoperative cytologic preparations showing malignant, poorly differentiated tumor cells arranged i n a pseudopapillary pattern (A); A smear of a rhabdoid tumor (B) with a mixed population of primitive neuroepithelial cells and rhabdoid cells (H&E, ×600). The inset shows rhabdoid cells with vesicular nuclei and prominent nucleoli

    * ◦ The cells are poorly differentiated, often epithelioid, and may consist of a variable component of typical rhabdoid cells with moderate size, pink cytoplasm, and a round, eccentrically placed nucleus having a prominent nucleolus (Fig. 9.12B inset).

    * ◦ Poorly differentiated cells with hyperchromatic nuclei and little cytoplasm (reminiscent of the "small blue cells" of a PNET) may be present (Fig. 9.12B).

    * ◦ Frequent mitosis, apoptosis, and cell wrapping can be seen.

  * Histology

    * ◦ Histology is variable and complex. It may show solely sheets of rhabdoid cells (Fig. 9.13), or may consist primarily of primitive neuroectodermal cells (Fig. 9.14).

Fig. 9.13

Histology of AT/RT showing sheets of epithelioid cells

Fig. 9.14

Region in an AT/RT showing poorly differentiated, primitive neuroepithelial cells or "small b lue cells" consistent with an embryonal neuroepithelial (PNET-like) component (H&E, ×400)

    * ◦ Lesions tend to be necrotic and hemorrhagic, and may contain foci of dystrophic calcification. Dilated, thrombosed blood vessels are sometimes seen as well.

    * ◦ Rhabdoid cells are poorly differentiated, with eccentric vesicular nuclei, prominent nucleoli, and eosinophilic (ground glass) cytoplasm containing distinct globular inclusions and with distinct cell borders (Fig. 9.15).

Fig. 9.15

Epithelioid (rhabdoid) cells with vesicular nuclei, prominent nucleoli, and abundant, eccentric, eosinophilic cytoplasm

    * ◦ Disparate tissues or cells, which are often recognizable without too much difficulty, may include spindled mesenchymal-type cells (Fig. 9.16A) or rare epithelium, which may be squamous (Fig. 9.16B) and/or adenomatous (Fig. 9.16C).

Fig. 9.16

Regional desmoplasia is a common finding in AT/RT with tissue culture type fibroblastic proliferati on (A), abrupt nests of squamous differentiation (B), and field of AT/RT containing a nest of squamous and glandular epithelium in the center (C), with a small amount of surrounding nondifferentiating, collagenous mesenchymal tissue and nests of primitive epithelial cells (upper left and lower right) (H&E, ×100)

    * ◦ Regional epithelial differentiation showing a papillary, adenomatous, or cordlike pattern (Fig. 9.17) may be seen. More commonly, evidence of epithelial differentiation is perceived only by antigen expression.

Fig. 9.17

Field of AT/RT comp osed of papillary structures and primitive neuroepithelial cells (H&E, ×100)

    * ◦ Regions of cells with prominent cytoplasmic vacuolization are frequent and should raise the differential diagnosis of AT/RT (Fig. 9.18).

Fig. 9.18

Regional cytoplasmic va cuolization is common and may involve large regions of an AT/RT (H&E, ×400)

    * ◦ Mesenchymal differentiation with a desmoplastic spindle cell pattern or frank sarcomatous differentiation may be seen (Fig. 9.19).

Fig. 9.19

Field consisting of elongated spindled cells resembling a sarcoma (H&E, ×250)

    * ◦ Mitotic activity is high, atypical mitoses can be readily identified, and cell wrapping may be seen.

    * ◦ A regional component of primitive neuroectodermal cells is frequently seen, but their presence is not required to reach a diagnosis of AT/RT. The fields of primitive neuroepithelial cells generally resembling the so-called classic medulloblastoma, which may exhibit Homer Wright rosettes, is seen in 60–70 % of AT/RTs.

    * ◦ Rarely, a classic neurotubular structure characteristic of medulloepithelioma is encountered.

    * ◦ The nodular architecture characteristic of desmoplastic or "neuroblastic" medulloblastoma is not found in AT/RTs, but distinguishing AT/RT from anaplastic and large cell medulloblastoma is challenging.

    * ◦ Tumors that occur in more than one site may exhibit histologic features that differ. For example, one may be composed entirely of rhabdoid cells, whereas another may be indisti nguishable from a PNET/medulloblastoma (PNET/MB).

## 9.5 Immunohistochemistry

  * The rhabdoid cells typic ally show immunopositivity for epithelial membrane antigen (EMA) (Fig. 9.20A) and vimentin (Fig. 9.20B), with variable expression of smooth muscle actin (SMA) (Fig. 9.20C).

Fig. 9.20

Photomicrographs of AT/RT demonstrating expression of various antigens: (A) Epithelial membrane antigen (EMA) (×400). (B) Vimentin (×400). (C) Smooth muscle actin (SMA) ( ×400). (D) AE1/AE3 pan-cytokeratin (keratin) (×400). (E) Glial fibrillary acidic protein (GFAP) (×250). (F) Synaptophysin (×400). (G) Neurofilament proteins (NFP) (×250). (H) INI1 (×400). Note positive immunostaining of the nuclei of endothelial cells and negative staining in tumor cells. (I, J) Fluorescence in situ hybridization (FISH) analysis of AT/RT shows heterozygous (allelic) deletion at the SMARCB1/INI1 (hSNF5) locus at 22q11.2 (I), with the ratio of the test probe (green) to the reference probe (red) ratio less than 0.8, and homozygous (biallelic) deletion at the SMARCB1/INI1 (hSNF5) locus at 22q11.2 (J). In this image, the test probe is red; the reference probe is green

  * Focal or regional positivity for cytokeratin (Fig. 9.20D), glial fibrillary acidic protein (GFAP) (Fig. 9.20E), and neuronal markers such as synaptophysin (Fig. 9.20F) and neurofilament proteins (NFP) (Fig. 9.20G) may be seen.

  * Immunostaining for SMARCB1/INI1 protein is negative in tumor cell nuclei but present in endothelial cell nuclei, which serve as an internal control (Fig. 9.20H).

    * ◦ Lack of expression of the INI1 antigen is most helpful in differentiating AT/RT from look-alikes and is an indication of the rhabdoid nature of the cells.

  * Ki-67 shows a high proliferation index, often rang ing between 25 % and 85 %.

## 9.6 Electron Microscopy

  * The characteristic ultrastructural feature of rhabdoid cells is the presence of whorls of interme diate filaments in the perikaryon (Figs. 9.21A and B).

Fig. 9.21

Ultrastructural fe atures of AT/RT: (A) Large mass of intracytoplasmic whorls of intermediate filaments (arrow). (B) Intracytoplasmic filaments (short arrow) and dilated endoplasmic reticulum (arrowhead). (C) Prominent cell junctions (arrow)

  * Undifferentiated neuroepithelial cells have a small cell body, most of which is occupied by the nucleus, with only a few organelles.

  * Differentiated neuroepithelial cells show intermediate filaments, microtubules, and/or dense core vesicles.

  * Epithelial cells exhibit desmosomes or longer junctions similar to zonulae adherentes, cilia, or other specific features of epithelial differentiation (Fig. 9.21C).

## 9.7 Differential Diagnosis

  * Major differential diagnoses include the classic type of PNET/MB, anaplastic and large cell medulloblasto ma, and choroid plexus carcinoma.

  * The divergent histologic features and immunophenotype often raise the possibility of a germ cell tumor, but the absence of differentiation into elements of the three germ layers can be helpful in distinguishing AT/RTs from germ cell tumors.

  * AT/RTs do not express desmin or germ cell markers such as alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-hCG).

  * Regions of cells with prominent cytoplasmic vacuolization may be a shared histologic feature with choroid plexus carcinoma and may be problematic with small biopsies, but choroid plexus carcinoma shows nuclear positivity for INI1 protein.

  * Interpretation of immunohistochemical findings may be complicated by the fact that PNET areas may express GFAP, NFP, vimentin, SMA, and, rarely, desmin. However, the primitive-appearing cells do not express EMA or keratin.

  * Biopsies with PNET-like features and negative nuclear staining for INI1 should be regarded as representing a PNET-like region of an AT/RT.

  * The neoplastic mesenchymal component in AT/RT may resemble a sarcoma. If this pattern predominates, it poses a major risk of misdiagnosis.

  * Tumors that occur in more than one site may exhibit histological features that differ. For example, one may be composed entirely of rhabdoid cells, whereas another may be indistinguishable from a PNET/MB.

  * Anaplastic or large cell medulloblastoma may mimic AT/RT but can be easily differentiated by nuclear positivity for INI1.

  * Rhabdoid meningioma shares th e rhabdoid morphology with AT/RT, but unlike AT/RT, it usually shows immunopositivity for INI1.

## 9.8 Molecular Pathology

  * A characteristic g enetic event seen in 85 % of AT/RTs involves the deletion of the SMARCB1/INI1 (hSNF5) locus at 22q11.2 and/or mutation of the INI gene (Fig. 9.20I).

  * Biallelic (homozygous) deletion (Fig. 9.20J) or mutation of one allele followed by the loss of the second allele during homologous recombination represents a mechanism of inactivation of INI1 expression.

  * Most of the mutations are nonsense or frameshift mutations leading to loss of expression of the INI1 protein.

  * Loss of expression of INI1 protein without demonstrable gene mutation or hypermethylation of the INI1 gene promoter region has been described.

  * Germline mutations involving the SMARCB1/hSNF5/INI1 gene are associated with a novel autosomal dominant syndrome, the rhabdoid predisposition syndrome (RPS), with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy. Some of these cases represent recurrent, interstitial deletions mediated by low copy repeats in 22q11.2, with a predisposition to cancer.

  * The spectrum of neoplasia that may be seen in RPS includes CNS AT/RTs, central PNETs, medulloblastoma, and choroid plexus carcinoma, as well as rhabdoid tumors in the kidneys and extrarenal tissues.

  * The mechanism of action of the wild-type INI protein in the prevention of neoplastic transformation is unclear.

  * Nonsense mutation and inactivation of SMARCA4 (BRG1) has been reported in a rare subset of AT/RTs showing no mutation of SMARCB1 and with retained nuclear expression of INI1 protein.

  * SMARCA4 is a subunit of several different SWI/SNF protein complexes. It enhances Notch-dependent proliferative signals, thereby promoting neural stem cell self-renewal and proliferation while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues.

## 9.9 Prognosis

  * Outcome in childr en less than 3 years of age is poor, with survival ranging between 11 months and 24 months.

  * Gene expression studies have identified two subgroups of AT/RTs with differing genetic signatures:

    * ◦ Group 1 AT/RTs are predominantly supratentorial and are highly enriched for genes involved in brain or neural development and axonal guidance, with upregulation of NOTCH developmental signaling pathway genes including FABP725 and ASCL1, which are markers of primitive neural lineage.

    * ◦ Group 2 AT/RTs are predominantly infratentorial and show enrichment of genes involved in mesenchymal differentiation and the bone morphogenetic protein (BMP) signaling pathway, including the BMP4, BAMBI, SOST, SERPINF1, FBN2, and MSX1 loci. Mitogen-activated protein kinase (MAPK) signaling pathway genes and genes regulating cell adhesion and migration are also enriched in group 2 tumors.

  * Expression of ASCL shows correlation with supratentorial location and superior 5-year overall survival.

  * Integrated analyses of molecular subgroupings with clinical prognostic factors has demonstrated three distinct clinical risk groups of tumors with different therapeutic outcomes:

    * ◦ Localized supratentorial tumor with high ASCL1 expression and complete surgical resection identifies a favorable risk category with a projected 5-year progression-free survival and overall survival of 60 %.

    * ◦ Metastatic or subtotally resected infratentorial tumor with no ASCL1 expression represents the worst prognostic group, with greater than 80 % mortality within 24 months.

    * ◦ High-risk patients with ASCL1-positivity, localized but subtotally resected supratentorial or infratentorial tumors, have intermediate outcome and progression.

  * CSF dissemination is a frequent terminal event (Fig. 9.22).

Fig. 9.22

Cluster of malignant cel ls in the CSF in a patient with disseminated AT/RT

  * Long-term survival has been observed i n some patients with AT/RTs in the setting of rhabdoid predisposition syndrome (RPS) .

Suggested Reading

Ammerlaan AC, Ararou A, Houben MP, Baas F, Tijssen CC, Teepen JL, et al. Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome. Br J Cancer. 2008;98:474–9.CrossRefPubMed

Burger PC, Yu IT, Tihan T, Friedman HS, Strother DR, Kepner JL, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol. 1998;22:1083–92.CrossRefPubMed

Giangaspero F, Rigobello L, Badiali M, Loda M, Andrieini L, Basso G, et al. Large cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol. 1992;16:687–93.CrossRefPubMed

Jackson EM, Shaikh TH, Gururangan S, Jones MC, Malkin D, Nikkel SM, et al. High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor. Hum Genet. 2007;122:117–27.CrossRefPubMed

Judkins AR, Mauger J, Rorke LB, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28:644–50.CrossRefPubMed

Judkins AR, Burger PC, Hamilton RL, Kleinschmidt-DeMasters B, Perry A, Pomeroy SL, et al. INI 1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol. 2005;64:391–7.CrossRefPubMed

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer (IARC); 2016.

Manhoff DT, Rorke LB, Yachnis AT. Primary intracranial atypical teratoid/rhabdoid tumor in a child with Canavan disease. Pediatr Neurosurg. 1995;22:214–22.CrossRefPubMed

Meyers SP, Khademian ZP, Biegel JA, Chuang SH, Korones DN, Zimmerman RA. Primary intracranial atypical teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes. AJNR Am J Neuroradiol. 2006;27:962–71.PubMed

Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56–65.CrossRefPubMed

Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet. 1999;65:1342–8.CrossRefPubMedPubMedCentral

Torchia J, Picard D, Lafay-Cousin L, Hawkins CE, Kim SK, Letourneau L, et al. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol. 2015;16:569–82.CrossRef70114-2)PubMed

# Part III
Tumors of the Meninges
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_10

# 10. Meningiomas

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

MeningiomaAtypical meningiomaAnaplastic meningiomaRhabdoid meningiomaPapillary meningiomaChordoid meningiomaClear cell meningiomaNeurofibromatosis type 2

## 10.1 Overview

  * Meningiomas are dural-based neoplasms derived from meningothelial (arachnoid) cells; they include a wide variety of histologic subtypes, ranging from benign WHO grade I variants to more biologically aggressive meningiomas encompassing WHO grades II and III.

  * Many pediatric meningiomas are sporadic, but a significant proportion arise in the context of a hereditary cancer predisposition syndrome, especially neurofibromatosis type 2 (NF2).

    * ◦Multiplicity of meningiomas is not uncommon in NF2, and the pediatric onset of meningioma should prompt further evaluation for clinical and genetic findings diagnostic of NF2.

    * ◦ Meningiomas are infrequently encountered with Gorlin syndrome. Recently, germline mutations involving SWI/SNF chromatic remodeling complex have been implicated in meningiomas. SMARCE1 mutations have been identified as a cause of clear cell meningiomas (both intracranial and spinal), and about 5 % of patients with schwannomatosis (due to SMARCB1 mutations) will also develop meningiomas.

  * Exposure to radiotherapy for prior neoplasm is another significant predisposing factor in the development of meningiomas, particularly within the pediatric age group.

## 10.2 Clinical Features

  * Though meningiomas are quite common in adults, they infrequently arise in the pediatric population, acco unting for less than 3 % of all intracranial tumors in that age group.

  * Pediatric meningiomas are more common in males, in contrast to the female predominance encountered in adults.

  * Specific manifestations depend on the tumor site and compression of adjacent structures. Signs and symptoms related to chronically elevated intracranial pressure (headaches, vomiting, papilledema), cranial nerve disorders and other focal neurologic deficits, and seizures have been reported in these children. Spinal meningiomas may present with pain, limb weakness and/or paresthesia, or gait disturbance, and are frequently associated with NF2.

## 10.3 Neuroimaging

  * In children, meningiomas most frequently arise at intracranial locations, including over the cerebral convexities, in parasagittal or parasellar regions, or at the cerebellopontine angle (Fig. 10.1). Intraventricular and intraparenchymal meningiomas are more frequent in the pediatric age group.

Fig. 10.1

T1-weighted post-gadolinium (post-Gd) axial (A) and coronal (B) MR images showing homogeneously enhancing pediatric meningiomas arising over the cerebral convexities and within the cerebellopontine angle, respectively. Note the characteristic "dural tail" in both images

  * Pediatric skull base meningiomas tend to be smaller at presentation, but are less likely to undergo complete resection.

  * Spinal meningiomas in children are most frequent at cervical or thoracic levels.

  * By MR imaging, most meningiomas are isointense to hypointense to gray matter on T1, hyperintense on T2 and FLAIR, and are accentuated strongly after contrast administration (Fig. 10.2A–E). The characteristic "dural tail" may be seen in over 50 % of cases. Over 20 % may have a large cystic component.

Fig. 10.2

This 8-year-old boy had a quite large parasagittal multilobulated, dural-based mass with solid and cystic components in the right posterior parietal lobe. The solid component showed heterogeneous signal intensity, being isointense to hypointense to cortex on T1-weighted MR imaging (A) and hyperintense on T2-weighted MRI (B) and FLAIR (C); it showed heterogeneous enhancement on T1-weighted post-Gd axial MR images (D). Note the accompanying peritumoral edema and midline shift, seen best in B and C. A sagittal T1-weighted post-Gd image (E) shows thickening (hyperostosis) of the overlying calvarial bone and scalp edema. Angiography (F) shows prominent tumor blush, with feeding vasculature arising from the right middle meningeal artery

  * Surrounding vasogenic edema frequently accompanies meningiomas, and is generally proportionate to tumor size (Fig. 10.2B and C); angiomatous, microcystic, or higher-grade variants may have disproportionate edema relative to their size. Intratumoral calcifications, hemorrhage, or necrosis are uncommon findings.

  * Invasion of adjacent cranial bone may cause hyperostosis, readily identifiable on imaging studies (Fig. 10.2E).

  * Angiography (typically performed when embolization is planned) shows a hypervascular tumor blush throughout the arterial phase of the middle meningeal artery injection, persisting into the late venous phase with slow washout (Fig. 10.2F).

  * Tumor seeding along the surgical trajectory, through CSF dissemination, or by metastases outside the CNS is encountered rarely; though more frequent with higher-grade tumors, histologically benign meningiomas have exhibited such behaviors.

## 10.4 Pathology

  * Gross pathology

    * ◦ Meningiomas are gene rally round or lobulated tan-yellow, firm masses (Fig. 10.3), frequently with dural attachment. Some tumors (usually skull-base lesions) grow in a flat "en plaque" pattern. A granular appearance may indicate psammoma bodies.

Fig. 10.3

Typical macroscopic appearance of meningioma, arising from the dura as a well-circumscribed, firm mass

    * ◦ Encasement of adjacent nerves or blood vessels, or invasion into bone or soft tissue, may be encountered.

    * ◦ WHO grade II and III meningiomas are usually larger and may contain areas of necrosis.

  * Intraoperative cytologic imprints or smears

    * ◦ Cytologic smears or squa sh preparations show cohesive, syncytial clusters of cells with oval to round nuclei (Fig. 10.4A).

Fig. 10.4

Helpful cytologic features that may be encountered on crush/squash preparations of meningioma inc lude the findings of cohesive syncytial clusters (A), whorls (B), and psammoma bodies (C). Careful inspection often reveals intranuclear cytoplasmic invaginations or pseudoinclusions, as seen here centrally (D). Similar findings are demonstrable on both conventional H&E (A–D) and Diff-Quik stained preparations (E, F)

    * ◦ Classic "whorl" formations, intranuclear cytoplasmic invaginations, and psammoma bodies are other helpful diagnostic features (Fig. 10.4B–F).

    * ◦ Unfortunately, cytologic preparations from several meningioma variants may pose a significant diagnostic challenge. For instance, the fibrous variant (Fig. 10.5A) with its elongated spindle cells, may mimic glioma, whereas the papillary variant (Fig. 10.5B) may be confused with carcinoma, and the rhabdoid variant (Fig. 10.5C) may be confused with atypical teratoid/rhabdoid tumor (AT/RT). Nuclear anaplasia, macronucleoli, mitoses, and shee ting suggest a higher-grade lesion.

Fig. 10.5

(A) Squash preparation of a fibr ous meningioma, showing elongated, spindled cells. (B) Papillary structures with multilayered covering of epithelioid cells may be seen in cytologic preparations of papillary meningioma. (C) Squash preparation of rhabdoid meningioma, containing discohesive cells with eccentrically situated nuclei and eosinophilic cytoplasmic "bellies," may be reminiscent of atypical teratoid/rhabdoid tumor (AT/RT)

  * Histology

    * ◦ Numerous meningioma histologic variants have been recognized. In general, WHO grade I meningiomas carry a low risk of recurrence and behave in a benign fashion, whereas WHO grade II and III tumors carry an incrementally higher likelihood of recurrence and aggressive behavior.

    * ◦ The higher-grade variants are notably more frequent in the pediatric population.

      * Note that pleomorphi c nuclei may be encountered in any of the meningioma variants, most often connoting a degenerative atypia as opposed to higher tumor grade.

    * ◦ WHO grade I variants

      * Meningothelial meningioma

        * Common variant with lobular architecture; these lobules contain syncytial arrays of cells with uniform, oval nuclei, often with intranuclear-cytoplasmic inclusions. Whorls and psammoma bodies are infrequent (Fig. 10.6A and B).

Fig. 10.6

Common WHO grade I variants. The meningothelial variant of meningioma is multilobular (A), containing syncytial arrays of cells with imperceptible cell borders and uniform oval nuclei, often containing intranuclear-cytoplasmic inclusions (B). Whorls are uncommon and poorly formed, and psammoma bodies are uncommon. Fibrous meningioma contains interwoven broad fascicles of bland spindle cells (C), often with multiple clear clefts amongst the fascicles (D); collagen content is variable. Transitional meningioma shows features of both the fibrous and meningothelial variants (E), typically containing numerous tight whorl formations (F) and numerous psammoma bodies (G). Striking nuclear pleomorphism may be encountered in any meningioma (H), though in the absence of other histologic features indicative of grade II or III designation, these should be viewed as degenerative in nature

      * Fibrous meningioma

        * These contain spindle cells arranged in parallel fascicles with an interwoven collagen matrix, which on occasion may be quite dense.

        * Focal intranuclear cytoplasmic inclusions and psammoma bodies may be seen (Fig. 10.6C and D).

      * Transitional (mixed) meningioma

        * By far the most recogniza ble variant, transitional meningiomas display a mixture of both meningothelial and fibrous patterns with numerous whorls and psammoma bodies (Fig. 10.6E–H).

    * WHO grade I variants uncommon in children

      * Psammomatous meningioma

        * These tumors contain more psammoma bodies than meningothelial tumor cells, the former often coalescing to form large calcified areas.

        * Whorl formations are common (Fig. 10.7A).

Fig. 10.7

Other WHO grade I variants. ( A ) In psammomatous meningioma, psammoma bodies may be so numerous as to make identification of the neoplastic meningothelium difficult. (B) Angiomatous meningioma contains numerous variably sized blood vessels, sometimes hyalinized, with a tendency for nuclear pleomorphism. (C) In addition to the numerous microcystic spaces, easily recognizable meningothelial cells are seen in this microcystic meningioma. (D) Secretory meningiomas contain islands of obvious epithelial differentiation. (E) Periodic acid–Schiff (PAS)–positive pseudopsammoma b odies are also found in secretory meningiomas. (F) Carcinoembryonic antigen (CEA)–positive pseudopsammoma bodies are another finding. (G) Metaplastic changes may also be seen in meningioma, as in this example with metaplastic bone formation

      * Angiomatous meningioma

        * Typified by more vascular structures than tumor cells, these tumors harbor abundant small- to medium-caliber, often hyalinized blood vessels of variable wall thickness.

        * Degenerative nuclear atypia may be marked (Fig. 10.7B).

      * Microcystic meningioma

        * Contain numerous intercellular microcystic spaces, sometimes containing eosinophilic mucinous secretions.

        * Similar to the angiomatous variant, nuclear pleomorphism may be a prominent feature (Fig. 10.7C).

      * Secretory meningioma

        * This variant is marked by the presence of focal epithelial differentiation consisting of intracellular lumens containing eosinophilic, periodic acid–Schiff (PAS)–positive secretions (pseudopsammoma bodies) (Fig. 10.7D and E).

        * These structures are also positive for carcinoembryonic antigen (CEA) (Fig. 10.7F).

        * Mast cells may be conspicuous.

      * Lymphoplasmacyte-rich meningioma

        * In this extremely rare variant, extensive chronic inflammatory cell infiltrate typically overshadows the meningothelial cells.

      * Metaplastic meningioma

        * These tumors contain mesenchymal components in the form of bone, cartilage, lipid, or myxoid tissues (Fig. 10.7G). Xanthomatous areas also may be present.

    * ◦ WHO grade II variants

      * Atypical meningioma

        * By definition, this is a meningioma with increased mitotic rate (>4/10 hpf in the area of highest mitotic activity) or at least three of the following histologic findings:

          * Hypercellularity

          * Small cell change

          * Prominent nucleoli

          * Sheet-like growth pattern

          * Foci of spontaneous or geographic necrosis (i.e., not induced by therapeutic embolization) (Fig. 10.8A–D)

Fig. 10.8

Microscopic feature s of atypical meningioma (WHO grade II) may include elevated mitotic rate and/or three or more of the following features: hypercellularity, small cell chan ge (A), prominent nucleoli (B), sheeting architecture (C), and foci of spontaneous necrosis (D). Brain-invasive meningiomas (E) have a rate of recurrence similar to atypical meningioma

        * From a prognostic standpoint, m eningiomas that are histologically benign (grade I) but show definite brain invasion should also be considered WHO grade II, as they have been documented as showing recurrence and mortality rates akin to other grade II meningiomas.

        * Brain-invasive m eningiomas will show tongue-like projections of tumor infiltrating into the underlying brain parenchyma (Fig. 10.8E).

      * Chordoid meningioma

        * Chordoid meningiomas are composed of cords and trabeculae of e osinophilic cells, sometimes with cytoplasmic vacuolization, within a mucoid or myxoid background closely mimicking chordoma (Fig. 10.9).

Fig. 10.9

With its distinctive cordlike a rchitecture (A), chordoid meningioma (WHO grade II) superficially resembles chordoma, but closer inspection reveals that it lacks the bubbly, physaliferous cells of that entity (B)

        * Most show mixing of this chordoid pattern with more typical meningioma morphology; pure examples are quite rare.

        * These tend to be large, supratentorial tumors typified by a high rate of recurrence if not completely resected.

      * Clear cell meningioma

        * Clear cell meningioma is a rare, aggressive meningioma variant, more common in children, containing cells with abundant clear glycogen-rich (PAS-positive) cytoplasm.

        * Dense "blocky" accumulations of collagen are a frequent finding (Fig. 10.10).

Fig. 10.10

A fascicular architect ure with occasional vague whorls is seen in clear cell meningioma, WHO grade II (A). Dense collagen blocks are a helpful diagnostic clue seen in most cases (B)

        * Psammoma bodies and whorl formations are not typical features.

        * Clear cell meningiomas tend to involve the cerebellopontine angle and spinal or cauda equina region. They frequently recur and may even show CSF dissemination.

    * ◦ WHO grade III variants

      * Anaplastic (malignant) meningioma

        * Anaplastic meningioma contains one or both of these obviously malignant histologic features:

          * Malignant cytol ogy (may resemble carcinoma, sarcoma, or melanoma) (Fig. 10.11A)

Fig. 10.11

Often barely reco gnizable as meningioma, anaplastic meningioma (WHO grade III) may resemble sarcoma, carcinoma, or melanoma (A) and may have a brisk mitotic index (B)

          * Markedly elevated mitotic index, defined as >20 mitoses/10 hpf (Fig. 10.11B).

        * Scattered regions showing at least vaguely recognizable meningioma architecture can be found in most examples, though rarely these lesions prove formidable diagnostic dilemmas necessitating extensive immunohistochemical, ultrastructural, and even molecular workup.

        * Although brain invasion is frequently (though not always) present, this feature alone is not sufficient to warrant a WHO grade III designation. (See note above under "Atypical meningioma".)

      * Papillary meningioma

        * This rare variant, more fre quent in young patients, shows a prominent pseudopapillary pattern (Fig. 10.12A and B)

Fig. 10.12

(A, B) Papillary meningioma (WHO grade III) contains broad, fibrovascular cores covered by neoplastic meningothelium . A careful search of tissue from these tumors should reveal at least few foci recognizable as meningioma

      * Rhabdoid meningioma

        * This uncommon variant, similarly more frequent in children, contains "rhabdoid cells" with eccentrically situated vesicular nuclei that often contain prominent nucleoli, and abundant eosinophilic cytoplasmic "bellies," many showing obvious globular or whorled inclusions (Fig. 10.13).

Fig. 10.13

(A, B) Rhabdoid meni ngioma (WHO grade III) characteristically contains discohesive nests of cells with eccentric nuclei, often with vesicular chromatin pattern and prominent nucleoli, in addition to eosinophilic cytoplasmic "bellies." Areas more r ecognizable as meningioma are usually identifiable elsewhere within these tumors, though this rhabdoid morphology may be the predominant morphology in some cases

        * The cells of this "rhabdoid phenotype" closely mimic those encountered in AT/RT and renal or extrarenal rhabdoid tumors, with definitive differentiation often requiring immunohistochemistry and/or molecular determination of INI1/BAF47 status. (See below for differential diagnosis.)

        * A mixture of rh abdoid cells and papillary/pseudopapillary architecture may be encountered.

        * Rhabdoid meningiomas frequently exhibit a high proliferative index and other aggressive histologic features.

## 10.5 Immunohistochemistry

  * Epithelial membrane antigen (EMA) and vimentin are positive in nearly all meningiomas (Fig. 10.14A), but some variants, particularly fibroblastic and higher-grade meningiomas, may show only faint, focal EMA staining.

Fig. 10.14

(A) Meningiom as are consistently immunopositive for epithelial membrane antigen (EMA). (B) Rhabdoid meningioma shows retained nuclear staining for INI1/BAF47 by immunohistoc hemistry; in true rhabdoid tumor or AT/RT, this nuclear staining is lost. (C) Meningioma ultrastructural findings include intercellular interdigitations and desmosomes

  * Claudin-1, a structural protein found in tight junctions, is detectable in up to 85 % of meningiomas and may be especially useful in diagnostically equivocal cases in which EMA staining is weak.

  * S-100 staining is variable.

  * Strong staining for CEA is typical of the pseudopsammoma bodies of secretory meningioma (Fig. 10.7F).

  * Ki-67, progesterone receptor (PR), and phosphohistone H3 (PHH3, a mitosis-specific antibody) staining may be useful from a prognostic standpoint. (See below.)

## 10.6 Electron Microscopy

  * Most meningiomas con tain intercellular complexes including desmosomes and interdigitations, as well as abundant intermediate filaments (Fig. 10.14C).

    * ◦ These features may be inconspicuous in the fibrous variant.

    * ◦ Microlumina, often with microvilli, are seen in secretory meningiomas.

## 10.7 Molecular Pathology

  * Alterations of various protei n 4.1 superfamily members are commonplace in meningiomas.

    * ◦ Inactivation of the neurofibromatosis 2 (NF2) gene on 22q12 and loss of its protein product merlin are detected in approximately half of sporadic meningiomas and nearly all NF2-associated meningiomas.

    * ◦ NF2 alterations are encountered in certain histologic variants (fibrous, transitional, and psammomatous) more frequently than in others (meningothelial).

    * ◦ Deletions involving protein 4.1B (DAL-1 or "differentially expressed in adenocarcinoma of the lung") are seen at a similar frequency overall in meningiomas, including pediatric examples.

    * ◦ Though the above alterations have not been shown to have prognostic relevance independent of histologic grading, their detection may be helpful from a diagnostic standpoint in selected cases (see below).

  * Multiplicity of the above abnormalities is more frequent in atypical and malignant meningiomas.

  * Deletions of chromosomes 1p and 14q are frequent in pediatric and NF2-associated meningiomas, often accompanying other aggressive histologic features and a tendency for recurrence.

  * A strong association between clear cell meningioma and mutations involving SMARCE1 has been recently reported.

  * In pediatric radiation-induced meningiomas, chromosome 1p deletion and loss of 22q12.2 have also been reported.

## 10.8 Differential Diagnosis

  * Spindle-cell lesions such as s chwannoma, solitary fibrous tumor, and hemangiopericytoma may resemble meningiomas, particularly the fibrous variant.

    * ◦ Unlike meningiomas, schwannomas are diffusely positive for S-100, and solitary fibrous tumors will be diffusely positive for CD34.

    * ◦ Hemangiopericytomas are more variable in their immunolabeling, with possible staining for EMA, vimentin, CD34, and factor XIIIa, to a greater or lesser extent. They will, however, show the ultrastructural feature of pericellular basement membrane material (similar to schwannoma), a feature not present in meningiomas.

  * Renal cell carcinoma may be distinguished from clear cell meningioma by virtue of its diffuse immunopositivity for cytokeratin; CD10, RCC-marker antibody, PAX2, and PAX8 may likewise be helpful.

    * ◦ Hemangioblastoma, another clear cell lesion, is positive for alpha inhibin and D2-40 and is generally EMA-negative. Careful inspection should divulge characteristic bubbly stromal cells.

  * Chordoid meningioma may closely mimic its namesake chordoma, but chordoma will show diffuse S-100 and cytokeratin positivity and contains typical physaliferous cells.

  * Though meningiomas may be quite vascular, they differ from arteriovenous malformations and other vascular lesions in that they contain meningothelial cells.

  * Grade III (anaplastic, rhabdoid, and papillary) meningiomas may frequently prove quite difficult to diagnose, as they may show significant histologic and even immunohistoch emical overlap with other high-grade neoplasms, including sarcomas, hemangiopericytomas, high-grade gliomas, AT/RT, and choroid plexus carcinoma.

    * ◦ Detection of deletions of 22q (NF2), 18p (Dal1), 1p, or 14q by fluorescence in situ hybridization (FISH) analysis would provide additional support for classification as meningioma in these instances, as these a lterations are not expected in the other tumors.

    * ◦ Immunohistochemical and/or molecular determination of INI1/BAF47 status is specifically helpful for differe ntiating rhabdoid meningioma from AT/RT, as INI1 should be lost (that is, not expressed) in AT/RT. Immunohistochemistry has been found to be a more reliable method in this instance, as deletions involving 22q are common to both tumor types, whereas INI1/BAF47 immunopositivity should be retained in rhabdoid meningiomas but not in AT/RT (Fig. 10.14B).

  * Melanocytoma may mimic benign meningioma, and malignant melanoma may mimic anaplastic/malignant meningioma. Unlike anaplastic meningioma, both of the melanocytic tumors are characteristically positive for S-100, HMB-45, and MART1, and negative for EMA.

  * Dural-based metastatic carcinomas, including choroid plexus carcinoma, may be effectively differentiated from meningiomas by virtue of their diffuse cytokeratin positivity.

## 10.9 Prognosis

  * Compared with meningiomas in adults, pediatric meningiomas generally have a poorer prognosis. The degree of initial tumor resection (dictated in part by tumor location), pathologic grade, and association with NF2 are the most important factors influencing prognosis in individual children.

  * Recurrence-free survival time is significantly related to WHO grade, but this does not appear to be the case for overall survival.

  * WHO grade III meningiomas, including anaplastic, rhabdoid, and papillary meningiomas, are all notable for markedly aggressive biologic behavior, typified by frequent invasion of brain and other nearby tissue, a higher rate of metastasis outside the CNS, and short recurrence-free and overall survival. Median overall survival is typically less than 2 years for adults with this tumor cohort, but it has not been well established in the pediatric population.

  * Radiation-associated pediatric meningiomas have an increased incidence of multiplicity at first presentation, as well as more frequent aggressive histologic variants.

  * Spinal pediatric meningiomas are frequent in association with NF2 and/or higher WHO grade subtype; they likewise have a higher propensity for recurrence.

Suggested Reading

Arivazhagan A, Devi BI, Kolluri SV, Abraham RG, Sampath S, Chandramouli BA. Pediatric intracranial meningiomas—do they differ from their counterparts in adults? Pediatr Neurosurg. 2008;44:43–8.CrossRefPubMed

Burkhardt JK, Neidert MC, Grotzer MA, Krayenbuhl N, Bozinov O. Surgical resection of pediatric skull base meningiomas. Childs Nerv Syst. 2013;29:83–7.CrossRefPubMed

Cai DX, Banerjee R, Scheithauer BW, Lohse CM, Kleinschmidt-Demasters BK, Perry A. Chromosome 1p and 14 q FISH analysis in clinico-pathologic subsets of meningioma: diagnostic and prognostic implications. J Neuropathol Exp Neurol. 2001;60:628–36.CrossRefPubMed

Elbabaa SK, Gokden M, Crawford JR, Kesari S, Saad AG. Radiation-associated meningiomas in children: clinical, pathological, and cytogenetic characteristics with a critical review of the literature. J Neurosurg Pediatr. 2012;10:281–90.CrossRefPubMed

Gasparetto EL, da Costa Leite C, Lucato LT, Barros CV, Marie SK, Santana P, et al. Intracranial meningiomas: magnetic resonance imaging findings in 78 cases. Arq Neuropsiquiatr. 2007;65:610–4.CrossRefPubMed

Lakhdar F, Arkha Y, El Ouahabi A, Melhaoui A, Rifi L, Derraz S, et al. Intracranial meningioma in children: different from adult forms? A series of 21 cases. Neurochirurgie. 2010;56:309–14.CrossRefPubMed

Liu Y, Li F, Zhu S, Liu M, Wu C. Clinical features and treatment of meningiomas in children: report of 12 cases and literature review. Pediatr Neurosurg. 2008;44:112–7.CrossRefPubMed

Perry A, Scheithauer BW, Stafford SL, Lohse CM, Wollan PC. "Malignancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer. 1999;85:2046–56.PubMed

Perry A, Giannini C, Raghavan R, Scheithauer BW, Banerjee R, Margraf L, et al. Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases. J Neuropathol Exp Neurol. 2001;60:994–1003.CrossRefPubMed

Pinto PS, Huisman TA, Ahn E, Jordan LC, Burger P, Cohen KJ, et al. Magnetic resonance imaging features of meningiomas in children and young adults: a retrospective analysis. J Neuroradiol. 2012;39:218–26.CrossRefPubMed

Raffalli-Ebezant H, Rutherford SA, Stivaros S, Kelsey A, Smith M, Evans DG, et al. Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case. Childs Nerv Syst. 2015;31:441–7.CrossRefPubMed

Rushing EJ, Olsen C, Mena H, Rueda ME, Lee YS, Keating RF, et al. Central nervous system meningiomas in the first two decades of life: a clinicopathological analysis of 87 patients. J Neurosurg. 2005;103:489–95.PubMed

Siddiqui MT, Mahon BM, Cochran E, Garruso P. Cytologic features of meningiomas on crush preparations: a review. Diagn Cytopathol. 2008;36:202–6.CrossRefPubMed

Smith MJ. Germline and somatic mutations in meningiomas. Cancer Genet. 2015;208:107–14.CrossRefPubMed

Stanuszek A, Piatek P, Kwiatkowski S, Adamek D. Multiple faces of children and juvenile meningiomas: a report of single-center experience and review of literature. Clin Neurol Neurosurg. 2014;118:69–75.CrossRefPubMed

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_11

# 11. Hemangiopericytoma and Other Mesenchymal Tumors

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

HemangiopericytomaAnaplastic hemangiopericytomaLipomaRhabdomyosarcomaEwing/PNET

## 11.1 Overview

  * A variety of mesenchymal tu mors, both benign and malignant, may occur within the CNS, most arising from the dura/meninges. These lesions are histologically identical to their non-CNS counterparts, and are thus named accordingly. Meningeal hemangiopericytoma (HPC) and the microscopically similar solitary fibrous tumor (SFT) are b y far the most commonly encountered tumors of this group.

  * Meningeal HPCs are highly cellular mesenchymal tumors exhibiting characteristic "staghorn" vasculature, akin to their soft-tissue counterparts.

    * ◦ Their definite cell of origin is uncertain; it has been suggested that they may be close relatives to SFTs.

  * In older terminology, HPCs were considered a variant of angioblastic meningioma. Though the 2007 WHO recognized hemangiopericytomas (grade II) and anaplastic hemangiopericytomas (grade III) as distinct from SFTs, given their markedly different biologic behaviors, subsequent genetic evidence indicates that these lesions are more closely related and may in fact represent a spectrum of the same entity.

  * Sarcomas may arise de novo or following cranial irradiation or previous trauma.

  * The antiquated term "meningeal sarcoma" should be avoided, as this term was previously used to describe a wide array of lesions including true sarcomas, as well as anaplastic/malignant meningiomas.

## 11.2 Clinical Features

  * The spectrum of clinical signs and symptoms generally mirrors that described for meningiomas, as th ese tumors present as dura l-based lesions and the clinical features depend largely on lesion localization.

  * Hemangiopericytomas

    * ◦ HPCs are quite uncommon in all age groups, representing less than 1 % of all CNS tumors and less than 3 % of dural-based lesions, but they are the most common mesenchymal, non-meningothelial primary CNS sarcoma.

    * ◦ They have a peak age range within the third and fourth decades, and arise less frequently in the elderly and pediatric age groups. Rare congenital lesions have been described.

    * ◦ There is a slight male predominance.

    * ◦ They may rarely present with acute intratumoral hemorrhage.

  * Solitary fibrous tumor

    * ◦ Most SFTs are dural-based, singular tumors, which are supratentorial more often than infratentorial.

    * ◦ Similar to meningiomas, they show a female predominance.

    * ◦ Most arise in young to middle-aged adults; few pediatric cases are reported.

  * Rhabdomyosarcoma and Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET) occur predominantly in children.

  * Meningeal fibromas arise most often in those less than 20 years of age and show a male predominance.

## 11.3 Neuroimaging

  * Hemangiopericytomas

    * ◦ HPCs are most commonly located intracrani ally, attached to dura in parasagittal and falcine regions; less frequently, they involve spinal dura. Rare intraparenchymal, intraventricular, and optic nerve sheath examples have been reported.

    * ◦ Unlike meningiomas, they are almost always solitary and do not contain calcifications. They may be solid or have cystic components, and have a predilection for proximity to venous sinuses.

    * ◦ Neuroimaging studies (both CT and MRI) show them to be dural-attached tumors that are lobulated or have irregular margins, with heterogeneous enhancement following contrast administration (Fig. 11.1A and B). They are most typically isointense on T1-weighted imaging and show heterogeneous high signal on T2-weighted imaging (Fig. 11.1B and C). Prominent intratumoral flow voids, peritumoral edema, and dural tail are other common findings.

Fig. 11.1

( A ) Coronal T1-weighted, post-gadolinium MR image of a small, parasagittal hemangiopericytoma (HPC) showing homogeneous contrast enhancement of this dural-based nodule. ( B ) Coronal T1-weighted post-Gd MR image of a huge HPC with solid and cystic areas and heterogeneous contrast enhancement. ( C ) Axial T2-weighted imaging from the same tumor shows heterogeneous signal intensity and multiple cysts. ( D ) Venous-phase angiography highlights tortuous feeder vessels entering this highly vascular lesion. ( E ) Coronal T1-weighted post-Gd MR image of a solitary fibrous tumor (SFT), arising as a homogeneously enhancing dural-based nodule (E , courtesy of Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA)

  * Angiography typically reveals extensive tumoral vascularity, often with dual cortical and meningeal supply, and sometimes corkscrew-shaped feeding vessels (Fig. 11.1D).

    * ◦ Skull base tumors may mimic aggressive primary bone tumors such as Ewing sarcoma, showing lytic destruction rather than the hyperostosis typical of meningioma.

  * Solitary fibrous tumors

    * ◦ SFTs appear as solitary, well-defined, rounded dural-based masses with hypointense, isointense, or mixed signal intensity on T1-weighted MRI. On T2-weighted MRI, a "black and white mixed" pattern of signal intensity may be seen, with heterogeneous contrast enhancement. Thickening of the meninges adjacent to the tumor is not uncommon (Fig. 11.1E).

  * Lipomas are the most common of the benign mesenchymal lesions, showing both intracranial (midline) and spinal localization and appearing as circumscribed lesions with high signal intensity on T1-weighted MR images.

  * Most sarcomas are supratentorial, except for rhabdomyosarcomas, which are often infratentorial.

  * Chondrosarcomas tend to arise in the region of the base of the skull.

  * Meningeal Ewing sarcoma may present as a heterogeneously enhancing lesion with a thick dural tail, often with skull and scalp erosion.

## 11.4 Pathology

  * Gross pathology

    * ◦ Resection specimens of HPCs and other sarcomas are usually composed of firm, fleshy to overtly hemorrhagic tissue, necrotic tissue, or both. HPCs often show grossly visible vascular spaces, and some show brain invasion.

    * ◦ Lipomas are bright yellow and lobulated.

  * Intraoperative cytologic imprints or smears

    * ◦ HPCs are notable for cells with oval to spindled nuclear profiles, inconspicuous nucleoli, and a "ferning out" of blood vessels (Fig. 11.2A).

Fig. 11.2

(A) Cytologic smear p reparation of HPC showing patternless sheets of spindled cells; whorls and intranuclear cytoplasmic invaginations (pseudoinclusions) are not present. (B, C) Typical histologic appearance of HPC showing randomly oriented, spindled cells with scant cytoplasm and indistinct cell borders, and the characteristic "staghorn" gaping vasculature. (D) Nuclei are fairly monotonous, with indistinct tiny nucleoli and a lack of nuclear pseudoinclusions. (E) Abundant reticulin is present, including investments around individual tumor cells

    * ◦ Sarcomas are quite variable in their cytomorphologic appearance. They most often contain variably pleomorphic, spindled cells, sometimes with identifiable mitoses, and a necrotic and/or hemorrhagic background.

    * ◦ Smear preps of lipomas show only mature adipocytes.

  * Histology

    * ◦ Meningeal HPCs re semble their non-CNS counterparts, with a number of typical findings:

      * A monomorphous population of randomly oriented oval to spindle-shaped cells with scant cytoplasm, indistinct cell borders, and a lack of nuclear pseudoinclusions or nucleoli (Fig. 11.2B and D).

      * Numerous thin-walled gaping vascular spaces in a characteristic "staghorn" configuration (Fig. 11.2B and C).

      * A rich reticulin network, with reticulin fibers surrounding individual tumor cells, is frequently present (Fig. 11.2E). Hyalinization and/or myxoid change may be seen, though it is more frequent in SFTs.

      * Anaplastic HPC (WHO grade III) harbors necrosis and/or an elevated mitotic rate (>5 mitoses per 10 high power fields) and at least two of the following features: hemorrhage, nuclear atypia, and hypercellularity (Fig. 11.3).

Fig. 11.3

Anaplastic HPCs have increased mitotic activity (A) and may have notable nuclear pleomorphism (B)

      * Areas of hypercellularity may be interrupted by more sparsely cellular regions with fibrosis, imparting a biphasic pattern.

      * Infiltration of adjacent bone or brain parenchyma is common; necrosis is uncommon, and calcifications are not seen.

    * ◦ SFTs show heterogen eous architecture with a mixture of alternating hypocellular and hypercellular areas.

      * A "patternless pattern" of spindle cells contains prominent bands of collagen, often with hyalinization.

      * Staghorn vasculature is present, at least focally, in most cases.

      * Reticulin deposition may be seen, generally surrounding tumor cell groups rather than around individual tumor cells.

    * ◦ The spectrum of mesenchymal tumors particularly arising in the pediatric age group is broad and includes benign lesions such as fibroma, fibrous histiocytoma, lipoma, fibromatosis, and a wide range of sarcomas, including rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, Ewing sarcoma/peripheral PNET, epithelioid sarcoma, fibrosarcoma, mesenchymal chondrosarcoma, osteosarcoma, myxofibrosarcoma, and pleomorphic sarcoma. All of these CNS examples are histologically identical to their counter parts arising elsewhere in the body (Fig. 11.4).

Fig. 11.4

(A) Ewing sarcoma /pPNET with monotonous sheets of small, round blue cells, showing strong membranous positivity for CD99. (B) Rhabdomyosarcoma with scattered characteristic strap cells (C) by immunohistochemistry, this tumor showed strong positivity for both desmin (D) and myogenin (E). (F) A pleomorphic sarcoma with numerous bizarre nuclei, several with prominent nucleoli

## 11.5 Immunohistochemistry

  * Hemangiopericytoma

    * ◦ The immunohistochemical profi le of HPC is identical to that of its soft-tissue counterpart, showing diffuse positivity for vimentin, CD99, and bcl-2, and more variable positivity for Leu-7, CD34, and factor XIIIa in individual tumor cells (Fig. 11.5).

Fig. 11.5

HPC is consiste ntly positive for bcl-2 (A) and CD99 (B). Factor XIIIa stains scattered individual tumor cells (C), but a similar staining pattern may be encountered in meningiomas. (Courtesy of Dr. Arie Perry, University of California, San Francisco)

    * ◦ CD34 positivity is generally patchy, as opposed to the diffuse positivity typical of SFT.

    * ◦ Unlike the strong diffuse positivity for epithelial membrane antigen (EMA) and claudin-1 displayed by meningiomas, staining is typically patchy and weak for these antibodies in HPC.

    * ◦ HPCs are negative for S-100, CD31, and progesterone receptor; actin, desmin, and cytokeratin (CAM5.2) staining is rare.

    * ◦ p53 immunoreactivity may be seen in about half of HPCs; it is not generally a feature of meningioma or SFT.

  * Solitary fibrous tumor

    * ◦ SFTs characteristically sh ow strong, diffuse positivity for CD34, as well as for vimentin, CD99, and BCL2; S100 and EMA are generally negative.

    * ◦ Focal staining for factor XIIIa is common.

  * A significant proportion of HPC and SFT have been shown to have nuclear positivity for Slug and Twist by immunohistochemistry, and to lack expression of E-cadherin, whereas meningiomas will show exactly the opposite immunoprofile.

  * As noted in Sect.  11.7 , nuclear STAT6 staining is present in most HPCs and SFTs but is not a feature of meningiomas.

  * The immunoprofile of other mesenchymal lesions likewise mirrors their non-CNS counterparts.

## 11.6 Electron Microscopy

  * Similarly, the ultrastructural findings of meningeal hemangiopericytoma are like those of hemangiopericytomas originating elsewhere in the body.

  * Characteristic features include tightly packed spindled cells, each surrounded by basement membrane-like material.

  * Junctional complexes, including desmosomes, are lacking.

## 11.7 Molecular Pathology

  * NAB2-STAT6 fusion is a co nsistent finding in both SFT and HPC of the CNS, a signature that they likewise share with peripheral SFTs. This gene fusion results in nuclear accumulation of STAT6, a useful feature that can be detected by immunohistochemistry. STAT6 nuclear positivity is not a feature of meningiomas.

  * Abnormalities of chromosomes 3, 6p, 7p, 12q, and 19q and homozygous deletions of p16 have been reported in adult series of HPC.

  * HPC and SFT lack deletions of 14q and protein 4.1b typical of meningioma; similarly, deletions of 1p and NF2 are extremely uncommon in HPC.

  * EWS-related translocations are characteristic of Ewing sarcoma/peripheral PNET, and FOXO1-related translocations are characteristic of alveolar rhabdomyosarcoma.

## 11.8 Differential Diagnosis

  * Schwannoma may resemble HPC, though HPC will lack S-100 positivity.

  * SFT, particularly the more hypercellular examples, will closely mimic HPC, including the staghorn vasculature. Though they do overlap in their immunohistochemical staining pattern, SFTs are typically more diffusely positive for CD34, contain frequent and diffuse areas of hyalinization and collagen deposition, have only rare mitoses, and have a sparse pattern of reticulin staining with positivity around clusters of cells, in contrast to the fine intercellular network typical of HPC.

  * Meningiomas also enter into the differential diagnosis of HPC and other mesenchymal tumors. HPCs can generally be differentiated by demonstration of strong staining for bcl-2 and CD99, and nuclear STAT6 staining; they likewise lack strong staining for EMA and claudin, which is most typical for meningioma.

  * Meningeal fibroma may mimic a variety of spindle-cell meningeal lesions, including fibrous meningioma and SFT. Meningeal fibroma is immunopositive only for vimentin, whereas fibrous meningioma would be expected to be immunopositive for EMA and claudin-1, and SFT for S-100.

## 11.9 Prognosis

  * Given the rarity of HPCs in children, survival statistics have not yet been worked out. Infantile HPCs arising in children less than 1 year old do tend to follow a more benign clinical course despite aggressive-appearing histopathology. In adults, the following prognostic factors have been described:

    * ◦ Local recurrence is frequent; gross total resection and application of postoperative radiotherapy correlate with improved local control.

    * ◦ Data linking a survival benefit to gross total resection plus radiotherapy in HPC is mixed, though one large study found significant survival benefit with this combined therapy.

    * ◦ Completeness of surgical resection, low tumor grade, smaller size (<7 cm) and absence of dural sinus invasion are associated with prolonged progression-free survival. Patients with anaplastic tumors live half as long as those with differentiated tumors and have a much higher rate of recurrence.

    * ◦ Effective control of recurrence may be afforded by additional excision, radiotherapy, or gamma knife radiosurgery.

    * ◦ Extraneural metastasis may be seen in up to 50 % of patients; common sites of metastasis include bone, lung, liver, abdominal cavity, and elsewhere within the CNS.

  * SFT of the CNS, though histologically, immunohistochemically, and genetically similar to HPC, exhibits significantly less aggressive biologic behavior (though again this statement is based mainly on tumor data in adults).

    * ◦ Gross total resection typically provides excellent long-term progression-free and overall survival rates, whereas recurrences are not uncommon following incomplete resection and/or elevated tumor cell proliferation by histology.

    * ◦ Occasional tumors may show more aggressive behavior, with CSF dissemination or even peripheral metastatic disease.

  * Whereas benign mesenchymal CNS lesions are curable surgically, sarcomas are quite aggressive and are associated with poor outcomes. Local recurrence and distant metastases, including outside the CNS, are common.

Suggested Reading

Bassiouni H, Asgari S, Hubschen U, Konig HJ, Stolke D. Intracranial hemangiopericytoma: treatment outcomes in a consecutive series. Zentralbl Neurochir. 2007;68:111–8.CrossRefPubMed

Bisceglia M, Galliani C, Giannatempo G, Lauriola W, Bianco M, D'Angelo V, et al. Solitary fibrous tumor of the central nervous system: a 15-year literature survey of 220 cases (August 1996–July 2011). Adv Anat Pathol. 2011;18:356–92.CrossRefPubMed

Bouvier D, Metellus P, de Paula AM, Vasiljevic A, Jouvet A, Guyotat J, et al. Solitary fibrous tumors and hemangiopericytomas of the meninges: overlapping pathological features and common prognostic factors suggest the same spectrum of tumors. Brain Pathol. 2012;22:511–21.CrossRefPubMed

Cavalheiro S, Sparapani FV, Moron AF, da Silva MC, Stavale JN. Fetal meningeal hemangiopericytoma. Case report. J Neurosurg. 2002;97:1217–70.CrossRefPubMed

Chen Q, Chen XZ, Wang JM, Li SW, Jiang T, Dai JP. Intracranial meningeal hemangiopericytomas in children and adolescents: CT and MR imaging findings. AJNR Am J Neuroradiol. 2012;33:195–9.CrossRefPubMed

Chiechi MV, Smirniotopoulos JG, Mena H. Intracranial hemangiopericytomas: MR and CT features. AJNR Am J Neuroradiol. 1996;17:1365–71.PubMed

D'Amore ES, Manivel JC, Sung JH. Soft-tissue and meningeal hemangiopericytomas: an immunohistochemical and ultrastructural study. Hum Pathol. 1990;21:414–23.CrossRef90204-I)PubMed

Ghia AJ, Chang EL, Allen PK, Mahajan A, Penas-Prado M, McCutcheon IE, et al. Intracranial hemangiopericytoma: patterns of failure and the role of radiation therapy. Neurosurgery. 2013;73:624–30. discussion 630–1.CrossRefPubMed

Gill SS, Bharadwaj R. Cytomorphologic findings of hemangiopericytoma of the meninges: a case report. Indian J Pathol Microbiol. 2007;50:422–5.PubMed

Huisman TA, Brandner S, Niggli F, Kacl G, Willi UV, Martin E. Meningeal hemangiopericytoma in childhood. Eur Radiol. 2000;10:1073–5.CrossRefPubMed

Jing Z, Wen-Yi L, Jian-Li L, Jun-Lin Z, Chi D. The imaging features of meningeal Ewing sarcoma/peripheral primitive neuroectodermal tumours (pPNETs). Br J Radiol. 2014;87:20130631.CrossRefPubMedPubMedCentral

Kakkar A, Sharma MC, Goyal N, Sarkar C, Suri V, Garg A, et al. Meningeal fibroma: a rare meningioma mimic. J Neurosurg Pediatr. 2014;14:155–9.CrossRefPubMed

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC; 2007.

Mama N, Ben Abdallah A, Hasni I, Kadri K, Arifa N, Ladib M, et al. MR imaging of intracranial hemangiopericytomas. J Neuroradiol. 2014;41:296–306.CrossRefPubMed

McHugh BJ, Baranoski JF, Malhotra A, Vortmeyer AO, Sze G, Duncan CC. Intracranial infantile hemangiopericytoma. J Neurosurg Pediatr. 2014;14:149–54.CrossRefPubMed

Melone AG, D'Elia A, Santoro F, Salvati M, Delfini R, Cantore G, et al. Intracranial hemangiopericytoma—our experience in 30 years: a series of 43 cases and review of the literature. World Neurosurg. 2014;81:556–62.CrossRefPubMed

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Mohajeri A, Tayebwa J, Collin A, Nilsson J, Magnusson L, von Steyern FV, et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer. 2013;52:873–86.CrossRefPubMed

Nagaishi M, Nobusawa S, Tanaka Y, Ikota H, Yokoo H, Nakazato Y. Slug, twist, and E-cadherin as immunohistochemical biomarkers in meningeal tumors. PLoS One. 2012;7:e46053.CrossRefPubMedPubMedCentral

Perry A, Scheithauer BW, Nascimento AG. The immunophenotypic spectrum of meningeal hemangiopericytoma: a comparison with fibrous meningioma and solitary fibrous tumor of the meninges. Am J Surg Pathol. 1997;21:1354–60.CrossRefPubMed

Rajaram V, Brat D, Perry A. Anaplastic meningioma vs. meningeal hemangiopericytoma: Immunohistochemical and genetic markers. Hum Pathol. 2004;35:1413–8.CrossRefPubMed

Schweizer L, Koelsche C, Sahm F, Pisa R, Capper D, Reuss D, et al. Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol (Berl). 2013;125:651–8.CrossRef

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_12

# 12. Melanocytic Lesions

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

MelanocytomaMelanomaMelanocytosisMelanomatosisNeurocutaneous melanosis

## 12.1 Overview

  * These dural-based lesions are thought to derive from the leptomeningeal melanocytes. They include circumscribed mass lesions, melanocytoma and malignant melanoma, and diffuse leptomeningeal melanocytosis (DLM) and its malignant counterpart, melanomatosis.

  * DLM and primary melanomas make up the bulk of pediatric melanocytic lesions; melanocytomas occur in all age groups, but most arise in middle-aged adults.

    * ◦ DLM is strongly linked to neurocutaneous melanosis (Touraine syndrome), a rare congenital, autosomal dominant phakomatosis. These patients also harbor large and/or multiple cutaneous congenital nevi. Neurocutaneous melanosis may also be accompanied by neurofibromatosis 1, Sturge-Weber syndrome, Dandy Walker syndrome, arachnoid cysts, or tethered cord.

    * ◦ Patients with DLM are at significantly heightened risk for development of leptomeningeal melanoma or melanomatosis.

  * Melanocytomas of Meckel's cave are associated with ipsilateral nevus of Ota.

## 12.2 Clinical Features

  * Children with DLM typically present before 2 years of age; there is no gender or racial bias.

  * Primary CNS melanomas are rarely reported before the second decade, except in the context of neurocutaneous melanosis.

  * The clinical presentation is variable and relates either to increased intracranial pressure secondary to hydrocephalus, or to localized parenchymal compromise due to compression with mass effect or direct parenchymal infiltration by malignant lesions. These patients may therefore manifest seizures, cranial nerve palsies, neuropsychiatric symptoms, or intracranial hemorrhage. Clinical deterioration is rapid in the context of malignant melanoma.

  * As noted above, melanocytomas uncommonly arise in children, generally presenting with focal neurologic deficits associated with their localization. There is a slight female predominance.

## 12.3 Neuroimaging

  * Leptomeninge al melanocytosis and melanomatosis may involve large expanses of the leptomeninges, with a predilection for the regions of the temporal lobes, cerebellum, and brainstem. Both may appear as diffuse thickening and contrast enhancement of the leptomeninges, sometimes with foci of nodularity.

  * Though they have been described throughout the neuraxis, melanocytomas most often involve the cervical and thoracic spinal regions, presenting as mass lesions that are dural-based or associated with the nerve roots. Rare intraventricular examples have been reported.

  * Because of their high melanin content, these melanocytic lesions are characteristically isointense to hyperintense on T1-weighted MR images, hypointense on T2, and hyperintense on fluid-attenuated inversion recovery (FLAIR) sequences; they show homoge neous contrast enhancement (Fig. 12.1A).

Fig. 12.1

( A ) This axial T1- w eighted post-gadolinium MR image shows a well-demarcated, homogeneously enhancing melanocytoma situated in the cerebellopontine angle, an uncommon location for this tumor. ( B ) At low power, this melanocytoma superficially resembles meningioma, with bland spindle cells forming broad fascicles. Note occasional darkly pigmented cells. ( C ) Pigmentation is more obvious in this example. ( D ) This melanocytoma shows vague whorl formations, with a small nest of lightly pigmented cells notable in the lower right corner. ( E ) At higher power, the same melanocytoma as in (B ) contains bland oval nuclei with small nucleoli. Pleomorphism and mitotic figures are lacking. (Courtesy of Dr. Robert Schmidt, Washington University, St Louis, MO, Dr. Arie Perry, University of California, San Francisco, and Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA)

## 12.4 Pathology

  * Gross pathology

    * ◦ Diffuse lesions (melanocytosis/melanomatosis) present as dense discoloration of the leptomeninges, ranging from a dusky, greenish clouding to dense, dark brown to black hyperpigmentation.

    * ◦ Melanocytoma and melanoma appear as solid extraaxial masses, their coloration dependent upon their overall melanin content; they may be black, brown, blue, or flesh-colored, and they may be quite vascular.

  * Cytology findings

    * ◦ Smear preparations of melanocytoma contain dispersed and perivascular aggregates of bla nd oval to spindle-shaped cells with small nucleoli and long cytoplasmic processes. Fine or coarse melanin pigment is easily detected, often more so than in frozen intraoperative specimens.

    * ◦ Malignant melanoma cells detected on smears or in samples of cerebrospinal fluid have a similar appearance to peripheral malignant melanomas, being epithelioid to spindled with significant nuclear pleomorphism, often with prominent nucleoli; cytoplasmic melanin may or may not be present.

  * Histology

    * ◦ All of these lesions are composed of cells with melanocytic differentiation, most showing melanin pigment within the tumor cells themselves, intermixed stromal cells, and melanin-laden macrophages.

    * ◦ Rare examples of amelanotic melanoma or melanocytoma occur; the diagnosis in these instances relies upon immunohistochemical and ultrastructural analysis.

    * • Diffuse leptomeningeal melanocytosis is a diffuse proliferation of cytologically bland leptomeningeal melanocytes varying in shape from spindled to epithelioid.

      * These cells often accumulate within Virchow-Robin spaces; overt invasion into CNS parenchyma constitutes evidence of malignant progression ( melanomatosis ) .

    * ◦ Melanocytomas are composed of variably pigmented, spindled to oval cells forming syncytial nests, sometimes with whorl or storiform formations resembling meningioma. Fascicular or sheeted architecture may be seen (Fig. 12.1B–D).

      * The cells have rounded to oval bland nuclei and small nucleoli (Fig. 12.1E).

      * Atypia and mitoses are not observed features.

      * CNS parenchymal invasion and elevated mitotic rate indicate a propensity for more aggressive biologic behavior.

    * ◦ Malignant melanomas are hist ologically akin to melanomas elsewhere in the body, composed of spindled to epithelioid cells with variable cytoplasmic pigment that are arranged in cohesive nests, sheets, or sweeping fascicles.

      * They frequently show significant cytologic atypia with enlarged pleomorphic nuclei, prominent nucleoli, and numerous mitoses, including atypical forms (Fig. 12.2).

Fig. 12.2

(A–C) Primary pe diatric leptomeningeal melanoma containing a generally patternless arrangement of variably pigmented cells, many with striking nuclear pleomorphism. Note the atypical mitotic figure (B, left of center)

      * Overt CNS parenchymal invasion, hemorrhage, and/or necrosis are commonly present.

## 12.5 Immunohistochemistry

  * All of these pigmented l esions share a similar immunohistochemical profile, being positive for S-100 (Fig. 12.3A) and melanocytic markers HMB-45, tyrosinase, and MART1 (Melan A) (Fig. 12.3B), with variable positivity for vimentin and neuron-specific enolase (NSE).

Fig. 12.3

Immunohistoche mical staining of the melanocytoma in Fig. 12.1B demonstrating strong diffuse positivity for S-100 (A) and MART1 (Melan A) (B). (Courtesy of Dr. Murat Gokden, University of Arkansas, Little Rock, AR, USA)

  * They are negative for epithelial membrane antigen (EMA), glial fibrillary acidic protein (GFAP), and cytokeratin.

  * Ki67 labeling is elevated in melanomatosis and melanomas.

## 12.6 Electron Microscopy

  * All of these lesions contain variable amounts of melanin, melanosomes, and/or premelanosomes.

  * They lack desmosomes and interdigitating cell processes (differentiating them from meningiomas) and also lack basement membrane material surrounding individual cells, as would be seen in schwannomas.

## 12.7 Molecular Pathology

  * Somatic mutations involving the GNAQ gene at codon 209 have been detected in about 50 % of me lanocytomas, though the incidence within the pediatric age range is yet to be determined.

  * Isochromosome 6p has been reported in primary meningeal melanoma, as have occasional GNAQ and BRAF V600E mutations.

  * NRAS mutations ha ve been detected in a substantial proportion of cutaneous and CNS melanocytic tumors from patients with neurocutaneous melanosis.

## 12.8 Differential Diagnosis

  * All of these primary CNS m elanocytic lesions need to be differentiated from the following tumors:

    * ◦ Metastatic malignant melanoma shares identical histologic, immunohistochemical, and ultrastructural features with primary CNS melanoma, so identification of a primary lesion outside the CNS by radioimaging or other studies is critical.

    * ◦ Meningioma may mimic these melanocytic lesions, especially melanocytoma, but as noted above, meningiomas are typically EMA positive, will lack melanocytic markers and melanosomes, and will have interdigitating cell processes and desmosomes by ultrastructural analysis.

    * ◦ A number of other primary CNS tumors may show pigmentation, including schwannoma, neurofibroma, medulloblastoma, choroid plexus tumors, and some gliomas. Thankfully, most do not resemble these melanocytic tumors from a histologic standpoint; in diagnostically difficult instances, immunohistochemical and ultrastructural evidence of the corresponding cell of origin can be accurately ascertained.

      * Schwannomas, for instance, have intervening basement membrane surrounding individual tumor cells, and likewise lack mutations of GNAQ codon 209, which may be found in a significant proportion of melanocytomas.

      * GFAP-positive intermediate filaments are a feature of gliomas.

      * Choroid plexus tumors are positive for transthyretin and cytokeratins, with surface microvilli and cilia.

## 12.9 Prognosis

  * Diffuse leptomeningeal mel anocytosis has a poor prognosis, independent of the increased risk of malignant progression to melanomatosis, and even in the absence of histologic malignancy. Most of these patients die before age 10; 50 % die within 3 years of the onset of neurologic symptoms.

  * Melanocytomas are unpredictable; often there is cure with complete resection, but occasional lesions will show local recurrence or may undergo malignant transformation. Frank CNS parenchymal infiltration correlates strongly with this tendency for aggressive biologic behavior. Adjuvant radiotherapy is recommended in most cases.

  * Melanomas are highly aggressive tumors that are radioresistant and carry a very poor prognosis, with frequent metastasis both within and outside the CNS to peripheral organs. When total resection can be achieved, these patients have a significantly better outcome. Postoperativ e radiotherapy is recommended in all cases.

Suggested Reading

Alcutt D, Michowiz S, Weitzman S, Becker L, Blaser S, Hoffman H, et al. Primary leptomeningeal melanoma: an unusually aggressive tumor in childhood. Neurosurgery. 1993;32:721–9.CrossRef

Brunsvig KL, Zenobi M, Rilliet B, El Hassani Y, de Haller R, Ansari M, et al. Primary leptomeningeal melanocytosis in a 10-year-old girl: a challenging diagnosis with a poor prognosis. J Child Neurol. 2011;26:1444–8.CrossRefPubMed

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Kinsler VA, Thomas AC, Ishida M, Bulstrode NW, Loughlin S, Hing S, et al. Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol. 2013;133:2229–36.CrossRefPubMedPubMedCentral

Kusters-Vandevelde HV, Klaasen A, Kusters B, Groenen PJ, van Engen-van Grunsven IA, van Dijk MR, et al. Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system. Acta Neuropathol. 2010a;119:317–23.CrossRefPubMed

Kusters-Vandevelde HV, van Engen-van Grunsven IA, Kusters B, van Dijk MR, Groenen PJ, Wesseling P, et al. Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis. Acta Neuropathol. 2010b;120:755–64.CrossRefPubMedPubMedCentral

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_13

# 13. Hemangioblastoma

Hope T. Richard1 and Christine E. Fuller2

(1)

Department of Pathology, Virginia Commonwealth University, 980662, 1101 E. Marshall Street, Richmond, VA 23298-0662, USA

(2)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

HemangioblastomaVon Hippel-LindauCapillary hemangioblastomaWeibel-Palade body

## 13.1 Overview

  * Hemangioblastomas are highly vascular tumors that are typically benign and slow-growing, corresponding to WHO grade I.

  * Sporadic occurrence is most common, or they may occur in the context of Von Hippel-Lindau (VHL) syndrome.

  * Historically, they have also been referred to as capillary hemangioblastomas. The stromal cell is clearly the neoplastic component in these tumors, but the underlying cell of origin has yet to be determined.

## 13.2 Clinical Features

  * Hemangioblastomas are u ncommon CNS tumors that occur in all age groups, most frequently arising in adults. They often present in children when associated with VHL. No gender predilection is apparent.

  * Clinical signs and symptoms are most often encountered with large tumors and are related to mass effect either from the tumor itself, from expansion of an accompanying cyst, or from peritumoral edema. Intracranial examples may cause ataxia, dysmetria, or hydrocephalus with signs and symptoms of increased intracranial pressure. Spinal tumors often cause radiculopathies, pain, or both.

  * Tumor production of erythropoietin may lead to polycythemia.

  * Spontaneous hemorrhage has occasionally been documented.

## 13.3 Neuroimaging

  * Sporadic hemangioblastomas most often arise within the cerebellar hemispheres, whereas those arising within the context of VHL may occur anywhere within the CNS, including the brainstem or cerebellopontine angle, spinal cord, cranial nerves, or nerve roots.

  * Supratentorial localization is uncommon; unusual sites of occurrence include the pineal region, filum terminale, and extraneural locations. Tumor multiplicity may be encountered in VHL patients.

  * Neuroimaging studies typically demonstrate a cystic lesion with a heterogeneously contrast-enhancing mural nodule (Fig. 13.1A).

Fig. 13.1

Hemangioblastoma. ( A ) An axial T1-weighted post-gadolinium MR image shows a classic posterior fossa loca tion with a cyst bearing an enhancing mural nodule. (B ) A T2-weighted image of same patient shows hyperintense cyst fluid and a solid nodule of heterogeneous intensity with scattered flow voids. (C ) An axial apparent diffusion coefficient (ADC) map shows a high signal corresponding to this tumor

  * Solid portions of tumor are isointense on T1 and hyperintense on T2-weighted MR images (Fig. 13.1B and 13.2A). High signal on apparent diffusion coefficient (ADC) mapping is typical (Fig. 13.1C).

Fig. 13.2

Hemangioblastoma. (A) Sagittal T2-weighted MR image shows a heterogeneously hyperintense hema ngioblastoma arising in the cervical cord. (B) Angiography confirms an arteriovenous malformation (AVM)–like tangle of vessels within the lesion

  * Flow voids corresponding to large vessels may be encountered, and angiography often shows a tangle of vessels resemblin g an arteriovenous malformation (AVM) (Fig. 13.2B).

## 13.4 Pathology

  * Gross pathology

    * ◦ Resection specimens are typica lly composed of firm, fleshy to overtly hemorrhagic tissue, often with grossly visible vascular spaces (Fig. 13.3).

Fig. 13.3

Hemangioblasto ma. (A) Intraoperative view of a cervicomedullary fleshy, red nodule with adjacent cyst and large feeder vessels. (B) Cut surface of a hemangioblastoma surgical specimen from a different patient shows firm, red-brown hemorrhagic tissue with variably sized vascular spaces

  * Intraoperative cytologic imprints or smears

    * ◦ Intraoperative smears and samples of cystic fluid often contain blood along with abundant stromal cells wit h hyperchromatic nuclei and lacelike vacuolated cytoplasm (Fig. 13.4).

Fig. 13.4

Cytologic smear pre paration (H&E) showing sheets of cells with abundant, sometimes vacuolated cytoplasm with hyperchromatic nuclei of variable configuration

    * ◦ Small vessels, stripped endothelial cells, macrophages, and calcified material may also be present.

  * Histology

    * ◦ Hemangioblastomas are composed of a combination of stromal cells and a rich vascular network.

      * The stromal cells, representing the neoplastic component of this lesion, vary in their morphologic appearance. They characteristically contain small, bland nuclei and abundant vacuolated, lipid-rich cytoplasm (Fig. 13.5A and B). Occasionally, they may have a more spindled morphology with less obvious cytoplasmic vacuolization and/or more prominent nuclear pleomorphism (Fig. 13.5C and D).

Fig. 13.5

Stromal cells of h emangioblastoma characteristically have small bland nuclei and abundant vacuolated cytoplasm (A); one may also encounter cells resembling clear cell renal cell carcinoma (B), spindle cell morphology (C), or cells with striking nuclear pleomorphism (D)

      * The vascular component consists of numerous capillaries sprinkled throughout the tumor, together with scattered larger feeding (and draining) vessels.

      * Either of these two components may be a predominant feature; abundant vasculature (Fig. 13.6A), intratumoral hemorrhage, or extensive sclerosis may significantly mask the stromal cell component.

Fig. 13.6

(A) Abundant vasculat ure in this hemangioblastoma effectively masks the diagnostic stromal cells. (B) Hemangioblastomas characteristically harbor a rich reticulin network

      * A reticulin-rich network is invariably present (Fig. 13.6B). It is especially prominent in the highly vascular reticular variant, notable for small, compact nests of stromal cells. In the cellular variant, broad sheets of stromal cells are uninterrupted by reticulin.

      * Mitotic figures are uncommon.

      * Mast cells and extramedullary hematopoiesis are frequently present.

      * These lesions are sharply demarcated with the surrounding brain, often showing a striking surrounding astrogliosis that may mimic a pilocytic astrocytoma, replete with Rosenthal fibers and eosinophilic granular bodies.

## 13.5 Immunohistochemistry

  * The stromal cell and vascula r components show significantly different immunoexpression patterns:

    * ◦ Stromal cells are consistently positive for vimentin, alpha inhibin, D2-40, and aquaporin, and variably positive for S-100, NCAM, neuron-specific enolase (NSE), erythropoietin, EGFR, VEGF, alpha-1-antitrypsin, and antichymotrypsin (Fig. 13.7A–C). Progesterone receptor and factor Xllla positivity have also been reported in a high percentage of cases. They may be focally positive for glial fibrillary acidic protein (GFAP), keratin, epithelial membrane antigen (EMA), or desmin. Specific neuronal markers (neurofila ment, synaptophysin, and chromogranin) and endothelial cell markers (CD31, CD34, and VWF) are typically negative.

Fig. 13.7

Stromal cells of hemangioblastoma are diffusely positive for vimentin (A) and variably positive for S-100 (B) and neu ron-specific enolase (NSE) (C). CD31-positive vessels (D) stand out from the background of nonstaining stromal cells

    * ◦ Endothelial cells are consistently positive for CD31, CD34, and VWF (Fig. 13.7D).

## 13.6 Electron Microscopy

  * At the ultrastructural level, hemangioblastomas contain three cell types: endothelial cells lining fenestrated vascular channels, pericytes ensheathed by basal lamina, and stromal cells. Stromal cells often contain lipid droplets and may contain intracellular caveolae consistent with early capillary lumina, or small Weibel-Palade bodies.

  * Transitional forms of these three cellular constituents may be present.

## 13.7 Molecular Pathology

  * Whereas germline mutatio ns of the VHL gene are the norm in familial (VHL disease–associated) hemangioblastoma, loss or inactivation of this gene also occurs in up to 50 % of sporadic cases.

  * Recent studies have indicated that inactivation of the ZAC1 gene (6q24-25) may also play a role in the development of hemangioblastoma, particularly non–VHL-associated cases.

## 13.8 Differential Diagnosis

  * Clear cell renal cell carcinoma (RCC) is an important diagnostic consideration, particularly in VHL patients who may have both hemangioblastoma and RCC.

    * ◦ Both tumors contain cells with clear, lipid-rich cytoplasm with variable vascular investments, though the cells of RCC tend to have more monotonous nuclear profiles and less reticulin positivity than hemangioblastoma.

    * ◦ Definitive diagnosis typically relies upon demonstration of immunopositivity for markers such as D2-40, inhibin, and aquaporin 1 in hemangioblastoma, and for CD10, RCC, EMA, and cytokeratin AE1/AE3 in RCC.

    * ◦ More recently, PAX2 and PAX8 (positive in RCC) in conjunction with inhibin (positive in hemangioblastoma) have been shown to be an effective panel in distinguishing these two entities.

  * Several meningioma vari ants may mimic hemangioblastoma, especially the microcystic, clear cell, and angiomatous subtypes, as well as those with xanthomatous areas.

    * ◦ Unlike hemangioblastoma, all of these meningiomas are expected to show diffuse EMA and claudin positivity and should lack expression of the multiple markers of hemangioblastoma listed above.

    * ◦ A negative brachyury (positive in hemangioblastoma) may also be useful in differentiating clear cell meningioma from hemangioblastoma.

  * Hemangioblastoma may mimic intraparenchymal vascular lesions, especially capillary hemangioma; the latter will lack vacuolated stromal cells.

  * Macrophages may closely resemble the bubbly stromal cells of hemangioblastoma; CD68 will confirm the identity of the macrophages.

## 13.9 Prognosis

  * Surgical resection is the treatment of choice and affords excellent recurrence-free and overall survival outcomes.

  * Management of hemangioblastoma in VHL patients is more difficult, given the tendency of these patients to develop multiple lesions.

  * Lifelong follow-up is required, with treatment indicated for symptomatic lesions and also for those asymptomatic tumors exhibiting radiographic progression.

  * Fractionated external beam radiotherapy may be helpful in those patients with extensive intracranial and/or spinal disease, and in treating residual or recurrent lesions.

  * Tumor emboliza tion in select cases may facilitate complete resection with reduced blood loss.

Suggested Reading

Barresi V, Vitarelli E, Branca V, Antonelli M, Giangaspero F, Barresi G. Expression of brachyury in hemangioblastoma: potential use in differential diagnosis. Am J Surg Pathol. 2012;36:1052–7.CrossRefPubMed

Carney E, Banerjee P, Ellis C, Albadine R, Sharma E, Chaux A, et al. PAX2(−)/PAX8(−)/Inhibin A(+) immunoprofile in hemangioblastoma: a helpful combination in the differential diagnosis with metastatic clear cell renal cell carcinoma to the central nervous system. Am J Surg Pathol. 2011;35:262–7.CrossRefPubMed

Chaudhry AP, Montes M, Cohn GA. Ultrastructure of cerebellar hemangioblastoma. Cancer. 1978;42:1834–50.CrossRef42%3A4<1834%3A%3AAID-CNCR2820420423>3.0.CO%3B2-Z)PubMed

Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D. Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery. 2001;48:55–62.PubMed

Glasker S. Central nervous system manifestations in VHL: genetics, pathology and clinical phenotypic features. Fam Cancer. 2005;4:37–42.CrossRefPubMed

Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2008;108:210–22.CrossRefPubMed

Koh ES, Nichol A, Millar BA, Menard C, Pond G, Laperriere NJ. Role of fractionated external beam radiotherapy in hemangioblastoma of the central nervous system. Int J Radiat Oncol Biol Phys. 2007;69:1521–6.CrossRefPubMed

Lach B, Gregor A, Rippstein P, Omulecka A. Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol. 1999;23:299–310.CrossRefPubMed

Lallu S, Naran S, Palmer D, Bethwaite P. Cyst fluid cytology of cerebellar hemangioblastoma: a case report. Diagn Cytopathol. 2008;36:341–3.CrossRefPubMed

Lemeta S, Jarmalaite S, Pylkkanen L, Bohling T, Husgafvel-Pursiainen K. Preferential loss of the nonimprinted allele of ZAC1 tumor suppressor gene in human capillary hemangioblastoma. J Neuropathol Exp Neurol. 2007;66:860–7.CrossRefPubMed

Rodesch G, Gaillard S, Loiseau H, Brotchi J. Embolization of intradural vascular spinal cord tumors: report of five cases and review of the literature. Neuroradiology. 2008;50:145–51.CrossRefPubMed

Roy S, Chu A, Trojanowski JQ, Zhang PJ. D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas. Acta Neuropathol (Berl). 2005;109:497–502.CrossRef

Weinbreck N, Marie B, Bressenot A, Montagne K, Joud A, Baumann C, et al. Immunohistochemical markers to distinguish between hemangioblastoma and metastatic clear-cell renal cell carcinoma in the brain: Utility of aquaporin1 combined with cytokeratin AE1/AE3 immunostaining. Am J Surg Pathol. 2008;32:1051–9.CrossRefPubMed

# Part IV
Tumors of Cranial and Spinal Nerves
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_14

# 14. Schwannoma

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Acoustic neuromaAntoni A & BNeurilemmaNeurilemmomaNeurinomaNF2Schwann cellSchwannomatosisVerocay bodyVestibular schwannoma

## 14.1 Overview

  * Schwannoma (ICD-O 9560/0) is a benign nerve sheath tumor of Schwann cells, also known as neurilemmocytes (thus the alternate name neurilemmoma or neurilemoma). It is sometimes associated with dysgenetic syndromes such as neurofibromatosis 2 (NF2) or schwannomatosis, a disorder genetically distinct from NF2, which includes multiple peripheral and intracranial schwannomas. This tumor disposition syndrome is discussed elsewhere in detail.

  * Schwannomas are typically seen in adults between the fourth and the sixth decades, and are extremely rare in children [1]. In a large referral center, only 0.7 % of all schwannomas during a 10-year period occurred in children. Pediatric schwannomas often occur in the setting of NF2.

  * Cellular schwann oma (same ICD-O code) is a variant of schwannoma lacking the classic biphasic pattern (mostly Antoni A pattern) or Verocay body formation, and with mitotic activity [2].

  * Both spinal and intracranial schwannomas show a predilection for sensory nerves, and the most common intracranial location is the vestibuloacoustic nerve complex. The incidence of vestibular schwannomas has been reported to be 0.6 per 100,000 person-years [1].

  * Schwannomas may be associated with irradiation during childhood, but such tumors are typically diagnosed later in life.

## 14.2 Clinical Features

  * Schwannomas affect all ages and both sexes equally. Schwannomas can be seen anywhere in the body, but the most common sites are the head and neck region and extremities.

  * Most sporadic schwannomas are solitary and asymptomatic unless they attain a large size. They rarely affect the visceral organs.

  * Most intracranial tumors are associated with tinnitus or hearing loss, but schwannomas may go unnoticed for years until they present with cerebellar symptoms or signs of increased intracranial pressure.

## 14.3 Neuroimaging

  * Schwannomas are often solid and occasionally solid-cystic extraaxial masses.

  * On CT scans, tumors often distort or enlarge the acoustic canal and can cause bony erosion (Fig. 14.1).

Fig. 14.1

Axial CT scan o f a cerebellopontine angle schwannoma in a 16-year-old child with neurofibromatosis 2

  * MRI reveals a well-defined mass that is isointense or hypointense on T1-weighted images and hyperintense on T2-weighted im ages (Fig. 14.2).

Fig. 14.2

Axial T2-weighted MR image of a cerebellopontine angle schwannoma. Note the variable hyperintensity and minimal mass effect

  * Most tumors show moderate to strongly homogenous enhancement on postcontrast T1-weighted images. Cystic tumors and tumors that have been embolized demonstrate variable contrast enhancement.

  * Solid portions of schwannomas are isointense to normal parenchyma on diffusion-weighted imaging (DWI) (no restriction).

  * Schwannomas are often seen as hypovascular masses on angiography.

## 14.4 Histopathological Features

  * Histopathological fea tures of Schwannomas in children are essentially similar to adult counterparts. However, due to the rarity of these neoplasms, a detailed comparison of histological patterns is lacking.

  * Intraoperative smears

    * ◦ The cohesive nature of schwannomas does not allow easy smearing and disaggregation into individual cells, even in forcefully prepared samples. This alone is often a fair hint of the possibility of diagnosis in the right clinical setting (Fig. 14.3).

Fig. 14.3

Intraoperative smears typically reveal irregular, convoluted nuclear morphology and a mesenchymal background. Note the absence of single cell and mainly large tissue fragments in an appropriately perfo rmed smear. The lack of disaggregation on smears can be a clue for the diagnosis (inset; original ×2 magnification)

    * ◦ Smears often yield valuable information on the mesenchymal and collagenous background and highly convoluted, irregular nuclei that distinguish them from meningiomas.

    * ◦ In most smears, there is nuclear pleomorphism, degenerative nuclear atypia, and occasional pseudoinclusions or calcifications. It is often difficult to determine the presence of a low-grade malignant peripheral nerve sheath tumor on the basis of cytological features.

  * Frozen section

    * ◦ Schwannomas often demonstrate marked nuclear freezing artifacts, and this may lead to an impression of a malignant neoplasm (Fig. 14.4).

Fig. 14.4

Frozen se ction of a cerebellopontine angle schwannoma in a 6-year-old c hild, showing a dense hyaline background and marked nuclear pleomorphism, caused partly by the freezing artifact

    * ◦ Tumors in children tend to appear much more cellular and homogenous than those in adults. Therefore, it is advisable to be cautious in interpreting the cellularity of schwannomas in frozen sections.

  * Routine microscopic features

    * ◦ The biphasic appearance of schwannoma is not a common feature in many pediatric schwannomas, but typical histological characteristics such as collagenous stroma, hyalinized vasculature, abortive Verocay body formations, distinct borders, a pattern resembling polar spongioblastoma, and Verocay body formation can be seen (Fig. 14.5).

Fig. 14.5

Histologic al features of schwannomas in children. The classic biphasic appearance seen in adults is not always conspicuous in pediatric tumors. (A) Densely cellular tumor with collagenous stroma. (B) Markedly hyalinized vasculature and abortive Verocay body formations. (C) Hypercellular nodule with distinct boundary. (D) Palisaded pattern resembling polar spongioblastoma. (E) Prominent Verocay body formation. (F) Marked myxoid change

      * Pediatric schwannomas are more or less uniformly hypercellular, and often demonstrate cellular patterns that include palisaded arrangement of cells.

      * The thickened and hyalinized vasculature of adult schwannomas is not a typical finding in pediatric tumors.

      * Schwannomas in children can have pleomorphic or bizarre nuclei, but these are few in number, and degenerative changes known as "ancient" schwannoma are rare.

      * Though a typical schwannoma lacks mitotic figures, rare mitoses can be seen in a pediatric schwannoma (Fig. 14.6).

Fig. 14.6

Increased nuclear pleomorphism in a schwannoma from the cerebellopontine angle tumor of a 9-year-old boy

      * Intracranial schwannomas in children are also likely to demonstrate hemosiderin deposits and reactive vascular changes.

      * Although most schwannomas in children appear somewhat hypercellular, true "cellular schwannoma" is extremely uncommon in the pediatric population [3]. A cellular schwannoma is diffusely hypercellular and shows conspicuous mitotic activity [3]. Cellular schwannoma is a variant showing a predominantly compact cellular growth, without appreciable cellular palisades or Verocay bodies, but with the typical ultrastructure of schwannomas. Architecturally, these tumors differ from conventional schwannomas by their lack of well-formed capsules and degenerative changes.

      * Exceedingly rare are peritumoral chronic inflammatory infiltrates, melanin or lipofuscin pigment, or the epithelioid pattern.

      * Plexiform schwannomas, rare variants regardless of age group, have been reported in children. These tumors are occasionally the first manifestation of NF2 [4].

## 14.5 Electron Microscopy

  * Schwannomas feature sp indle, bipolar cells with aligned and tangled processes.

  * A single or duplicated layer of pericellular basement membrane separates the cells, with only rudimentary forms of intercellular junctions [5].

  * Striated clusters of "long-spacing collagen" (also known as "Luse bodies") are present in many conventional schwannomas (Fig. 14.7). There are scattered arrays of intracellular and extracellular intermediate filaments.

Fig. 14.7

Ultrastructural features of schwannoma. The typical finding is "long-spaced" collagen, also known as the Luse b ody (arrow), and the prominent basement membrane formation around tumor cells. Also note the abundant extracellular collagen

  * Schwann cells often contain elaborate perinuclear collections of lysosomes and demonstrate a rich, rough endoplasmic reticulum network. The vessels often reflect the extent of hyalinization through thick and prominent basement membranes.

## 14.6 Immunohistochemistry

  * Schwannomas show strong and diffuse cytoplasmic and nuclear immunoreactivity with antibodies against S-100 protein and vimentin. This immunopositivity is also readily observed in cellular schwannomas.

  * Most schwannomas are reactive for Leu 7, a monoclonal antibody against human natural killer cells with the same antigenic determinant as myelin-associated glycoprotein. Calretinin is also suggested to be positive in most schwannomas [6].

  * Staining for laminin and collagen type IV highlights the elaborate basement membrane material and can aid in differentiating schwannomas from meningiomas.

  * Even though most schwannomas are negative for neurofilament protein (thus allowing differentiation from neurofibromas), neurofilament-positive axons have been found to be present in conventional and cellular variants of schwannoma, confounding this issue (Fig. 14.8).

Fig. 14.8

Immunohistochem ical staining for neurofilament protein (SM311), showing a rare neurofilament-positive fibril. Neurofilament positivity is far less prominent in schwannomas than in neurofibromas and can be helpful in their differential diagnosis

  * Most schwannomas are diffusely and strongly positive for the CD34 antibody (Fig. 14.9) as well as diffuse nuclear staining with the SOX-10 antibody [7].

Fig. 14.9

Immunohistoch emical staining for CD34, showing strong, diffuse positive staining in a typical schwannoma

  * Pertinent negatives are epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP).

  * Cellular schwannomas share the same immunohistochemical profile as conventional lesions.

## 14.7 Molecular Pathology

  * Recent advances in molecular biology have led to a better understanding of the etiology and pathogenesis of schwannomas [8–10]. Mutations in the NF2 gene have been well known both in sporadic and NF-associated tumors [11].

  * A significant portion of schwannomas demonstrate allelic losses in chromosome 22 and NF2 gene inactivation, which is considered an early event in tumor development. Interactions of merlin, the protein product of the NF2 gene, with other cellular proteins are beginning to give us a better idea of NF2 function and the pathogenesis of vestibular schwannomas. These insights are yet to be translated into routine practice for children with NF2 or schwannomas.

## 14.8 Differential Diagnosis

  * The differential diagnosis of a schwannoma is considered in terms of its location in the spinal cord, skull base, or cerebellopontine angle.

    * At each of these locations, the differential diagnosis includes a host of lesions, but typically narrows down to a small group of extra-axial entities including meningiomas, mesenchymal non-meningothelial tumors, and other rare entities including non-neo plastic lesions.

  * Schwannomas and meningiomas share common features such as spindled cells, foci rich in collagen, xanthoma cells, and rarely palisading of cells.

    * Psammoma bodies and tight whorls are distinctive features of the meningiomas, but poorly-formed whorls may be seen in NF2-associated schwannomas, and some can even harbor psammoma bodies.

    * Reticulin stains show a rich, elaborate, and distinctly pericellular network of basal membrane formation in schwannomas, and this feature is also highlighted by laminin or collagen IV immunostaining; this feature is not typically seen in meningiomas.

    * Staining for S-100 protein, although typical of schwannomas, is not a reliable criterion. Approximately 20 % of meningiomas show immunoreactivity for this protein, yet staining is typically more focal and less intense than in schwannomas.

    * In addition, meningiomas are reactive for epithelial membrane antigen and Somatostatin Receptor type 2A (SSTR2A), whereas schwannomas do so only infrequently or almost never for SSTR2A, and lack membranous staining.

  * A second differential diagnosis is between neurofibroma and schwannoma, and more often problematic issue than with meningioma. While neurofibromas appear to blend with or infiltrate into peripheral nerves, schwannomas are often solid and have a well-defined capsule. Staining for neurofilament protein highlights far more of the background axonal elements in neurofibroma as compared to that in schwannoma.

## 14.9 Prognosis

  * The standard treatment f or schwannomas is surgical resection [12]. Some reports also suggest using vascular embolization prior to surgery. It is important to be aware of prior embolization when interpreting histological features of a schwannoma.

  * Children are more likely to regain full function following a successful surgery.

  * Outcomes of patients with NF2 are typically worse than those of patients with sporadic schwannomas [13].

References

1.

Propp JM, McCarthy BJ, Davis FG, Preston-Martin S. Descriptive epidemiology of vestibular schwannomas. Neuro Oncol. 2006;8:1–11.CrossRefPubMedPubMedCentral

2.

Woodruff JM, Godwin TA, Erlandson RA, Susin M, Martini N. Cellular schwannoma: a variety of schwannoma sometimes mistaken for a malignant tumor. Am J Surg Pathol. 1981;5:733–44.CrossRefPubMed

3.

White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM. Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors. Cancer. 1990;66:1266–75.CrossRef66%3A6<1266%3A%3AAID-CNCR2820660628>3.0.CO%3B2-E)PubMed

4.

Miyakawa T, Kamada N, Kobayashi T, Hirano K, Fujii K, Sasahara Y, et al. Neurofibromatosis type 2 in an infant with multiple plexiform schwannomas as first symptom. J Dermatol. 2007;34:60–4.CrossRefPubMed

5.

Huang HY, Park N, Erlandson RA, Antonescu CR. Immunohistochemical and ultrastructural comparative study of external lamina structure in 31 cases of cellular, classical, and melanotic schwannomas. Appl Immunohistochem Mol Morphol. 2004;12:50–8.CrossRefPubMed

6.

Fine SW, McClain SA, Li M. Immunohistochemical staining for calretinin is useful for differentiating schwannomas from neurofibromas. Am J Clin Pathol. 2004;122:552–9.CrossRefPubMed

7.

Nonaka D, Chiriboga L, Rubin BP. Sox10: a pan-schwannian and melanocytic marker. Am J Surg Pathol. 2008;32:1291–8.CrossRefPubMed

8.

Oh JE, Ohta T, Satomi K, Foll M, Durand G, McKay J, et al. Alterations in the NF2/LATS1/LATS2/YAP pathway in schwannomas. J Neuropathol Exp Neurol. 2015;74:952–9.CrossRefPubMed

9.

Chen Y, Wang ZY, Wu H. P14ARF deficiency and its correlation with overexpression of p53/MDM2 in sporadic vestibular schwannomas. Eur Arch Otorhinolaryngol. 2015;272:2227–34.CrossRefPubMed

10.

Chen H, Zhang X, Zhang Z, Yang T, Wang Z, Wu H. The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals. Mol Cell Biochem. 2014;392:145–52.CrossRefPubMed

11.

Mérel P, Hoang-Xuan K, Sanson M, Moreau-Aubry A, Bijlsma EK, Lazaro C, et al. Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas. Genes Chromosomes Cancer. 1995;13:211–6.CrossRefPubMed

12.

Kulkarni A, Srinivas D, Somanna S, Indira DB, Ananthakrishna CB. Pediatric spinal schwannomas: an institutional study. J Pediatr Neurosci. 2012;7:1–3.CrossRefPubMedPubMedCentral

13.

MacNally SP, Rutherford SA, King AT, Freeman S, Thorne J, Mawman D, et al. Outcome from surgery for vestibular schwannomas in children. Br J Neurosurg. 2009;23:226–31.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_15

# 15. Neurofibroma

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Atypical neurofibromaDiffuse neurofibromaLocalized neurofibromaIntraneural neurofibromaPlexiform neurofibromaNeurofibrominNF1Peripheral nerve sheath tumorSchwann cell

## 15.1 Overview

  * Neurofibromas (ICD-O 9540/0) are infiltrative, benign tumors of peripheral nerves that can occur as solitary or diffuse masses in the dermis, subcutis, soft tissues, or peripheral nerves. Neurofibromas are considered W orld Health Organization (WHO) grade I neoplasms [1].

  * The tumor is believed to consist of a mixture of cell types including Schwann cells, perineurial cells, and fibroblasts.

  * Some neurofibromas, especially plexiform neurofibromas, almost exclusively occur in the setting of neurofibromatosis 1 (NF1).

  * Variants of neurofibrom as:

    * ◦ Localized cutaneous neurofibroma: small, isolated neurofibroma within the dermis

    * ◦ Diffuse cutaneous neurofibroma: ill-defined plaquelike masses within the dermis that are not confined to a single focus

    * ◦ Localized intraneural neurofibroma: a circumscribed mass without a capsule inside a nerve fascicle

    * ◦ Plexiform neurofibroma (ICO-O 9550/0): a multilobulated, infiltrative tumor that involves multiple fascicles (referred to as a "bag of worms") and is almost always found in association with neurofibromatosis 1 [2].

    * ◦ Atypical and cellular neurofibromas (ICO-O 9540/0): tumors with unusual histological features including degenerative nuclear atypia or increased cellularity with hyperchromatic nuclei. Some atypical and cellular types were reported to have a propensity to grow, especially in NF1 patients [3, 4]. Currently, a specific variant for either of these groups does not exist in the WHO classification scheme.

## 15.2 Clinical Features

  * Most cutaneous neurofibromas pres ent as slow-growing, painless masses that are freely movable under the skin.

  * Localized intraneural neurofibromas are often associated with disturbance of function of the involved nerve (either motor, sensory, or both).

  * Spinal cord examples can present with sensory loss and weakness; they are typically seen in the setting of NF1. Spinal neurofibromas in NF1 are more likely to result in the sacrifice of the nerve root.

  * Stigmata for NF1 should be sought in patients with neurofibromas, especially with multiple or plexiform lesions [5].

  * Plexiform neurofibromas often grow slowly or not at all, but rare examples may lead to malignant peripheral nerve sheath tumors [6].

## 15.3 Neuroimaging

  * Neurofibromas are mode rately to strongly enhancing, infiltrating masses that appear "worm-like" within the scalp or the orbit.

  * Plexiform neurofibromas are highly tortuous, enhancing masses along the larger peripheral nerves (Fig. 15.1) and may grow in an invasive pattern [7].

Fig. 15.1

Contrast-enhanced CT image of a plexiform neurofibroma involving the brachial plexus of a 16-year-old boy with NF 1

  * On MRI, neurofibroma is isointense on T1 and hyperintense on T2-weighted images and often enhances strongly. Tumors can be seen in close association with nerve roots or peripheral nerves (Fig. 15.2).

Fig. 15.2

Coronal, co ntrast-enhanced T1-weighted image of numerous neurofibromas involving the nerve roots in a 12-year-old patient with NF1. Some of the tumors are associated with spinal cord compression, leading to localizing symptoms

  * Neurofibromas are radiologically similar to schwannomas [8].

## 15.4 Pathology

  * Intraoperative smears

    * ◦ Neurofibromas, like schwannomas, are difficult to smear, and often do not yield single cells or small cell clusters. The large fragments in smear preparations can suggest a spindled neoplasm with variably myxoid background (Fig. 15.3).

Fig. 15.3

Intraoper ative smear preparation of a neurofibroma, demonstrating dense clusters of cells with few or no isolated cells in a variably myxoid background, and wavy nuclei

  * Frozen section

    * ◦ Neurofibromas may sh ow marked pleomorphism on frozen sections, but the spindled and wavy nature of the tumor cells is characteristic (Fig. 15.4).

Fig. 15.4

Frozen section f rom a brachial plexus neurofibroma, showing the wavy and occasionally larger, irregularly shaped nuclei in a fibromyxoid, collagenous background

    * ◦ Some cellular neurofibromas are difficult to distinguish from schwannomas on frozen sections. Neurofibromas typically expand and distort the peripheral nerve and are composed of a haphazard proliferation of wavy spindle cells in a myxoid and collagenous background.

  * Routine sections

    * There is a variable amount of myxoid matrix and a variable degree of collagenous background (Fig. 15.5A).

Fig. 15.5

Typical histolog ic features of neurofibroma. (A) Monotonous tumor with variable amounts of myxoid and collagenous background. (B) Wavy nuclei (sometimes referred to as "shredded carrots" nuclei) in a markedly myxoid background. (C) Rare "atypical" or large nuclei in an otherwise unusual neurofibroma is not uncommon. (D) Clusters of tumor cells that are somewhat reminiscent of Verocay bodies, and with some features of the so-called traumatic neuroma

    * The tumor often has a markedly myxoid matrix and wavy nuclei, often referred to as "shredded carrots " (Fig. 15.5B).

      * ◦ Most neurofibromas contain occasional but easily identifiable mast cells.

      * ◦ Most tumor cells have slender, moderately hyperchromatic nuclei, but rare tumor cells exhibit large and occasionally bizarre nuclei (Fig. 15.5C).

      * ◦ In some areas, tumors resemble so-called traumatic neuromas and may also harbor structures that may be misrecognized as Verocay bodies (Fig. 15.5D)

      * ◦ The tumors often blend with the adjacent normal peripheral nerve; in such areas, a clear separation is not possible (Fig. 15.6A).

Fig. 15.6

Neurofibromas. (A) Infiltrative border of tumor and fibroadipose tissue in a paraspinal tissue resection. (B) Trapped ganglion cells in a spinal tumor invading the root ganglion in a child with NF1. (C) Trapped adnexal structures in a diffuse cutaneous neurofibroma. (D) Immunohistochemical stain for neurofilament protein demonstrating trapped axons within a neurofibroma

    * Some neurofibromas trap normal elements such as ganglion cells (Fig. 15.6B) or adnexal structures (Fig. 15.6C), as well as normal axonal elements that can be recognized immunohistochemically with the neurofilament antibody (Fig. 15.6D).

      * Reactive changes, hemosiderin, or pigmentation is extremely rare.

      * The vascular network is often delicate, and hyalinized vessels are rare. The myxoid matrix in neurofibromas is often positive with Alcian blue stain.

      * Some neurofibromas contain melanin-pigmented cells.

      * Exceptionally, neurofibromas may show divergent differentiation, but this feature is more typical of malignant peripheral nerve sheath tumors.

  * Variants

    * ◦ Locali zed cutaneous neurofibroma is typically a solitary subcutaneous nodule that is well-defined but not encapsulated. The lesion is usually not associated with a peripheral nerve and is located within the subcutis.

    * ◦ Diffuse neurofibroma is a larger, poorly delineated lesion that often involves the adjacent soft tissue beyond the peripheral nerve. Growth of tumor cells around vessels and adnexal structures is often seen.

    * ◦ Plexiform neurofibroma (Fig. 15.7) is composed of large and small bundles of distended abnormal fascicles harboring a haphazard growth of cells and myxoid background. The proportion of myxoid and collagenous elements, as well as cellularity, varies greatly. Foci of tumor show patterns resembling specialized neural structures such as Pacinian corpuscles.

Fig. 15.7

Low-power magnification of plexiform neurofibroma involving multiple nerve fascicles and infiltrating the epineurial tissues

  * Typical plexiform neurofibromas do not harbor hypercellular regions, mitotic figures, or frank anaplastic change, any of which constitutes evidence for the emergence of a malignant peripheral nerve sheath tumor.

  * Atypical neurofibromas are diffusely hypercellular tumors with hyperchromatic nuclei (Fig. 15.8); cellular neurofibromas are densely hypercellular tumors with occasional mitoses.

Fig. 15.8

Atypical neurofib romas are tumors that have numerous degenerative-appearing, atypical cells, without increased mitotic rate or necrosis

## 15.5 Immunohistochemistry

  * Neurofibromas show strong and diffuse cytoplasmic and nuclear immunoreactivity with antibodies against S-100 protein (Fig. 15.9), as well as diffuse cytoplasmic positivity with antibodies against vimentin.

Fig. 15.9

Immunohistochemical stain with the S-100 protein antibody demonstrating diffuse strong positivity in tumor cells, along with scattered nuclear positivity. The degree of staining is often diffuse and strong in neurofibromas, unlike low-grade or high-grade malignant peripheral nerve sheath tumors

  * Neurofibromas also harbor many neurofilament-positive axons, which can aid in differentiating from schwannoma variants (see Fig. 15.6D).

  * CD34 and CD57 are focally and variably positive in most neurofibromas.

  * SOX10 is often diffusely and strongly positive in neurofibromas (Fig. 15.10)

Fig. 15.10

Immunohistochemical s tain with the SOX10 antibody, demonstrating strong nuclear positivity in tumor cells. This antibody is often strongly positive in all tumors arising from the peripheral nerve sheath

  * Plexiform neurofibromas share the same immunohistochemical profile as conventional neurofibromas.

  * Pertinent negatives are epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP).

## 15.6 Molecular Pathology

  * Allelic loss of the NF1 gene region in chromosome 17 occurs with both sporadic and NF1-related neurofibromas [9].

  * The NF1 gene and its product neurofibromin act as tumor suppressors and a negative regulator of the ras proto-oncogene.

  * A number of mechanisms have been postulated to account for biallelic inactivation of the NF1 gene.

  * Some studies report abnormalities of chromosome 17, 19, 22q, and 9p in neurofibromas [10].

## 15.7 Differential Diagnosis

  * The differential di agnosis of neurofibroma is considered in terms of tumor location: spinal cord, peripheral nerve, soft tissue, or skin.

    * In each of these locations the differential potentially includes a host of lesions, but typically narrows down to schwannoma, meningioma, and other rare mesenchymal lesions.

  * Some schwannomas appear indistinguishable from neurofibromas.

    * Neurofibromas often blend with or infiltrate into peripheral nerves, while schwannomas are often solid with a well-defined fibrous rim/capsule.

    * Staining for neurofilament protein highlights far more of the background axonal elements in neurofibroma as opposed to that in schwannoma.

    * It has been suggested that weak and rare calretinin positivity can distinguish neurofibromas from schwannomas that are diffusely and strongly positive for this antibody.

  * Rarely, a solitary fibrous tumor or a myxofibrosarcoma can be considered in the differential diagnosis of soft tissue lesions, but can be easily distinguished on both morphological and immunohistochemical grounds.

## 15.8 Prognosis

  * Neurofibromas ar e benign tumors with little or no potential for malignant transformation, particularly in the absence of NF1, but rare examples of malignant transformation of neurofibromas have been reported [11].

  * Plexiform neurofibromas can rarely progress to malignant peripheral nerve sheath tumors.

  * Atypical neurofibromas are suggested to be slow-growing tumors, but they can rarely progress to malignant peripheral nerve sheath tumors [3].

References

1.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumors of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2007.

2.

Nguyen R, Kluwe L, Fuensterer C, Kentsch M, Friedrich RE, Mautner VF. Plexiform neurofibromas in children with neurofibromatosis type 1: frequency and associated clinical deficits. J Pediatr. 2011;159:652–5.CrossRefPubMed

3.

Beert E, Brems H, Daniels B, De Wever I, Van Calenbergh F, Schoenaers J, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011;50:1021–32.CrossRefPubMed

4.

Lin BT, Weiss LM, Medeiros LJ. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am J Surg Pathol. 1997;21:1443–9.CrossRefPubMed

5.

Kim A, Gillespie A, Dombi E, Goodwin A, Goodspeed W, Fox E, et al. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009;73:1273–9.CrossRefPubMedPubMedCentral

6.

Nguyen R, Dombi E, Widemann BC, Solomon J, Fuensterer C, Kluwe L, et al. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7:75.CrossRefPubMedPubMedCentral

7.

Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Funsterer C. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology. 2006;48:160–5.CrossRefPubMed

8.

Jee WH, Oh SN, McCauley T, Ryu KN, Suh JS, Lee JH, et al. Extraaxial neurofibromas versus neurilemmomas: discrimination with MRI. AJR Am J Roentgenol. 2004;183:629–33.CrossRefPubMed

9.

Beert E, Brems H, Renard M, Ferreiro JF, Melotte C, Thoelen R, et al. Biallelic inactivation of NF1 in a sporadic plexiform neurofibroma. Genes Chromosomes Cancer. 2012;51:852–7.CrossRefPubMed

10.

Liu K, DeAngelo P, Mahmet K, Phytides P, Osborne L, Pletcher BA. Cytogenetics of neurofibromas: two case reports and literature review. Cancer Genet Cytogenet. 2010;196:93–5.CrossRefPubMed

11.

Kawachi Y, Tanaka R, Fujisawa Y, Furuta J, Nakamura Y, Ishii Y, Otsuka F. Superficial malignant peripheral nerve sheath tumor arising from a solitary cutaneous neurofibroma in a non-NF1 patient. Eur J Dermatol. 2011;21:125–6.PubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_16

# 16. Malignant Peripheral Nerve Sheath Tumors

Yazgi Koy1 and Tarik Tihan2

(1)

Department of Pathology, Bagcilar Research and Training Hospital, Merkez Mah. Mimar Sinan Cad. 6 Sok, Bagcilar, Istanbul, Turkey

(2)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Malignant neurofibromaMalignant schwannomaPeripheral nerve sheath tumorMPNSTSchwann cell

## 16.1 Overview

  * Malignant peripheral nerve sheath tumors (MPNSTs) (ICD-O 9540/3) are rare soft-tissue sarcomas that arise predominantly from Schwann cells. A malignant spindle-cell tumor with histological, immunohistochemical, and ultrastructural features of Schwann cell differentiation, they usually arise in the setting of neurofibromatosis 1 (NF1) or may be seen sporadically in children.

    * ◦ Patients generally present with a painful, enlarging mass.

    * ◦ The unequivocal recognition of a high-grade sarcoma as an MPNST requires demonstration of a peripheral nerve origin or origin from a benign peripheral nerve sheath tumor such as a neurofibroma or schwannoma, or demonstration of histological, immunohistochemical, and ultrastructural evidence of peripheral nerve tissue differentiation [1].

    * ◦ MPNSTs tend to have high local recurrence and are generally associated with poor prognosis.

    * ◦ Treatment often involves a multimodal approach including resection, radiotherapy, and chemotherapy.

  * Epithelioid malignant peripheral nerve sheath tumor (ICO-O 9542/3) is a rare variant of MPNST composed of plump epithelioid cells with abundant eosinophilic cytoplasm and showing epithelial features and lobulated growth. This form is often not associated with NF1.

  * Malignant triton tumor (ICD-O 9561/3) is an MPNST showing skeletal muscle differentiation.

## 16.2 Clinical Features

  * MPNSTs rarely occur in childhood; they constitute approximately 5–10 % of all pediatric soft tissue tumors [2, 3].

  * Pediatric MPNSTs are often associated with NF1, but they are otherwise far less common than in the adult population.

  * The tumor often presents as an enlarging mass with pain. Other clinical symptoms are paresthesias, motor weakness, or radicular pain.

  * Stigmata for NF1 should be sought in patients with MPNST, especially those with multiple or plexiform lesions [4].

  * Plexiform neurofibromas often grow slowly or not at all, but rare examples may lead to MPNST [5].

## 16.3 Neuroimaging

  * There are no specific radiogr aphic features that distinguish MPNSTs from other sarcomas. The radioimaging features are similar to other soft tissue tumors that can occur in the same region (Fig. 16.1). MPNSTs appear more infiltrative and heterogeneous than benign peripheral nerve sheath tumors [6].

Fig. 16.1

Coronal, contrast-en hanced T1-weighted image of a retroperitoneal malignant peripheral nerve sheath tumor (MPNST) in a 14-year-old child

  * Several features are suggestive for malignancy: heterogeneity, size larger than 5 cm, ill-defined borders, prominent vascularity or enhancement, rapid growth, and lack of target sign on T2-weighted images [7].

## 16.4 Pathology

  * Resection specimens

    * ◦ MPNSTs are often large and appear infiltrative. Plexiform tumors are complex fusiform, multilobular expansions of peripheral nerves.

    * ◦ Most MPNSTs have tan-white, fleshy cut surfaces with hemorrhagic and/or necrotic foci (Fig. 16.2).

Fig. 16.2

Gross appearance of an MPNST in a 10-year-old child with NF1. Note that the tumor wraps around major vessels (arrow)

  * Intraoperative smears

    * ◦ Similar to most mesenc hymal tumors, some MPNSTs are difficult to smear and often do not yield single cells or small cell clusters. MPNSTs often yield large, cohesive clusters.

    * ◦ They are mostly reminiscent of a neurofibroma, but they have more hyperchromatic and pleomorphic nuclei (Fig. 16.3) and may also demonstrate mitotic figures or cellular debris suggestive of necrosis.

Fig. 16.3

Intraoperative s mear of an MPNST showing coherent clusters of cells with wavy, hyperchromatic, overlapping nuclei and scant cytoplasm

    * ◦ MPNSTs may be indistinguishable from other mesenchymal neoplasms.

    * ◦ The large fragments in smear preparations can suggest a spindled neoplasm with variably myxoid background.

    * ◦ Some examples can show extensive cellular pleomorphism and anaplasia.

  * Frozen sections

    * ◦ Varied histologic patterns may be seen in frozen sections, but typically the overall impression is t hat of a high-grade sarcoma (Fig. 16.4).

Fig. 16.4

Froze n section of MPNST with marked cellularity and collagenous background. Note that the histological features are indistinguishable from those of a cellular schwannoma

    * ◦ Cellular pleomorphism is often exaggerated, and the typical architectural features may not be readily identifiable.

    * ◦ One distinctive pattern is the palisaded or polar spongioblastoma-like appearance (Fig. 16.5).

Fig. 16.5

Histological features of an MPNST with a palisaded appearance also referred to as a polar spongioblastoma-like pattern. Because such a pattern can also occur in benign peripheral nerve sheath tumors, it is not considered diagnostic of MPNST

  * Routine sections

    * ◦ Microscopically, most tumors are highly cellular and are composed of spindle cells with hyperchromatic nuclei, faintly eosinophilic cytoplasm, and indistinct cell borders.

    * ◦ Tumors can show a variety of architectural patterns including fascicular, whorled, palisaded, biphasic, small cell, nested, and focally myxoid patterns (Fig. 16.6). MPNSTs occasionally show fibroblastic or myofibroblastic features.

Fig. 16.6

Histological patter ns in MPNST: epithelioid (A), fascicular (B), myxoid (C), hemangiopericytoma-like (D), small cell component resembling primitive neuroectodermal tumor (PNET) (E), and pleomorphic (F)

    * ◦ Tumor nuclei are spindled, hyperchromatic, and at least triple the size of most normal or benign tumor nuclei.

    * ◦ Geographic necrosis can be seen.

    * ◦ MPNSTs often demonstrate brisk mitotic activity.

    * ◦ Most tumors have low-grade foci with convoluted or wavy nuclei reminiscent of a neurofibroma.

    * ◦ The tumor cells may form a loose, angiocentric arrangement around thin-walled, delicate blood vessels, akin to the so-called hemangiopericytoma (Fig. 16.6D).

    * ◦ Rare examples have foci of small, primitive malignant cells reminiscent of primitive neuroectodermal tum or (PNET) (Fig. 16.6E).

    * ◦ Rare examples demonstrate glandlike formations, goblet cells, or columnar epithelial arrangements.

    * ◦ A rhabdoid pattern can be observed in some pediatric tumors.

    * ◦ Divergent differentiation, which may include osteoid, chondromatous, angiosarcomatous, and liposarcomatous areas, can be seen in about a quarter of the tumors.

    * ◦ Some tumors may arise in the setting of a preexisting neurofibroma or, less commonly, a schwannoma.

    * ◦ Tumors with epithelial differentiation have been classified under the epithelioid variant, but glandular formations also exist in otherwise usual MPNSTs.

    * ◦ Heterologous elements, such as skeletal muscle, bone, cartilage, and blood vessels, are present in approximately 15 % of tumors.

    * ◦ Triton tumor or malignant triton tumor is a variant of MPNST with rhabdomyoblastomatous differentiation; it carries a grim prognosis. Triton tumors have been described in children but are extremely rare.

  * Histological grading

    * ◦ Grading of MP NSTs has been controversial, and there is no prognostically relevant grading that will readily identify behavior. The grading criteria that were successfully applied to other sarcomas are known to be ineffective in distinguishing between low-grade and high-grade MPNSTs based on histological criteria.

    * ◦ A few histological characteristics may help in the interpretation of MPNSTs:

      * Almost all MPNSTs in the pediatric population appear as high-grade sarcomas, and distinguishing them from other high-grade sarcomas is often challenging.

      * Low-grade MPNST is extremely rare, so this diagnosis should be made with great caution, especially in the absence of NF1.

      * MPNSTs often lose many of the typical PNST tumor markers, such as S-100 protein, SOX10, and p16.

    * ◦ An exceptional MPNST can arise from a schwannoma, but emergence from a neurofibroma (especially in the setting of NF1) is more typical.

## 16.5 Electron Microscopy

  * MPNSTs have nonspeci fic ultrastructural features and are difficult to diagnose on electron microscopy. A typical MPNST is composed of spindled tumor cells with varying nuclear morphology, inconspicuous cytoplasmic processes, rudimentary cell junctions, and wisps of surface basal lamina.

  * Low-grade MPNSTs show more convincing ultrastructural features of Schwann cell differentiation, such as thick, intersecting cytoplasmic processes joined by rudimentary cell junctions and discontinuous basal lamina. Intermediate filaments and microtubules are rarely seen.

  * Rhabdomyoblastic differentiation is seen in malignant triton tumor.

  * Glandular differentiation with surface microvilli is present in rare examples; an exceptional small-cell component may exhibit dense-core granules.

## 16.6 Immunohistochemistry

  * Less than half of MPNSTs are focally positive for S-100 protein, and only 20–30 % of cases are focally positive for glial fibrillary a cidic protein (GFAP).

  * In some tumors, better-differentiated or lower-grade areas may be positive for S-100 protein, whereas the small cell or high-grade areas may be entirely negative (Fig. 16.7).

Fig. 16.7

Immunohistochemical s taining for S-100 protein in a biphasic MPNST with a PNET-like small cell component. The spindle cells appear low-grade and are positive with the S-100 antibody, but the small cell component is entirely negative

  * Diffuse staining for S-100 protein is rarely compatible with conventional MPNST, and may suggest other possibilities such as cellular schwannoma, melanoma, clear cell sarcoma, or interdigitating dendritic cell sarcoma.

  * Epithelioid MPNST is strongly and diffusely positive for S-100 protein but lacks staining for melanoma markers and SMARCB1 (INI1).

  * SOX10 is often focally and strongly positive in benign peripheral nerve sheath tumors [8] but is only focal in MPNST. SOX10 staining, along with p16, may be negative in some MPNSTs [9].

  * MPNSTs may also show keratin and Leu-7 positivity and may contain a variable number of neurofilament protein–positive trapped neural elements.

  * CD34 and CD57 are focally and variably positive in most cases of MPNST.

  * Well-differentiated MPNSTs may be positive with basal lamina stains such as collagen type 4 and laminin.

  * Plexiform neurofibromas share the same immunohistochemical profile as conventional neurofibromas.

## 16.7 Molecular Pathology

  * There are no specific chromosomal translocations in MPNST. Molecular genetic events associated wit h the development of both NF1-associated and sporadic MPNST involve inactivation of the TP53 and RB pathways of cell cycle regulation.

  * MPNSTs seen in the setting of NF1 have biallelic inactivation of the NF1 gene [10].

  * MPNSTs are presumed to arise from currently poorly defined stem cells. In NF1, these stem cells appear to originate from "dedifferentiated" Schwann cells.

## 16.8 Differential Diagnosis

  * The most critical differential diagnosis of a low grade MPNST in the setting of NF-1 includes a cellular benign peripheral nerve sheath tumor.

    * Although the boundary between a cellular schwannoma and a low grade MPNST may be subjective, a low grade MPNST should be favored in the presence of increased cellularity, atypia, and frequent mitosis.

  * A second set of neoplasms considered in the differential diagnosis of high grade MPNSTs, includes primary soft tissue neoplasms such as fibrosarcoma, leiomyosarcoma, synovial sarcoma, mesenchymal chondrosarcoma and hemangiopericytoma/solitary fibrous tumor.

    * The combination of clinical, histopathological, and immunohistochemical features, as well as ultrastructural findings can identify a nerve sheath origin (or differentiation) and distinguish MPNST from other sarcomas.

  * Differentiating a malignant melanoma from a high grade MPNST can also be challenging on rare occasions.

    * Both neoplasms can be composed of spindle cells and show variable S-100 positivity, and some melanomas do not contain appreciable amounts of melanin pigment.

    * Use of additional stains such as melan-A, HMB-45, tyrosinase, neurofilament, Leu-7, and myelin basic protein, and sometimes electron microscopy can aid in the recognition of a melanoma and its distinction from MPNST.

## 16.9 Prognosis

  * MPNSTs have usually aggressive outcome, high local recurrence risk, and distant metastases.

  * Histological tumor grade and location are the most important factors for prognosis. Among children and adults, high-grade tumors (grades III or IV) and location in the trunk or body core were associated with the highest mortality risk.

  * Female sex and non-Hispanic black race/ethnicity were reported to be significantly associated with worse outcome [2].

  * Particularly aggressive are MPNSTs larger than 5 cm and those with necrosis, high cellularity, increased mitotic index, local recurrence, or association with NF1, as well as malignant triton tumors.

  * MPNSTs often metastasize to the lungs, followed by bone and solid organs. Other sites of metastasis include liver, brain, soft tissue, skin, and retroperitoneum. Lymph node involvement is uncommon.

References

1.

Fletcher CDM, World Health Organization, International Agency for Research on Cancer. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon: IARC Press; 2013. p. 468.

2.

Amirian ES, Goodman JC, New P, Scheurer ME. Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program. J Neurooncol. 2014;116:609–16.CrossRefPubMed

3.

Bates JE, Peterson CR, Dhakal S, Giampoli EJ, Constine LS. Malignant peripheral nerve sheath tumors (MPNST): a SEER analysis of incidence across the age spectrum and therapeutic interventions in the pediatric population. Pediatr Blood Cancer. 2014;61:1955–60.CrossRefPubMed

4.

Kim A, Gillespie A, Dombi E, Goodwin A, Goodspeed W, Fox E, et al. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology. 2009;73:1273–9.CrossRefPubMedPubMedCentral

5.

Nguyen R, Dombi E, Widemann BC, Solomon J, Fuensterer C, Kluwe L, et al. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7:75.CrossRefPubMedPubMedCentral

6.

Wasa J, Nishida Y, Tsukushi S, Shido Y, Sugiura H, Nakashima H, et al. MRI features in the differentiation of malignant peripheral nerve sheath tumors and neurofibromas. AJR Am J Roentgenol. 2010;194:1568–74.CrossRefPubMed

7.

Kivrak AS, Koc O, Emlik D, Kiresi D, Odev K, Kalkan E. Differential diagnosis of dumbbell lesions associated with spinal neural foraminal widening: imaging features. Eur J Radiol. 2009;71:29–41.CrossRefPubMed

8.

Kang Y, Pekmezci M, Folpe AL, Ersen A, Horvai AE. Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma. Mod Pathol. 2014;27:55–61.CrossRefPubMed

9.

Pekmezci M, Reuss DE, Hirbe AC, Dahiya S, Gutmann DH, von Deimling A, et al. Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas. Mod Pathol. 2015;28:187–200.CrossRefPubMed

10.

Upadhyaya M. Genetic basis of tumorigenesis in NF1 malignant peripheral nerve sheath tumors. Front Biosci. 2011;16:937–51.CrossRef

# Part V
Neuronal and Mixed Neuronal-Glial Tumors
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_17

# 17. Desmoplastic Infantile Astrocytoma and Ganglioglioma

Adekunle M. Adesina1

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Desmoplastic infantile astrocytomaDesmoplastic infantile ganglioglioma

## 17.1 Overview

  * Desmopla stic infantile astrocytomas and gangliogliomas are rare, superficial cerebral cortical and leptomeningeal large cystic tumors with dural attachment.

  * They primarily occur in infants, with most patients less than 2 years of age.

  * They account for 1.25 % of all childhood brain tumors, with a 1.5:1 male-to-female ratio.

  * These tumors are characterized by neoplastic neuroepithelial cells in a desmoplastic stroma showing variable astrocytic differentiation (desmoplastic infantile astrocytoma [DIA]) or combined astrocytic and neuronal differentiation (desmoplastic infantile ganglioglioma [DIG]).

    * ◦ An immature neuroepithelial component is often present.

  * These tumors are classified as World Health Organization (WHO) grade I, with favorable prognosis.

## 17.2 Clinical Features

  * Patients often have massive tumors resulting in macrocephaly and associated features of r aised intracranial pressure.

  * Rapidly in creasing head circumference, progressive lethargy, seizures, and localizing signs such as hemiplegia are consistent with a massive intracranial mass lesion.

## 17.3 Neuroimaging

  * These tumo rs present as a l arge, multicystic mass (often mainly cystic) with a solid component. On MRI, the solid component is isointense to adjacent cortex on T1-weighted images and hyperintense on T2-weighted images. It shows enhancement after contrast administration (Figs. 17.1 and 17.2).

Fig. 17.1

Desmoplast ic infantile astrocytoma (DIA). (A) Multicystic hemispheric mass, isointense on axial T1-weighted images. (B) Same tumor showing contrast enhancement

Fig. 17.2

This axial T2 postcontrast image from the same patient as in Fig. 17.1 demonstrates hyperintensity within the cysts and mild hypointensity in the solid component

  * MR spectroscopy shows slight elevation of the choline peak and only a slight reduction of the N-acetylaspartate (NAA) peak, consistent with low cellularity.

## 17.4 Pathology

  * These specimens are large, uniloculated or multiloculated, firm, grey-white fleshy tissue with attached d ura.

  * The tumor border is well demarcated.

  * These tumors are characterized by three components:

    1. 1)

Fibroblastic spindled cells forming reticulin or collagenous matrix (Fig. 17.3A)

Fig. 17.3

Desmoplastic i nfantile ganglioglioma (DIG) shows variable histologic features: florid desmoplasia (A), gemistocytic astrocytes in a desmoplastic matrix (B), astrocytes in a spindled or fascicular pattern (C), and interface between the astrocytic component and a small cell, poorly differentiated neuroepithelial component (D)

    2. 2)

Neoplastic astrocytic cells, some with abundant (gemistocyte-like) eosinophilic cytoplasm (Fig. 17.3B)

      * ◦ Spindled forms may be arranged in fascicles or storiform pattern (Fig. 17.3C).

      * ◦ In DIG, a component of ganglionic or ganglioid cells with neuronal differentiation is also present.

    3. 3)

A variable population of immature, small, round hyperchromatic neuroepithelial cells (Fig. 17.3D)

  * Calcification may be present.

  * Mitosis is infrequent and necrosis is uncommon.

  * No endothelial proliferation is seen.

  * Rare examples of DIG with anaplastic features, frequent mitosis, and elevated proliferation index as high as 40 % have been reported.

## 17.5 Immunohistochemistry and Molecular Pathology

  * Immunoreactivity for glial fibrillary acidic pr otein (GFAP) is widespread (Fig. 17.4) and is seen in all of the compone nts of DIA.

Fig. 17.4

Variable ex pression of glial fibrillary acidic protein (GFAP) is seen between the astrocytic spindled cell region (A) and the small cell neuroepithelial component (B) of DIA

  * Vimentin expression and pericellular reticulin demonstrable by reticulin silver stain or anti collagen type IV antibody is present.

  * Neuronal markers such as synaptophysin, neurofilament protein (NF-H), MAP2 (Fig. 17.5A), and NeuN (Fig. 17.5B) are often demonstrable in DIG.

Fig. 17.5

Neuronal marke rs MAP2 (A) and NeuN (B) are expressed in the small neuroepithelial component of this DIG

  * Smooth muscle actin and desmin may be demonstrable.

  * A lack of expression of myogenin or MyoD excludes myoid differentiation.

  * Ki67 shows a low proliferation index of less than 2 %.

  * Epithelial markers such as epithelial membrane antigen (EMA), pancytokeratin (AE1/AE3), and CAM 5.2 are absent.

  * Molecular data are very limited on these tumors. Recent reports indicate the presence of BRAF V600E mutation in a small subset of DIA/DIG tumors.

## 17.6 Differential Diagnosis

  * Prominent spindle c ell fibroblastic components raise the differential diagnosis of fibromatosis or solitary fibrous tumor.

## 17.7 Prognosis

  * This is a tu m or with good prognosis; some reports show good survival with a 15.1-year follow-up.

  * Good survival has also been reported for the rare anaplastic variants.

Suggested Reading

Duffner PK, Burger PC, Cohen ME, Sanford RA, Krischer JP, Elterman R, et al. Desmoplastic infantile gangliogliomas: an approach to therapy. Neurosurgery. 1994;34:583–9. discussion 589.CrossRefPubMed

Koeller KK, Henry JM. From the archives of the AFIP: superficial gliomas: radiologic-pathologic correlation. Armed Forces Institute of Pathology. Radiographics. 2001;21:1533–56.CrossRefPubMed

Koelsche C1, Sahm F, Paulus W, Mittelbronn M, Giangaspero F, Antonelli M, et al. BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma. Neuropathol Appl Neurobiol. 2014;40:337–44.CrossRefPubMed

Kros JM, Delwel EJ, de Jong TH, Tanghe HL, van Run PR, Vissers K, Alers JC. Desmoplastic infantile astrocytoma and ganglioglioma: a search for genomic characteristics. Acta Neuropathol. 2002;104:144–8.CrossRefPubMed

Louis DN, von Deimling A, Dickersin GR, Dooling EC, Seizinger BR. Desmoplastic cerebral astrocytomas of infancy: a histopathologic, immunohistochemical, ultrastructural, and molecular genetic study. Hum Pathol. 1992;23:1402–9.CrossRef90061-7)PubMed

Mallucci C, Lellouch-Tubiana A, Salazar C, Cinalli G, Renier D, Sainte-Rose C, et al. The management of desmoplastic neuroepithelial tumours in childhood. Childs Nerv Syst. 2000;16:8–14.CrossRefPubMed

Setty SN, Miller DC, Camras L, Charbel F, Schmidt ML. Desmoplastic infantile astrocytoma with metastases at presentation. Mod Pathol. 1997;10:945–51.PubMed

Sugiyama K, Arita K, Shima T, Nakaoka M, Matsuoka T, Taniguchi E, et al. Good clinical course in infants with desmoplastic cerebral neuroepithelial tumor treated by surgery alone. J Neurooncol. 2002;59:63–9.CrossRefPubMed

Tamburrini G, Colosimo Jr C, Giangaspero F, Riccardi R, Di Rocco C. Desmoplastic infantile ganglioglioma. Childs Nerv Syst. 2003;19:292–7.CrossRefPubMed

Trehan G, Bruge H, Vinchon M, Khalil C, Ruchoux MM, Dhellemmes P, Ares GS. MR imaging in the diagnosis of desmoplastic infantile tumor: retrospective study of six cases. AJNR Am J Neuroradiol. 2004;25:1028–33.PubMed

VandenBerg SR. Desmoplastic infantile ganglioglioma and desmoplastic cerebral astrocytoma of infancy. Brain Pathol. 1993;3:275–81.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_18

# 18. Dysembryoplastic Neuroepithelial Tumor

Adekunle M. Adesina1  and Ronald A. Rauch2

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Dysembryoplastic neuroepithelial tumorCortical dysplasiaEpilepsyFloating neuronsPilocyticNeurocytic

## 18.1 Overview

  * Dysembryoplastic neuroepithelial tumors (DNETs) are superficial, cortical, benign glioneuronal neoplasms of World Health Organization (WHO) grade I. Characteristicall y, these tumors are uninodular or multinodular lesions accompanied by cortical dysplasia.

  * DNETs are often associated with a long-standing history of refractory partial complex seizures. They represent 13.5 % of histologic findings in children undergoing epilepsy surgery, compared with 12 % in adults.

  * Although cases of DNET have been observed in young adults, most patients are less than 20 years of age at presentation; there is a male predominance.

## 18.2 Clinical Features

  * Most patients pres ent with a long-standing history of partial complex seizures that are poorly responsive or resistant to standard antiepileptic therapy.

  * Presentation as mass lesions in noncortical sites such as basal ganglia, brainstem, and cerebellum has been reported.

  * Occasional presentation in the context of neurofibromatosis 1 (NF1) and XYY syndrome has been reported.

## 18.3 Neuroimaging

  * DNETs show a prim ary superficial cortical location, often without mass effect or peritumoral edema (Fig. 18.1).

Fig. 18.1

Dysembryoplastic neuroepithelial tumor (DNET) is seen as a bright (hyperintense) left temporal lobe lesion with no mass effect or midline shift on an axial fluid-attenuated in version recovery (FLAIR) MR image (A) and a T2-weighted image (B)

  * The cortical lesions are best seen on MRI as well-defined, hypointense lesions on T1-weight ed images (Fig. 18.2A) and hyperintense lesions on T2-weighted images (Fig. 18.1B).

Fig. 18.2

(A) This cortical DNET is dark (hypointense) on this sagittal T1-weighted precontrast MRI. (B) The s ame lesion shows no postcontrast enhancement

  * The tumor may contain cystic regions.

  * Enhance ment after contrast administration is variable (Figs. 18.2B, 18.3, and 18.4); the lesion may be nonenhancing.

Fig. 18.3

Left temporal hyperintense mass lesions with confirmed histologic features of a complex DNET show lack of e nhancement on axial (A) and coronal (B) T1-weighted postcontrast images

Fig. 18.4

This coronal T1-wei ghted postcontrast image shows enhancement of a left mesiotemporal mass lesion

  * In up to 33 % of cases, enhancement may be solid or heterogeneous.

  * DNETs usually show increased diffusion o n diffusion images (Fig. 18.5).

Fig. 18.5

Axial diffusio n-weighted image (DWI) showing unrestricted diffusion in the same lesion as in Fig. 18.1

  * The appearance of malformed gyri with or without a pseudocystic component is common.

  * Abnormalities of the overlying calvarium due to skull remodeling may be seen. These abnormalities are probably more common in DNET than in other tumors because of the DNET's superficial location and slow growth.

  * The tumor is usually hypodense to white matter, without associated edema on CT scan (Fig. 18.6A and B).

Fig. 18.6

(A, B) Axial CT scans of a right temporal lobe DNET showing no calcification. (C, D) Axial C T scans of a left temporal lobe DNET showing the presence of calcification

  * Intratumoral calcification is seen in approximately 20 % of DNETs. When present, it is demonstrable on CT scans (Fig. 18.6) but may be suggested on MRI.

  * MR spectroscopy may show normal spectra or an elevated choline peak (Fig. 18.7).

Fig. 18.7

MR spectroscopy showing elevated choline and a small n-acetyl aspartate (NAA) peak (TE, 13 6 ms)

## 18.4 Pathology

  * Gross pathology

    * DNETs may appear as elevated and expanded "macrogyri" varying in size from a few millimeters to several centimeters.

  * Histology

    * Histopathologic features can be classified as several forms:

      * Complex form

        * Composed of a mixture of a multinodular component of glial nodules and intervening "sp ecific glioneuronal" component (Fig. 18.8).

Fig. 18.8

Low-power view of a complex DNET with multiple nodules of the "glioneuronal" component

        * Glial nodules are composed of oligodendroglia-like cells (Fig. 18.9) with perinuclear halo, mucinous matrix, an d delicate vasculature (Fig. 18.10); they may show calcification (Fig. 18.11).

Fig. 18.9

Regional cluster of proliferating "oligodendroglia-like" cells in a microcystic background

Fig. 18.10

Delicate vasculature arranged in a "chicken wire" configuration and intermixed with "oligo-like" cells

Fig. 18.11

Multifocal c alcification randomly distributed within a DNET

        * Intraoperative smears often show a population of uniform or monomorphic small, round cells representing oligodendroglia-like cells with interspersed larger vesicular nuclei and prominent nucleoli representing the neuronal component (Fig. 18.12).

Fig. 18.12

Smear preparation showing a uniform population of oligo-like cells, few interspersed neuronal nuclei, and delicate capillaries in a fibrillary background

        * Nodules may also have histologic features of pilocytic astrocytoma (Fig. 18.13), diffuse astrocytoma, or ganglioglioma.

Fig. 18.13

Region of pilocytic astrocytoma within a DNET. Note the piloid astrocytic cells, Rosenthal fib ers, and numerous microcysts

        * The specific glioneuronal component is composed of two elements: (1) vertical columns of neuriti c processes perpendicular to the cortical surface, on which are arranged columns of oligodendroglia-like cells in a microcystic (Figs. 18.14 and 18.15), mucinous, Alcian blue–positive matrix; and (2) mature ganglion cells referred to as "floating neuro ns" seen in the pools of mucin present between the columns (Fig. 18.16).

Fig. 18.14

Diffuse microcystic pattern in a DNET

Fig. 18.15

Diffuse microcystic patter n at a higher magnification

Fig. 18.16

Columns of oligodendroglia-like cells, a diffuse microcystic pattern with a mucinous content, an d intracystic "floating" neurons (top left corner inset) represent the classic features of the specific glioneuronal component of a DNET

      * Simple form

        * This form of DNET consists primarily of the specific glioneuronal component without the nodular pattern as a component.

      * "Nonspecific" histologic variants

        * Histologically similar to classic, low-grade gliomas, these tumors have neither the specific glioneuronal component nor the multinodular architecture. Classification as a DNET is largely influenced by the clinical presentation.

        * These variants present with similar clinical features of a long-standing history of partial seizures and radiologic features similar to those in the complex form of DNET.

        * The need for these clinical features to classify these otherwise low-grade gliomas as DNET makes this category controversial.

      * Cortical dysplasia

        * Cortical tissue adjoining DNET mass lesions often shows varying degrees of cortical dysplasia, with features of cortical dyslamination or disorganization (microdysgenesis), including irregular neuronal clustering, irregular neuronal orientation, accentuation of vertical columnar architecture, and diffuse white-matter neuronal heterotopia.

        * The association of DNETs with cortical dysplasia suggests a developmental malformative origin.

## 18.5 Immunohistochemistry

  * Immunostaining for glial fibrillary acidic protein (GFAP), a glial marker, identifies an astrocytic component (Figs. 18.17 and 18.18).

Fig. 18.17

Region of more dist inct astrocytic differentiation within a DNET

Fig. 18.18

Glial fibrillary ac idic protein (GFAP) immunostain showing a diffuse and fibrillary stromal positivity as well as cytoplasmic positivity in differentiating astrocytic cells

  * Oligodendroglia-like cells show diffuse immunoreactivity for S-100 and focal positivity for neuronal markers including NeuN, neurofilament protein, and class III β-tubulin.

    * Dense core neurosecretory granules can be demonstrated within some of these neurocytic cells (Fig. 18.19).

Fig. 18.19

Electron micrograph of the neurocytic cells within a DNET, showing dense core neurosecre tory granules consistent with neuronal differentiation

  * Synaptophysin is often diffusely positive in the neuropil (Fig. 18.20A) and in the neuronal components of the "specific glioneuronal element," but it is weakly positive to negative in the oligodendroglia-like cells.

Fig. 18.20

(A) Diffuse stro mal positivity for synaptophysin in a DNET. (B) Floating neurons showing immunopositivity for chromogranin in a DNET

  * The neuronal component is also positive for chromogranin (Fig. 18.20B) and other neuronal markers.

  * The reported demonstration of myelin-associated glycoprotein in some oligodendroglia-like cells suggests oligodendroglial differentiation in these cells.

    * The proliferation index by MIB1 immunostaining is usually less than 1 % (Fig. 18.21), but a proliferation index as high as 8 % has been reported.

Fig. 18.21

Immunostain with th e MIB1 antibody showing a paucity of Ki-67 positive cells consistent with a low proliferation index

## 18.6 Molecular Pathology

  * Molecular events associated with prognosis in oligodendroglioma, such as 1p36 and 19q13 deletions or progression-related genetic events in fibrillary astrocytoma such as 17p13 deletion or p53 gene mutation are absent in DNET.

  * BRAF V600E mu tations have been reported in about 30–50 % of DNETs. It is unclear whether there is a correlation between BRAF V600E positivity and the presence of a pilocytic astrocytoma component in these tumors.

## 18.7 Differential Diagnosis

  * Identification of the specific glioneuronal element is key to recognition of the simple and complex forms of DNET.

  * Tumors with the presence of nonspecific histologic patterns including pilocytic astrocytoma or oligodendroglioma-like or ganglioglioma-like patterns in addition to the specific glioneuronal component should be classified as DNET.

  * In the absence of the specific glioneuronal element, diagnosis of nonspecific histologic patterns as DNET can be problematic and is currently controversial.

    * Designation of such lesions as DNET is favored by the presence of a classic history of poorly controlled, long-standing seizures and radiologic findings compatible with a diagnosis of DNET.

## 18.8 Prognosis

  * DNETs are gen erally regarded as benign tumors. Long-term follow-up shows no evidence of recurrence following gross total resection or progression following subtotal resection.

  * A rare case of malignant transformation following radiation and chemotherapy has been reporte d.

Suggested Reading

Chappé C, Padovani L, Scavarda D, Forest F, Nanni-Metellus I, Loundou A, et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol. 2013;23:574–83.CrossRefPubMed

Daumas-Duport C. Dysembryoplastic neuroepithelial tumours. Brain Pathol. 1993;3:283–95.CrossRefPubMed

Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws Jr ER, Vedrenne C. Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery. 1988;23:545–56.CrossRefPubMed

Daumas-Duport C, Varlet P, Bacha S, Beuvon F, Cervera-Pierot P, Chodkiewicz JP. Dysembryoplastic neuroepithelial tumors: nonspecific histological forms—a study of 40 cases. J Neurooncol. 1999;41:267–80.CrossRefPubMed

Deb P, Sharma MC, Tripathi M, Sarat Chandra P, Gupta A, Sarkar C. Expression of CD34 as a novel marker for glioneuronal lesions associated with chronic intractable epilepsy. Neuropathol Appl Neurobiol. 2006;32:461–8.CrossRefPubMed

Hirose T, Scheithauer BW. Mixed dysembryoplastic neuroepithelial tumor and ganglioglioma. Acta Neuropathol. 1998;95:649–54.CrossRefPubMed

Hirose T, Scheithauer BW, Lopes MB, VandenBerg SR. Dysembryoplastic neuroepithelial tumor (DNET): an immunohistochemical and ultrastructural study. J Neuropathol Exp Neurol. 1994;53:184–95.CrossRefPubMed

Honavar M, Janota I, Polkey CE. Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases. Histopathology. 1999;34:342–56.CrossRefPubMed

Ishizawa K, Terao S, Kobayashi K, Yoshida K, Hirose T. A neuroepithelial tumor showing combined histological features of dysembryoplastic neuroepithelial tumor and pleomorphic xanthoastrocytoma—a case report and review of the literature. Clin Neuropathol. 2007;26:169–75.CrossRefPubMed

Lee D, Cho YH, Kang SY, Yoon N, Sung CO, Suh YL. BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas. J Surg Oncol. 2015;111:359–64.CrossRefPubMed

Maher CO, White JB, Scheithauer BW, Raffel C. Recurrence of dysembryoplastic neuroepithelial tumor following resection. Pediatr Neurosurg. 2008;44:333–6.CrossRefPubMed

O'Brien DF, Farrell M, Delanty N, Traunecker H, Perrin R, Smyth MD, Park TS. The Children's Cancer and Leukaemia Group guidelines for the diagnosis and management of dysembryoplastic neuroepithelial tumours. Br J Neurosurg. 2007;21:539–49.CrossRefPubMed

Ostertun B, Wolf HK, Campos MG, Matus C, Solymosi L, Elger CE, et al. Dysembryoplastic neuroepithelial tumors: MR and CT evaluation. AJNR Am J Neuroradiol. 1996;17:419–30.PubMed

Park JY, Suh YL, Han J. Dysembryoplastic neuroepithelial tumor. Features distinguishing it from oligodendroglioma on cytologic squash preparations. Acta Cytol. 2003;47:624–9.CrossRefPubMed

Prayson RA. Composite ganglioglioma and dysembryoplastic neuroepithelial tumor. Arch Pathol Lab Med. 1999;123:247–50.PubMed

Prayson RA, Castilla EA, Hartke M, Pettay J, Tubbs RR, Barnett GH. Chromosome 1p allelic loss by fluorescence in situ hybridization is not observed in dysembryoplastic neuroepithelial tumors. Am J Clin Pathol. 2002;118:512–7.CrossRefPubMed

Sakuta R, Otsubo H, Nolan MA, Weiss SK, Hawkins C, Rutka JT, et al. Recurrent intractable seizures in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor. J Child Neurol. 2005;20:377–84.CrossRefPubMed

Sherburn EW, Bahn MM, Gokden M, Silbergeld DL, Rich KM. Dysembryoplastic neuroepithelial tumor and oligodendroglioma: the diagnostic value of magnetic resonance spectroscopy. Case report and review of the literature. Neurosurg Focus. 1998;4:e6.CrossRefPubMed

Stanescu Cosson R, Varlet P, Beuvon F, Daumas-Duport C, Devaux B, Chassoux F, et al. Dysembryoplastic neuroepithelial tumors: CT, MR findings and imaging follow-up: a study of 53 cases. J Neuroradiol. 2001;28:230–40.PubMed

Sung CO, Suh YL. Different pattern of expression of nestin in the non-specific form of dysembryoplastic neuroepithelial tumors compared to the simple and complex forms. J Neurooncol. 2009;92:7–13.CrossRefPubMed

Takahashi A, Hong SC, Seo DW, Hong SB, Lee M, Suh YL. Frequent association of cortical dysplasia in dysembryoplastic neuroepithelial tumor treated by epilepsy surgery. Surg Neurol. 2005;64: 419–27.CrossRefPubMed

Taratuto AL, Pomata H, Sevlever G, Gallo G, Monges J. Dysembryoplastic neuroepithelial tumor: morphological, immunocytochemical, and deoxyribonucleic acid analyses in a pediatric series. Neurosurgery. 1995;36:474–81.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_19

# 19. Gangliocytoma and Ganglioglioma

Carrie A. Mohila1, Ronald A. Rauch2 and Adekunle M. Adesina1

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

GangliogliomaGlioneuronalPilocyticGangliocytomaDNET-ganglioglioma overlap

## 19.1 Overview

  * These are neuroepithelial tumors composed of mature neurons (gangliocytoma) or a mixed population of ganglion cells and glial cells (ganglioglioma).

  * Well-differentiated gangliocytomas are classified as World Health Organization (WHO) grade I.

  * Gangliogliomas may be classified as WHO grade I or grade II, although criteria for WHO grade II tumors are not yet established.

  * Anaplastic gangliogliomas with a malignant glial component are classified as WHO grade III.

  * Gangliogliomas and gangliocytomas may occur in all age groups, but they are frequently seen in the young, with a peak between the ages of 10 and 30 years. They represent about 0.4 % of all tumors in the central nervous system (CNS).

  * They can occur in all regions of the CNS but have a higher frequency in the brain, with an incidence of 1.3 % of all brain tumors.

  * More than 80 % of gangliogliomas and gangliocytomas occur in the temporal lobe; they represent the tumors most frequently associated with epilepsy.

## 19.2 Clinical Features

  * The clinical p resentation reflects the localized tumor effect and complications of raised intracranial pressure.

  * A long-standing history of seizures (ranging from a few months to decades) is frequent for tumors involving the cerebral hemisphere.

  * They are the most frequent tumors in patients with temporal lobe epilepsy requiring surgical intervention for control of seizures.

  * Tumors involving the brainstem and spinal cord often have a short duration of symptoms related to pressure effect.

## 19.3 Neuroimaging

  * These tumors classically present as a cyst with a mural nodule (Fig. 19.1), but they may also present as a circ umscribed solid mass (Fig. 19.2) or a mass with multiple cysts.

Fig. 19.1

Gangliocytoma appears on axi al T2-weighted (A) and fluid-attenuated inversion recovery (FLAIR) MRI (B) as a cystic right temporal lobe mass with mural nodule and subtle T2 hyperintensity

Fig. 19.2

This noncontrast CT scan 15 months earlier from the same patient as in Fig. 19.1 shows a calcified mass in the right temporal lobe

  * On MRI, the tumo rs typically appear hypointense on T1-weighted images (Fig. 19.3) and hyperintense on T2-weighted images (Fig. 19.4). Enhan cement with contrast is variable but of ten present (Figs. 19.5 and 19.6).

Fig. 19.3

(A) A coronal T1-weighted pre-gadolinium (Gd) MR image shows a hypointense to isointense right temporal lob e lesion inferior to the hippocampus. (B) A coronal T1-weighted post-Gd image shows an enhancing nodule in the right temporal lobe

Fig. 19.4

(A) An axial T2-weighted image obtained 15 months earlier from the same patient as in Fig. 19.1 shows a le sion of the right temporal lobe that is isointense to gray matter. (B) The apparent diffusion coefficient (ADC) map shows no diffusion restriction

Fig. 19.5

An axial T1-weigh ted post-Gd image obtained 15 months earlier from the same patient as in Fig. 19.1 shows a lesion of the right temporal lobe with subtle or minimal enhancement

Fig. 19.6

Coronal FLAIR (A), axia l FLAIR (B), axial T1-weighted pre-Gd (C), and axial T1-weighted post-Gd (D) images showing a T2-hyperintense and contrast-enhancing lesion of the left frontal cortex with expansion of the involved cortex

  * CT scans may sho w calcification (Figs. 19.2 and 19.7). The solid portion of the tumor itself is often hypodense but may be isodense compared with brain.

Fig. 19.7

Noncontrast CT sca n showing tumor calcification

  * Calvarial bone remodeling changes due to prolonged tumor mass effect on skull may be seen.

## 19.4 Pathology

  * Macroscopically, these tu mors often are seen as a cystic lesion with a mural nodule. They may also be seen as a well-circumscribed mass lesion

  * Intraoperative smear preparations

    * Smear preparations show a mixed population of fibrillary astrocytic cells and a variable number of ganglioid and ganglion cells with vesicular nuclei and prominent nucleoli (Figs. 19.8 and 19.9).

Fig. 19.8

Cellular smear p reparation showing many "ganglioid" cells with vesicular nuclei and distinct nucleoli in a fibrillary astrocytic matrix

Fig. 19.9

Higher magnification of the same region as in Fig. 19.8

  * Histology

    * The histologic hallmark of a gangliocytoma is a tumor with disorganized, variably cellular, noninfiltrative (well-circumscribed) aggregates of large and small neurons (Fig. 19.10) and n o glial component.

Fig. 19.10

Gangliocytoma with atypic al ganglion cells in a microcystic and vacuolated stroma. Note the lack of a proliferating glial component

    * Neuronal differentiation is recognized by the presence of large cells with vesicular nuclei, prominent n ucleoli and variably abundant amphophilic cytoplasm (Fig. 19.11).

Fig. 19.11

Aggregates of tumor cells showing varying degrees of neuronal differentiation, from "ganglioid" cells to well-differentiated ganglion cells

    * Neurons show varying degrees of dysmorphism, including irregular accumulation of Nissl substance , cytoplasmic vacuolization, neurofibrillary tangles, granulovacuolar degeneration, and binu cleation (Fig. 19.12).

Fig. 19.12

Gangliogli oma showing a binucleated ganglion cell in a background of proliferating glial cells

    * Often present are less mature neurons with intermediate differentiation, designated as "ganglioid cells" (Fig. 19.13).

Fig. 19.13

Ganglioglio ma with regional predominance of proliferating ganglioid and ganglion cells

    * Gangliogliomas show both populations of neoplastic neurons and glia (astrocytes), which may be arranged as separate and distinct clusters of cell populations or may be intimately mixed.

    * Reticulin and collag en-rich stroma may be seen in lobular clusters of ganglion cells.

    * The proportion of neuronal component is variable, ranging from being predominant to being a minor component (Figs. 19.14, 19.15, and 19.16).

Fig. 19.14

Ganglioglioma with regional predominance of proliferating glia cells

Fig. 19.15

Low-cellulari ty glial component and proliferating ganglion cells in a grade I ganglioglioma

Fig. 19.16

Eosinophilic granular bodies (EGBs) in a ganglioglioma with mixed population of proliferating ganglion and glial cells

    * The glial component may represent a diffuse fibrillary pattern or a pilocytic pattern (Fig. 19.17).

Fig. 19.17

Pilocytic glial compo nent of a ganglioglioma showing abundant EGBs

    * Periodic acid–Schiff (PAS)–positive eosinophilic granular bodies (EGBs) are a frequent feature of ganglion cell tumors.

    * Lymphoc ytic infiltrate arranged in a perivascular pattern is also common (Fig. 19.18). Microcalcifications and florid microcystic changes may be seen.

Fig. 19.18

Prominent periv ascular infiltrate of lymphocytes in a ganglioglioma

    * A delicate capillary network may be seen, especially in gangliocytomas.

    * Subarachnoid tumor growth is a frequent histologic observation and does not imply subarachnoid dissemination or poor prognosis (Fig. 19.19).

Fig. 19.19

Florid subarac hnoid tumor growth in a ganglioglioma, at low (A) and high (B) magnification

    * Cortical dysplasia may occur in adjoining cortical tissue, especially for lesions removed for seizure control.

    * High-grade astrocytic features such as increased cellularity, pleomorphism, and mitotic activity suggest anaplastic ganglioglioma, which is usually due to malignant progression in the glial component (Figs. 19.20 and 19.21).

Fig. 19.20

Gangl ioglioma showing increased cellularity and pleomorphism following progression to anaplastic ganglioglioma, WHO grade III

Fig. 19.21

Anapla stic ganglioglioma with spindle-cell appearance of the glial component (A), increased cellularity, and increased mitotic activity (B)

## 19.5 Immunohistochemistry

  * Using a panel of neu ronal markers including synaptophysin (Fig. 19.22), MAP2 (Fig. 19.23), chromogranin, neurofilament protein (NFP), and NeuN to demonstrate neuronal differentiation is recommended.

Fig. 19.22

Ganglion cell c omponent of a ganglioglioma showing positivity for synaptophysin

Fig. 19.23

MAP2-po sitive ganglion cell component of a ganglioglioma

    * Synaptophysin shows a granular surface membrane staining of perisomatic synapses with or without cytoplasmic staining.

    * MAP2 frequently shows strong cytoplasmic staining.

    * Chromogranin shows granular cytoplasmic staining but may be less diffusely positive.

    * NFP shows variable cytoplasmic staining; NeuN shows nuclear positivity.

    * Although MAP2 positivity may be seen in diffuse gliomas, it is less frequently positive in the astrocytic component of gangliogliomas.

  * CD34 has been reported as frequently (about 70–80 %) positive in gangliogliomas.

  * Glial fibrillary acidic protein (GFAP) positivity is present in the astrocytic component of gangliogliomas (Fig. 19.24).

Fig. 19.24

Glial fibrillary acidic protein (GFAP)–positive astrocytic glial component of a ganglioglioma

  * The Ki67 proliferation index in gangliocytomas and gangliogliomas is very low; the index is elevated with malignant progression in anaplastic gangliogliomas.

## 19.6 Electron Microscopy

  * Neuronal differentiation in a ganglion cell tumor is often readily demonstrable by the presence of d ense core neurosecretory granules, which are often abundant in the more differentiated cells.

  * Abundant microtubules and demonstrable synaptic-type junctions support neuronal differentiation.

## 19.7 Differential Diagnosis

  * The major dif ferential diagnostic issue is the need to differentiate between a ganglion cell tumor and an infiltrating glioma with entrapped neurons. A few clues are helpful in making the distinction:

    * Neoplastic ganglion cells tend to form abnormal clusters and are variable in size, with abnormal orientation of neuronal apical dendrites.

    * Binucleation is the ultimate proof of neoplasia.

    * Dysmorphic neurons are frequently seen in ganglion cell tumors.

  * Dysembryoplastic neuroepithelial tu mors (DNETs) may show a mixed glioneuronal phenotype.

    * A characteristic mucinous component with "floating" neurons is a feature of DNETs not seen in ganglion cell tumors.

    * Multinodular architecture with oligodendroglia-like cells and characteristic neuroimaging features including superficial location favor a DNET.

    * Transitional tumors with mixed features of DNET and ganglioglioma occur but are very rare (Fig. 19.25). These tumors pose a significant diagnostic dilemma when attempts are made to fit them into either the DNET or ganglioglioma categories.

Fig. 19.25

Proliferating ganglioid cells in a background of microcysts and floating neurons in a transitional tumor with dysembryoplastic neuroepithelial tumor (DNET)–ganglioglioma phenotypic overlap, shown at low magnification (A) and high magnification (B)

## 19.8 Molecular Pathology

  * MAP kinase pathway a ctivation

    * BRAF V600E mutations occur frequently in gangliogliomas, with positivity rates ranging from 13 % to 67 %; variations are based on patient age and tumor location. BRAF V600E mutations are seen in approximately 45 % of pediatric gangliogliomas.

    * The KIAA1549-BRAF fusion gene is rare and has been reported only in infratentorial gangliogliomas with prominent pilocytic glial components.

  * Although examples of the occurrence of ganglioglioma in patients with neurofibromatosis 1 (NF1), NF2, and Peutz-Jeghers syndrome have been reported, no mutations in the NF1, NF2, or LKB1 genes, respectively, have been demonstrated in gangliogliomas.

  * Gains of chromosome 5, 6, 7, 8 and 12 have been reported in gangliogliomas.

  * Losses of chromosomes 9, 10, and 22q have also been described.

  * Genetic events described in typical fibrillary astrocytomas, such as p53 and PTEN mutations and CDK4 and EGFR amplification, are infrequent in gangliogliomas.

  * Polymorphisms in intron 4 and exon 41 of TSC2 are overrepresented in individuals with ganglioglioma.

## 19.9 Prognosis

  * These tumors are generally slow-growing, low-grade tumors classified as WHO grade I with a 7.5-year pr ogression-free survival rate of 94 %.

  * Malignant progression is uncommon. When it occurs, it is usually related to malignant progression of the glial/astro cytic component, showing increased cellularity, increased mitotic activity, endothelial proliferation, and necrosis with poorer prognosis.

Suggested Reading

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_20

# 20. Central Neurocytoma and Extraventricular Neurocytoma

Carrie A. Mohila1, Ronald A. Rauch2 and Adekunle M. Adesina1

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Central neurocytomaBrain tumorExtraventricular neurocytoma

## 20.1 Overview

  * These are low- grade (WHO grade II) ventricular tumors (central neurocytoma) or extraventricular tumors composed of a monomorphic population of uniform, round, neurocytic cells.

  * They are more common in the lateral and third ventricles but may occur in the fourth ventricle and e xtraventricular sites including the cerebral hemispheric parenchyma and spinal cord.

  * They occur predominantly in young adults, with a peak incidence in the third and fourth decades. The incidence in the first and second decades is low.

## 20.2 Clinical Features

  * Localization in th e region of the foramen of Monro and the third ventricle leads to raised intracranial pressure.

  * A pressure effect on the hypothalamus may be associated with hormonal disturbance.

## 20.3 Neuroimaging

  * Tumors are well-c ircumscribed and usually attached to the intraventricular septum.

  * On CT, the tumors are isodense or slightly hypodense and are associated with contrast enhancement.

  * Calcification and cystic degeneration may occur.

  * MRI shows a well-circumscribed mass lesion isointense to gray matter on T1-weighted images (Figs. 20.1A and 20.2A) and variably hyperintense on T2-weighted images (Fig. 20.1B) and fluid-attenuated inversion recovery (FLAIR) imaging, with variable mild to marked gadolinium enhancement (Figs. 20.2B and 20.3).

Fig. 20.1

Intraventricular central neurocytoma. (A) An axial T1-weighted precontrast image show i sointensity. (B) A T2-weighted precontrast image shows hyperintensity

Fig. 20.2

Another example (sagittal view) of central neurocytoma, showing isointensity on precontrast T1 -weighted imaging (A) and homogenous enhancement on T1-weighted postcontrast imaging (B)

Fig. 20.3

Axial (A) and coronal (B) T1-weighted postcontrast images on the same patient in Fig. 20.2, confir ming homogenous tumor enhancement

## 20.4 Pathology

  * Macroscopically, these tumors are grey and friable; they may be calcified.

  * The classic histologic fe atures are those of a monomorphic population of round cells arranged in variable clusters with intervening fibrillary neuropil-like regions (Fig. 20.4A).

Fig. 20.4

(A) Histology of central neurocytoma showing a monomorphic population of round cells arrang ed in irregular clusters with intervening acellular neuropil islands. (B) Oligodendroglioma-like histologic features with perinuclear halos and delicate vasculature

  * Oligodendroglioma-like features with perinuclear halos and delicate, arborizing capillary vasculature may be present (Fig. 20.4B).

  * Areas showing perivascular pseudorosette-like formations may cause confusion with an ependymoma.

  * Homer Wright rosettes and ganglioid or ganglionic differentiation (Figs. 20.5 and 20.6) are rare; they may be more common with the extraventricular variant.

Fig. 20.5

Regio ns of ganglioid cells with vesicular nuclei and distinct nucleoli are illustrated (arrows)

Fig. 20.6

Mature ganglionic differentiation (arrow) is seen focally in this example of central neurocytoma

  * Mitoses are rare and tumors generally show a low proliferation index.

  * Anaplastic transformat ion is rare. When present, it is characterized by brisk mitosis and microvascular proliferation.

## 20.5 Immunohistochemistry

  * The hallmark of central neurocytoma is a diffuse neuropil and perivascular immunore activity for synaptophysin (Fig. 20.7). Diffuse nuclear positivity for NeuN and cytoplasmic positivity for MAP2 (Fig. 20.8) is common.

Fig. 20.7

Diffuse perikaryal immunopositivity for synaptophysin in central neurocytoma. Note the pr esence of and positivity in acellular islands, a major distinguishing feature from an oligodendroglioma

Fig. 20.8

Immunostainin g for MAP2 with regional positivity in central neurocytoma

  * Ganglioid cells, when present, are immunopositive for neurofilament protein and chromogranin A, whereas neurocytes are generally negative for these markers.

  * The Ki-67 proliferation index (MIB-1 staining) is usually low, often less than 2 %.

  * "Atypical" neurocytoma with proliferation index greater than 2–3 % is associated with shorter time to recurrence or progression-free survival.

## 20.6 Electron Microscopy

  * Neurocytic differentia tion is present and is characterized by the formation of intermingled cell processes containing microtubules, dense core neurosecretory granules, and clear vesicles.

  * Synaptic junctions may be seen.

  * Other organelles, including the presence of mitochondria, rough endoplasmic reticulum, and prominent Golgi, are nonspecific.

## 20.7 Molecular Pathology

  * No consistent genetic signature has been described. 1p36 and 19q13 deletions are uncommon in central neurocytomas.

  * Rare examples of chromosomal gains involving chromosomes 2p, 7, 10q, 13q, and 18q have been reported.

  * TP53 mutation is uncommon in central neurocytoma.

  * Rare occurrences of these tumors in association with von Hippel-Lindau disease have been described.

  * The cell of origin is unknown; a putative origin from a neuroglial precursor cell from the subependymal region or from the circumventricular organ has been suggested.

## 20.8 Differential Diagnosis

  * Central ne urocytoma shares the characteristic perinuclear halo and delicate vasculature with oligoden droglioma. Unlike central neurocytoma, oligodendrogliomas do not have the acellular, synaptophysin-positive intervening neuropil.

  * The uncommon tendency to form vague, perivascular pseudorosettes and the presence of perinuclear halos raise a differential diagnosis of clear cell ependymoma. Ependymomas show dotlike immunoreactivity for epithelial membrane antigen (EMA), a feature not seen with neurocytomas, allowing distinction between these two entities.

## 20.9 Prognosis

  * After gross tot al resection, these tumors generally run a benign course, but incomplete resection is often associated with local recurrence.

  * Anaplastic features, inc luding proliferation index greater than 2–3 % is associated with poorer prognosis and shorter recurrence-free intervals.

  * Infiltration of periventricular tissue is likewise a poor prognostic feature.

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_21

# 21. Papillary Glioneuronal Tumor

Marie Rivera-Zengotita1, Anna Illner2 and Adekunle M. Adesina3

(1)

Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health College of Medicine, Box 100275, Gainesville, FL 32610, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

(3)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Mixed glioneuronal tumorsPapillary glioneuronal tumorPseudopapillary ganglioglioneurocytomaPseudopapillary neurocytoma with glial differentiation

## 21.1 Overview

  * Papillary glioneuro nal tumor (PGNT) is a benign (WHO grade I), relatively circumscribed, biphasic cerebral neoplasm occurring predominantly in the temporal lobe; it most commonly affects young adults.

  * No population-based epidemiologic data are available to date.

  * PGNT was initially described as "pseudopapillary ganglioglioneurocytoma" or "pseudopapillary neurocytoma with glial differentiation."

    * ◦ Established as a distinct clinicopathologic entity in 1998 by Komori et al.

    * ◦ Regarded as a variant of ganglioglioma in the 2000 World Health Organization (WHO) classification of central nervous system tumors.

    * ◦ Added as a new entity in the 2007 WHO classification.

## 21.2 Clinical Features

  * PGNT occurs over a wide age range (4–75 years), with a mean age at presentation of 27 years. It is more prevalent in the second and third decades of life.

  * No gender predilection has been reported.

  * The most common clinical manifestations include headache and seizures.

  * Patients may also present with nausea, vertigo, visual and gait disturbances, focal sensorimotor deficits, syncope, memory loss, and mood changes.

## 21.3 Neuroimaging

  * The tumor presents as well-defined, circumscribed lesion centered in subcortical or periventricular cerebral white matter. Small lesions lack peritumoral edema. Mass effect and mild peri tumoral edema are present with large lesions.

    * ◦ PGNT occurs in all lobes, with the temporal lobe being the most commonly involved.

    * ◦ Rare intraventricular examples have been reported.

    * ◦ MRI: The tumors are typically heterogeneous on T2-weighted imaging, although small lesions may be homogeneous, and marked hyperintensity may be present in cystlike regions (Figs. 21.1 and 21.2).

Fig. 21.1

Papillary glioneuronal tumor (PGNT). Coronal T2-weighted MRI shows a heterogeneous tumor in the left periventricular white matter, with a markedly hyperintense central cystlike com ponent and a less intense peripheral nodular component

Fig. 21.2

Axial fluid-a ttenuated inversion recovery (FLAIR) MRI showing attenuation of signal in the central, cystlike component. Note the lack of peritumoral edema

    * ◦ PGNTs are usually hypointense on T1-weighted imaging (Fig. 21.3) unless intratumoral hemorrhage is present.

Fig. 21.3

Sagittal T1-weighted MRI shows a well-circumscribed tumor with marked hypointensity in t he central, cystlike component

    * ◦ These tumors may show postcontrast enhancement (Fig. 21.4), with the enhancing component isoi ntense or hyperintense to cortex on T1-weighted imaging.

Fig. 21.4

Axial T1-weighted postcontrast images showing a PGNT with irregular peripheral nodular enhance ment. The central, cystlike component does not enhance

    * ◦ Enhancement may be peripheral, solid, or peripheral with mural nodule.

    * ◦ Diffusion weighted im aging (DWI) usually shows no restriction of diffusion (Fig. 21.5).

Fig. 21.5

Axial diffusion weighted imaging (DWI) shows no diffusion restriction within the tumor

    * ◦ CT scans: Calcification and intratumoral hemorrhage are uncommon.

## 21.4 Pathology

  * Smear preparations

    * ◦ Smear prepar ations reveal a mixture of cells (Figs. 21.6, 21.7, and 21.8), including ganglion cells with large, eccentric nuclei; prominent nucleoli; delicate nuclear membranes; and Nissl substance in the cytoplasm. Intermediate cells with less prominent nucleoli and relatively scant cytoplasm also are seen. Cells with dense nuclei, scant cytoplasm, and occasional processes represent perivascular astrocytes.

Fig. 21.6

I ntraoperative cytologic preparation showing a mixed cell population with some of the cells having eosinophilic cytoplasm and eccentric nuclei

Fig. 21.7

Intraopera tive cytologic preparation showing pseudopapillary architecture

Fig. 21.8

Intrao perative cytologic preparation showing fibrillary background

  * Histology

    * ◦ Two distinct histologic components are identified: glial and neuronal.

      * The glial component consists of pseudopapillary structures with hyalinized blood vessels surrou nded by a single or pseudostratified layer of cuboidal glial cells (Figs. 21.9 and 21.10). These cells have rounded nuclei, moderately dense chromatin, and scant eosinophilic cytoplasm and do not elaborate perivascular cytoplasmic processes. Mitotic activity and cellular atypia are absent in this component.

Fig. 21.9

Charact eristic pseudopapillary pattern in PGNT

Fig. 21.10

Highe r magnification showing the core of pseudopapillary structures and the mixed glioneuronal population of cells

      * The neuronal component consists of interpapillary sheets or focal collections of neurocytes, gangli on cells, and intermediate "ganglioid cells" in a fibrillary, neuropil-like matrix.

    * ◦ Neurocytic cells have dark, round, uniform nuclei; scant cytoplasm; and sometimes an oligo-like halo (Fig. 21.11). The ganglion cells feature large, vesicular nuclei; prominent nucleoli; and abundant cytoplasm with well-developed Nissl substance.

Fig. 21.11

Intervenin g cells with clear cytoplasm may be seen

      * The intermediate-sized "ganglioid cells" feature less-abundant cytoplasm and smaller nucleoli.

      * Occasional pleomorphic and binucleated ganglion cells are identified.

    * ◦ Minigemistocyt es with eccentrically placed nuclei and eosinophilic hyaline cytoplasm may be found in the interpapillary regions or nestled among neuronal cell types (see Figs. 21.6 and 21.10).

    * ◦ A narrow zone of tumor infiltration or a discrete pushing border may be seen with the adjacent neural parenchyma. In this region, prominent gliosis, Rosenthal fibers, eosinophilic granular bodies, hemosiderin deposition, foamy cell infiltration, and dystrophic calcifications may be identified.

    * ◦ Mitotic activity is usually inconspicuous.

    * ◦Necrosis and microvascular proli feration, when present, are exceptional.

## 21.5 Immunohistochemistry

  * The small, cuboidal glial cells surrounding the hyalinized vascular pseudopapillae are positive for glial fibrillary acidic protein (GFAP) (Fig. 21.12) and S-100.

Fig. 21.12

A large subp opulation of tumor cells are positive for glial fibrillary acidic protein (GFAP)

  * Neuronal cells of all sizes are immunopositive for synaptophysin (Fig. 21.13), neuron-specific enolase (NSE), and class III β-tubulin (MAP2) (Fig. 21.14).

Fig. 21.13

Synapto physin positivity is granular but patchy

Fig. 21.14

Diffuse positivity for microtubule-associated protein 2 (MAP2) is observed in this tumor

  * Most of the neuronal cells are also positive for NeuN; immunopositivity for neurofilament protein (NFP) is confined to ganglion cells and intermediate "ganglioid cells."

  * Chromogranin A expression has not been observed.

  * Minigemistocytes show intense GFAP immunoreactivity.

  * Tanaka et al. described a subpopulation of cells that fail to label with GFAP and neuronal markers but express the Olig2 transcription factor. These cells are mainly found in the interpapillary areas surrounding GFAP-positive perivascular elements. They also found that minigemistocytes are in close association with these Olig2-positive cells and may be derived from them.

  * MIB-1 labeling indices are low, in the range of 1–2 %.

## 21.6 Electron Microscopy

  * The perivascular glial cells show cytoplasmic bundles of intermediate filaments and form juxtavascular basal lamina.

  * The neuronal cells exhibit cytoplasmic extensions filled with aligned microtubules, dense-core granules, clear vesicles, and synaptic contacts of varying organization.

  * A third cell component of poorly differentiated cells has been described at the ultrastructural level. These cells contain mitochondria, ribosomes, occasional dense bodies, intermediate filaments, and microtubules, but no definitive dense-core granules. They are thought to represent glioneuronal progenitor cells.

  * Hybrid glioneuronal cells have not been described.

## 21.7 Molecular Pathology

  * PGNT has been reported in patients with cleft lip and orbital schwannoma, but association with familial syndromes has not been established.

  * Several cases have been studied for 1p status by fluorescence in situ hybridization (FISH) and have been found to be intact.

  * Faria et al. reported a case of PGNT with gains and alterations involving chromosome 7p22. Using comparative genomic hybridization, they also observed high-level amplification at 7p14 ~ q12.

  * SLC44A1-PRKCA fusion has been detected in several cases of PGNT, thus suggesting a potential biomarker for this tumor.

  * Mutations in IDH1 or IDH2 are not detected in PGNT.

## 21.8 Differential Diagnosis

  * The pseudopapillae with surrounding astrocytic cells may resemble the perivascular pseudorosettes of ependymoma, but cellular processes radiating to the vessel wall are not seen in PGNT. In addition, PGNT does not show ultrastructural evidence of ependymal differentiation.

  * The presence of neurocytic, ganglionic, and glial components may raise the possibility of ganglioglioneurocytoma as a differential diagnosis, but the presence of pseudopapillary glio-vascular structures and the broad spectrum of neuronal differentiation in PGNT help distinguish between the two entities.

  * PGNT should be distinguished from dysembryoplastic neuroepithelial tumor (DNET), which also presents at a young age with seizures. Histologically, DNET is characterized by the specific glioneuronal element, microcysts with floating neurons, and cortical dysplasia in the adjacent cortex. None of these features are seen in PGNT.

## 21.9 Prognosis

  * In general, PGNT s hows a favorable clinical outcome.

  * Gross total resection without adjuvant therapy results in recurrence-free, long-term survival in the majority of cases.

  * One case of atypical papillary glioneuronal tumor has been reported as showing mitotic activity and an MIB-1 labeling index of 15 %. The patient remained symptom-free without tumor recurrence 5 years after radical resection and radiotherapy.

  * Very rare examples of tumor recurrence or progression have also been reported.

Suggested Reading

Bridge JA, Liu XQ, Sumegi J, Nelson M, Reyes C, Bruch LA, et al. Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. Brain Pathol. 2013;23:121–8.CrossRefPubMed

Faria C, Miguéns J, Antunes JL, Barroso C, Pimentel J, Martins MC, et al. Genetic alterations in a papillary glioneuronal tumor. J Neurosurg Pediatr. 2008;1:99–102.CrossRefPubMed

Hainfellner JA, Scheithauer BW, Giangaspero F, Rosenblum MK. Rosette-forming glioneuronal tumour of the fourth ventricle. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of tumours of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer; 2007. p. 113–4.

Komori T, Scheithauer BW, Anthony DC, Rosenblum MK, McLendon RE, Scott RM, et al. Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol. 1998;22:1171–83.CrossRefPubMed

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.CrossRefPubMedPubMedCentral

Matyja E, Grajkowska W, Pucko E, Kunert P, Marchel A. Papillary glioneuronal tumor with an unusual bilateral intraventricular localization. Clin Neuropathol. 2015;34:6–12.CrossRefPubMed

Myung JK, Byeon SJ, Kim B, Suh J, Kim SK, Park CK, et al. Papillary glioneuronal tumors: a review of clinicopathologic and molecular genetic studies. Am J Surg Pathol. 2011;35:1794–805.CrossRefPubMed

Nagaishi M, Nobusawa S, Matsumura N, Kono F, Ishiuchi S, Abe T, et al. SLC44A1-PRKCA fusion in papillary and rosette-forming glioneuronal tumors. J Clin Neurosci. 2016;23:73–5.CrossRefPubMed

Rosenblum MK. The 2007 WHO classification of nervous system tumors: newly recognized members of the mixed glioneuronal group. Brain Pathol. 2007;17:308–13.CrossRefPubMed

Schlamann A, von Bueren AO, Hagel C, Zwiener I, Seidel C, Kortmann RD, Müller K. An individual patient meta-analysis on characteristics and outcome of patients with papillary glioneuronal tumor, rosette glioneuronal tumor with neuropil-like islands and rosette forming glioneuronal tumor of the fourth ventricle. PLoS One. 2014;9:e101211.CrossRefPubMedPubMedCentral

Tanaka Y, Yokoo H, Komori T, Makita Y, Ishizawa T, Hirose T, Ebato M, et al. A distinct pattern of Olig2-positive cellular distribution in papillary glioneuronal tumors: a manifestation of the oligodendroglial phenotype? Acta Neuropathol. 2005;110:39–47.CrossRefPubMed

Vaquero J, Coca S. Atypical papillary glioneuronal tumor. J Neurooncol. 2007;83:319–23.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_22

# 22. Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle

Marie Rivera-Zengotita1 and Adekunle M. Adesina2

(1)

Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health College of Medicine, Box 100275, Gainesville, FL 32610, USA

(2)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Mixed glioneuronal tumorsCerebellar dysembryoplastic neuroepithelial tumorCerebellar neurocytomaRosette-forming tumor of fourth ventricle

## 22.1 Overview

  * Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a rare, slow-growing, biphenotypic tumor arising in the region of the fourth ventricle.

  * It shows a beni gn histology and favorable postoperative course corresponding to grade I in the 2007 World Health Organization (WHO) classification.

  * RGNT most commonly affects young adults. Population-based incidence rates are not yet available.

  * RGNT was first recognized and characterized as a distinct tumor in a report of 11 cases by Komori et al. in 2002 and recently added as a new entity in the 2007 WHO classification of tumors of the central nervous system.

    * ◦ Previous reports of cerebellar dysembryoplastic neuroepithelial tumor (DNET) may represent the same entity.

## 22.2 Clinical Features

  * RGNT affects predominantly young adults (mean age, 33 years).

  * The age range of reported cases is between 12 and 59 years, with a slight female predominance.

  * The most common signs and symptoms include ataxia and headache secondary to obstructive hydrocephalus.

  * Patients have also presented with visual disturbances, vertigo, and neck pain and rigidity.

## 22.3 Neuroimaging

  * RGNTs aris e in the posterior fossa, often in the midline, and are centered in the fourth ventricle.

    * The tumor may extend to the cerebellar vermis, brainstem, pineal gland, thalamus, and cerebral aqueduct.

    * Supratentorial location has been rarely described.

  * MRI reveals a relatively circumscribed solid or multicystic tumor that is hyperintense on T2-weighted images and hypointense on T1.

  * These tumors show focal or multifocal contrast enhancement with a nodular, linear, ring, or spot-like pattern.

  * Peritumoral edema is minimal.

  * Multicentric cases have been described.

## 22.4 Pathology

  * Intraoperative smear preparations

    * ◦ Smear preparations usually demonstrate the biphenotypic nature of the tumor, including neurocytic cells with round, uniform nuclei; granular chromatin; inconspicuous nucleoli; scant cytoplasm; and a glial piloid component.

      * Rosettes and ganglion cells are not usually identified on smear preparations.

  * Histology

    * ◦ Two distinct histological components are mainly seen: neurocytic and glial.

      * The neurocytic component consists of a uniform population of small cells with round nuclei, finely granular chromatin, inconspicuous nucleoli, and scant cytoplasm with delicate cytoplasmic processes (Figs. 22.1 and 22.2).

        * These cells form neurocytic and/or perivascular pseudorosettes.

        * When viewed along the longitudinal plane, the rosettes assume a columnar arrangement resembling the specific glioneuronal element of dysembryoplastic neuroepithelial tumor (DNET).

        * Microcysts with myxoid material may also be seen.

      * The glial component usually predominates and consists of spindled astrocytic tumor cells with oval nuclei, dense chromatin, and cytoplasmic processes that form a compact fibrillary background.

        * Microcysts, oligodendroglia-like cells, Rosenthal fibers, eosinophilic granular bodies, microcalcifications, and hemosiderin deposits may be encountered.

        * The glial component resembles pilocytic astrocytoma.

Fig. 22.1

Rosette-forming glione uronal tumor of the fourth ventricle (RGNT). Low magnification (A) and intermediate magnification (B) show a diffuse rosetting pattern in this example

Fig. 22.2

Higher magnific ation shows the biphenotypic cellular population often seen in RGNT

    * Occasionally, dysmorphic ganglionlike cells may be embedded in the astrocytic component.

    * ◦ Mitoses are inconspicuous, and necrosis is usually absent.

    * ◦ Dilatated, hyalinized, thrombosed, and glomeruloid vessels may be present.

    * ◦ Cortical dysplasia or neuronal ectopias are not found in the adjacent cerebellar cortex.

    * ◦ RGNT usually shows a relatively sharp margin with the adjacent cerebellar parenchyma and lacks diffuse infiltration.

## 22.5 Immunohistochemistry

  * The center of the neurocytic rosettes and the neuropil of the perivascular pseudorosettes are positive for synaptophysin, with a granular pattern of staining (Fig. 22.3).

Fig. 22.3

Synaptophysin immuno positivity is present in the acellular core of the rosettes in RGNT

  * The cytoplasm and cytoplasmic processes of neurocytic cells are positive for MAP-2 and neuron-specific enolase (NSE).

  * Ganglion cells are immunopositive for synaptophysin and neurofilament protein (NFP), and often negative for chromogranin A.

  * The glial component is positive for glial fibrillary acidic protein (GFAP) and S-100.

  * Oligodendroglia-like cells are negative for GFAP and synaptophysin, and immunopositive for S-100.

  * MIB-1 labeling indices ar e low (range, 0.35–3.07 %; mean, 1.58 %).

## 22.6 Electron Microscopy

  * The neurocytic cells show cytoplasmic processes containing parallel microtubules and dense-core granule s, forming well-developed synaptic contacts.

  * When forming rosettes, these neurocytic cells are closely apposed with the cytoplasmic processes seen towards the center of the rosette.

  * The glial component shows numerous bundles of intermediate filaments within the cytoplasm.

  * Cilia or microvilli are not present.

## 22.7 Molecular Pathology

  * No association with familial tumor syndromes has been reported.

  * Only one repo rted patient had a Chiari type I malformation.

  * FGFR1 mutations, specifically FGFR1 N546K and FGFR1 K656E, have been identified in cases of RGNT.

  * RGNT does not harbor KIAA1549-BRAF duplication/fusion or BRAF V600E mutations, which are characteristic of pilocytic astrocytoma.

## 22.8 Differential Diagnosis

  * The main differe ntial diagnosis is DNET. DNET is a supratentorial, benign, intracortical tumor occurring in children and young adults (usually less than 20 years of age) and highly associated with seizures.

  * The key histological featur e of DNET is the specific glioneuronal element composed of a columnar arrangement of oligodendroglia-like cells and microcysts with "floating neurons."

    * In addition, cortical dysplasia is commonly found in the adjacent cortex in DNET.

    * On the contrary, all reported cases of RGNT have been described in the posterior fossa. Patients usually present at an older age and with progressive neurologic deficits; these features are atypical for a DNET.

    * Seizures are not a characteristic finding in RGNT.

    * Histologically, a distinguishing feature of RGNT is the formation of neurocytic and perivascular pseudorosettes, which are not seen in DNETs.

  * Another diagnostic consideration is central neurocytoma. A prominent glial component, as seen in RGNT, is not a feature of neur ocytoma.

## 22.9 Prognosis

  * RGNT shows an indolent clinical behavior; thus it is classified as a WHO 2007 grade I tumor.

  * Gross total resection without adjuvant therapy results in recurrence-free, long-term survival.

    * ◦ Only a rare example of tumor recurrence occurring 10 years after initial resection has been reported.

    * ◦ Only a rare example of tumor-associated fatality is on record. In this example, the patient was a 52-year-old woman who was treated with partial resection and irradiation. She subsequently developed progressive bulbar dysfunction and a new ring-enhancing lesion near the operative bed. Autopsy was not performed and the cause of death remains unclear.

Suggested Reading

Beuriat PA, Tauziede-Espariat A, Pages M, Varlet P, Di Rocco F. Rosette-forming glioneuronal tumor outside the fourth ventricle: a case-based update. Childs Nerv Syst. 2016;32:65–8.CrossRefPubMed

Gessi M, Lambert SR, Lauriola L, Waha A, Collins VP, Pietsch T. Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT). J Neurooncol. 2012;110:21–5.CrossRefPubMed

Gessi M, Moneim YA, Hammes J, Goschzik T, Scholz M, Denkhaus D, et al. FGFR1 mutations in rosette-forming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol. 2014;73:580–4.CrossRefPubMed

Gessi M, Waha A, Setty P, Waha A, Pieetsch T. Analysis of KIAA1549-BRAF fusion status in a case of rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Neuropathology. 2011;31:654–7.CrossRefPubMed

Hainfellner JA, Scheithauer BW, Giangaspero F, Rosenblum MK. Rosette-forming glioneuronal tumour of the fourth ventricle. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of tumours of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer; 2007. p. 115–6.

Komori T, Scheithauer BW, Hirose T. A rosette-forming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor? Am J Surg Pathol. 2002;26:582–91.CrossRefPubMed

Louis DN, Ohgaki H, Wiestler OD, Cavence WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.CrossRefPubMedPubMedCentral

Rosenblum MK. The 2007 WHO classification of nervous system tumors: newly recognized members of the mixed glioneuronal group. Brain Pathol. 2007;17:308–13.CrossRefPubMed

Schlamann A, von Bueren AO, Hagel C, Zwiener I, Seidel C, Kortmann RD, Müller K. An individual patient meta-analysis on characteristics and outcome of patients with papillary glioneuronal tumor, rosetted glioneuronal tumor with neuropil-like islands and rosette forming glioneuronal tumor of the fourth ventricle. PLoS One. 2014;9:e101211.CrossRefPubMedPubMedCentral

Xiong J, Liu Y, Chu SG, Chen H, Chen HX, Mao Y, Wang Y. Rosette-forming glioneuronal tumor of the septum pellucidum with extension to the supratentorial ventricles: rare case with genetic analysis. Neuropathology. 2012;32:301–5.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_23

# 23. Malignant Epithelioid Glioneuronal Tumor

Marie Rivera-Zengotita1, Ronald A. Rauch2 and Adekunle M. Adesina3

(1)

Department of Pathology, Immunology and Laboratory Medicine, University of Florida Health College of Medicine, Box 100275, Gainesville, FL 32610, USA

(2)

Department of Radiology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

(3)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Glioneuronal tumorsMalignant glioneuronal tumorsEpithelioid tumorsMEGNT

## 23.1 Overview

  * Malignant epithelioid glioneuronal tumor (MEGNT) is the name proposed for a high-grade tumor showing both glial and neuronal differentiation. This tumor is not included in the 2007 World Health Organization (WHO) classification of tumors of the central nervous system, but examples described so far have shown aggressive behavior.

  * We have seen a number of cases in our practice and a handful of single case reports and poster presentations at neuropathology meetings over the past 14 years.

## 23.2 Clinical Features

  * The initial report included three pediatric and three adult cases with an age range between 5 and 84 years old.

  * The three pediatric cases occurred in males, while the adult cases occurred in one female and two males.

  * Patients usually present with signs and symptoms of increased intracranial pressure or symptoms related to the location of the lesion.

## 23.3 Neuroimaging

  * All reported cases are supratentorial, with a predilection for the frontoparietal region.

  * MRI scans show large, heterogeneous lesions with associated edema and mass effect (Figs. 23.1–23.3).

Fig. 23.1

Malignant epitheli oid glioneuronal tumor (MEGNT). (A) Sagittal T1-weighted image showing a frontal lobe mass lesion. (B) Coronal T1-weighted postcontrast image with heterogeneity and ring-type contrast enhancement. (C) Axial T2-weighted image with massive peritumoral edema. (D) Diffusion-weighted image showing regions of increased and mildly restricted diffusion

Fig. 23.2

MEGNT. (A) Axia l T1-weighted image showing a partially cystic frontoparietal mass. (B) Axial T1-weighted postcontrast image showing heterogeneous enhancement. (C) Axial T2-weighted image showing heterogeneous signal intensity in a mass with surrounding edema. (D) Apparent diffusion coefficient (ADC) map showing increased diffusion around the mass and restricted diffusion in central parts of the mass

Fig. 23.3

MEG NT. (A) Axial T1-weighted image showing a parietal lobe mass lesion. (B) Coronal T1-weighted postcontrast image with heterogeneous contrast enhancement. (C) Axial T2-weighted image with a cystic component and minimal peritumoral edema. (D) Diffusion-weighted image showing mild restricted diffusion in the mass

  * The lesions enhance after contrast administration either with a ring-enhancing pattern (Fig. 23.1B), a solid enhancing component (Fig. 23.2B), or heterogeneous contrast enhancement (Fig. 23.3B).

  * A cystic, necrotic-appearing component may be seen.

  * Multicentric lesions were described in two adult patients.

  * CT scans are characterized by hyperdense lesions.

## 23.4 Pathology

  * Gross pathology

    * ◦ At surgery, t he tumors are relatively well circumscribed and highly vascular.

    * ◦ Dural attachment has been described in two cases.

    * ◦ Grossly, the tumors are circumscribed and show a variegated appearance with solid, cystic, and necrotic regions (Figs. 23.4 and 23.5).

Fig. 23.4

Well-circumscribed tumor excised from the same patient as in Fig. 23.1

Fig. 23.5

The cut surface shows a tan "fish flesh" solid component and a yellow necrotic component

  * Intraoperative cytologic imprints or smears

    * ◦ Hypercellularity i s characteristic, with a mixed population of tumor cells (Fig. 23.6) including large epithelioid cells, small undifferentiated cells, spindle cells, and sometimes infiltrating lymphocytes (Fig. 23.7).

    * ◦ Cell wrapping may be prominent (Fig. 23.6).

Fig. 23.6

Intraoper ative smear preparation showing discohesive cells with large vesicular nuclei and nucleoli. Some of the cells have a rhabdoid appearance with abundant eosinophilic cytoplasm and eccentric nucleus. Cell wrapping is readily appreciated. There is a background tumor diathesis in this touch preparation

Fig. 23.7

Intraoperative s mear preparation from another example, with a component of infiltrating lymphoid cells

  * Histology

    * ◦ The most striki ng histologic feature of these tumors is an epithelioid cell component consisting of large cells with open chromatin and prominent nucleoli (Figs. 23.8 and 23.9).

    * ◦ Epithelioid cells have abundant eosinophilic cytoplasm—often vacuolated (Fig. 23.10A), clear (Fig. 23.10B), or xanthomatous (Fig. 23.11)—and with well-defined cell borders.

    * ◦ Multinucleated forms may be present.

    * ◦ Cells may have a ganglioid and/or rhabdoid appearance (Fig. 23.12).

    * ◦ Other cellular components include small, undifferentiated cells resembling primitive neuroec todermal tumor (PNET) (Figs. 23.13 and 23.14), an undifferentiated cell-epithelioid cell transition (Fig. 23.15), and spindle cells arrang ed in short fascicles (Fig. 23.16).

    * ◦ The tumors may have an ill-defined nodular architecture. In some areas, a sharp circumscription with adjacent brain is identified; in other regions, fish-flesh, solid-component tumor cells are seen infiltrating brain parenchyma.

    * ◦ Vascular proliferation has been identified in all pediatric cases.

    * ◦ Necrosis, including pseudopalisading necrosis (Fig. 23.17) is usually present.

    * ◦ Mitotic activity is conspicuous.

Fig. 23.8

Low-power overvi ew of MEGNT shows a mixed population of epithelioid tumor cells and lymphocytes

Fig. 23.9

Higher magnific ation shows sheets of epithelioid cells with large vesicular nuclei and prominent nucleoli

Fig. 23.10

(A) Epithelioid cells with a variable number of infiltrating lymphocytes and a few cells with cyt oplasmic vacuolation. (B) Epithelioid cells with clear cell features

Fig. 23.11

Region of epi thelioid cells with some of the cells showing xanthomatous change

Fig. 23.12

Region of MEGNT showing epithelioid cells with a rhabdoid or ganglioid appearance ( upper field) and a sheet of undifferentiated small cells (lower field), with little indistinct cytoplasm

Fig. 23.13

An over view of the intimate intermixture of epithelioid cell clusters and undifferentiated small cells

Fig. 23.14

A close-up showing the poorly differentiated small-cell component in another tumor

Fig. 23.15

A transition o r progressive differentiation from small, undifferentiated cells (left upper field) to epithelioid cells (right lower field) is present in this MEGNT

Fig. 23.16

MEGNT region wit h tumor cells showing an oval to spindle cell configuration

Fig. 23.17

Pseudopallisade d necrosis may be present and is a feature shared with high-grade glioma or glioblastoma

## 23.5 Immunohistochemistry

  * The tumors are posi tive for glial fibrillary acidic protein (GFAP) (Fig. 23.18), vimentin (Fig. 23.19), S-100, and one or a combination of the following neuronal markers: synaptophysin (Fig. 23.20A), chromogranin A (Fig. 23.20B), neurofilament protein (Fig. 23.20C), NeuN (Fig. 23.20D), and MA P2 (Fig. 23.20E).

Fig. 23.18

Strong gl ial fibrillary acidic protein (GFAP) positivity is seen in the tumor cells

Fig. 23.19

Variabl e expression of vimentin is often present in MEGNT

Fig. 23.20

Expre ssion of neuromarkers may include diffuse expression of synaptophysin (A), focal expression of chromogranin (B), a diffuse neurofilament protein (C), nuclear expression of NeuN (D), and diffuse expression of MAP2 (E)

  * P53 immunoreactivity has also been described.

  * Coexpression of GFAP, synaptophysin, and chromogranin A has been observed.

  * Positivity for epithelial membrane an tigen (EMA) (Fig. 23.21) and aberrant desmin (Fig. 23.22) has been described in the pediatric tumors.

Fig. 23.21

Expression of epit helial membrane antigen (EMA) i s seen in a subset of tumor cells

Fig. 23.22

Aberrant expressi on of desmin in the absence of myogenin or myoD1 may be seen

  * All pediatric tumors were positive for INI1 protein expression (Fig. 23.23).

Fig. 23.23

Tumor cell s showing INI1 protein expression. This feature excludes MEGNT from the group of atypical teratoid/rhabdoid tumors

  * Tumor cells are consistently negative for cytokeratins, smooth muscle actin, myogenin, and MyoD1.

  * MIB-1 show s variable but generally high labeling indices, with a proliferation index up to 60 % (Fig. 23.24).

Fig. 23.24

Immunostai n for Ki67 in a tumor showing high proliferation index

## 23.6 Electron Microscopy

  * A mixed population of tumor cells is identified, including large and small undifferentiate d cells.

  * Evidence of n euronal differentiation includes synaptic junctions (Fig. 23.25), dense-core neurosecretory granules, and cytoplasmic processes with mic rotubules (Fig. 23.26).

Fig. 23.25

Electro n microscopy showing cellular formation of a synaptic junction

Fig. 23.26

MEGNT c ells form cytoplasmic processes containing microtubules and dense-core neurosecretory granules

  * Intermediate filaments are also ident ified (Fig. 23.27).

Fig. 23.27

Intermediate filaments c onsistent with glial differentiation are present in the tumor cells

## 23.7 Molecular Pathology

  * Cytogenetic studies performed in two of the pediatric cases failed to show any consistent abnormality.

  * Fluorescence in situ hybridization (FISH) for HSNF5/INI1 locus deletion and chromosome 22 monosomy showed no abnormalities when performed in one pediatric case.

## 23.8 Differential Diagnosis

  * The mixed populatio n of large epithelioid cells and small undifferentiated cells may raise atypical teratoid/rhabdoid tumor (AT/RT) as a major differential diagnosis, especially in the pediatric population.

    * ◦AT/RT is more common in the posterior fossa.

    * ◦ FISH with an INI1 locus–specific probe shows allelic deletion in AT/RT, giving rise to negative INI1 immunohistochemistry. This deletion is not seen in MEGNT.

  * The biphenotypic population of cells also raises anaplastic ganglioglioma as part of the differential diagnosis, but evidence of a preceding low-grade ganglioglioma is not found in MEGNT cases.

  * The rhabdoid appearance of the epithelioid cells may raise the possibility of pleomorphic rhabdomyosarcoma.

    * ◦ MEGNT is negative for MyoD1 and myogenin, which are positive in pleomorphic rhabdomyosarcoma.

    * ◦ In addition, there is no ultrastructural evidence of myogenic differentiation in MEGNT.

  * Epithelioid glioblastoma is another important differential diagnosis, especially in adults. The epithelioid cells in glioblastoma should not show immunopositivity for neuronal markers, as is seen in MEGNT.

## 23.9 Prognosis

  * The described cases have shown an aggressive behavior with rapid progression and death in less than a year after diagnosis despite aggressive surgery, radiation, and chemotherapy.

  * Varlet et al. described 40 cases of malignant glioneuronal tumors, of which 22 (55 %) had epithelioid features. They reported that their subset of malignant glioneuronal tumors may have a better prognosis than typical malignant gliomas, with gross total surgical resection being curative in some cases, but the tumors they reported may represent a different subset of glioneuronal tumors, distinct from the ones described above as MEGNT.

  * Further characterization of subgroups of glioneuronal tumors should allow more appropriate classification and reliable definition of prognosis.

Suggested Reading

Rivera-Zengotita M, Whitehead W, Jea A, Chintagumpala M, Fuller GN, Jones J, Adesina AM. Malignant epithelioid glioneuronal tumor: unusual phenotype or new entity? Modern Pathol. 2008;21 Suppl 1:324A.

Rodriguez FJ, Scheithauer BW, Port JD. Unusual malignant glioneuronal tumors of the cerebrum of adults: a clinicopathologic study of three cases. Acta Neuropathol. 2006;112:727–37.CrossRefPubMed

Varlet P, Deepa S, Miguel C, Roux FX, Meder JF, Chneiweiss H, Daumas–Duport C. New variants of malignant glioneuronal tumors: a clinicopathologic study of 40 cases. Neurosurgery. 2004;55:1377–92.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_24

# 24. Paraganglioma

Andreana L. Rivera1 and Adekunle M. Adesina2

(1)

Department of Pathology, Weil Cornell Medical College, The Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA

(2)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

ParagangliomaExtra-adrenalFilum terminaleMelanotic paraganglioma

## 24.1 Overview

  * Paragan glioma is an encapsulated, benign neoplasm composed of neuroendocrine cells arranged in a lobular fashion arising from the autonomic ganglia (paraganglia) of the sympathetic and parasympathetic chains.

  * The parasympathetic variety tends to arise predominantly in the head and neck region, often along the jugular veins and carotid arteries, with direct extension into the cranial vault.

  * Sympathetic paragangliomas are typically retroperitoneal.

  * The best-characterized paragangliomas of the central nervous system (CNS) are those of the filum terminale (WHO grade I).

## 24.2 Clinical Features

  * Paragangliomas of the CNS are relatively uncommon. Most are located in the lumbar cistern (particularly associated with the cauda equina).

  * Of cauda eq uina lesions, paragangliomas make up only about 3–4 %. Other spinal levels are far less commonly involved.

  * Intracranial paragangliomas are usually seen as a result of direct extension of jugular lesions (glomus jugulare) or carotid body lesions. Rare purely intracranial paragangliomas have been reported in the sellar region, the cerebellum, and the cerebral hemispheres.

  * Age distribution is wide-ranging, from children to older adults, with peak age in the fifth decade. There is a slight male predominance.

  * Presenting symptoms are typically related to the location of the lesion.

  * Intracranial lesions, particularly glomus jugulare, present with pulsatile tinnitus or cranial nerve dysfunction.

  * Paragangliomas of the cauda equina often present with low back pain; paralysis or sensory deficits can occur rarely.

  * The vast majority of paragangliomas of the CNS are nonfunctional; rare functional intracranial and cauda equina lesions have been reported.

## 24.3 Neuroimaging

  * On MRI, the lesions often have a well-circumscribed, cystic appearance that is hypointense or isoint ense to the spinal cord on T1-weighted images (Fig. 24.1).

Fig. 24.1

Abnormal expansion of the cauda equina by a mass lesion that is hyperintense on T2-weighted MR imaging (A), and isointense on T1-weighted imaging (B). Radiologic differential diagnosis includes paraganglioma and myxopapillary ependymoma

  * In the cauda equina, the presence of congested, ectatic vessels and a rim of low signal intensity or "cap sign" on T2-weighted images may be helpful in distinguishing this lesion from myxopapillary ependymoma radiographically, given the vascularity of paragangliomas compared with ependymomas.

  * A rare intracranial and hemispheric paraganglioma is isointense on T1- and hyperintense on T2-weighted imaging, with diffuse postgadolinium contrast enhancement (Figs. 24.2 and 24.3).

Fig. 24.2

Melanotic paraganglioma arising in the temporal horn of the lateral ventricle after radiation therapy fo r Langerhans histiocytosis. (A) Sagittal T2-weighted image. (B) Sagittal T1-weighted postgadolinium image with intraventricular cyst and diffuse enhancement of the solid component

Fig. 24.3

Axial fluid-a ttenuated inversion recovery (FLAIR) (A) and coronal T1-weighted (B) postgadolinium images showing a cystic component, a solid component, and peritumoral edema

  * CT scans with contrast sho w the lesion as an isodense, homogenously enhancing mass lesion, but noncontrast scans may not detect the lesion.

## 24.4 Pathology

  * Gross appearance

    * ◦ Soft, tan-pink to red-brown, encapsulated tissue. Lesions of the cauda equina have a classic ovoid or "sausage-shape" appearance, are well-encapsulated, and are often attached to the filum or nerve root.

  * Histology

    * ◦ Despite their location, paragangliomas have a microscopic appearance that closely resembles normal paraganglia.

    * ◦ They ar e composed of bland neuroendocrine cells (chief cells) arranged in nests or "Zellballen" structures separated by fine fibrovas cular sep ta (Figs. 24.4, 24.5, 24.6, and 24.7).

    * ◦ Interspersed among the nests of chief cells are spindled cells with long, inconspicuous processes termed sustentacular cells; these are better visualized with S-100 protein immunostain (Fig. 24.8).

    * ◦ Some paragangliomas can have ganglion cell differentiation with the presence of ganglion cells in varying proportions.

    * ◦ Melanotic par agangliomas have also bee n reported (Figs. 24.9, 24.10, 24.11, 24.12, and 24.13).

    * ◦ Focal necr osis an d rare mitoses can be seen but do not impact prognosis.

Fig. 24.4

A lobulated or org anoid/nesting pattern with intervening fibrovascular septa

Fig. 24.5

Reticulin stains d emonstrating the reticulin framework underlying the nesting pattern

Fig. 24.6

Plastic section showing the classic "Zellballen" pattern characteristic of paraganglioma

Fig. 24.7

Close-up view of the "chief cells" representing the neoplastic cells of paraganglioma

Fig. 24.8

Immunosta in for S-100 protein highlights the sustentacular cells

Fig. 24.9

Intraoperative touch preparation showing the monomorphic population of benign tumor cells and pi gmentation in a melanotic paraganglioma. Note the lack of anaplasia that is typically seen in malignant melanoma

Fig. 24.10

Diffuse pigmentation resulting from melanocytic differentiation, as seen here, is uncommon in par aganglioma

Fig. 24.11

Immunopositivity f or S-100 protein in the sustentacular cells allows a differentiation of melanotic paraganglioma from meningeal melanocytoma and malignant melanoma

Fig. 24.12

Melanotic pa raganglioma demonstrating only a rare cell positivity for HMB-45

Fig. 24.13

Paraga ngliomas show variable but generally low proliferation index by immunostaining for Ki-67

## 24.5 Immunohistochemistry

  * The chief cells are positive f or neuronal markers such as synaptophysin and chromogranin.

    * ◦Neurofilament and neuron-specific enolase can also be used, but are less sensitive.

  * The sustentacular cells are positive for S-100 protein (Figs. 24.8 and 24.11), and may show focal positivity with glial fibrillary acidic protein (GFAP).

  * More recently, expression of SOX10, a neural crest transcription factor, has been reported in sustentacular cells and ganglion cells within paragangliomas.

  * GATA-3 immunohistochemical stain has also been reported to be positive in 55 % of paragangliomas.

## 24.6 Electron Microscopy

  * The classic feature is the presence of neurosecretory granules in the chief cells, which also have interdigitating processes.

  * Basal lamina is seen at the interface between the "Zellballen" structures and intervening septa.

## 24.7 Molecular Pathology

  * No genetic alte ration is specific for CNS paragangliomas, but some genes have been associated with a predisposition to the formation of paragangliomas and pheochromocytomas.

  * Familial or inherited syndromes associated with paragangliomas include von Hippel-Lindau disease (VHL gene 3p25-26), neurofibromatosis type 1 (NF1 gene 17q11.2), and multiple endocrine neoplasia type 2 (RET gene 10q11.2).

  * Mutations in the succinate dehydrogenase genes subunits B, C, and D (SDHB, SDHC, SDHD) have been shown to be associated with systemic paragangliomas, SDHD with multiple paragangliomas of the head and neck, and SDHB with pheochromocytomas.

  * A rare example of germline SDHD mutation has been described in a paraganglioma of the spinal cord.

## 24.8 Differential Diagnosis

  * The main differential di agnosis for cauda equina paraganglioma is myxopapillary ependymoma. The clinical presentation, location, and gross appearance are nearly identical, but these lesions can be easily differentiated microscopically.

  * Primary cerebral melanotic paraganglioma must be distinguished from primary CNS malignant melanoma or pigmented choroid plexus carcinoma—both of which are relatively easily distinguished by their high-grade anaplastic features—and from meningeal melanocytoma, which shows a diffuse nuclear immunopositivity for S-100 protein.

## 24.9 Prognosis

  * Prognosis of CN S paragangliomas is favorable, with outcome correlating more closely with location and extent of tumor growth at the time of presentation than with histologic appearance.

  * Metastasis of CNS paragangliomas is rare.

    * ◦ Metastasis occurs in approximately 5 % of carotid body and glomus jugulare tumors.

    * ◦ Recurrence is commonly seen in these locations.

    * ◦ Metastasis of a spinal paraganglioma is exceedingly rare, with few cases reported.

  * Cerebrospinal fluid seeding has been reported.

  * Paragangliomas in the cauda equina are curable with complete resection.

    * Recurrence occurs in 4 % of cases.

Suggested Reading

Kliewer KE, Wen DR, Cancilla PA, Cochran AJ. Paragangliomas: assessment of prognosis by histologic, immunohistochemical, and ultrastructural techniques. Hum Pathol. 1989;20:29–39.CrossRef90199-8)PubMed

Lack EE, Cubilla AL, Woodruff JM. Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients. Hum Pathol. 1979;10:191–218.CrossRef80008-8)PubMed

Lau N, Hari D, French S. SOX10 expression in a gangliocytic paraganglioma—a case report. Exp Mol Pathol. 2015;98:99–101.CrossRefPubMed

Levy RA. Paraganglioma of the filum terminale: MR findings. AJR Am J Roentgenol. 1993;160:851–2.CrossRefPubMed

Masuoka J, Brandner S, Paulus W, Soffer D, Vital A, Chimelli L, et al. Germline SDHD mutation in paraganglioma of the spinal cord. Oncogene. 2001;20:5084–6.CrossRefPubMed

Moran CA, Rush W, Mena H. Primary spinal paragangliomas: a clinicopathological and immunohistochemical study of 30 cases. Histopathology. 1997;31:167–73.CrossRefPubMed

Naggara O, Varlet P, Page P, Oppenheim C, Meder JF. Suprasellar paraganglioma: a case report and review of the literature. Neuroradiology. 2005;47:753–7.CrossRefPubMed

Nonaka D, Chiriboga L, Rubin BP. SOX10: a pan-schwannian and melanocytic marker. Am J Surg Pathol. 2008;32:1291–8.CrossRefPubMed

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Scheithauer BW, Brandner S, Soffer D. Spinal paraganglioma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al., editors. WHO Classification of tumours of the central nervous system. 4th ed. Lyon, France: IARC; 2007. p. 117–9.

Sonneland PR, Scheithauer BW, LeChago J, Crawford BG, Onofrio BM. Paraganglioma of the cauda equina region. Clinicopathologic study of 31 cases with special reference to immunocytology and ultrastructure. Cancer. 1986;58:1720–35.CrossRef58%3A8<1720%3A%3AAID-CNCR2820580824>3.0.CO%3B2-U)PubMed

Strommer KN, Brandner S, Sarioglu AC, Sure U, Yonekawa Y. Symptomatic cerebellar metastasis and late local recurrence of a cauda equina paraganglioma. Case report. J Neurosurg. 1995;83:166–9.CrossRefPubMed

Weissferdt A, Kalhor N, Liu H, Rodriguez J, Fujimoto J, Tang X, et al. Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases. Hum Pathol. 2014;45:2463–70.CrossRefPubMed

Yang SY, Jin YJ, Park SH, Jahng TA, Kim HJ, Chung CK. Paragangliomas in the cauda equina region: clinicopathoradiologic findings in four cases. J Neurooncol. 2005;72:49–55.CrossRefPubMed

Yoo JH, Rivera A, Naeini RM, Yedururi S, Bayindir P, Megahead H, et al. Melanotic paraganglioma arising in the temporal horn following Langerhans cell histiocytosis. Pediatr Radiol. 2008;38:571–4.CrossRefPubMed

# Part VI
Neurocutaneous Syndromes
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_25

# 25. Neurofibromatosis 1

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

NeurilemmomaNeurilemomaNeurofibromatosisMerlinSchwannomaSchwannomin

## 25.1 Overview

  * Neurofibromatosis 1 (NF1) is an inherited, multisystem disorder that is characterized by the formation of numerous tumors, the majority of which are neurofibromas.

  * The incidence of NF1 is approximately 1 in every 2500–3000 births.

  * The National In stitutes of Health (NIH) have established a set of diagnostic criteria [1], in which the diagnosis of NF1 requires two or more of the following findings:

    * ◦ Six or more "café au lait" macules that are greater than 0.5 cm in children

    * ◦ Two or more cutaneous or subcutaneous neurofibromas or one plexiform neurofibroma

    * ◦ Axillary or groin freckling

    * ◦ Optic glioma (pilocytic astrocytoma of the optic tract)

    * ◦ Two or more Lisch nodules

    * ◦ Bone dysplasia with or without pseudoarthrosis

    * ◦ First-degree relative with documented NF1

## 25.2 Clinical Features

  * Most cutaneous neurofibromas present as slow-growing, painless masses that are freely movable under the skin.

  * Localized intraneural neurofibromas are often associated with the disturbance of function of the involved nerve, either motor or sensory or both.

  * Spinal cord examples can present with sensory loss or weakness and are typically seen in the setting of NF1. Spinal neurofibromas in NF1 are more likely to result in the sacrifice of the nerve root. Many patients have multiple spinal or paraspinal neurofibromas (Fig. 25.1).

Fig. 25.1

Coronal T1-weighted image of a young boy with neurofibromatosis 1 (NF1), showing numerous neurofibro mas arising from virtually all nerve roots, with associated severe scoliosis

  * Stigmata for NF1 should be sought in patients with neurofibromas, especially those with multiple or plexiform lesions.

  * Plexiform neurofibromas are more often symptomatic than cutaneous examples [2].

  * Rapid growth of dermal or deep-seated tumors may be indicative of a malignant peripheral nerve sheath tumor in patients with NF1 [3 ].

## 25.3 Neuroimaging

  * Typically the neuroim aging features of lesions in NF1 are those of neurofibromas and astrocytic neoplasms. Plexiform neurofibromas are detected radiologically in up to half of all patients with NF1.

  * Plexiform neurofibromas appear as heterogeneous masses with low T1 signal intensity compared with brain tissue; they show variable gadolinium enhancement.

  * Plexiform neurofibromas rarely occur intracranially; when they do, they can extend into the orbital space, cavernous sinus, and paranasal spaces. Intraspinal or paraspinal plexiform neurofibromas have a slightly higher signal intensity than skeletal muscle on T1-weighted images and have variable intensity on T2-weighted images [4].

  * Pilocytic astrocytomas often involve the optic nerve in a fusiform fashion and are hyperintense on T2-weighted images. Contrast-enhanced images demonstrate tumor filling the optic nerve sheath without a cystic component.

  * Pilocytic astrocytomas also can occur outside the optic nerve and are similar to sporadic examples.

  * T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images often demonstrate multiple small, hyperintense lesions within the white matter of patients with NF1. These lesions do not appear on T1-weighted images and do not enhance. Such lesions are well recognized in NF1 and should not be confused with infiltrating gliomas [5].

## 25.4 Histopathological Features

  * Neurofibroma

    * ◦ Plexiform neurofibrom as are typical of NF1. They cause diffuse enlargement of large nerves and involve multiple roots or fascicles, resulting in a typical "ropelike" or bosselated appearance macroscopically (Fig. 25.2).

    * ◦ Plexiform neurofibromas are microscopically ill defined, with a nodular architecture and infiltrative pattern (Fig. 25.3).

    * ◦ Some neurofibromas in the setting of NF1 may have cellular and atypical histological features [6] (Fig. 25.4).

Fig. 25.2

Plexifo rm neurofibroma causing marked nodular enlargement of large nerves involving multiple roots. The macroscopic appearance is referred to as "ropelike" or bosselated

Fig. 25.3

Micros copic appearance of plexiform neurofibromas, showing diffuse infiltration of the nerve and nerve fascicles expanded by tumor, imparting a nodular pattern

Fig. 25.4

S ome neurofibromas in the setting of NF1 may have cellular and atypical histological features

  * Malignant peripheral nerve sheath tumor (MPNS T)

    * ◦ Most MPNSTs that occu r in the setting of NF1 are high-grade sarcomas.

    * ◦ The tumors often have regions resembling benign peripheral nerve sheath tumors, but they also harbor pleomorphic, epithelioid, and myxoid patterns (Fig. 25.5).

    * ◦ The definition of a high-grade MPNST often includes a highly increased mitotic rate and cellular anaplasia, as well as pleomorphic nuclei and necrosis.

Fig. 25.5

Malignant pe ripheral nerve sheath tumors (MPNSTs) often have regions resembling benign peripheral nerve s heath tumors, but they also harbor pleomorphic, epithelioid, and myxoid patterns

  * Astrocytoma

    * ◦ Most a strocytic neoplasms seen in the setting of NF1 are pilocytic astrocytomas, but infiltrating astrocytomas (including glioblastomas) also can be seen.

    * ◦ Macroscopic and histological features of infiltrating astrocytomas in NF1 are essentially identical to features of sporadic examples.

    * ◦ The so-called optic nerve glioma is histologically pilocytic astrocytoma.

  * Tumors out side the central nervous system (CNS)

    * ◦ NF1 is associated with an increased incidence of a number of non-CNS neoplasms, including soft tissue tumors and neuroendocrine neoplasms.

      * Soft tissue neoplasms include rhabdomyosarcoma, juvenile xanthogranuloma, gastrointestinal stromal tumor, and paraganglioma.

      * Neuroendocrine neoplasms include pheochromocytoma, ganglioneuroma, carcinoid t umors, and medullary thyroid carcinoma.

## 25.5 Immunohistochemistry

  * The immuno histochemistry of individual tumor types in patients with NF1 is the same as that of sporadic examples (see Chaps. 15 and 16).

## 25.6 Molecular Pathology

  * The gene for NF1 was cloned on chromosome 17q11.2 and is composed of 60 exons [7]. The cytoplasmic protein product of the gene is neurofibromin, which acts as a tumor suppressor and is widely expressed in the CNS. Neurofibromin is considered to be within the GTPase-activating protein (GAP) family.

  * Almost half of the cases represent new mutations; the remaining cases are familial.

  * One of the major functions of neurofibromin is to inactivate the p21 Ras, thereby inhibiting cell proliferation [8].

  * Other chromosomal losses in chromosomes 17, 19, and 22 have been reported [9].

  * A recent study has identified Arg1809Cys substitution in patients with a milder form of NF1 without neurofibromas [10].

## 25.7 Prognosis

  * Prognosis of NF1 is highly dependent on its extent and the location and types of tumors in a patient; prediction is difficult, but patients' life expectancy is shorter [11, 12]. Certain issues are associated with a worse prognosis:

    * ◦ Emergence of an MPNST

    * ◦ High-grade infiltrating astrocytomas

    * ◦ Late-onset long bone fractures with nonunion

References

1.

Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44:81–8.CrossRefPubMed

2.

Nguyen R, Kluwe L, Fuensterer C, Kentsch M, Friedrich RE, Mautner VF. Plexiform neurofibromas in children with neurofibromatosis type 1: frequency and associated clinical deficits. J Pediatr. 2011;159:652–5.CrossRefPubMed

3.

King AA, Debaun MR, Riccardi VM, Gutmann DH. Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am J Med Genet. 2000;93:388–92.CrossRef93%3A5<388%3A%3AAID-AJMG8>3.0.CO%3B2-#)PubMed

4.

Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Funsterer C. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology. 2006;48:160–5.CrossRefPubMed

5.

Lopes Ferraz Filho JR, Munis MP, Soares Souza A, Sanches RA, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1. Pediatr Radiol. 2008;38:305–10.CrossRefPubMed

6.

Lin BT, Weiss LM, Medeiros LJ. Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. Am J Surg Pathol. 1997;21:1443–9.CrossRefPubMed

7.

Xu GF, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990;62:599–608.CrossRef90024-9)PubMed

8.

Widemann BC, Acosta MT, Ammoun S, Belzberg AJ, Bernards A, Blakeley J, et al. CTF meeting 2012: translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies. Am J Med Genet A. 2014;164A:563–78.CrossRefPubMed

9.

Koga T, Iwasaki H, Ishiguro M, Matsuzaki A, Kikuchi M. Losses in chromosomes 17, 19, and 22q in neurofibromatosis type 1 and sporadic neurofibromas: a comparative genomic hybridization analysis. Cancer Genet Cytogenet. 2002;136:113–20.CrossRef00527-7)PubMed

10.

Pinna V, Lanari V, Daniele P, Consoli F, Agolini E, Margiotti K, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015;23:1068–71.CrossRefPubMed

11.

Evans DG, O'Hara C, Wilding A, Ingham SL, Howard E, Dawson J, et al. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19:1187–91.CrossRefPubMedPubMedCentral

12.

Duong TA, Sbidian E, Valeyrie-Allanore L, Vialette C, Ferkal S, Hadj-Rabia S, et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980–2006 in France. Orphanet J Rare Dis. 2011;6:18.CrossRefPubMedPubMedCentral
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_26

# 26. Neurofibromatosis 2

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

NeurilemmomaNeurofibromatosisMerlinSchwannomaSchwannomin

## 26.1 Overview

  * Neurofibromatosis 2 (NF2) is an inherited autosomal dominant syndrome that is characterized by the formation of numerous circumscribed neoplasms, including schwannomas, meningiomas, and ependymomas.

  * NF2 has a birth incidence of approximately one in every 20,000–30,000 births; males and females are equally affected.

  * The most common tumor associated with the syndrome for all ages is schwannoma, followed by meningioma.

  * The diagnosis of NF2 requires the following criteria [1]:

    * ◦ Bilateral vestibular schwannomas OR

    * ◦ Early onset unilateral vestibular schwannoma (<30 years old) AND two other lesions (schwannoma, meningioma, neurofibroma, glioma, or juvenile cortical cataract)

    * ◦ First-degree relative with NF2 AND two other lesions (schwannoma, meningioma, neurofibroma, glioma, juvenile cortical cataract)

    * ◦ Multiple meningiomas AND unilateral vestibular schwannoma AND one other lesion (schwannoma, glioma, juvenile cortical cataract)

## 26.2 Clinical Features

  * The clinical presentati on of children with NF2 is more diverse than the presentation of adults; numerous tumors at presentation is typical. A careful search for all possible lesions is warranted.

  * Children with NF2 present with cranial meningiomas, spinal cord tumors, and subcutaneous schwannomas more often than adult patients [2].

  * Skin tumors and cataracts in children suggest NF2 with a slightly more aggressive course [3].

  * Café-au-lait spots can be seen in NF2, but they are smaller and fewer than in NF1.

  * Bilateral vestibular schwannomas are virtually diagnostic of NF2 and are present in many patients with NF2.

  * It is important to distinguish schwannomatosis from NF2 in a patient with multiple schwannomas [4].

## 26.3 Neuroimaging

  * Bilateral vestibular schwannomas are typical (Fig. 26.1).

Fig. 26.1

Axial, contrast-enhanc ed T1-weighted image of a cerebellopontine angle schwannoma in a 12-year old child with neurofibromatosis 2 (NF2)

  * Radioimaging features of neoplasms seen in the setting of NF2 are similar to those of sporadic examples, as discussed in other chapters.

  * The modality of choice for NF2 is contrast-enhanced MRI, which is better than CT at visualizing small schwannomas and meningiomas.

  * Both intracranial and intraspinal schwannomas are present in almost all patients. Schwannomas can be intradural or extradural in the spinal cord. They are isointense to spinal cord on T1-weighted images and hyperintense on T2-weighted images. They also show uniform, and in rare occasions, variable enhancement on gadolinium.

  * Aneurysms and arteriovenous malform ations can also be detected on MR imaging.

## 26.4 Histopathological Features

  * The histological features of neoplasms seen in the setting of NF2 are similar to their sporadic counterparts, as discussed in their respective chapters.

  * In addition to schwannomas, meningiomas, and ependymo mas, the following lesions can be seen:

    * Meningoangiomatosis or meningioangiomatosis (Fig. 26.2)

    * Intraneural or cutaneous Schwann cell nodules (Fig. 26.3)

    * Heterotopic ependymal clusters, particularly in the spinal cord

    * Cortical hamartomas or dysplastic lesions (Fig. 26.4)

    * Hamartomas of the retina and retinal pigmented epithelium [5]

Fig. 26.2

Additional lesions other than schwannomas, meningiomas, and ependymomas seen in the setting of NF2 include meningioangiomatosis. This medium-power image demonstrates meningothelial cells within the Virchow-Robin spaces. A similar picture can be seen in tissues adjacent to meningiomas

Fig. 26.3

Medium-power magnification of a paraspinal Schwann cell nodule in a child with NF2

Fig. 26.4

High-power magnification of a dysplastic focus associated with seizures in child with NF2. The special silver stain (Bielschowsky) demonstrates bizarre dysplastic neurons in the seizure focus

## 26.5 Immunohistochemistry

  * The immunohistochemistry of peripheral nerve sheath tumors, meningiomas, and ependymomas in patie nts with NF2 is the same as discussed in their respective chapters.

## 26.6 Molecular Pathology

  * The gene for NF2 has been cloned on chromosome 22q11.2 and contains 17 exons, encoding a 595–amino acid pro tein, known as schwannomin or merlin.

  * Schwannomin is widely expressed in Schwann cells, arachnoid cells, and the lens. The protein functions to link the actin cytoskeleton to cell membrane glycoproteins. It is also known to influence cell cycle and proliferation [6].

  * The gene is considered to be a tumor suppressor and regulator of Schwann cell and arachnoidal cell proliferation.

  * The most common genetic mutations in NF2-related schwannomas and meningiomas span exons 1–15 and involve C > T transitions that change arginine codons to stop codons [7].

  * Recently, segmental disease involving a single extremity or a limited segment of the body has been described [8].

## 26.7 Prognosis

  * Early onset of t he initial symptoms is associated with reduced survival in children with NF2, and the presence of cranial nerve schwannomas is associated with a poorer outcome [9].

  * In general, the prognosis for children with NF2 is slightly less favorable than that of adults.

  * The type and aggressiveness of meningiomas in NF2 patients do not appear to be significantly different than those of sporadic tumors [10].

  * In addition to age at diagnosis, the presence of meningiomas and the type of mutation in the NF2 gene appear to affect prognosis [11].

References

1.

Baser ME, Friedman JM, Joe H, Shenton A, Wallace AJ, Ramsden RT, Evans DG. Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med. 2011;13:576–81.CrossRefPubMed

2.

Choi JW, Lee JY, Phi JH, Wang KC, Chung HT, Paek SH, et al. Clinical course of vestibular schwannoma in pediatric neurofibromatosis type 2. J Neurosurg Pediatr. 2014;13:650–7.CrossRefPubMed

3.

Casado-Verrier B, Feito-Rodriguez M, Noval S, Martinez-Glez V, Lapunzina P, De Lucas-Laguna R. Cutaneous and ophthalmic signs as a clue to early diagnosis of severe neurofibromatosis type 2: report of a novel mutation that predicts this poor prognosis. Clin Exp Dermatol. 2014;39:557–9.CrossRefPubMed

4.

Chen SL, Liu C, Liu B, Yi CJ, Wang ZX, Rong YB, et al. Schwannomatosis: a new member of neurofibromatosis family. Chin Med J (Engl). 2013;126:2656–60.

5.

Mautner VF, Hazim W, Pohlmann K, Berger R, Kluwe L, Haase W. Ophthalmologic spectrum of neurofibromatosis type 2 in childhood. Klin Monbl Augenheilkd. 1996;208:58–62 (article in German).CrossRefPubMed

6.

Beltrami S, Kim R, Gordon J. Neurofibromatosis type 2 protein, NF2: an unconventional cell cycle regulator. Anticancer Res. 2013;33:1–11.PubMedPubMedCentral

7.

Baser ME. Contributors to the International NFMD. The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene. Hum Mutat. 2006;27:297–306.CrossRefPubMed

8.

Castellanos E, Bielsa I, Carrato C, Rosas I, Solanes A, Hostalot C, et al. Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb. BMC Med Genomics. 2015;8:2.CrossRefPubMedPubMedCentral

9.

Aboukais R, Zairi F, Bonne NX, Baroncini M, Schapira S, Vincent C, Lejeune JP. Causes of mortality in neurofibromatosis type 2. Br J Neurosurg. 2014;25:1–4.

10.

Goutagny S, Bah AB, Henin D, Parfait B, Grayeli AB, Sterkers O, et al. Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features. Neuro Oncol. 2012;14:1090–6.CrossRefPubMedPubMedCentral

11.

Baser ME, Friedman JM, Aeschliman D, Joe H, Wallace AJ, Ramsden RT, et al. Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet. 2002;71:715–23.CrossRefPubMedPubMedCentral
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_27

# 27. Von Hippel-Lindau Disease

Tarik Tihan1  and Adekunle M. Adesina2

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

(2)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Von Hippel-LindauvHLHemangioblastomaRetinal angiomaPheochromocytomaEndolymphatic sac tumor

## 27.1 Overview

  * Von Hippel-Lindau (vHL) disease has been attributed to descriptions by Eugen von Hippel of retinal angiomatosis in 1904 and by Arvid Lindau of angiomatous tumors in the cerebellum and spinal cord in 1927. These tumors were later categorized as hemangioblastomas [1].

  * The disease is an autosomal dominant disorder characterized by hemangioblastomas in the cereb ellum, spine, and cerebellum; retinal angiomas; clear cel l renal carcinoma; pheochromocytoma; neuroendocrine tumors or cysts of the pancreas; epididymal cystadenomas; and endolymphatic sac tumors [2].

  * The disease is cau sed by mutations of the vHL gene located on the short (p) arm of chromosome 3 (3p25.3) and encodes a ubiquitously expressed 4.7-kilobase (kb) messenger ribonucleic acid (mRNA) that encodes three alternately spliced exons. The resultant two encoded von Hippel-Lindau protein (pvHL) products, a 30-kDa full-length form (p30) and a 19-kDa form (p19), shuttle between the nucleus and the cytoplasm, where they form complexes with other proteins. These protein complexes have many functions: the regulation of senescence, the oxygen-sensing pathway, microtubule stability and orientation, cilia formation, and many other critical cellular functions [3].

  * The germline mutation is present in most patients with vHL disease. The disease has high pene tration, and almost all individuals with germline mutations develop vHL disease during their lifetime.

  * Clinical diagn ostic criteria for the diagnosis of vHL include one of the following three elements:

    * ◦ More than one hemangioblastoma (ICD-O: 9161/1) in the central nervous system (CNS) or retina

    * ◦ A single hemangioblastoma of the CNS or retina PLUS a visceral complication (multiple renal, pancreatic, or hepatic cysts; pheochromocytoma; renal cell carcinoma) OR unilateral or bilateral endolymphatic sac tumor (ICD-O: 8140/3)

    * ◦ Any one of the above manifestations with a family history

## 27.2 Clinical Features

  * Type 1 vHL syndrome refers to angiomas without pheochromocytoma; Type 2 refers to angiomas with ph eochromocytoma.

  * Loss of vision is one of the more common presentations of patients with vHL because of retinal hemangioblastomas (angiomas) [4].

  * Retinal hemangioblastomas occur in one of every three patients with vHL disease. They can be multiple, often located in the peripheral retina.

  * Paraneoplastic polycythemia is seen in some patients with vHL, owing to decreased inactivation of erythropoietin.

  * Patients with pheochromocytomas can present with paroxysmal or sustained hypertension.

  * Hearing loss is often associated with endolymphatic sac tumors.

  * Patients with cerebellar hemangioblastomas may present with ataxia, dysmetria, and coordination difficulties.

  * Patients with spinal hemangioblastomas present with various motor or sensory problems based on the tumor locatio n.

## 27.3 Neuroimaging

  * Tumors at various sites require different imaging modalities. MRI is the modality of choice for d iagnosis and for screening of patients with vHL syndrome [5].

  * Hemangioblastomas are typically well-defined solid or solid-cystic masses with homogenous enhancement of the solid component [6].

  * Endolymphatic sac tumors can be detected both on CT and MRI; they appear as irregular, bone-destructive masses with "moth-eaten" borders. They may be bilateral in some vHL patients. Most endolymphatic sac tumors have multiple calcified foci, and they variably enhance on contrast administration.

  * CT scans can be helpful to detect renal cell carcinomas, but MR is the modality of choice for a renal mass and cortical or multifocal tumors.

  * Retinal hemangioblastomas may be recognized on routine MR images.

## 27.4 Histopathological Features

  * Histologically, hemangioblastomas in vHL syndrome are essentially identical to sporadic hemangioblastomas.

  * Retina l angiomas are also considered capillary hemangioblastomas and are histologically indistinguishable from cerebellar or spinal examples.

  * Endolymphatic sac tumors arise from the petrous aspect of the temporal bone and are characterized by papillary architecture with gland formation in a colloid-like matrix. The papillae are often lined by a single columnar epithelium with limited cytological atypia. The tumor often shows erosion into bone and may be associated with an inflammatory infiltrate. Occasionally, cuboidal epithelial cells may have cilia.

  * Pheoc hromocytomas are more common in children with vHL and have histological features identical to sporadic pheochromocytomas.

  * Renal cell carcinomas can complicate vHL in children, but are distinctly more common in adults.

## 27.5 Immunohistochemistry

  * Retinal, cer ebellar, and spinal hemangioblastomas in vHL exhibit markers identical to the sporadic examples, as discussed in the hemangioblastoma chapter.

  * Endolymphatic sac tumors are often positive for antibodies against cytokeratins, epithelial membrane antigen (EMA), and vimentin, and are negative for S-100 protein, glial fibrillary acidic protein (GFAP), synaptophysin, or chromogranin.

## 27.6 Molecular Pathology

  * The vHL gene is located on the short arm of chromosome 3 and encodes a 4.7-kb mRNA with three alternately spliced exons, resulting in two different vHL proteins.

  * The vHL protein complexes with a number of proteins and functions to ubiquinate various substrates for degradation. Two of the key targets of the vHL protein are the hypoxia inducible factors (HIFs) HIF-1 alpha and HIF-2 alpha.

  * Loss of vHL protein results in accumulation of HIFs that results in the transcription of numerous hypoxia response genes, such as genes encoding vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

  * The fate of cells lacking the vHL gene is increased proliferation and limited or disrupted differentiation.

  * Genetic alterations in vHL include a variety of aberrations, including missense, frameshift, nonsense, and splice mutations; in-frame deletions or insertions; and large or complete exonic deletions [7].

  * Genetic counseling and screening is a critical component of care for vHL patients and their relatives, and should be implemented.

## 27.7 Prognosis

  * The outco me of patients with vHL disease is varied and partly depends on the type of tumors in a given patient.

  * The most serious cause of mortality is the presence of renal cell carcinoma (accounting for about half of all deaths in vHL disease). Intracranial hemangioblastomas are the second most frequent cause of death.

  * Occurrence of renal cell carcinoma in children with vHL disease is particularly rare.

  * Retinal capillary hemangioblastomas can cause retinal detachment or serious visual loss unless the lesions are detected and treated early.

  * Late-onset long-bone fractures with nonunion also negatively affect long-term prognosis.

References

1.

Cushing H, Bailey P. Tumors arising from the blood vessels of the brain: angiomatous malformations and hemangioblastomas. Springfield, IL: Charles C. Thomas; 1928. p. 9–102.

2.

Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006;36:337–43.CrossRefPubMed

3.

Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617–23.CrossRefPubMedPubMedCentral

4.

Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, et al. Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci. 2002;43:3067–74.PubMed

5.

Smirniotopoulos JG. Neuroimaging of phakomatoses: Sturge-Weber syndrome, tuberous sclerosis, von Hippel-Lindau syndrome. Neuroimaging Clin N Am. 2004;14:171–83.CrossRefPubMed

6.

Sankaredja J, Brac B, Thines L, Baroncini M, Zairi F, Cardot-Bauters C, et al. Epidemiology, treatment and follow-up of central nervous system hemangioblastomas in von Hippel-Lindau disease. Rev Neurol (Paris). 2014;170:288–96.CrossRef

7.

Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31:521–37.PubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_28

# 28. Tuberous Sclerosis Complex

Tarik Tihan1  and Adekunle M. Adesina2

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

(2)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Bourneville diseaseHamartinSubependymal noduleTSCTuberinTuberous sclerosisSubependymal giant cell astrocytoma

## 28.1 Overview

  * Tuberous sclerosis complex (TSC) is an autosomal dominant dysgenetic disorder characterized by hamartomas and neoplasms involving the central nervous system (CNS) and various other tissues.

  * The causative mutatio ns are in the TSC1 and TSC2 genes located on 9q and 16p, respectively.

  * Worldwide, 1–2 million individuals are affected by TSC. The estimated prevalence is 1 out of every 5000–6000 births.

  * The definitive diagn osis of TSC is established if either the genetic or the clinical criteria are met [1]:

    * ◦ Genetic diagnostic criteria: The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins.

    * ◦ Clinical diagnostic criteria: Definite diagnosis implies two major features or one major feature with two or more minor features:

      * Major features

        * Hypomelanotic macules (≥3, at least 5 mm diameter)

        * Angiofibromas (≥3) or fibrous cephalic plaque

        * Ungual fibromas (≥2)

        * Shagreen patch

        * Multiple retinal hamartomas

        * Cortical dysplasias

        * Subependymal nodules

        * Subependymal giant cell astrocytoma (SEGA)

        * Cardiac rhabdomyoma

        * Lymphangioleiomyomatosis (LAM)

        * Angiomyolipomas (≥2)

      * Minor features

        * "Confetti" skin lesions

        * Dental enamel pits (>3)

        * Intraoral fibromas (≥2)

        * Retinal achromic patch

        * Multiple renal cysts

        * Nonrenal hamartomas

## 28.2 Clinical Features

  * About half of TSC patients have a positive family history.

  * Children with TSC can present with seizures, and seizures are present in the majority of pediatric patients [2].

  * Patients with SEGA may present with signs of hydrocephalus associated with blockage of cerebrospinal fluid (CSF) circulation, but early diagnosis of SEGA may be difficult because smaller tumors are often asymptomatic.

  * Cognitive and mental dysfunction and developmental delay are commonly seen in children with TSC.

## 28.3 Neuroimaging

  * Several characteristic lesions can be seen in patients with TSC. Neuroimaging may underestimate the extent of neuropathological changes in TSC patients [3]. More recently, 7-T imaging was able to identify lesions not recognized with lower-resolution magnets [4].

  * Subependymal nodules often protrude into the ventricle; they are often isointense to white matter on T1-weighted images, and are hypointense on T2-weighted images. They show limited and variable enhancement after contrast administration.

  * SEGA is an almost entirely intraventricular tumor, which rarely demonstrates a parenchymal component. Tumors are isointense to hypointense on T1-weighted images and isointense to hyperintense on T2-weighted images; they show strong, diffuse enhancement on gadolinium administration.

  * Cortical tubers are often multiple cerebral lesions with variable calcifications, sometimes in a gyriform fashion. The MR appearance of cortical tubers varies with the age of the patient. The signal changes over time that slowly become isointense to white matter should be interpreted with caution. Tubers are often hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR) modalities and typically do not enhance [5]. Calcifications often accompany cortical tubers as T2 dark foci (Fig. 28.1).

Fig. 28.1

Sagittal fluid-attenuated inversion recovery (FLAIR) image of a young boy with tuberous sclerosis complex (TSC), d emonstrating numerous cortical tubers that are hyperintense to white matter. Note the dark, calcified nodule in the posterior parietal and superior occipital region

## 28.4 Histopathological Features

  * Subependymal nodules are often calcified and partially covered by a layer of ependymal cells. They are mostly composed of large cells with glial phenotype and multinucleated cells with extensive glial processes. There is little or no cytological difference between the predominant cell in subependymal nodule and the cells of SEGA. Most cells in subependymal nodules have ambiguous expression of glial and neuronal markers, as in SEGA.

  * SEGA is a well-cir cumscribed neoplasm and is consider ed World Health Organization (WHO) grade I. The tumor is characterized by gemistocyte-like cells with ample glassy, eosinophilic cytoplasm and eccentric nuclei with p rominent nucleoli in a "streaming" pattern (Fig. 28.2). This pattern portends a more spindled morphology for some of the tumor cells, and some tumors may display a striking pleomorphism. There is a striking glial background with rich fibrillarity. Binucleated or occasionally mul tinucleated cells may be seen within the neoplasm, as well as rare mast cells. Some tumors demonstrate perivascular lymph ocytic infiltrates. Typically, the tumor cells are positive for glial fibrillary acidic protein (GFAP), but similar to subependymal nodules, many cells in SEGA demonstrate an ambiguous glial/neuronal immunohistochemical pattern. The proliferation indices are often very low. Rare mitotic figures can be encountered in SEGA. Exceptional cases demonstrate necrosis, but this is often in the form of geographic, and not palisaded necrosis.

Fig. 28.2

Medium magnification of subependymal giant cell astrocytoma (SEGA) composed of gemistocyte-like cell s arranged in a sweeping fashion and in fascicl es. This tumor appears somewhat discohesive, but most examples demonstrate a solid architecture with no intervening parenchyma

  * Cortical tubers ar e firm, wartlike protrusions that are composed of jumbled-up elements of neuropil with bizarre ganglionlike cells with short processes (Fig. 28.3). These bizarre cells are often found in clusters with a gliotic background and large collections of glial processes. Microcalcifications are often present.

Fig. 28.3

High-magnification image of balloon cells in a cortical tuber from the patient in Fig. 28.1. The typical cortical tuber s hows a markedly disorganized cortex, with abnormal glial proliferations, bizarre neurons, and balloon cells

## 28.5 Immunohistochemistry

  * SEGAs are often positive with the neuronal antibodies such as neurofilament proteins, class III beta-tu bulin, synaptophysin, and NeuN. The latter is only focally positive in a small percentage of cells, but the staining is variable among tumors.

  * SEGA is variably positive for staining with GFAP and S-100 protein antibodies.

  * Recent studies suggest thyroid transcription factor 1 (TTF-1) positivity in SEGAs [6].

  * Olig-2, which is positive with most glial neoplasms, is almost entirely negative in SEGAs [7]. CD34 (positive in most glioneuronal tumors) is also negative.

## 28.6 Electron Microscopy

  * Electron micros copy shows evidence of glial as well as neuronal differentiation.

  * Microtubules, occasional dense-core granules, and, rarely, synapses can be observed.

## 28.7 Molecular Pathology

  * Linkage studies have provided evidence for two distinct TSC loci on chromosome 9q34 (TSC1) and on chromosome 16p13.3 (TSC2).

  * TSC1 and TSC2 gene product s are components of a heterodimer that is critical in regulation of a number of cellular functions including proliferation; they are considered to be tumor suppressor genes. Gene products tuberin and hamartin form a complex that integrates and transmits cellular growth factor and stress signals to the PI3K/PKB signaling pathway, and negatively regulates mTOR activity.

  * Loss of either TSC1 or TSC2 seems to result in a similar clinical picture, supporting the suggestion that both genes are involved in the same regulatory pathway [8].

  * Mutations of the TSC2 gene are more common than TSC1 gene mutations.

  * Virtually all mutations of TSC1 seem to result in a truncated gene product.

  * Mutations in the TSC2 gene are more varied and include deletions, missense and nonsense mutations, frameshift deletions or insertions, and splice junction mutations.

## 28.8 Prognosis

  * SEGA is essentially a benign neoplasm and often can be cured by resection.

  * In recent years, rapamycin therapy has been suggested for cases where a gross total resection cannot be achieved [9].

  * A last-resort treatment is gamma knife surgery for incompletely resected or chemotherapy-resistant tumors.

  * Even though the prognosis of SEGA is quite favorable, the overall prognosis of TSC patients is dependent on the type and extent of CNS and extra-CNS lesions.

References

1.

Northrup H, Krueger DA. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243–54.CrossRefPubMedPubMedCentral

2.

Kotulska K, Jurkiewicz E, Domanska-Pakiela D, Grajkowska W, Mandera M, Borkowska J, et al. Epilepsy in newborns with tuberous sclerosis complex. Eur J Paediatr Neurol. 2014;18:714–21.CrossRefPubMed

3.

Ruppe V, Dilsiz P, Reiss CS, Carlson C, Devinsky O, Zagzag D, et al. Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex. Epilepsia. 2014;55:539–50.CrossRefPubMed

4.

Chalifoux JR, Perry N, Katz JS, Wiggins GC, Roth J, Miles D, et al. The ability of high field strength 7-T magnetic resonance imaging to reveal previously uncharacterized brain lesions in patients with tuberous sclerosis complex. J Neurosurg Pediatr. 2013;11:268–73.CrossRefPubMed

5.

Pinto Gama HP, da Rocha AJ, Braga FT, da Silva CJ, Maia Jr AC, de Campos Meirelles RG, et al. Comparative analysis of MR sequences to detect structural brain lesions in tuberous sclerosis. Pediatr Radiol. 2006;36:119–25.CrossRefPubMed

6.

Hewer E, Vajtai I. Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis. Clin Neuropathol. 2015;34:128–31.CrossRefPubMed

7.

Barrows BD, Rutkowski MJ, Gultekin SH, Parsa AT, Tihan T. Evidence of ambiguous differentiation and mTOR pathway dysregulation in subependymal giant cell astrocytoma. Turk Patoloji Derg. 2012;28:95–103.PubMed

8.

Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, Lewin-Kowalik J, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol. 2004;63:1236–42.CrossRefPubMed

9.

Jozwiak S, Mandera M, Mlynarski W. Natural history and current treatment options for subependymal giant cell astrocytoma in tuberous sclerosis complex. Semin Pediatr Neurol. 2015;22:274–81.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_29

# 29. Lhermitte-Duclos Disease and Cowden Disease

Hidehiro Takei1, Hiroyoshi Suzuki2 and Adekunle M. Adesina3

(1)

Department of Pathology, Weil Cornell Medical College and Baylor College of Medicine, The Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA

(2)

Department of Pathology, Sendai Medical Center Hospital, 2-9-9 Miyagino, Miyagino-ku, Sendai, Miyagi, Japan

(3)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Lhermitte-Duclos diseaseDysplastic gangliocytoma of the cerebellumCowden disease

## 29.1 Overview

  * Lhermitte-Duclos disease

    * ◦ Lhermitte-Duclos disease (LDD), also known as dysplastic cerebellar gangliocytoma, is a rare, slowly enla rging cerebellar mass lesion composed of dysplastic ganglion cells.

    * ◦ It has features of both hamartoma and benign neoplasm (WHO grade I).

    * ◦ The exact incidence is unknown, but most reports indicate that it is a rare condition.

    * ◦ In the cerebellum, no cases of gangliocytoma have been reported except in the context of LDD.

  * Cowden disease

    * ◦ Cowden diseas e (CD) is an autosomal dominant disorder with age-related penetrance.

    * ◦ The incidence of CD is estimated at 1 in 200,000–250,000 (probably an underestimate owing to underrecognition of this disease).

    * ◦ It is characterized by multiple hamartomas in a variety of tissues (i.e., multiple hamartoma syndrome) and a high risk of breast, thyroid, and endometrial cancers.

    * ◦ It is caused by germline mutations in the PTEN gene, a tumor suppressor gene located at chromosome10q23.3, and is allelic to the Bannayan-Riley-Ruvalcaba syndrome, with overlapping clinical phenotypes.

    * ◦ When the diagnosis of CD is made, a long-term follow-up of the patient, as well as a thorough familial screening (and genetic consultation) is necessary.

  * Association between LDD and CD

    * ◦ LDD may occur as a sporadic, isolated disease or in association with CD.

    * ◦ LDD is listed as one of the major diagnostic criteria of CD established by the International Cowden Consortium.

    * ◦ The frequency of LD D in patients with CD is unknown.

    * ◦ In most cases, the diagnosis of LDD precedes the final diagnosis of CD.

    * ◦ All patients with LDD must be thoroughly investigated for concomitant neoplasms associated with CD.

## 29.2 Clinical Features

  * Lhermitte-Duclos disease

    * ◦ LDD presents with a longstanding history of vague neurological symptoms or cerebellar signs related to a progressive posterior fossa mass. Additional signs and symptoms attributable to increased intracranial pressure may be seen.

    * ◦ Occas ionally, it manifests as sudden neurological deterioration due to acute or decompensated chronic hydrocephalus.

    * ◦ Most cases have been identified in young adults, although there is reportedly a broad range of age at diagnosis, from the neonatal period to the eighth decade of life.

    * ◦ The treatment is surgical resection for decompression of the posterior fossa. Recurrence is not rare, probably because the ill-defined margins of the lesion preclude complete excision. Only a rare case of possible malignant transformation has so far been reported.

  * Cowden's disease

    * ◦ Cowden's dise ase presents with pathognomonic mucocutaneous lesions, characterized by facial trichilemmomas, acral keratosis, and papillomatous papules, which occur in over 90 % of patients.

    * ◦ Other major diagnostic criteria include the presence of breast carcinoma, thyroid (nonmedullary) carcinoma, macrocephaly (megalencephaly), LDD, and endometrial carcinoma.

    * ◦ Reported central nervous system (CNS) manifestations include LDD, mental retardation (a minor diagnostic criterion), and vascular malformations (e.g., venous and cavernous angiomas) or developmental venous anomalies.

## 29.3 Neuroimaging of LDD

  * MRI demonstrates the characteristic "tiger-striped" variegated appearance of the cerebellum; this feature is often sufficient for diagnosis, although the histopathological findings defin itively confirm the diagnosis.

  * On T2-weighted MR images, the lesion has a unique striated pattern consisting of alternating bands of high signal intensity and normal signal intensity relative to cerebellar gray matter (Fig. 29.1).

Fig. 29.1

Lhermitte-Duclos disease (LDD). T2-weighted MR images showing a striated, tigroid pattern consisting of alter nating bands of high signal intensity and normal signal intensity in the cerebellum

  * On T1-weighted MR images, the striations are hypointense and isointense to cerebellar gray matter, with slight or no enhancement following gadolinium-DTPA administration.

  * Evidence of mass effect and hydrocephalus is common, with compression of the fourth ventricle and occasional tonsillar herniation.

## 29.4 Pathology

  * Histopathology of LDD

    * ◦ Macroscopically, thickened and distorted folia are observed.

    * ◦ Microscop ically, overgrowth of dysplastic or hypertrophic ganglion cells is seen, with massive replacement of the internal granule cell layer of the cerebellum (Fig. 29.2A and B).

    * ◦ The overlying molecular layer contains abnormally myelinated fibers in parallel arrays primarily in its outer portion (Fig. 29.2C), which are highlighted with myelin stain (Luxol fast blue) (Fig. 29.2D). Increased cellularity composed of neuronal elements may be seen in the molecular layer or subpial region.

    * ◦ The Purkinje cell layer is attenuated or absent.

    * ◦ Microscopic calcification and hypervascular parenchyma are common.

    * ◦ Vacuolization of the cerebellar white matter and molecular layer is often seen.

    * ◦ Mitotic figures are absent.

Fig. 29.2

(A, B) Cerebellum showing distortion of normal cerebellar architecture by overgrowth of dysplastic or hypertrophic ganglion cells and massive replacement of the internal granule cell l ayer of the cerebellum. (C) Abnormally myelinated fibers in parallel arrays are seen in the peripheral region of the molecular layer. (D) These fibers are highlighted with the Luxol fast blue (myelin) stain

## 29.5 Immunohistochemistry of LDD

  * Dysplastic ganglion cells express neuronal markers including synaptophysin (with a ringlike pa ttern of membranous labeling) (Fig. 29.3A), neurofilament protein (Fig. 29.3B), and neuronal nuclear antigen (NeuN) (Fig. 29.3C). NeuN immunoreactivity is characteristically seen in native granule cell neurons, but usually it is not expressed by Purkinje cells and dentate-nuclei neurons in the cerebellum.

Fig. 29.3

D ysplastic ganglion cells are identified by neuronal markers including synaptophysin (with cells displaying a ringlike pattern of membranous labeling) (A), neurofilament protein (B), and NeuN (C)

  * The MIB-1 (Ki-67) labeling index of dysplastic ganglion cells is usually zero.

  * Loss of PTEN protein (Fig. 29.4A) and expression of phospho-AKT and phospho-S6 (Fig. 29.4B) is reportedly observed in the dysplastic ganglion cells, indicating activation of the PTEN/AKT/mTOR pathway.

Fig. 29.4

Dysplastic g anglion cells showing loss of PTEN protein expression (arrow) (A). The loss of PTEN expression is associated with downstream expression and immunopositivity for phospho-S6 (B) and mTOR (C) and is consistent with constitutive activation of the PTEN/AKT/mTOR pathway

    * Demonstrable mTOR positivity supports this hypothesis (Fig. 29.4C).

## 29.6 Molecular Pathology

  * Germline intrag enic mutations in PTEN are detectable in approximately 80 % of patients with CD. Most germline PTEN mutations are found in exon 5 (31.5 %), which encodes for the phosphatase core motif.

    * ◦ PTEN is a tumor-s uppressor gene, which codes for a phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. mTOR phosphorylates ribosomal S6 kinase (S6K), which in turn leads to increased levels of phospho-S6.

    * ◦ Proper PTEN signaling leads to G1 cell-cycle arrest and/or apoptosis.

  * Mutations in the PTEN promoter are reported to account for a subset of apparently mutation-negative patients with CD.

  * Mouse studies reveal that selective inactivation of Pten in cerebellar neurons results in a progressive increase in neuronal soma size with no change in cell number (producing a phenotype with striking similarities to human LDD) and elevated phosphorylation of Akt.

  * It is reported that a PTEN mutation was detected in all tissue samples from patients with adult-onset LDD; samples from patients with childhood-onset LDD were all found to be without mutations.

  * The immunohistochemical pattern seen in dysplastic ganglion cells in LDD, consisting of PTEN(−)/phospho-AKT(+)/mTOR(+)/phospho-S6(+), indicates dysregulation of the PTEN/AKT/mTOR pathway, which supports the hypothesis that this signaling pathway plays a major role in histogenesis of LDD.

  * BRAF V600E mutation and KIAA1549-BRAF fusions are not detected.

## 29.7 Differential Diagnosis

  * The main differ ential diagnosis of LDD is cerebellar ganglioglioma (GG), which is an uncommon tumor in the posterior fossa.

  * LDD may have areas of reactive glial cells in addition to typical dysplastic ganglion cells, thus raising GG as a major histologic differential diagnosis, especially in a small biopsy.

  * The histological distinction between "reactive" glial cells in LDD and "neoplastic" glial cells in GG is virtually impossible.

  * The most common presenting symptoms of cerebellar GG are similar to those of LDD, in contrast to supratentorial GGs, which commonly present with a long history of seizures.

  * Radiologically, nearly half of cerebellar GGs are cystic, and most also show contrast enhancement. Without clinicoradiological correlation, the histologic distinction from LDD may be very difficult.

  * BRAF V600E mutat ion analysis may be helpful: If it is mutated, GG is favored rather than LDD.

Suggested Reading

Abel TW, Baker SJ, Fraser MM, Tihan T, Nelson JS, Yachnis AT, et al. Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol. 2005;64:341–9.CrossRefPubMed

Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29:396–403.CrossRefPubMed

Bonneau D, Longy M. Mutation of the human PTEN gene. Hum Mutat. 2000;16:109–22.CrossRef16%3A2<109%3A%3AAID-HUMU3>3.0.CO%3B2-0)PubMed

Eberhart CG, Wiestler OD, Eng C. Cowden disease and dysplastic gangliocytoma of the cerebellum/Lhermitte-Duclos disease. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. World Health Organization classification of tumours of the central nervous system. Lyon: IARC Press; 2007. p. 226–8.

Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–30.CrossRefPubMedPubMedCentral

Gupta K, Orisme W, Harreld JH, Qaddoumi I, Dalton JD, Punchihewa C, et al. Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups. Acta Neuropathol Commun. 2014;2:18.CrossRefPubMedPubMedCentral

Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.CrossRefPubMed

Lok C, Viseux V, Avril MF, Richard MA, Gondry-Jouet C, Deramond H, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine (Baltimore). 2005;84:129–36.CrossRef

Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analysis in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507–15.CrossRefPubMed

Meltzer CC, Smirniotopoulos JG, Jones RV. The striated cerebellum: an MR imaging sign in Lhermitte-Duclos disease (dysplastic gangliocytoma). Radiology. 1995;194:699–703.CrossRefPubMed

Rosenblum MK, Yachnis AT. Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). In: McLendon RE, Rosenblum MK, Bigner DD, editors. Russell & Rubinstein's pathology of tumors of the nervous system. 7th ed. London: Hodder Arnold; 2006. p. 379–89.

Tan WH, Baris HN, Burrows PE, Robson CD, Alomari AI, Mulliken JB, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet. 2007;44:594–602.CrossRefPubMedPubMedCentral

Waite KA, Eng C. Protean PTEN: form and function. Am J Hum Genet. 2002;70:829–44.CrossRefPubMedPubMedCentral

Wolf HK, Buslei R, Schmidt-Kastner R, Schmidt-Kastner PK, Pietsch T, Wiestler OD, Blümcke I. NeuN: a useful neuronal marker for diagnostic histopathology. J Histochem Cytochem. 1996;44:1167–71.CrossRefPubMed

Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell M, Reifenberger G, Eng C. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet. 2003a;73:1191–8.CrossRefPubMedPubMedCentral

Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinostol-3-kinase/Akt pathway. Am J Hum Genet. 2003b;73:404–11.CrossRefPubMedPubMedCentral

# Part VII
Tumors in the Region of the Pituitary Fossa
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_30

# 30. Pituitary Adenomas

Yazgi Koy1 and Tarik Tihan2

(1)

Department of Pathology, Bagcilar Research and Training Hospital, Merkez Mah. Mimar Sinan Cad. 6 Sok, Bagcilar, Istanbul, Turkey

(2)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

ACTHAdenohypophysisAdenomaCrooke's hyalinCrooke cell adenomaFSHGrowth hormoneLHProlactinProlactinomaTSH

## 30.1 Overview

  * Pituitary adenomas are benign neoplasms arising from adenohypophysis, which are reviewed within the context of tumors of endocrine organs in the World Health Organization (WHO) classification schemes.

    * ◦ Pituitary Adenoma (ICD-O 8272/0) is a benign neoplasm arising from or associated with the anterior pituitary cells; it may or may not produce one or more of the hormones normally secreted by the anterior pituitary.

    * ◦ Atypical Adenoma (ICO-O 8272/1) is a pituitary tumor with certain histological features associated with a greater propensity for recurrence or local spread. An unambiguous definition of atypical pituitary adenoma is still elusive.

    * ◦ Pituitary Carcinoma (ICO-O 8272/3) is a tumor arising from or associated with the anterior pituitary that, by definition, metastasizes to other sites. Histological features of pituitary carcinomas are akin to other epithelial carcinomas. Nearly all cases of pituitary carcinomas reported to date have been in adults.

  * Algorithms for the classification of pituitary adenomas include a functional classification, etiological classification, and classification based on cell of origin.

  * Functional definitions

    * ◦ Clinic ally functioning adenoma: clinical and biochemical evidence of serum hormone elevation

    * ◦ No evidence of serum hormone elevation

    * ◦ Indeterminate

  * Classification ba sed on cell of origin [1]

    * ◦ Adrenocorticotropic hormone (ACTH)–secreting family

    * ◦ Growth hormone–prolactin–thyroid-stimulating hormone (TSH)–secreting family

      * Mammosomatotroph

      * Lactotroph

      * Thyrotroph

    * ◦ Gonadotroph family

    * ◦ Unclassified

  * Classification based on si ze or radiological features

    * ◦ Enclosed (confined within the sella turcica)

      * Grade I: Microadenoma (<10 mm)

      * Grade II: Adenoma (>10 mm) with or without suprasellar expansion

    * ◦ Invasive

      * Grade III Localized Adenoma (bone erosion with or without suprasellar extension)

      * Grade IV Diffuse Adenoma (bone, suprasellar, cavernous sinus, and other perisellar tissue involvement)

  * Pituitary ade nomas rarely occur in childhood and adolescence, but their mass effect and endocrine abnormalities can affect the quality and length of life.

  * Pituitary adenomas in children are more often functional and tend to be larger than those in adults. The most common type is prolactinoma, followed by ACTH-producing adenoma.

  * The treatment of pituitary adenomas is primarily surgical.

## 30.2 Clinical Features

  * The typical signs a nd symptoms of pituitary neoplasia in adults are also commonly seen in children. Visual deterioration, headaches, and endocrinopathies constitute the most common presenting problems.

  * Seizures are an exceedingly uncommon form of presentation.

  * Most pituitary adenomas in children are hormonally active.

  * Disruption of hormone regulation often begins with growth hormone, followed by disruption of TSH.

  * Gonadotroph adenomas often present with disruption of growth and/or sexual maturation.

  * Pituitary apoplexy can occur in some children with pituitary adenomas. Sudden development of headaches, vomiting, fever, and meningeal syndrome, along with deficiencies of one or more serum pituitary hormone levels, are indicative of pituitary apoplexy [2].

  * Earlier works suggested more aggressive behavior [3] and a higher rate of endocrine hyperfunction [2] in pituitary adenomas affecting the pediatric population.

  * Comprehensive subtype classification of pituitary adenomas is critical in children, as in adults [4].

  * It is important to remember that pituitary adenomas can originate from ectopic tissues located in the nasal cavity, nasopharynx, temporal bone, clivus, and third ventricle; these tumors should not be mistaken for metastatic pituitary carcinoma or invasive pituitary adenomas [4].

## 30.3 Neuroimaging

  * Imaging characteri stics of pituitary adenomas in children are similar to those in adults. There is often distortion of the sella turcica. There may be deviation of the pituitary stalk away from the side of the lesion. Macroadenomas can extend into the suprasellar space.

  * MRI typically reveals a mass that is T1-hypointense and hyperintense or isointense on T2-weighted images. Exceptionally, the adenomas can be hyperintense on T1-weighted images due to blood products or high-protein content.

  * Macroadenomas often show diffuse contrast enhancement after gadolinium administration, but tumors with hemorrhage may show heterogeneous enhancement (Fig. 30.1).

Fig. 30.1

Sagittal contrast-enhanced T1-weighted image of a pituitary adenoma in a 16-year-old. Note the hypointense are as within the mass, indicative of intratumoral hemorrhage

## 30.4 Pathology

  * Intraoperative smears

    * ◦ Adenomas are often composed of a monotonous population of cells with abundant, well-defined c ytoplasm in a discohesive pattern (Fig. 30.2).

    * ◦ Rarely, papillary structures can be observed.

    * ◦ When admixed with a significant amount of normal pituitary, the homogenous characteristic of the smear may be lost.

    * ◦ Normal pituitary tissue is substantially more difficult to smear than adenomas.

Fig. 30.2

Histological appearance of a pituitary adenoma on an intraoperative smear preparation. Note the discohesive and monotonous epithelial cells with nuclear irregularities and nucleoli and a rare nuclear inclusion

  * Frozen section

    * ◦ Typically, rou tine cases of pituitary adenomas do not necessitate a frozen section evaluation. Almost all cases that require frozen section are unusual examples and should be approached with caution (Fig. 30.3).

    * ◦ The loss of lobular architecture and the monotonous population of cells are also readily identified on frozen sections.

    * ◦ In some cases, the nested appearance of the tumor may simulate normal pituitary, and rare tumors also show some cytological heterogeneity, confounding an accurate diagnosis (Fig. 30.4).

    * ◦ The key to diagnosis of an adenoma is the architectural patterns and loss of the normal heterogeneity of the epithelial cells. Cytological features other than uniformity can be misleading.

    * ◦ A tissue sample should always be saved for routine analysis.

Fig. 30.3

Frozen section of a pituitary adenoma in a 14-year-old child. Note the faded appearance of monotonous cells and that vague nested pattern

Fig. 30.4

Frozen s ection of a pituitary adenoma simulating normal pituitary, with a nested appearance and a heterogeneous population of cells

  * Histology

    * ◦ The t umor is composed of loosely cohesive epithelial cells forming nests, ribbons, festoon-like structures, diffuse sheets, and occasionally papillary formations (Fig. 30.5).

    * ◦ Adenomas do not harbor any peritumoral fibrotic tissue or a true capsule.

    * ◦ Mitotic figures can be seen in a number of adenomas, along with isolated bizarre cells. Mitoses are more easily identified in adenomas from children than in those from adults.

    * ◦ Adenomas rarely exhibit calcifications, focal necrosis, and or microcystic degeneration [2].

    * ◦ Most resection specimens also include a fragment of compressed and distorted normal pituitary at the periphery, which can aid in the diagnosis.

    * ◦ Microadenomas need to be sampled adequately for accurate diagnosis, and may require special studies.

    * ◦ Rare tumors present with sudden hemorrhage; they may be difficult to recognize on routine stains and need special studies.

    * ◦ ACTH-producing adenomas can exhibit Crooke's hyaline change, which can also be seen in nonneoplastic pituitary (Fig. 30.6).

    * ◦ One of the most useful special stains is reticulin, which highlights the lobular architecture of the normal pituitary and the destruction of this network in adenomas. Use of this stain can be particularly helpful for microadenomas (Fig. 30.7).

    * ◦ The periodic acid–Schiff (PAS) stain is useful to highlight secretory granules of corticotrophs, thyrotrophs, and gonadotrophs.

    * Atypical pituitary adenoma

      * Some pi tuitary adenomas demonstrate "atypical" histological features that have been associated with slightly more aggressive behavior.

      * These features include invasive growth, Ki-67 (MIB-1) labeling index greater than 3 % (Fig. 30.8), and positivity of p53 protein immunohistochemistry. The significance of p53 staining is highly dubious.

      * No other morphological features can distinguish atypical from typical adenomas.

      * No morphological features can distinguish atypical adenomas from carcinomas when the tumor is confined to the sella turcica.

Fig. 30.8

Immunohistoche mical staining with the antibodies against Ki-67 (MIB-1) in an atypical pituitary adenoma demonstrating a high Ki-67 labeling index

Fig. 30.5

Histological patte rns of typical pituitary adenoma in children: nested (A), papillary (B), diffuse (C), ribbon-like (D), pseudoglandular (E), and clear-cell (F)

Fig. 30.6

Crooke's hy aline change (arrow) in an adrenocorticotropic hormone (ACTH)–producing adenoma

Fig. 30.7

Reticulin staining in normal pituitary (A) and pituitary adenoma (B). Note the disruption of the nested reticulin pattern in the adenoma

## 30.5 Electron Microscopy

  * Ultrastructural an alysis is often helpful in recognizing the neuroendocrine nature of the tumor, with abundant neurosecretory granules within the cytoplasm of tumor cells (Fig. 30.9).

Fig. 30.9

Ultrastructural featur es in a typical pituitary adenoma, showing multiple neurosecretory granules

  * Most prolactinomas show a limited number of neurosecretory granules.

  * The tumor cells also display cell junctions and a well-developed endoplasmic reticular network. Typically, intermediate filaments are sparse.

  * Crooke's hyalin or Crooke cell adenomas demonstrate a marked perinuclear accumulation of intermediate filaments (cytokeratin), which may trap numerous neurosecretory granules.

## 30.6 Immunohistochemistry

  * The most common set of stains used for pituitary adenomas are the antibodies against pituitary hormones, and most pediatric pituitary adenomas demonstrate positive staining with either prolactin (Fig. 30.10A), growth hormone, gonadotrophins, ACTH, or TSH.

Fig. 30.10

Typical immu nohistochemical staining of prolactinomas. (A) Immunohistochemical staining with prolactin antibodies, showing cytoplasmic, and mostly perinuclear, dotlike positivity. (B) The tumor nuclei are also strongly positive with the Pit-1 antibody

  * Currently, the three transcription factors are critical in the characterization of pituitary adenomas: Pit-1 (Fig. 30.10B), T-pit, and SF-1.

  * A minority of tumors show no hormonal staining, compatible with a null-cell adenoma.

  * Staining for collagen type IV is a more sensitive and expensive substitute for reticulin stain.

  * Tumors are diffusely positive for chromogranin and synaptophysin. An absence of chromogranin staining should raise the suspicion of a technical error or a different neoplasm.

  * Staining for cytokeratin can be diffuse, perinuclear, or mixed. In addition, low molecular weight cytokeratin antibodies highlight the fibrous bodies that are pathognomonic of sparsely granulated somatotroph adenomas.

  * Staining for p53 has been associated with a more aggressive biological behavior, but this association is highly debatable and poorly reproducible.

  * The MIB-1 or Ki-67 labeling index has been used to determine biological aggressiveness, and some suggest that atypical adenomas show a higher labeling index than typical adenomas.

  * In rare instances, use of other stains such as GATA-2 or Neuro D1 may be helpful in identifying a tumor as a pituitary adenoma, but these markers are often unavailable.

  * The suggested immunohistochemistry panel for routine use includes all six pituitary hormones, CAM 5.2, Ki-67, and the three pituitary transcription factors (if available). Some suggest the use of p53, but we d o not find this stain particularly helpful or associated with aggressive behavior.

## 30.7 Molecular Pathology

  * Different genes or genetic alterations have been suggested for different cell types within the pituitary.

  * Expression of some transcription factors, as mentioned above, may help identify the cell of origin of pituitary adenomas.

  * Oncogenes such as Gsp, Ras, CyclinD1, and a group of other pituitary-derived kinases, and tumor suppressor genes such as MEN1, P53, p16/CDKN2A, and p27/KIP1 have been associated with tumorigenesis in specific types of pituitary adenomas. Currently, no specific genetic alteration of practical utility has been identified for pituitary adenomas.

## 30.8 Differential Diagnosis

  * The first important differential diagnosis includes nonneoplastic pituitary gland. Especially during intraoperative consultations, a normal or edematous pituitary gland may be mistaken for an adenoma. Monomorphic and discohesive tumor cells with abnormal architectural patterns should be sought before a diagnosis of pituitary adenoma is rendered. Hyperplasia or lymphocytic or granulomatous hypophysitis should be considered in the differential diagnosis of a pituitary mass.

  * Differentiating between an olfactory neuroblastoma and a pituitary adenoma is challenging if the tumor extends into the paranasal sinuses without much distortion of the sella turcica. Pituitary adenomas may be difficult to distinguish from olfactory neuroblastomas on pathological examination, especially if the tumor location and radioimaging features are not available to the pathologist. Both tumors will be positive for synaptophysin and chromogranin, and they may have similar histological patterns. If staining for cytokeratin shows focal, dotlike positivity, this finding can be considered supportive evidence for pituitary adenoma, but the distinction may rely on immunohistochemistry, as discussed above.

## 30.9 Prognosis

  * Because surge ry is the mainstay of treatment, the extent of resection is the most critical prognostic factor for pituitary adenomas. Currently, transsphenoidal surgery can be safely applied to many patients with few or no complications [5].

  * Incompletely excised tumors may be treated with radiation therapy, which has been associated with a low rate of radiation-associated damage or tumorigenesis. Radiation treatment presents additional challenges in the pediatric age group [6].

  * The prognosis of atypical and typical adenomas, as defined by high Ki-67 and p53 immunohistochemistry, have not appeared to differ in some studies [7].

  * According to one study [8], fibroblast growth factor receptor 4 (FGFR4), matrix metalloproteinase (MMP), pituitary tumor transforming gene (PTTG), MIB-1, miRNA profile, and deletions in chromosome 11p were suggested as promising candidates to guide the management o f patients with aggressive pituitary adenomas.

References

1.

Mete O, Asa SL. Therapeutic implications of accurate classification of pituitary adenomas. Semin Diagn Pathol. 2013;30:158–64.CrossRefPubMed

2.

Webb C, Prayson RA. Pediatric pituitary adenomas. Arch Pathol Lab Med. 2008;132:77–80.PubMed

3.

Kunwar S, Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab. 1999;84:4385–9.CrossRefPubMed

4.

Mete O, Asa SL. Clinicopathological correlations in pituitary adenomas. Brain Pathol. 2012;22:443–53.CrossRefPubMed

5.

Halvorsen H, Ramm-Pettersen J, Josefsen R, Ronning P, Reinlie S, Meling T, et al. Surgical complications after transsphenoidal microscopic and endoscopic surgery for pituitary adenoma: a consecutive series of 506 procedures. Acta Neurochir (Wien). 2014;156:441–9.CrossRef

6.

Cannavo S, Venturino M, Curto L, De Menis E, D'Arrigo C, Tita P, et al. Clinical presentation and outcome of pituitary adenomas in teenagers. Clin Endocrinol (Oxf). 2003;58:519–27.CrossRef

7.

Chiloiro S, Doglietto F, Trapasso B, Iacovazzo D, Giampietro A, Di Nardo F, et al. Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis. Neuroendocrinology. 2015;101:143–50.CrossRefPubMed

8.

Mete O, Ezzat S, Asa SL. Biomarkers of aggressive pituitary adenomas. J Mol Endocrinol. 2012;49:R69–78.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_31

# 31. Rare Pituitary Tumors Other Than Adenomas

Yazgi Koy1 and Tarik Tihan2

(1)

Department of Pathology, Bagcilar Research and Training Hospital, Merkez Mah. Mimar Sinan Cad. 6 Sok, Bagcilar, Istanbul, Turkey

(2)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Granular cell tumorInfundibulomaPituicytomaSellar gliomaSellar ependymomaSpindle cell oncocytoma

## 31.1 Overview

  * In recent years, many tumors have been described that are considered under the generic category of gliomas arising from the sella turcica. The low-grade sellar neoplasms in this distinct group have unclear histogenesis, but emerging data suggest that they most likely represent a spectrum of closely related neoplasms. Some suggest that they may even be members of a single nosologic entity [1].

  * The three types of rare sellar neoplasms in this category are pituicytoma, granular cell tumor of the pituitary gland, and spindle cell oncocytoma. In addition, a vanishingly rare entity, sellar ependymoma, is also considered to be in this category [2].

  * These rare neoplasms have been mostly described in adults; none is particularly seen in children. Detailed information on their nature and behavior is limited.

  * Pituicyto ma (ICD-O 9432/1), also previously referred to as infundibuloma, is a well-circumscribed neoplasm composed of elongated, bipolar glial cells admixed with scattered inflammatory cells. The current World Health Organization (WHO) classification scheme adopted the term pituicytoma for distinct, low-grade gliomas originating from the specialized glia of the neurohypophysis. These extremely rare tumors are considered WHO grade I neoplasms and have been reported in adults.

  * Granular c ell tumor of the sella (ICD-O 9582/0) arise within or in association with the neurohypophysis and are composed of clusters of large, neuroepithelial cells with granular cytoplasm. They are considered WHO grade I neoplasms and are morphologically similar to granular cell tumors elsewhere in the body.

  * Spindle cell o ncocytoma (ICD-O 8291/0) is an epithelioid, adenohypophysial tumor. It is probably the least known among the rare sellar neoplasms, and has also been reported exclusively in adults [3].

## 31.2 Clinical Features

  * Pituicytoma

    * ◦ Pituicytomas are located in proximity to the infundibulum and can be large, extend ing into suprasellar space. Their actual incidence is unknown, and there is no clear sex preponderance, though some studies report more males.

    * ◦ The tumors clinically present like nonfunctioning adenomas.

    * ◦ Visual field defects are common, as with other tumors in this group.

    * ◦ They are radiologically solid lesions that are uniformly contrast-enhancing.

  * Granular cell tumor of the sella

    * ◦ Granular cell tumors do not have specific clinical features that distinguish them from pituitar y adenomas.

  * Spindle cell oncocytoma

    * ◦ This tumor is similar to pituicytoma and granular cell tumors, in that it presents as a solid sellar mass with predominantly clinical signs and symptoms related to the mass, akin to nonfunctioning adenomas.

## 31.3 Neuroimaging

  * All three tumor s present as sellar solid, enhancing masses that are not distinguishable from nonfunctioning adenomas [4].

  * All thre e types of tumors appear highly vascular on imaging.

  * Granular ce ll tumors are solid, and some examples can be rather large. Most typically appear as solid, T2-hyperintense masses that show prominent contrast enhancement.

## 31.4 Histopathology

  * Pituicytoma

    * ◦ These tumors are composed of spindled glial cells in fascicles and bundles intermixed with scattered lymphoplasmacytic cells.

    * ◦ Utrastructurally, pituicytomas exhibit abundant cytoplasmic intermediate filaments and a variable amount of mitochondria, along with lysosomes and rare desmosome-like intermediate junctions [5].

  * Granular cell tumor of the sella

    * ◦ Histol ogically, these tumors are composed of large, abundantly granular, eosinophilic cells forming clusters, nests, and large lobules. They may show marked nuclear pleomorphism, scattered mitotic figures, and rare multinucleated cells.

    * ◦ Granular tumors are often composed of large polygonal cells with eccentric nuclei and distinct eosinophilic granular cytoplasm. The intracytoplasmic granules are periodic acid–Schiff (PAS)-positive.

    * ◦ Ultrastructurally, the granular cells are loaded with abundant intracytoplasmic lysosomes containing electron-dense material.

  * Spindle cell oncocytoma

    * ◦ The tumor is composed of spindle cells occasionally arranged in fascicles, as well as nodules or lobules of tumor cells with epithelioid cells and brightly eosinophilic cytoplasm.

    * ◦ Spindle cell oncocytomas are characterized by spindle-shaped or polygonal tumor cells with well-formed desmosomes and intermediate filaments, as well as cytoplasm filled with mitochondria.

## 31.5 Immunohistochemistry

  * All three tumors often demonstrate strong, diffuse positivity for the thyroid transcription factor 1 (TTF-1) antibody, which was suggested to imply a common origin for these neoplasms [6].

  * Pituicytoma

    * ◦ Pituicyto mas are positive for vimentin and S-100 protein, and variably for glial fibrillary acidic protein (GFAP). They are negative for hormonal markers, chromogranin, synaptophysin, and cytokeratins. A recent study has identified TTF-1 as another marker for pituicytomas.

  * Granular cell tumor of the sella

    * ◦ These tumors often stain strongly with TTF-1 and S-100 protein, and variably for CD68 and alpha -1 antitrypsin. They are negative for GFAP, neurofilament, cytokeratin, chromogranin, and synaptophysin.

  * Spindle cell oncocytoma

    * ◦ These tumors are positi ve for TTF-1 and are negative for hormonal stains, chromogranin, or synaptophysin, as well as cytokeratins. They express vimentin, S-100 protein, epithelial membrane antigen (EMA), and mitochondrial antigens that can be detected with mitochondria-specific antibodies.

## 31.6 Molecular Pathology

  * The molecular characteristics of these three neoplasms are largely unknown. The typical molecular altera tions seen in solid or infiltrating c erebral gliomas are not observed in this group of tumors.

## 31.7 31.7 Prognosis

  * All of these tum ors are considered WHO grade I neoplasms and are associated with an indolent course. Though the long-term prognoses are not clear, all of these entities are expected to behave in a benign fashion.

    * ◦ Pituicytomas are indolent lesions, and gross total resection is considered curative.

    * ◦ Typically, the granular cell tumors are benign lesions and total surgical removal is considered curative.

    * ◦ The natural course and prognosis of spindle cell oncocytomas have not been characterized.

References

1.

Mete O, Lopes MB, Asa SL. Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma. Am J Surg Pathol. 2013;37:1694–9.CrossRefPubMed

2.

Scheithauer BW, Swearingen B, Whyte ET, Auluck PK, Stemmer-Rachamimov AO. Ependymoma of the sella turcica: a variant of pituicytoma. Hum Pathol. 2009;40:435–40.CrossRefPubMed

3.

Roncaroli F, Scheithauer BW, Cenacchi G, Horvath E, Kovacs K, Lloyd RV, et al. 'Spindle cell oncocytoma' of the adenohypophysis: a tumor of folliculostellate cells? Am J Surg Pathol. 2002;26:1048–55.CrossRefPubMed

4.

Covington MF, Chin SS, Osborn AG. Pituicytoma, spindle cell oncocytoma, and granular cell tumor: clarification and meta-analysis of the world literature since 1893. AJNR Am J Neuroradiol. 2011;32:2067–72.CrossRefPubMed

5.

Phillips JJ, Misra A, Feuerstein BG, Kunwar S, Tihan T. Pituicytoma: characterization of a unique neoplasm by histology, immunohistochemistry, ultrastructure, and array-based comparative genomic hybridization. Arch Pathol Lab Med. 2010;134:1063–9.PubMedPubMedCentral

6.

Lee EB, Tihan T, Scheithauer BW, Zhang PJ, Gonatas NK. Thyroid transcription factor 1 expression in sellar tumors: a histogenetic marker? J Neuropathol Exp Neurol. 2009;68:482–8.CrossRefPubMed
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_32

# 32. Adamantinomatous Craniopharyngioma

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

AdamantinomaAdamantinomatousCraniopharyngiomaPapillary craniopharyngiomaSquamous epitheliomaStellate reticulumWet keratin

## 32.1 Overview

  * Craniopharyngiomas are typically midline tumors with two distinct variants: adamantinomatous and papillary. The adamantinomatous variant, which is identical to adamantinoma of the jaw bones, is the only varia nt seen in the pediatric population. It is also seen in adults.

  * Adamantinomatous craniopharyngioma (ICD-O 9350/1, 9351/1) is a low-grade neoplasm composed of epithelial cells that form basal palisading, loose "stellate reticulum," and keratinous material known as "wet keratin." Most of these tumors are defined by CTNNB1 mutations and nuclear accumulation of beta-catenin [1].

  * Although adamantinomatous craniopharyngiomas are currently considered World Health Organization (WHO) grade I neoplasms, they are known to be locally aggressive and may require numerous surgeries and occasionally adjuvant treatment.

  * The papillary craniopharyngioma, which is similar to a squamous papilloma, is nearly exclusive to adults and exceedingly rare in children [2].

## 32.2 Clinical Features

  * Adamantinomat ous craniopharyngioma occurs mostly in children and young adults; it is rarely seen in adults.

  * Craniopharyngiomas are rare tumors, constituting 0.8 % of all primary central nervous system (CNS) tumors in the United States [3].

  * The worldwide incidence of craniopharyngioma is approximately 1–2 cases per million population [4].

  * The most common location is the third ventricle and the supresellar region, followed by the pineal region. Exceptional cases involve the sinuses or the posterior fossa.

  * Endocrine, visual, and behavioral symptoms can be encountered. Even though some reports suggest that they are more common in males, the incidence for both sexes is nearly equal.

  * Cognitive impairment and personality changes are also seen in up to half of all cases.

  * Some patients may suffer significant morbidity, such as obesity or metabolic syndromes, following surgery [5].

## 32.3 Neuroimaging

  * CT scans are helpful to define the cystic component and calcifications in adamantinomatous craniopharyngioma. MRI offers a more detailed assessment of the tumor extent.

  * The tumors often appear as lobulated masses and may encase larger vessels around the third ventricle or the suprasellar/sellar region.

  * The cystic component of adamantinomatous craniopharyngioma is often uniformly bright on fluid-attenuated inversion recovery (FLAIR) and T2-weighted MR sequences (Fig. 32.1).

Fig. 32.1

Coronal T-2 weighted image of adamantinomatous craniopharyngioma in a 14-year-old boy. The tumor involves the sellar, suprasellar, and hypothalamic regions and appears predominantly cystic. Note that the cyst contents are hypoi ntense to cerebrospinal fluid (CSF)

  * On T1-weighted sequences, the cysts can be hyperintense. Calcifications appear as T2-hypointense areas within the solid component. Otherwise, the solid component is isointense [6].

  * The solid component of the tumor enhances on contrast (Fig. 32.2).

Fig. 32.2

Axial FLAIR image of adamantinomatous craniopharyngioma involving the suprasellar region and the third ventricle, wit h extension into the sella and temporal lobe. Note the solid-cystic composition of the tumor and multiloculated cystic structures

  * MR spectroscopy demonstrates a large lipid-lactate peak typical for adamantinomatous craniopharyngiomas.

  * Papillary craniopharyngi omas are solid masses with homogeneous enhancement and without obvious cystic elements (Fig. 32.3).

Fig. 32.3

Sagittal contrast-enhanced T1-weighted image of an intrasellar craniopharyngioma with partial distortion of the sella tu rcica and avid enhancement. The tumor has small cystic elements but appears mostly solid

## 32.4 Histopathology

  * Intraoperative smears

    * ◦ Craniopharyngiomas smear poorly and often form sheets of epithelial cells (Fig. 32.4). Wet keratin and stellate ret iculum can also be seen on smears.

Fig. 32.4

Intraoperative smear of an adamantinomatous craniopharyngioma. Note the sheetlike and clustered appearanc e, with only rare, scattered single cells

  * Frozen section

    * ◦ The typical features of a frozen section are cholesterol clefts and the amorphous "wet-keratin"; epithelial cells may be absent.

    * ◦ When present, epithelial cell with palisading and stellate reticulum are readily diagnostic.

    * ◦ The epithelial component may show significant crush artifact and palisades; stellate reticulum may not be readily recognized (Fig. 32.5).

Fig. 32.5

Intraoperative frozen section of adamantinomatous craniopharyngioma demonstrating compressed, glandlike epithelial structures and compact-appearing areas. The basal palisading is not well defined and the stellate reticulum is not well appreciated

  * Macroscopic features

    * ◦ The contents of t he cysts in craniopharyngiomas are often described as "machine oil."

    * ◦ The tumor is often discrete and variable in color and texture with multiple cysts containing the machine oil–like fluid.

  * Microscopic features

    * ◦ Histological features of craniopharyngiomas are identical to those of ameloblastoma.

    * ◦ The adamantinomatous craniopharyngioma is composed of nodules of epithelial cells that are arranged in palisades around a loose stromal element, with more spindled cells also known as "stellate reticulum" (Fig. 32.6).

Fig. 32.6

Three ty pical components of adamantinomatous craniopharyngioma can be seen from right to left in this section: wet keratin, epithelial cells arranged in palisades, and stellate reticulum

  * "Wet keratin " (a cluster of eosinophilic and necrotic, keratinized cells also known as ghost cells) is a classic histological finding and is often diagnostic (Fig. 32.7).

Fig. 32.7

"Wet keratin" or "ghos t cells" refer to brightly eosinophilic, keratinous material devoid of nuclear material and a lamellar pattern. In smaller biopsies, epithelial cells and stellate reticulum may not be present, and the only clue to a craniopharyngioma could be the wet keratin

  * Tissue adjacent to the tumor may harbor Rosenthal fibers and reactive changes and may be mistaken for a pilocytic astrocytoma (Fig. 32.8).

Fig. 32.8

In sections adjacent to adamantinomatous craniopharyngioma, there is significant gliotic reaction with Ros enthal fibers, which may lead to an erroneous diagnosis of pilocytic astrocytoma. In this section, the presence of wet keratin embedded in this gliotic parenchyma provides the clue to the correct diagnosis

  * The tumors often contain a mixture of necrotic-appearing, acellular material with calcifications, giant cells, and cholesterol clefts [7] (Fig. 32.9).

Fig. 32.9

In some small samples, there may be only reactive tissue with abundant cholesterol clefts, lymphocy tic inflammation, and multinucleated giant cells. Wet keratin often accompanies this picture, but the epithelial elements or the stellate reticulum may be difficult to find or absent

  * A compact, sheetli ke arrangement of epithelial cells can be seen in adamantinomatous craniopharyngiomas, which can be confused with the papillary variant (Fig. 32.10).

Fig. 32.10

Some microscopic areas of adamantinomatous craniopharyngioma may resemble the papillary cranioph aryngioma, and such tumors have been reported as hybrid adamantinomatous/papillary tumors. In most such cases, however, the tumor cells in both regions have the same molecular alteration, which is often the presence of nuclear beta-catenin staining, confirming the diagnosis of adamantinomatous craniopharyngioma

  * Rare examples demonstra te malignant features, including areas resembling squamous cell carcinoma [8].

## 32.5 Immunohistochemistry

  * The epithelial component is strongly positive for cytokeratins, especially CK7, CK19, and other high molecular-we ight cytokeratin antibodies.

  * The tumors are typically negative for germ-cell markers, glial fibrillary acidic protein (GFAP), and S-100 protein.

  * High Ki-67 (MIB-1) labeling of tumors has been associated with a higher rate of recurrence, but Ki-67 does not have any role in grading or diagnosis of craniopharyngioma.

  * Adamantinomatous craniopharyngiomas show diffuse, strong nuclear positivity with beta-catenin antibodies as evidence of CTNNB1 mutations [9] (Fig. 32.11). Beta-catenin immunopositivity aids in the differential diagnosis of adamantinomatous cranopharyngiomas from Rathke cleft cysts in rare occasions where the histological features are ambiguous [10].

Fig. 32.11

Nearly all adamantinomatous craniopharyngiomas demonstrate nuclear beta-catenin positivity, consisten t with the CTNNB1 gene mutation

## 32.6 Molecular Pathology

Typically, adamantinoma tous craniopharyngiomas demonstrate somatic mutations in the CTNNB1 gene [11]. Almost all mutations are missense mutations affecting the serine/threonine residues at GSK-3β phosphorylation sites or an amino acid flanking the first serine residue. The result is stabilization of the protein and subsequent nuclear translocation [9].

## 32.7 Prognosis

  * The most common critical prognostic factor is the extent of resection. The rate of recurrence following g ross total resection is significantly lower [2].

  * Adamantinomatous craniopharyngiomas are associated with a significant rate of recurrence despite multiple surgeries. Age, sex, and histological parameters do not seem to affect outcome within the adamantinomatous craniopharyngiomas.

  * Tumor size has been associated with outcome, in that larger tumors are suggested to have a more adverse long-term prognosis. This variable is not independent of extent of resection, however, suggesting that larger tumors may not be easily removed in toto.

References

1.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumors of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2007.

2.

Pekmezci M, Louie J, Gupta N, Bloomer MM, Tihan T. Clinicopathological characteristics of adamantinomatous and papillary craniopharyngiomas: University of California, San Francisco experience 1985–2005. Neurosurgery. 2010;67:1341–9. discussion 1349.CrossRefPubMed

3.

Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17 Suppl 4:iv1–iv62.CrossRefPubMed

4.

Nielsen EH, Feldt-Rasmussen U, Poulsgaard L, Kristensen LO, Astrup J, Jorgensen JO, et al. Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults. J Neurooncol. 2011;104:755–63.CrossRefPubMed

5.

Sahakitrungruang T, Klomchan T, Supornsilchai V, Wacharasindhu S. Obesity, metabolic syndrome, and insulin dynamics in children after craniopharyngioma surgery. Eur J Pediatr. 2011;170:763–9.CrossRefPubMed

6.

Pusey E, Kortman KE, Flannigan BD, Tsuruda J, Bradley WG. MR of craniopharyngiomas: tumor delineation and characterization. AJR Am J Roentgenol. 1987;149:383–8.CrossRefPubMed

7.

Zhang YQ, Wang CC, Ma ZY. Pediatric craniopharyngiomas: clinicomorphological study of 189 cases. Pediatr Neurosurg. 2002;36:80–4.CrossRefPubMed

8.

Kristopaitis T, Thomas C, Petruzzelli GJ, Lee JM. Malignant craniopharyngioma. Arch Pathol Lab Med. 2000;124:1356–60.PubMed

9.

Sekine S, Shibata T, Kokubu A, Morishita Y, Noguchi M, Nakanishi Y, et al. Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol. 2002;161:1997–2001.CrossRef64477-X)PubMedPubMedCentral

10.

Hofmann BM, Kreutzer J, Saeger W, Buchfelder M, Blumcke I, Fahlbusch R, et al. Nuclear beta-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and Rathke cleft cysts: a clinico-pathologic approach. Am J Surg Pathol. 2006;30:1595–603.CrossRefPubMed

11.

Buslei R, Nolde M, Hofmann B, Meissner S, Eyupoglu IY, Siebzehnrubl F, et al. Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathol. 2005;109:589–97.CrossRefPubMed

# Part VIII
Choroid Plexus Neoplasms
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_33

# 33. Choroid Plexus Neoplasms

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

Choroid plexus papillomaChoroid plexus carcinomaAtypical choroid plexus papillomaRhabdoid predisposition syndromeTP53

## 33.1 Overview

  * Intraventricular neo plasms derived from choroid plexus epithelium include choroid plexus papilloma (WHO grade I), atypical choroid plexus papilloma (WHO grade II), and choroid plexus carcinoma (WHO grade III).

  * As a group, most of these tumors are sporadic, but a significant proportion of patients with choroid plexus carcinoma (CPC) will have demonstrable hereditary cancer predisposition syndromes, including the Li Fraumeni syndrome (with germline mutations of TP53) and rhabdoid predisposition syndromes (with mutations of hSNF5/ INI1 /SMARCB1). Choroid plexus papillomas (CPPs) are also a component of Aicardi syndrome, the affected patients showing agenesis of the corpus callosum, chorioretinal lacuna, and infantile spasms. Rarely, CPP arises in the context of von Hippel-Lindau disease.

  * CPPs are at le ast five times more common than CPCs.

## 33.2 Clinical Features

  * These tumor s may occur at any age, but the peak incidence is within the first decade. Rare congenital and fetal examples have been described.

  * Though they are rare brain tumors overall, choroid plexus tumors are more frequent in the pediatric population, representing approximately 4 % of all brain tumors in children under 15 years of age, and up to 20 % of those arising within the first year of life.

  * The majority of CPCs occur in children, where they account for one third of all choroid plexus tumors.

  * Patients present with signs and symptoms related to blockage of cerebrospinal fluid (CSF) pathways and hydrocephalus, including macrocephaly and bulging fontanelles, papilledema, ataxia, headache, strabismus, irritability, nausea and vomiting, and altered consciousness.

## 33.3 Neuroimaging

  * These tumor s typically arise within the lateral (50 %), fourth (40 %), or third (5 %) ventricles, and rarely are seen at the cerebellopontine angle or other locations (intraparenchymal, suprasellar, spinal epidural region). Rarely, multiple ventricles are involved by tumor.

  * Most lateral ventricular tumors present within the first two decades of life, whereas fourth ventricle tumors have a more diverse age distribution.

  * CPPs are characteristically solid, well-demarcated intraventricular masses that on MRI are isointense to grey matter on T1, hyperintense on T2, and show marked contrast enhancement (Fig. 33.1). They are isodense to hyperdense on CT images.

Fig. 33.1

Coronal T1-weighted post-gadolinium MR image of a choroid plexus papilloma (CPP) showing an in traventricular, densely enhancing, well-circumscribed lesion involving the left lateral and third ventricles with accompanying hydrocephalus

  * CPCs are generally larger, with MRI showing more heterogeneous intensities on both T1 and T2, with irregular enhancement, and edema (often indicative of invasion of adjacent brain). Flow voids, cysts, and areas of intratumoral hemorrhage or necrosis are not uncommon (Fig. 33.2). On CT they are heterogeneous and isodense, with calcifications and necrosis.

Fig. 33.2

Axial (A) and sagittal (B) T1-weighted post-gadolinium MR images of a choroid plexus carcinoma (C PC) showing a large mass arising within the right lateral ventricle with heterogeneous signal intensity and enhancement, central necrosis, hydrocephalus, and significant mass effect with midline shift

  * Atypical CPP (aCPP) may show imaging features intermediate between typical CPP and CPC, often with surrounding edema evident on T2 and fluid-attenuated inversion recovery (FLAIR) images (Fig. 33.3).

Fig. 33.3

These MR images depict a right intraventricular tumor which microscopically proved to be an atypical CPP (WHO grade II). (A) This axial T1-weighted post-gadolinium MR image shows so lid, homogeneously enhancing tumor. (B) This T2-weighted coronal MR image indicates more heterogeneous signal intensity ranging from isointense to hyperintense, with associated periventricular edema. Hydrocephalus was not prominent in this case

  * Hydrocephalus, sometimes massive, typically accompanies choroid plexus lesions (Fig. 33.1).

  * Leptomeningeal enhancement correlates with CSF dissemination of tumor, which often may be encountered with CPC and rarely with CPP.

  * On MR spectrosc opy, CPPs have higher levels of myoinositol and lower levels of choline than CPCs.

## 33.4 Pathology

  * Gross pathology

    * ◦ Surgical specimens of CPP are typically globular, soft, and red-brown or pink, with stippled surfaces (correlating with papillary microarchitecture); intratumoral hemorrhage, cysts, or calcifications may be present.

    * ◦ CPCs are often punctuated by areas of hemorrhage and necrosis.

    * ◦ In autopsy br ains, CPPs ar e found as cauliflower-like masses, often adherent to the ventricular walls but otherwise well demarcated from the surrounding brain tissue. CPCs, on the other hand, are frequently invasive into the periventricular brain parenchyma.

  * Intraoperative cytologic imprints/smears

    * ◦ Cytologic pr eparations of CPPs are typified by multiple well-formed papillary clusters, sheets or monolayers (often with honeycomb-type architecture), and isolated single tumor cells that are cuboidal to columnar with bland round or oval nuclei, dispersed chromatin, and a moderate amount of cytoplasm. Microcalcifications occasionally may be present (Fig. 33.4).

Fig. 33.4

(A) A cytologic squash preparation of CPP showing well-formed papillary structures along with sc attered, bland-appearing individual tumor cells. (B) Higher magnification of this CPP sample reveals cells with bland round to oval nuclei, micronucleoli, and a single microcalcification. Honeycomb architecture is noted in these cellular sheets

    * ◦ CPC squash or smear preparations tend to be hypercellular, containing three-dimensional clusters and singly dispersed anaplastic-appearing cells with prominent nuclear irregularities (indentations or lobulations), a high nuclear to cytoplasmic ratio, and frequent macronucleoli. Cellular cytoplasm may contain hyaline globules or vacuoles. Papillary architecture may be retained in some areas. Mitotic figures, apoptotic bodies, and back ground necrosis may be seen (Fig. 33.5).

Fig. 33.5

(A) Squash preparation of a CPC showing three-dimensional clusters, some having a papillary a rchitecture with a complex, multilayer covering of neoplastic epithelium. (B) Numerous isolated, anaplastic-appearing cells with prominent nuclear irregularities—many with a high nucleocytoplasmic ratio—are present, as are scattered apoptotic cells and mitotic figures

  * Histology

    * ◦ Most CPPs show similar microscopic features, whereas higher-grade choroid plexus lesions—particularly CPCs—are quite variable in their appearance.

    * ◦ Choroid plexus papilloma (WHO grade I) contains numerous fibrovascular papillary projection s covered by a single layer of cuboidal to columnar epithelium with monotonous bland nuclei (Fig. 33.6A).

      * Though they may superficially resemble non-neoplastic choroid plexus (Fig. 33.6B), CPPs show more cellular crowding or stratification, a mildly elevated nuclear to cytoplasmic ratio, nuclear hyperchromasia and/or mild nuclear pleomorphism, loss of the hobnail configuration of the normal choroid plexus, and rare mitoses.

      * The epithelial cytoplasm is quite variable and may be abundant and eosinophilic, vacuolated, or clear (Fig. 33.6C–E).

      * Notable but uncommon histologic features include oncocytic change (Fig. 33.6F), glandular metaplasia, mucinous degeneration, melanin pigment, focal ependymal differentiation, neuropil-like islands, and osseous or cartilaginous metaplasia.

      * Degenerative changes may include xanthomatous change, angioma-like increase of blood vessels, hyalinization, or calcification (Fig. 33.6G).

      * Foci of necrosis, increased cellularity, or loss of papillary architecture are rarely encountered in grade I CPP.

    * ◦ Atypical choroid plexus papillomas (WHO grade II) represent those CPPs with elevated mi totic activity (>2 mitoses per ten high power fields) (Fig. 33.7A).

      * Additional histologic features often present in aCPPs include hypercellularity, nuclear pleomorphism, focal loss of papillary architecture or solid growth pattern, and necrosis (Fig. 33.7B and C).

      * Complex architectural arrangements with cribriforming and anastomosing papillary formations may be seen.

    * ◦ Choroid plexus carcinoma (WHO grade III) shows frank features of malignancy, with solid sheets of var iably pleomorphic epithelioid cells with frequent mitoses (Fig. 33.8A and B).

      * Foci of papillary architecture may be retained in some CPCs (Fig. 33.8C).

      * Brain invasion (Fig. 33.8D) and necrosis are common findings.

      * Malignant choroid plexus epithelium may have eosinophilic cytoplasm (Fig. 33.8A–C), or it may be amphophilic (Fig. 33.8E) or clear (Fig. 33.8F).

      * Cells exhibi ting a distinctly rhabdoid morphology may be the overwhelming feature of some CPCs, resulting in significant overlapping histology with atypical teratoid/rhabdoid tumors (AT/RTs) (Fig. 33.9).

Fig. 33.9

CPCs may display a distinctly rhabdoid morphology. Though their appearance is often rather spin dled at low power (A), these lesions harbor cells with large, eccentric vesicular nuclei and prominent nucleoli (B), virtually identical to the rhabdoid cells of atypical teratoid/rhabdoid tumors (AT/RTs)

      * Likewise, some CPCs harbor smaller cells with a high nuclear to cytoplasmic ratio, reminiscent of primitive neuroectodermal tumors (PNETs) or medulloblastoma (Fig. 33.10A and B).

Fig. 33.10

Occasionally, CPCs may show a small cell morphology mimicking primitive neuroectod ermal tumor (PNET) and other small, round, blue cell tumors of infancy. The neoplastic cells, with their high nucleocytoplasmic ratio and minimal surrounding cytoplasm, may arrange in patternless sheets (A) or ribbon-like patterns (B)

      * Other uncommon histologic features similar to those listed above for CPPs (partic ularly melanin pigment and onc ocytic morphology) may be rarely encountered.

Fig. 33.6

CPP (A) characterized by fibrovascular papillary projections covered by a single layer of cuboidal to columnar epithelium. Normal choroid plexus (B) with small intercellular spaces, imparting a cobblestone appearance. The epithelium of CPP lacks these spaces and may d isplay abundant eosinophilic cytoplasm (C), cytoplasmic vacuoles (D), or optically clear cytoplasm (E). Though tumoral calcifications are not uncommon (F), oncocytic change (as seen in the middle of this photomicrograph) is infrequent. Papillae may show dense hyalinization of stromal cores (G)

Fig. 33.7

Atypical CPPs (A) are defined by their elevated mitotic rate; in addition to multiple mitotic fig ures, cell crowding, pseudostratification, and focal nuclear pleomorphism are seen in this example. Complex architecture (B) and solid areas (C) are additional features

Fig. 33.8

CPCs contain solid sheets of variably pleomorphic epithelioid cells with frequent mitoses (A, B), sometim es with focally retained papillary architecture (C). Invasion into the surrounding brain parenchyma is common (D). Though their cytoplasm is often eosinophilic, the malignant epithelioid cells of CPC may also have amphophilic (E) or clear (F) cytoplasm

## 33.5 Immunohistochemistry

  * Choroid plexus papillomas are almost uniformly positive for cytokeratins, vimentin, and podoplanin. V ariable patterns of positivity for CK7 and CK20 may be encountered, the most frequent being CK7+/CK20+.

    * ◦ Epithelial membrane antigen (EMA) is usually negative, whereas up to 90 % will show some positivity for S-100 protein.

    * ◦ Though it is not found in normal choroid plexus, glial fibrillary acidic protein (GFAP) staining may be detected at least focally in up to 50 % of CPPs.

    * ◦ Transthyretin is positive in the majority of CPPs, though this stain is not entirely specific to choroid plexus tumors.

    * ◦ Synaptophysin may be paradoxically positive in some cases.

  * Choroid plexus carcinomas similarly show immunopositivity for cytokeratins, but S-100 and transthyretin are less reliably positive than for CPPs (Fig. 33.11A).

Fig. 33.11

CPCs are typically positive for cytokeratin (A) and synaptophysin (B). Nuclear positivity for immunohistochemical stain for INI1 (BAF47) (C) is helpful in discriminating CPC from AT/RT. The Ki67 (MIb-1) labeling index of proliferation (D) is often brisk. At the ultrastructural level (E), choroid plexus tumors contain epithelioid cells with surface microvilli and cilia, have tight junctions (upper right), and rest upon basement membrane

    * ◦ Synaptophysin (Fig. 33.11B), GFAP, EMA, CD44, and CA19-9 may all be at least focally positive.

    * ◦ Retained nuclear staining for INI1 is helpful in differentiating these tumors from AT/RTs (Fig. 33.11C).

    * ◦ The proliferation index as detected by MIB-1 (Ki67) is variable but typically brisk (Fig. 33.11D).

    * ◦ Most CPCs show nuclear positivity for p53.

  * Lack of staining for carcinoembryonic antigen (CEA), HEA 125, Ber EP4, or positive staining for excitatory amino acid transporter-1 (EAAT1) or Kir7.1 help to differentiate choroid plexus tumors from metastatic carcinomas from other body sites and from endolymphatic sac tumors.

## 33.6 Electron Microscopy

  * Ultrastructural analysis of CPP or CPC may show tight junctions and membrane interdigitations, cell surface spe cializations including microvilli and cilia, and basement membrane (Fig. 33.11E).

## 33.7 Molecular Pathology

  * High-resolution genomic analyses have indicated recurrent focal chromosomal gains common to all choroid plexus tumors, in particular 14q21-q22 (OTX2), 7q22 (LAMB1), and 9q21.12 (TRPM3).

    * ◦ Both CPP and aCPP are frequently hyperdiploid; though they differ in grade and histologic characteristics, no significantly distinct molecular alterations between CPP and aCPP have been observed thus far. Chromosome 3 VHL allele losses may be encountered in those CPPs arising in association with von Hippel-Lindau disease.

    * ◦ Notch signaling pathway activation has been implicated in a subset of CPPs.

    * ◦ Choroid plexus carcinomas show mainly chromosomal losses, and can be divided into hypodiploid and hyperdiploid subgroups. Hyperdiploid CPCs tend towards acquired uniparental disomy events.

    * ◦ Somatic TP53 mutations may be present in over 50 % of CPCs, and individuals with CPCs harboring two copies of mutant p53 have been found to exhibit poorer progression-free and overall survival than those with CPCs with only one mutant p53 copy.

    * ◦ Alternative lengthening of telomeres (ALT) may be present in about 25 % of CPCs. ALT may attenuate the effect of TP53 mutations in CPCs, with significantly prolonged 5-year overall survival documented for ALT-positive TP53-mutant tumors versus their ALT-negative counterparts.

    * ◦ Nuclear immunopositivity with BAF-47 (anti-INI1) is a reliable method to differentiate CPCs with a rhabdoid phenotype from true AT/RTs (which lack nuclear INI1 staining) (Fig. 33.11C).

    * ◦ Expression and amplification of platelet-derived growth factor (PDGF) receptors is frequent in CPC.

## 33.8 Differential Diagnosis

  * CPPs need to be distinguished from non-neoplastic choroid plexus and villous hypertrophy (a dif fuse enlargement of the choroid plexus). Demonstrable mitoses and/or MIB-1/Ki67 (proliferation marker) labeling, together with cytomorphologic and architectural features as noted above, should reliably accomplish this differentiation in favor of CPP.

  * Papillary ependymoma exhibits distinctive papillary architecture similar to CPP, but CPP has basement membrane beneath epithelium, shows strong positivity for cytokeratin, and lacks the perivascular pseudorosettes and strong positivity for GFAP shown by the ependymomas.

  * Similarly, CPC may resemble anaplastic ependymoma, and likewise can be differentiated from that tumor by virtue of strong cytokeratin positivity, lack of significant GFAP staining, and lack of true and perivascular pseudorosettes.

  * Medulloepithelioma and the germ cell tumor embryonal carcinoma both enter the differential of CPC. However, medulloepithelioma, with its multilayered, primitive neural tube–like structures, is typically immunoreactive for vimentin and nestin, and embryonal carcinomas are characteristically positive for placental alkaline phosphatase (PLAP).

  * As discussed previously, CPCs may contain variable populations of cells with rhabdoid morphology, thus raising AT/RT as a diagnostic consideration. Nuclear staining with anti-INI1 (BAF-47) in this context reliably differentiates CPC from AT/RT, which characteristically has an absence of staining with BAF-47.

  * Transthyretin and/or S-100 protein expression may be helpful features (though by no means 100 % reliable) in differentiating choroid plexus tumors from metastatic carcinomas (papillary or otherwise) from other sites. GFAP and synaptophysin positivity, often encountered in choroid plexus tumors, is likewise typically not a signature of metastatic carcinomas. Other immunostains (CEA, HEA 125, Ber EP4, EAAT1) may provide ancillary assist ance in this differential diagnosis, as noted elsewhere.

## 33.9 Prognosis

  * Prolonged recurrence-free and overall survival is typical for CPP, with 5-year survival rates approaching 100 % following complete surgical excision. CPCs are significantly more aggressive, with survival rates approximately half those encountered in CPPs. Survival rates for atypical CPPs fall somewhere between these two extremes; tumor recurrences are more frequent with aCPPs than with CPPs, though malignant transformation of papillomas of either grade are quite rare.

  * Resection of all choroid plexus tumors is technically difficult because of their extensive vascularity and propensity to bleed.

  * In addition to high tumor grade, other histologic features portend poor prognosis:

    * ◦ Decreased S-100 protein expression

    * ◦ Mitoses

    * ◦ Lack of immunopositivity for transthyretin

    * ◦ Brain invasion

    * ◦ Necrosis

  * Surgical excision is the standard first-line therapy for all choroid plexus tumors, with gross total resection curative for most CPP and aCPP. Localized CPCs with complete resection have a favorable outcome realized with the addition of adjuvant chemotherapy or radiotherapy. Craniospinal irradiation may be necessary in those cases of CPC with subtotal resection and/or disseminated leptomeningeal disease, but it may be avoided in some very young children with the use of myeloablative chemotherapy with autologous stem cell resc ue.

Suggested Reading

Beschorner R, Schittenhelm J, Schimmel H, Iglesias-Rozas JR, Herberts T, Schlaszus H, et al. Choroid plexus tumors differ from metastatic carcinomas by expression of the excitatory amino acid transporter-1. Hum Pathol. 2006;37:854–60.CrossRefPubMed

Cannon DM, Mohindra P, Gondi V, Kruser TJ, Kozak KR. Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management. J Neurooncol. 2015;121:151–7.CrossRefPubMed

Gozali AE, Britt B, Shane L, Gonzalez I, Gilles F, McComb JG, et al. Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children's Hospital Los Angeles (CHLA) experience, 1991–2010. Pediatr Blood Cancer. 2012;58:905–9.CrossRefPubMed

Guermazi A, De Kerviler E, Zagdanski A-M, Frija J. Diagnostic imaging of choroid plexus disease. Clin Radiol. 2000;55:503–16.CrossRefPubMed

Japp AS, Gessi M, Messing-Junger M, Denkhaus D, Zur Muhlen A, Wolff JE, et al. High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors. J Neuropathol Exp Neurol. 2015;74:110–20.CrossRefPubMed

Jeibmann A, Hasselblatt M, Gerss J, Wrede B, Egensperger R, Beschorner R, et al. Prognostic implications of atypical histologic features in choroid plexus papilloma. J Neuropathol Exp Neurol. 2006;65:1069–73.CrossRefPubMed

Jeibmann A, Wrede B, Peters O, Wolff JE, Paulus W, Hasselblatt M. Malignant progression in choroid plexus papillomas. J Neurosurg. 2007;107:199–202.PubMed

Judkins AR, Burger PC, Hamilton RL, Kleinschmidt-Demasters BK, Perry A, Pomeroy SL, et al. INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol. 2005;64:391–7.CrossRefPubMed

Koh EJ, Wang KC, Phi JH, Lee JY, Choi JW, Park SH, et al. Clinical outcome of pediatric choroid plexus tumors: retrospective analysis from a single institute. Childs Nerv Syst. 2014;30:217–25.CrossRefPubMed

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC; 2007.

Mangerel J, Price A, Castelo-Branco P, Brzezinski J, Buczkowicz P, Rakopoulos P, et al. Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors. Acta Neuropathol. 2014;128:853–62.CrossRefPubMed

Matsushima T, Inoue T, Takeshita I, Fukui M, Iwaki T, Kitamoto T. Choroid plexus papillomas: an immunohistochemical study with particular reference to the coexpression of prealbumin. Neurosurgery. 1988;23:384–9.CrossRefPubMed

Merino DM, Shlien A, Villani A, Pienkowska M, Mack S, Ramaswamy V, et al. Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups. Clin Cancer Res. 2015;21:184–92.CrossRefPubMed

Paulus W, Janisch W. Clinicopathologic correlations in epithelial choroid plexus neoplasms: a study of 52 cases. Acta Neuropathol (Berl). 1990;80:635–41.CrossRef

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# Part IX
Pineal-Based Tumors
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_34

# 34. Pineal Parenchymal Tumors

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Flexner-Wintersteiner rosettesPineal parenchymal tumor of intermediate differentiationPineoblastomaPineocytoma

## 34.1 Overview

  * Pineal parenchy mal tumors range from the indolent pineocytoma (PC) to pineal parenchymal tumors of intermediate differentiation (PPTID) and finally to the highly malignant pineoblastoma (PB).

    * ◦ Pineocytoma (ICD-O 9361/1) is a rare, slow-growing pineal neoplasm (WHO grade I) composed of mature-appearing pineocytes and forming pineocytomatous rosettes.

    * ◦ Pineal pa renchymal tumor of intermediate differentiation (ICD-O 9362/3) is a rare, intermediate-grade malignant tumor (WHO grade II or III) with diffuse sheets of tumor cells with low or moderate level of mitotic activity.

    * ◦ Pineo blastoma (ICD-O 9362/3) is a highly malignant embryonal tumor (WHO grade IV) typically s een in children; it has primitive, blastlike cells and frequent recurrence or dissemination.

  * A recently described rare neoplasm, papillary tumor of the pineal, is typically a tumor of adults and will not be discussed in this chapter [1].

## 34.2 Clinical Features

  * All primary pineal parenchymal neoplasms, as well as other pineal region masses, may be associated with Parinaud syndrome in the young (dorsal midbrain syndrome), which includes upward gaze paralysis, accommodative paresis, nystagmus, and eyelid retraction.

  * Pineal region masses can also cause significant cerebrospinal fluid (CSF) obstruction leading to headaches, nausea and vomiting, and other signs related to increased intracranial pressure. These symptoms are not specific to pineal parenchymal neoplasms.

  * Pineocyto ma (PC) is less common in the pediatric age group; the rare PC typically presents with signs of increased intracranial pressure and occasionally visual disturbances. The few studies on PC in children report a more frequent local recurrence than in adults, but this finding requires validation with the current WHO grading scheme.

  * Pineal paren chymal tumor of intermediate differentiation (PPTID) is even less frequent in children and its clinical presentation is less well defined; it is considered similar to PC. These tumors have a greater tendency for loc al recurrence, but an objective comparison of recurrence risk between PPTID and PC is not possible on the basis of the available data [2].

  * Pineoblastoma (PB) is the most common pediatric pineal parenchymal tumor, and the majority of tumors occur within the first two decades of life. The interval between initial symptoms and the need for surgical intervention is much shorter than for other pineal parenchymal tumors. Signs and symptoms of intracranial pressure are often present and may worsen rapidly with cerebrospinal dissemination.

## 34.3 Neuroimaging

  * Neuroimaging does not provide specific information that can reliably distinguish pineal parenchymal tumo rs from other neoplasms such as germinomas [3].

  * PC is often a well-defined mass that is typically less than 3–4 cm. These tumors are hypointense or isointense on T1-weighted images, and hyperintense on T2-weighted images. The tumors avidly en hance upon gadoli nium administration. Some PCs demonstrate calcifications on CT or MRI (Fig. 34.1).

Fig. 34.1

Coronal no ncontrast T1-weighted image of a pineal mass in a 17-year-old boy, showing a small cystic pineal gland. The lesion was histologically confirmed as a pineocytoma (PC)

  * PPTID is often indistinguishable from PC and may also demonstrate calcifications or hemorrhage on imaging s tudies. PPTID may be more solid and diffusely enhancing than PC.

  * PB is often a large tumor, rarely seen in association with unilateral or bilateral retinoblastoma. The tumors are often larger, with brighter T2-weighted signals, and are hypointense on T1-weighted images. There is marked gadolinium enhancement, and the tumors are much more variable in their appearance, with calcific ations, necrosis, or hemorrhage. The boundaries of PB may not always be well defined (Fig. 34.2).

Fig. 34.2

Sagittal, contrast-enhanced T1-weighted MR image of a pineoblastoma (PB) in a 4-year-old child, wit h mass effect and hydrocephalus

## 34.4 Histopathology

  * PCs are macroscopically gray, granular, and discrete masses that often fill the pineal recess and the subjacent aqueduct.

    * ◦ The tumors are composed of cells with large nuclei, open chromatin density, and ample surrounding cytoplasm (Fig. 34.3).

Fig. 34.3

Typical histological appearance of pineocytoma (PC). The tumor is sparsely cellular and is compose d of monomorphous, small, mature neuronal cells and neuropil-like background

  * The tumor cells are typically monomorphous with only occasional cells with nuclear pleomorphism or hyperchromasia.

    * ◦ Necrosis or mitotic figures are exceptionally rare. In some foci, cytological atypia can be interpreted as "degenerative change."

    * ◦ PCs often harbor pineocytomatous rosettes formed by conglomeration of tumor cell processes in a circular or stellate form and are slightly more eosinophilic than the neuropil.

    * ◦ The structure of a pineocytomatous rosette is similar to a pineoblastic or Homer-Wright rosette, but it is conspicuously less cellular and larger; the majority of cells have ample cytoplasm.

    * ◦ PCs can show isolated or clustered large ganglion-like cells and focal islands of neuropil, but these findings are rar e (Fig. 34.4).

Fig. 34.4

Histolog ical features of pineocytoma. Less common features include a rich, neuropil-like matrix and rare ganglion-like cells

  * PPTID shows focally diffuse or lobular architecture. Some PPTIDs resemble pineocytoma with more hypercellularity and occasional mitoses and abundant neuropil, but others look like small blue r ound cells wit h no mitoses and intervening neuropil (Fig. 34.5).

Fig. 34.5

Pineal parenchymal tumor of intermediate differentiation (PPTID) composed of a mixture of small and ma ture cells presenting a mixed appearance between pineocytoma and pineoblastoma

    * ◦ The tumors have high or moderate cellularity with focally overlapping nuclei, cells with scant cytoplasm, and scattered mitotic figures.

    * ◦ PPTID may harbor focal PC-like areas admixed with sheets of tumor cells or lobules with increased cellularity (Fig. 34.5).

    * ◦ Rarely, these tumors contain giant cells or moderate nuclear atypia (Fig. 34.6), and occasionally Homer Wright–type rosettes or large ganglion-like cells.

Fig. 34.6

Cytol ogic atypia in PPTID showing rare multin ucleated cells and large, bizarre yet degenerative-appearing nuclei

    * ◦ Grading of PPTID is controversial, and a clear distinction between grade II and grade III neoplasms has not emerged. The use of proliferation rate and a grading scheme to segregate WHO grade II from grade III tumors showed no survival difference [4].

    * ◦ A grading scheme based on mitotic rate and neurofilament staining was proposed earlier [5]:

      * WHO grade II PPTID has fewer than six mitoses per ten high power fields and strong immunostaining with neurofilament antibody.

      * WHO grade III PPTID has more than six mitoses per ten high power fields and little or no staining with neurofilament antibody.

  * PB is macroscopically soft, gelatinous, and focally hemorrhagic and necrotic. These irregular neoplas ms can be quite large.

    * ◦ PB has been described as similar to medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET). The most recent WHO classification has abandoned the term PNET, and refer to such tumors as Embryonal Tumor, NOS as of 2016. The tumors are composed of small, blue round cells with scant cytoplasm and hyperchromatic nuclei (Fig. 34.7).

Fig. 34.7

Pine oblastoma composed of highly cellular, small blue round cells with numerous mitotic figures

    * ◦ The cells are often arranged in sheets or discohesive clusters. The tumor cells typically form Flexner-Wintersteiner rosettes in which the cells are radially arranged around a small luminal s tructure (Fig. 34.8).

Fig. 34.8

Retinobla stic (Flexner-Wintersteiner) rosette in pineoblastoma (arrow)

    * ◦ In addition, neuroblastic-type Homer-Wright rosettes identical to those seen in medulloblastomas can be observed (Fig. 34.9).

Fig. 34.9

Neurob lastic (Homer-Wright) rosettes in pineoblastoma

    * ◦ PB has conspicuous mitotic figures, which can be numerous in some areas. Occasional giant cells, hemorrhage, and calcification are also commonly present.

    * ◦ Rare tumor cel ls may harbor melanin pigment, but the pigment more often is hemosiderin.

## 34.5 Immunohistochemistry

  * As a general rule, with the increasing grade of the tumor, neurofilament immunostaining decreases and Ki-67 proliferation rate increases [6]. A WHO grade III PPTID has only focal neurofilament staining (Fig. 34.10).

Fig. 34.10

Immunohistochemical staining for neurofilament protein in PPTID, with only patchy stainin g. With a high rate of mitotic figures, this tumor was graded as WHO grade III, but this patient did not have a recurrence following near-total gross resection

  * PC typically demonstrates strong positivity for S-100 protein, neuron-specific enolase (NSE), synaptophysin, and chromogranin, with variable immunoreactivity to neurofilament proteins [7].

    * ◦ The tumors are also focally positive for glial fibrillary acidic protein (GFAP), retinal-S antigen, and rhodopsin.

  * PPT ID is similar to PC, with strong positivity for synaptophysin, NSE, and S-100 protein. Antibodies for neurofilament proteins stain the tumors focally, and in some cases isol ated cells within the tumor show intense staining.

    * ◦ The staining for GFAP and retinal-S antigen is variable; some tumors may be negative for these two markers.

  * PB exhibits a le ss pronounced retinoblastomatous differentiation but is often equally positive for synaptophysin as the other pineal parenchymal tumors.

    * ◦ Chromogranin is positive in only a small percentage of tumors and in a limited number of tumor cells (Fig. 34.11).

Fig. 34.11

Immunohist ochemical staining for chromogranin in pineoblastoma. Note the patchy staining of the cytoplasm

  * S-100 protein and retinal-S antigen are typically negative, with rare weak positivity only in an occasional tumor.

## 34.6 Molecular Pathology

  * The RB1 gene encodes a protein that acts as a cell cycle checkpoint at the G1 phase. Some patie nts suffering from retinoblastoma and PB harbor germline losses of the RB1 gene.

  * Trilateral retinoblastoma, a heritable form of bilateral retinoblastoma in association with PB, has a rather dismal prognosis. The disease is associated with germline deletion of the RB1 gene from chromosome 13.

  * A subgroup of PB demonstrates DICER1 mutations, including some patients with germline mutations of this gene [8].

## 34.7 Prognosis

  * The following characteristics were found to influence outcome in pineal neoplasms [9]:

    * ◦ Tumor histological grade

    * ◦ Tumor volume

  * Tumors with a pineoblastomatous component have a much worse overall survival than the other histological types.

  * Gross total resection seems to portend a better prognosis, even for patients with PB [10].

  * Aggressi ve chemotherapy and radiotherapy has been suggested to increase survival for patients with PB [11].

References

1.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds). WHO classification of tumours of the central nervous system (Revised 4th Edition) International Agency for Research on Cancer (IARC); Lyon 2016.

2.

Ito T, Kanno H, Sato K, Oikawa M, Ozaki Y, Nakamura H, et al. Clinicopathologic study of pineal parenchymal tumors of intermediate differentiation. World Neurosurg. 2014;81:783–9.CrossRefPubMed

3.

Kakigi T, Okada T, Kanagaki M, Yamamoto A, Fushimi Y, Sakamoto R, et al. Quantitative imaging values of CT, MR, and FDG-PET to differentiate pineal parenchymal tumors and germinomas: are they useful? Neuroradiology. 2014;56:297–303.CrossRefPubMed

4.

Fevre-Montange M, Vasiljevic A, Frappaz D, Champier J, Szathmari A, Aubriot Lorton MH, et al. Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study. Neuropathol Appl Neurobiol. 2012;38:87–94.CrossRefPubMed

5.

Jouvet A, Saint-Pierre G, Fauchon F, Privat K, Bouffet E, Ruchoux MM, et al. Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases. Brain Pathol. 2000;10:49–60.CrossRefPubMed

6.

Arivazhagan A, Anandh B, Santosh V, Chandramouli BA. Pineal parenchymal tumors—utility of immunohistochemical markers in prognostication. Clin Neuropathol. 2008;27:325–33.CrossRefPubMed

7.

Coca S, Vaquero J, Escandon J, Moreno M, Peralba J, Rodriguez J. Immunohistochemical characterization of pineocytomas. Clin Neuropathol. 1992;11:298–303.PubMed

8.

de Kock L, Sabbaghian N, Druker H, Weber E, Hamel N, Miller S, et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol. 2014;128:583–95.CrossRefPubMedPubMedCentral

9.

Fauchon F, Jouvet A, Paquis P, Saint-Pierre G, Mottolese C, Ben Hassel M, et al. Parenchymal pineal tumors: a clinicopathological study of 76 cases. Int J Radiat Oncol Biol Phys. 2000;46:959–68.CrossRef00389-2)PubMed

10.

Mandera M, Marcol W, Kotulska K, Olakowska E, Golka D, Malinowska I, et al. Childhood pineal parenchymal tumors: clinical and therapeutic aspects. Neurosurg Rev. 2010;34:191–6.CrossRefPubMed

11.

Farnia B, Allen PK, Brown PD, Khatua S, Levine NB, Li J, et al. Clinical outcomes and patterns of failure in pineoblastoma: a 30-year, single-institution retrospective review. World Neurosurg. 2014;82:1232–41.CrossRefPubMed

# Part X
Germ Cell Tumors
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_35

# 35. Germ Cell Tumors

Tarik Tihan1

(1)

Department of Pathology, Neuropathology Division, 505 Parnassus Avenue, Room M551, San Francisco, CA 94143-0102, USA

Tarik Tihan

Email: tarik.tihan@ucsf.edu

Keywords

Alpha fetoproteinAFPBeta human chorionic gonadotropinbHCGChoriocarcinomaDysgerminomaEmbryonal carcinomaEndodermal sinus tumorGerminomaGerm cell tumorPlacental alkaline phosphatasePLAPSeminomaTeratomaYolk-sac tumor

## 35.1 Overview

  * Germ cell tumors of the central nervous system (CNS) are typically midline lesions commonly affecting the pineal and suprasellar regions; they can often spread along the ventricular surfaces.

  * They are most common among children and young adults, but may exceptionally be seen in later years.

  * Germ cell tumors include germinoma, teratoma, embryonal carcinoma, endodermal sinus (yolk-sac) tumor, and choriocarcinoma. In addition, mixtures of these components can be found in the "mixed germ cell tumor" category. The histological and immunohistochemical features of CNS germ cell tumors are essentially the same as those of extracranial germ cell tumors.

  * Thediagnosis o f germ cell tumors may be challenging because of their inaccessibility and the limited size of biopsies, as well as tissue artifacts due to their friable nature.

  * Immunohistochemistry is often useful in the correct identification of the tumor type, and PLAP, SALL4, LIN28A, OCT 3/4, c-Kit are all potentially useful markers for diagnosis, as discussed below.

  * Germinoma (9064/3), the most common histological type, is a highly radiosensitive tumor composed of large malignant cells with centralized macronucleoli and mature small lymphocytes.

  * Teratomas (9080/0–3) make up another significant percentage of pediatric intracranial germ cell tumors. These tumors harbor tissue components from ectodermal, endodermal, and mesodermal elements with predominantly mature and occasionally immature cells. "Mature" teratomas are composed exclusively of adult-type terminally differentiated cells with little or no mitotic activity. "Immature" teratomas (9080/3) contain cells that resemble fetal tissues with poor or little differentiation and with mitotic activity. Teratoma with malignant transformation (9084/3) often has a dismal prognosis.

  * Embryonal carcinoma (9070/3) is comp osed of large, conspicuously anaplastic cells, resembling a carcinoma forming papillary structures and glands.

  * Endodermal sinus (yolk-sac) tumor (9071/3) is a hypercellular, highly malignant neoplasm composed of epithelial cells often invested in a myxoid matrix resembling the yolk sac endoderm and forming ana stomosing channels, sinusoidal patterns, and distinctive papillations (Schiller-Duval bodies).

  * Choriocarcinoma (9100/3) is a highly malignant tumor composed of cytotrophoblasts, syncytiotrophoblasts, and large, anaplastic cells.

  * Mixed germ cell tumor (9085/3) refers to any combination of two or more types of germ cell elements found in the sa me tumor. Most intracranial mixed germ cell tumors contain germinoma and teratoma. All other combinations are rare.

## 35.2 Clinical Features

  * Germ cell tumors a re more common in children and young adults, with the overwhelming majority occurring within the first two decades [1]. A unique exception to this is congenital teratomas, which are often discovered during the neonatal period or in utero.

  * Two thirds of all germ cell tumors in children are germinomas.

  * Even though earlier studies suggested that some countries (such as Japan) have a higher incidence of germinoma, recent studies show similar incidence rates in Japan and the United States [2].

  * Males are slightly more commonly affected than females. Pineal tumors tend to occur more commonly in males [2], whereas sellar or suprasellar tumors are slightly more common in females.

  * The pineal region tumors often present with signs and symptoms of hydrocephalus as well as upward gaze palsy due to compression of the midbrain, known as Parinaud syndrome.

  * One of the most common presentations of germ cell tumors in the suprasellar or infundibular region is diabetes insipidus.

  * Suprasellar tumors can present with visual disturbance, pituitary failure, or abnormal sexual maturation. Basal ganglia involvement is associated with hemiparesis.

  * Some germ cell tumors are associated with precocious puberty.

  * Serum (or CSF) levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (bHCG), and carcinoembryonic antigen (CEA) levels can be elevated and should be analyzed in a patient with a suspected germ cell tumor. Serum bHCG levels can be normal in up to 50 % of patients [3].

  * Some tumors, especially multifocal examples, are difficult to access surgically.

  * Most germinomas can be easily managed with radiotherapy, but long-term cognitive deficits following treatment have prompted studies to test the efficacy of chemotherapy to reduce the radiation dose [4].

  * Choriocarcinomas are exceedingly rare and have a poor prognosis. An occasional choriocarcinoma is likely to be metastatic rather than primary.

  * Mixed germ cell tumors, especially those containing embryonal carcinoma or endodermal sinus tumor, are more aggressive and less responsive to treatment.

## 35.3 Neuroimaging

  * Most germinomas involving the pineal are well-delineated and are isointense to hypointense to g ray matter on T1-weighted images, isointense or hyperintense on T2-weighted images, and often demonstrate strong and uniform contrast enhancement (Fig. 35.1). Germinomas have restricted diffusion due to high cellularity [5].

Fig. 35.1

Sagittal, contrast-enhanced, T1-weighted image showing marked, homogeneous contrast enhancement of a pineal germinoma in a 12-year-old boy

  * Suprasellar or infundibular examples are less well defined and appear infiltrative.

  * Mixed germ cell tumors and teratomas with mixed elements and have both hyperintense and hypointense regions on T2-weighted images and may show heterogeneous enhancement.

  * Subependymal linear enhancements often represent local tumor spread.

  * Occasionally, there may be synchronous pineal and suprasellar masses with periventricular or infundibular involvement.

  * Teratomas may be hyperintense on T1-weighted images because of adipose content. Enhancement is typical for solid components, but may be limited (Fig. 35.2).

Fig. 35.2

Axial fluid-attenuated inversion recovery (FLAIR) image of a teratoma with predominantly mature elements. Note t he variable intensity of different tissue types. This tumor contained cartilaginous, mesenchymal dermal elements and small amounts of adipose tissue

  * MRI evaluation of the entire neuraxis is needed before surgery for germ cell tumors.

## 35.4 Histopathology

  * Germinoma

    * ◦ Germinoma is the most common germ cell tumor type.

    * ◦ Most biopsy spe cimens from germinomas are small and suffer from crush artifact. Thus, a thorough evaluation of the smear and frozen section slide is often necessary, and smears are always helpful.

    * ◦ Two populations of cells are typical: mitotically active large cells with vacuolated cytoplasm, round vesicular nuclei, and central macronucleoli, and mature lymphocytes (Fig. 35.3).

Fig. 35.3

The typical histological appe arance of two populations of cells in a germinoma: large, anaplastic cells with irregular, hyperchromatic nuclei and prominent nucleoli; and mature, reactive lymphocytes

    * ◦ The large neoplastic cells often appear discohesive, reminiscent of a malignant lymphoma.

    * ◦ Recognition of the combination of large cells and lymphocytes is very helpful in smears and intraoperative consultations (Fig. 35.4).

Fig. 35.4

Intraoperative smear of a germinoma is often confounded by crush artifact leading to purple streaks of nuclear mater ial, but the biphasic nature of the cellular composition, with large malignant cells and mature lymphocytes, is conspicuous and pathognomonic

    * ◦ Occasional examples can also show granuloma formation and dense lymphocytic infiltrates with germinal centers (Fig. 35.5).

Fig. 35.5

Some germino mas demonstrate brisk granuloma formation and abundant inflammatory cells (predominantly lymphocytes and plasma cells), which may be confusing. Finding the typical large malignant cells with macronucleoli is a clue to the diagnosis

    * ◦ Syncytiotrophoblastic giant cells can be seen, but are uncommon.

    * ◦ Germinomas show focal positive cytoplasmic periodic acid–Schiff (PAS) staining, which is digested by diastase treatment.

    * ◦ Rarely, a germinoma may involve the brain parenchyma and give the false impression of an infiltrating malignant glioma.

  * Teratoma

    * ◦ Both mature and immature teratomas in the CNS are aggressive neoplasms. They are the second most common germ cell tumors after germinoma.

    * ◦ Typical mature teratoma consists of histologically mature tissue that differentiates along all three germ layers. The most common elements are ectodermal, such as epidermal and dermal tissues (Fig. 35.6).

Fig. 35.6

Typical histological components of mature teratomas. (A) Epidermal and dermal elements are commonly encountered, along with adnexal tissue. (B) Cartilaginous tissue, glandular eleme nts, and mesenchymal proliferations are also typically seen in most teratomas. (C) Mature brain tissue can also be seen in a small percentage of teratomas. Some of the mesenchymal elements raise the possibility of "immature" elements and may require further analysis with immunohistochemical stains to determine their differentiation and proliferation levels

    * ◦ Immature teratomas contain variable amounts of tissue resembling fetal tissue without a particular maturation to a recognizable adult tissue. Even a minor component is considered sufficient to classify a neoplasm in this category (Fig. 35.7A). Some of these elements can be primitive neuroepithelial tissue (Fig. 35.7B).

Fig. 35.7

Immature teratomas often demonstrate populations of cells that are not readily recognized as matur e adult tissue. (A) In most cases, highly cellular mesenchymal proliferations with mitotic figures that are not readily recognized as adult tissue can be seen. (B) In addition, the presence of germinal matrix-like cells and primitive neuroepithelial cells with rosettes identify an immature teratoma

    * ◦ The most typical immature tissue type is the stroma reminiscent of fetal mesenchymal tissue, but immature epithelium, bone, or cartilage is also common (Fig. 35.8).

Fig. 35.8

Immature bone, cartilage, or mesenchymal tissue with mitotic figures constitutes the majority of "immature " tissue seen in teratomas. These immature tissues often harbor rare mitotic figures and demonstrate an intermediate level of Ki-67 proliferation index, which should be near zero in the mature components

    * ◦ In addition to mature and immature tissues, some teratomas contain foci that are reminiscent of malignant neoplasms such as a carcinoma or a sarcoma. These neoplasms are believed to act more aggressively, and are considered "teratomas with malignant transformation" (Fig. 35.9). A detailed study of this phenomenon in the CNS is lacking.

Fig. 35.9

Highly anaplastic tumor with markedly hyperchromatic nuclei, along with glandular formations with fran kly anaplastic cells, abundant mitoses, and necrosis are clues to the "malignant degeneration" of a teratoma. The appearance of these foci is often similar to adenocarcinoma or sarcoma, with markedly high proliferation indices and anaplasia

    * ◦ Sampling is critical for teratomas, because some elements may be focal.

  * Endodermal sinus (yolk-sac) tumor

    * ◦ These tumors are more likely to be seen in the pineal region.

    * ◦ Primary intracranial yolk-sac tumor is extremely rare, and it constitutes a rare component o f a mixed, non-germinomatous germ cell tumor.

    * ◦ The histological appearance is identical to yolk sac tumors of the gonads (Fig. 35.10).

Fig. 35.10

Endodermal sinus (yolk-sac) tumors are composed of highly anaplastic, hyperchromati c cells forming papillary-alveolar structures, harboring mitoses. The formation of the alveolar structures by these glandular cells is referred to as "Schiller-Duval bodies"

    * ◦ The tumors are often highly aggressive and are associated with a poor prognosis.

    * ◦ Pure or predominantly yolk-sac tumors are exceedingly rare.

  * Embryonal carcinoma

    * ◦ This tumor histologically resembles a metastatic carcinoma; it is composed of anaplastic epithelial cells without a discernable glandular pattern (Fig. 35.11).

Fig. 35.11

Embryonal carcinomas are highly anaplastic tumors reminiscent of poorly differentiated carcinomas. (A) Malignant cells can have a conspicuous or vague glandular formation and may have cells with clear, vacuolated, or granular cytoplasm. (B) Many embryonal carcinomas harbor sheets of anaplastic cells with abundant mitoses and apoptotic cells without an obvious clue to their differentiation

    * ◦ Alveolar, tubular, papillary, and nested patterns can be observed.

    * ◦ Mitotic figures are abundant, and giant cells can be seen.

    * ◦ Tumors can mimic early embryonal structures.

  * Choriocarcinoma

    * ◦ Choriocarcinoma is defined by the presence of multinucleated syncytiotrophoblasts and cytotro phoblasts (Fig. 35.12).

Fig. 35.12

Chorio carcinomas are highly pleomorphic tumors with multinucleated syncytiotrophoblasts and cytotrophoblasts in a conspicuously hemorrhagic background. Choriocarcinomas in older children or young adults are more likely to be metastatic (from an extracranial germ cell tumor) than primary

    * ◦ Choriocarcinomas are typically more hemorrhagic foci.

    * ◦ Choriocarcinoma portends a worse prognosis than other germ cell tumors.

  * Mixed germ cell tumors

    * ◦ The presence of germinoma along with teratoma, or teratoma with either embryonal carcinoma or endodermal sinus tumor, can be seen in a small percentage of germ cell tumors. Some teratomas can harbor microscopic foci of germinoma (Fig. 35.13).

Fig. 35.13

The mos t common mixed germ cell tumor in the CNS in a teratoma with a germinoma component. In this tumor, the epithelial component above is undermined by a population of malignant cells that make up the germinoma component

## 35.5 Immunohistochemistry

  * Germinoma

    * ◦ The typical routine immunohistochemical profile of germinoma includes positivity with c-kit, D2- 40, and placental alkaline phosphatase (PLAP) (Fig. 35.14) [6–8].

Fig. 35.14

Immunohis tochemical stain for placental alkaline phosphatase (PLAP) in a germinoma, showing diffuse cytoplasmic positivity. PLAP can be positive in the majority of germ cell tumors, except for mature teratomas

    * ◦ Germinomas are also strongly and diffusely positive with spalt-like transcription factor 4 (SALL4) [9] (Fig. 35.15) and LIN28A antibodies. NANOG, a homeodomain transcription factor, is also helpful in diagnosing germinoma, but is less commonly used [10].

Fig. 35.15

SALL-4 is a zi nc-finger nuclear transcription factor that plays a role in a number of pathways, including the Wnt signaling pathway, and is positive in virtually all germ cell tumors

    * ◦ OCT 3/4 and octamer binding transcription factor are also strongly positive in tumor nuclei (Fig. 35.16).

Fig. 35.16

OCT 3/4 (octam er binding transcription factor) is also a nuclear marker that is positive in germinomas and embryonal carcinomas. This marker is often negative in teratomas, yolk-sac tumors, and choriocarcinomas

    * ◦ Rare cells may show CD30, cytokeratin, or bHCG positivity.

    * ◦ The proliferation rate as seen in Ki-67 (MIB-1) is often very high.

  * Teratomas

    * ◦ Immunohistochemistry is not essential, but Ki-67 (MIB-1) staining may be helpful in confirming im mature elements within teratomas.

    * ◦ Teratomas are often positive for epithelial membrane antigen (EMA) and are rarely positive for CD30.

    * ◦ Focal c-kit positivity can be seen in teratomas.

  * Endodermal sinus (yolk-sac) tumors

    * ◦ Most yolk-sac tumors are positive for AFP and cytokeratin.

    * ◦ PLAP and anti-1 antitrypsin are occasionally positive in some tumors.

    * ◦ hCG is often negative in yolk-sac tumors.

  * Embryonal carcinoma

    * ◦ Embryonal carcinoma is often positive for CD30, OCT4, and cytokeratin.

    * ◦ The tumors are negative or weakly positive for CEA, hCG, CD117, and D2-40.

  * Choriocarcinoma

    * Choriocarc inomas are positive for hCG (syncytiotrophoblasts) and cytokeratin.

    * PLAP may be positive in half of choriocarcinomas.

## 35.6 Molecular Pathology

  * Typically, all types of CN S germ cell tumors demonstrate multiple genetic aberrations.

  * Gain of chromosome 12p appears to be the most common gain in CNS germ cell tumors, similar to testicular germ cell tumors in adults [11].

  * Other gains include chromosomes 1q, 8q, and 20q.

  * Chromosomal losses can be seen in 1p, 4q, 6q, 11, 13, and 18.

## 35.7 Prognosis

  * The most commonly cited prognostic factors include age, tumor location, histological type and grade, tumor stage, extent of resection, and the tumor markers AFP and bHCG.

  * Theprognosis has b een strongly related to pathological classification as either pure germinoma or mixed germ cell or nongerminomatous germ cell tumor.

  * The presence of serum or CSF tumor marker elevation has been helpful in determining response to treatment [12].

  * Age of onset also influences the modality and success of treatment.

  * Germinomas are highly radiosensitive. The 5-year survival probability is about 90 %.

  * Recent efforts are focused on reducing the radiation dose by adjuvant chemotherapy, to avoid long-term cognitive problems [13].

  * Surgery (beyond biopsy to make the diagnosis) provides no significant survival advantage.

References

1.

Goodwin TL, Sainani K, Fisher PG. Incidence patterns of central nervous system germ cell tumors: a SEER Study. J Pediatr Hematol Oncol. 2009;31:541–4.CrossRefPubMed

2.

McCarthy BJ, Shibui S, Kayama T, Miyaoka E, Narita Y, Murakami M, et al. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries. Neuro Oncol. 2012;14:1194–200.CrossRefPubMedPubMedCentral

3.

Allen J, Chacko J, Donahue B, Dhall G, Kretschmar C, Jakacki R, et al. Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer. 2012;59:1180–2.CrossRefPubMedPubMedCentral

4.

Osorio DS, Finlay JL, Dhall G, Goldman S, Eisenstat D, Brown RJ. Feasibility of dasatinib in children and adolescents with new or recurrent central nervous system germinoma. Pediatr Blood Cancer. 2013;60:E100–2.CrossRefPubMed

5.

Liang L, Korogi Y, Sugahara T, Ikushima I, Shigematsu Y, Okuda T, et al. MRI of intracranial germ-cell tumours. Neuroradiology. 2002;44:382–8.CrossRefPubMed

6.

Gao Y, Jiang J, Liu Q. Clinicopathological and immunohistochemical features of primary central nervous system germ cell tumors: a 24-years experience. Int J Clin Exp Pathol. 2014;7:6965–72.PubMedPubMedCentral

7.

Takeshima H, Kuratsu J. A review of soluble c-kit (s-kit) as a novel tumor marker and possible molecular target for the treatment of CNS germinoma. Surg Neurol. 2003;60:321–4. discussion 324–5.CrossRef00430-0)PubMed

8.

Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol. 2005;29:368–71.CrossRefPubMed

9.

Camparo P, Comperat EM. SALL4 is a useful marker in the diagnostic work-up of germ cell tumors in extra-testicular locations. Virchows Arch. 2013;462:337–41.CrossRefPubMed

10.

Santagata S, Hornick JL, Ligon KL. Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG. Am J Surg Pathol. 2006;30:1613–8.CrossRefPubMed

11.

Sukov WR, Cheville JC, Giannini C, Carlson AW, Shearer BM, Sinnwell JP, et al. Isochromosome 12p and polysomy 12 in primary central nervous system germ cell tumors: frequency and association with clinicopathologic features. Hum Pathol. 2010;41:232–8.CrossRefPubMed

12.

Kim D, da Lee H, Choi J, Shim KW, Kim SH. Validation of tumor markers in central nervous system germ cell tumors by real-time reverse transcriptase polymerase chain reaction using formalin-fixed paraffin-embedded tissues. Mol Med Rep. 2013;7:337–41.PubMed

13.

Khatua S, Dhall G, O'Neil S, Jubran R, Villablanca JG, Marachelian A, et al. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer. 2010;55:42–6.PubMed

# Part XI
Paraneoplastic Disorders
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_36

# 36. Paraneoplastic Disorders of the Central Nervous System

Christine E. Fuller1

(1)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

Christine E. Fuller

Email: christine.fuller@cchmc.org

Keywords

Paraneoplastic encephalomyelitisCerebellar degenerationOpsoclonus-myoclonus-ataxiaLimbic encephalitis

## 36.1 Overview

  * Paraneoplastic dis orders of the central nervous system (CNS) are inflammatory disorders affecting various parts of the brain and spinal cord in the setting of a peripheral cancer.

  * Ganglia , the peripheral nervous system, the retina, and the neuromuscular junction may also be involved.

  * These syndromes appear to represent a group of autoimmune disorders in which antibodies mounted against peripheral cancers target antigens normally expressed within cells (particularly neurons) of the nervous system (i.e., onconeural antibodies).

  * The paraneoplastic disorders of CNS fall into a few main categories:

    * ◦ Paraneoplasti c encephalomyelitis (PEM), with subcategories based on localization:

      * Limbic encephalitis

      * Brainstem encephalitis

      * Cerebellar encephalitis

      * Myelitis

    * ◦ Paraneoplastic ce rebellar degeneration (PCD)

    * ◦ Opsoclonus-my oclonus-ataxia syndrom e (OMA)

  * These syndromes may also occur in the presence of infiltration of the nervous system by tumor cells or as adverse effects of cancer therapy. In addition, onconeural antibodies (often with accompanying CNS clinical manifestations) may arise in the absence of demonstrable neoplasm.

## 36.2 Clinical Features

  * All of these disorders may present in children, though they are more frequently encountered in adults in association with lung, breast, or gynecologic malignancie s.

  * In the pediatric age group, PEM most often accompanies neuroblastoma or rhabdomyosarcoma.

  * PCD may be seen with Hodgkin's lymphoma.

  * OMA may occur with neuroblastoma.

  * Often these syndromes will precede a diagnosis of cancer by weeks to months.

  * Symptoms and signs reflect different patterns of CNS involvement:

    * ◦ Limbic encephalitis: short-term memory loss, seizures, confusion, psychosis

    * ◦ Myelitis: pain, numbness, loss of proprioception

    * ◦ OMA: eye movement disturbance, myoclonus ("dancing eyes and dancing feet"), ataxia, and sometimes developmental retardation. Unlike the other paraneoplastic disorders, OMA may have a relapsing-remitting course.

    * ◦ Cerebellar degeneration (PCD): ataxia, truncal and hemispheric cerebellar dysfunction

## 36.3 Neuroimaging

  * MR imaging in limbic encephalitis typically demonstrates hyperintense areas within limbic structures on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. Contrast enhancement is not a feature.

  * MR images may be normal in PCD, though edema or atrophy may be seen in some cases.

  * MR imaging is also frequently normal in OMA, though pontine tegmental abnormalities and cerebellar atrophy have been reported.

  * Fluorodeoxyglucose-PET (FDG-PET) may be useful in confirming the presence of an occult neoplasm when conventional CT and MR imaging fail to detect a lesion. FDG-PET sometimes may reveal areas of increased uptake within the CNS itself, correlating with the inflammatory process.

## 36.4 Pathology

  * Gross pathology

    * ◦ With the exception of mild cerebellar cortical atrophy detectable in some cases of PCD, gross examination is typically unremarkable.

  * Cytology findings

    * ◦ Cerebrospinal fluid (CSF) samples often show a cellular pleocytosis; additional findings may include elevated protein level and/or oligoclonal bands.

  * Histology

    * ◦ All these disorders share several unifying findings:

      * Neuronal loss

      * Astrocytosis (gliosis)

      * Microglial proliferation, often with microglial nodule formation or active neuronophagia

      * Perivascular chronic inflammatory infiltrate of lymphocytes (mainly T cells) and occasional plasma cells (Fig. 36.1A–E)

Fig. 36.1

Histologic findings in paraneoplastic CNS disorders. (A) Low-power view of a case of limbic encephalitis, showing perivascular inflammatory infiltrate and increased cellularity within the gray matter, with some cell clustering. (B) This area shows extensive reactive astrocytosis with accompanying neuronal loss in the hippocampal neurons. (C) Examination at higher magnification confirms the presence of numerou s reactive astrocytes with brightly eosinophilic cytoplasmic "bellies" and elongated processes (arrows), together with a microglial proliferation. (Note hyperchromatic, rod-shaped nuclei towards the center of the field.) (D) Active neuronophagia is apparent (arrow). (E) Microglial nodules may also be seen. (F) This example of paraneoplastic ganglionitis shows the typical lymphocytic inflammatory infiltrate, in some areas surrounding individual ganglion cells. (Courtesy of Dr. Robert Schmidt, Washington University, St Louis, MO)

    * ◦ Gray matter is predominantly involved, though there may be secondary white matter loss; leptomeningitis is frequently present.

    * ◦ In limbic encephalitis, neuronal loss or inflammation is localized in the medial temporal and inferior frontal lobes, insular cortex, and cingulate gyrus.

    * ◦ Brainstem encephalitis mainly involves the medulla.

    * ◦ Cerebellar encephalitis of PEM involves neuronal loss in deep structures and nuclei of the cerebellum, with sparing of cortex.

    * ◦ PCD involves severe loss of Purkinje cells with accompanying Bergman gliosis; cortex is involved.

    * ◦ In myelitis, neuronal loss or inflammation may diffusely involve most of the spinal cord or may be more localized to a few segments.

    * ◦ OMA is not characterized by any specific pathologic feature. Approximately half of patients show loss of Purkinje cells, and often there is neuronal loss and inflammation within the brainstem, though localization is variable.

    * ◦ Ganglioneuronopathy with dorsal root ganglion cell loss or inflammation and dorsal column degeneration may accompany PEM (Fig. 36.1F).

## 36.5 Immunohistochemistry

  * CD68 will highlight mic roglia (Fig. 36.2A), whereas T-cell and B-cell markers (CD3 and CD20 respectively) decorate the perivascular lymphoid infiltrates.

Fig. 36.2

(A) CD68 stain highlights the numerous microglia of these paraneoplastic processes. (B) Glial fibrillary acidic protein (GFAP) decorates the cytoplasm of reactive astrocytes

  * Glial fibrillary acidic protein (GFAP) highlights numerous reactive astrocytes (Fig. 36.2B).

  * Immunohistochemical assessment for various viral agents, as well as routine stains for spirochetes (Warthin-Starry stain) or fungal organisms (Gomori methenamine silver [GMS] stain) may be helpful in ruling out various infectious encephalitides.

## 36.6 Electron Microscopy

  * Electron microsc opy serves no significant role in the direct diagnosis of paraneoplastic CNS disorders.

  * It may, however, be useful in identifying some microorganisms that cause infectious encephalitis that may otherwise closely mimic the histologic features of paraneoplastic disorders, such as microgliosis and perivascular chronic inflammation.

## 36.7 Differential Diagnosis

  * The histologic features of these paraneoplastic CNS disorders may closely mimic infectious (particularly viral or rickettsial) encephalomyelitis. Careful histologic inspection for viral cytopathic effect, use of immunohistochemical stains, tissue culture, and genetic or polymerase chain reaction (PCR) analysis to detect viral or rickettsial genetic material are helpful adjuncts to diagnosis in ruling out infectious etiologies.

  * The detection of specific antineuronal antibodies in the serum and/or CSF may serve as a diagnostic tool that directs the search for the tumor to a specific organ system.

    * ◦ Anti-Tr can be detected in the CSF of some children with PCD arising in the setting of Hodgkin's lymphoma.

    * ◦ Autoantibodies of the IgG3 subclass have been found in pediatric patients with OMA in the setting of neuroblastoma. Anti-Ri has been identified in some.

    * ◦ Elevated serum concentrations of chemokines CCL22, CCL17, and CCL21 have been detected in cases of pediatric OMA; CCL21 and CCL22 may serve as potential candidate biomarkers for adrenocorticotropic hormone (ACTH) or a corticosteroid effect in this setting.

  * Anti-Hu, Ma, and glutamic acid decarboxylase (GAD), and voltage-gated potassium channel (VGKC) antibodies have been found in cases of pediatric limbic encephalitis, tho ugh often these cases prove not to be paraneoplastic.

## 36.8 Prognosis

  * In most instances, the most effective treatment for the paraneoplastic CNS disorders is the removal o r treatment of the primary peripheral neoplasm, together with immunomodulatory therapies.

  * Despite tumor resection and immunosuppressive therapy, some patients with pediatric OMA have poor outcomes that may include developmental and behavioral problems.

Suggested Reading

Bernal F, Shams'ili S, Rojas I, Sanchez-Valle R, Saiz A, Dalmay J, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology. 2003;60:230–4.CrossRefPubMed

Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Griswold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135–40.CrossRefPubMedPubMedCentral

Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123:1481–94.CrossRefPubMed

Haberlandt E, Bast T, Ebner A, Holthausen H, Kluger G, Kravljanac R, et al. Limbic encephalitis in children and adolescents. Arch Dis Child. 2011;96:186–91.CrossRefPubMed

Honnorat J, Didelot A, Karantoni E, Ville D, Ducray F, Lambert L, et al. Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. Neurology. 2013;80:2226–32.CrossRefPubMed

Linke R, Voltz R. FDG-PET in paraneoplastic syndromes. Recent Results Cancer Res. 2008;170:203–11.CrossRefPubMed

Mitchell WG, Davalos-Gonzalez Y, Brumm VL, Aller SK, Burger E, Turkel SB, et al. Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics. 2002;109:86–98.CrossRefPubMed

Polizzi A, Ruggieri M, Clover L, La Spina M, Pulvirenti A, Amyes E, et al. A pilot study on neurological manifestations and antibodies against antigens in children with hematological and other cancers. Eur J Paediatr Neurol. 2013;17:97–101.CrossRefPubMed

Pranzatelli MR, Tate ED, McGee NR, Colliver JA, Ransohoff RM. CCR4 agonists CCL22 and CCL17 are elevated in pediatric OMS sera: rapid and selective down-regulation of CCL22 by ACTH or corticosteroids. J Clin Immunol. 2013a;33:817–25.CrossRefPubMed

Pranzatelli MR, Tate ED, McGee NR, Ransohoff RM. CCR7 signaling in pediatric opsoclonus-myoclonus: upregulated serum CCL21 expression is steroid-responsive. Cytokine. 2013b;64:331–6.CrossRefPubMed

Rutherford GC, Dineen RA, O'Connor A. Imaging in the investigation of paraneoplastic syndromes. Clin Radiol. 2007;62:1021–35.CrossRefPubMed

# Part XII
Tumours of the Hematopoietic System
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_37

# 37. Malignant Lymphoma

Adekunle M. Adesina1

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Malignant lymphomaT-cell lymphomaB-cell lymphomaNon-Hodgkin's lymphomaEBVMantle cell lymphomaBcl-2Bcl-6Primary central nervous system lymphomaPrimary CNS lymphoma

## 37.1 Overview

  * Primary centra l nervous system (CNS) extranodal lymphomas should be distinguished from clinical scenarios in which the CNS is involved secondarily by a primary nodal or extranodal systemic lymphoma.

  * Primary central nervous system lymphoma (PCNSL) represents 5 % of all primary brain tumors in adults.

  * PCNSL occurs primarily in older individuals or in immunocompromised states.

  * A significan t rise in incidence was noted in the 1980s and 1990s, partly due to AIDS.

  * An increased incidence was also noted in the immunocompetent (particularly young adults), but current data suggest that the incidence has stabilized.

  * The more common form of involvement of the CNS by hematologic malignancies is secondary leptomeningeal involvement; this involvement is the rationale for CNS prophylaxis in childhood leukemias.

  * PCNSL is fre quently seen in the context of immunosuppression:

    * Acquired immunodeficiency syndrome (AIDS)

    * Posttransplant immunosuppression

    * Inherited immunodeficiency states such as Wiskott-Aldrich syndrome

    * Immunosuppression associated with treatment for immune-mediated disorders such as rheumatoid arthritis or Sjögren syndrome, or treatment for malignancies such as Hodgkin's lymphoma or acute lymphoblastic leukemia

  * The demonstration of the presence of Epstein -Barr virus (EBV) genome (including Epstein-Barr nuclear antigen [EBNA] 1–6 and the Epstein-Barr virus–e ncoded small RNAs EBER1 and EBER2) in more than 95 % of tumors developing in immunocompromised patients implicates the loss of immune surveillance and EBV-induced cell proliferation in the pathogenesis of these tumors.

  * PCNSL is uncommon in children and the young who are immunocompetent; children age 18 years or younger represent only 1 % of all PCNSL patients.

  * In contrast to the adult population, when PCNSL occurs in children, it is more often seen in the immunocompetent.

  * In the first two decades of life, PCNSL is also frequently associated with inherited immunodeficiency syndromes and posttransplant immunosuppression.

  * B-cell lymphoma is most common, accounting for about 80 % of cases; T-cell lymphoma accounts for approximately 20 % of cases in children, with anaplastic large-cell lymphoma representing a common histologic subtype.

## 37.2 Clinical Features

  * The typical PCNSL seen in an immunocompetent adult presents as a supratentorial, deep-s eated, generally solitary mass. The most common locations are the frontal lobe, basal ganglia, corpus callosum, periventricular region, and deep white matter.

  * In children, the most frequent tumor locations are the parietal lobe, frontal lobe, cerebellum, pituitary stalk, and hypothalamus.

  * These tumors often present as symptomatic mass lesions that may be associated with focal neurologic deficits, signs of raised intracranial pressure, seizures, or a combination of these features.

  * About 50 % of cases of posttransplant CNS lymphoma develop within the first year after transplantation.

## 37.3 Neuroimaging

  * MRI shows tumors as isointense to hypointense relative to gray matter on T2-weighted, fluid-attenuated inversion recovery (FLAIR) images, and T1-weighted images; postcont rast enhancement is homogeneous (Figs. 37.1, 37.2, and 37.3).

Fig. 37.1

Tumors of primary central nervous system lymphoma (PCNSL). (A, B) Coronal T1-weighte d postcontrast MR images showing multiple enhancing lesions in a patient who is immunosuppressed after bone marrow transplantation for Hurler's syndrome. Ring enhancement is seen in (A)

Fig. 37.2

(A) Axial T1-weighted postcontrast image showing heterogeneous and ring enhancement. (B) Axial T2-weighted postcontrast image showing less intense tumor enhancement and peritumoral hyperintensity due to severe peritumoral edema

Fig. 37.3

(A) This axial fluid-attenuated inversion recovery (FLAIR) postcontrast image from the same patient as Fig. 37.2 shows similar changes to Fig. 37.2B. (B) An apparent diffusion coefficient (ADC) map shows a heterogeneous diffusion pattern with regions of restricted diffusion in solid parts of tumor and increased diffusion in areas of peripheral edema

  * Lesions may be located in the central gray matter, may be cortical, or may involve the optic nerve or parasellar regions; rarely do they involve the spinal cord.

  * Tumors are often accompanied by significant peritumoral edema.

  * Bilateral, symmetrical mass lesions in the deep gray matter are very characteristic of PCNSL, but they must be distinguished from toxoplasmosis by biopsy.

  * In children, contrast-enhanced CT scans usually show a characteristic heterogeneous pattern, marked edema, and a prominent mass effect with a ringlike peripheral pattern of enhancement similar to the pattern seen in Figs. 37.1A and 37.2A.

  * PCNSL occasionally may present with a predominant leptomeningeal involvement and no evidence of an intracranial mass.

  * Diffusion imaging usually demonstrates restricted diffusion within the solid component of the mass.

## 37.4 Pathology

  * Gross pathology

    * The tumors tend to be large (>2 cm) and vary in circumscription.

    * Some are well-circumscribed masses that are pale in color with a relatively homogeneous appearance on the cut surface, but others are diffusely infiltrative and indistinguishable from surrounding brain.

  * Intraoperative cytologic smears

    * Smears ar e characterized by a monomorphic population of discohesive cells often showing vesicular nuclei and variably sized nucleoli in a necrotic background with frequent apoptosis.

    * Lack of a fibrillary background allows the exclusion of a high-grade glioma.

  * Histopathology

    * Histologic subtypes are similar to those seen in systemic lymphoma, including high-grade diffuse large-cell lymphoma, Burkitt's-type lymphoma, T-cell lymphoma, and anaplastic large-cell lymphoma (ALCL), as well as low-grade diffuse lymphocytic, lymphoplasmacytic, mucosa-associated lymphoid tissue (MALT)–type, or marginal-zone B-cell lymphoma (MZBCL). Follicular lymphoma and primary intracranial Hodgkin's lymphoma are extremely rare.

      * In adults, large-B-cell lymphoma accounts for more than 90 % of PCNSL.

      * Diffuse large-B-cell lymphoma (Fig. 37.4) is also the most common subtype in children, accounting for 30 % of PCNSL in this age group.

      * Tumors are composed of large cells with distinct nucleoli representing cytologic equivalents of centroblasts or immunoblasts.

      * Distinct perivascular distribution (Fig. 37.5) and localization of viable tumor cel ls is often associated with perivascular reticulin formation (accounting for a now-antiquated designation, reticulum-cell sarcoma).

      * Necrosis is usually prominent.

      * The brain-tumor interface may be well delineated or may show an infiltrative pattern.

      * Prior steroid therapy may be associated with extensive tumor lysis, marked apoptosis, and an often nondiagnostic biopsy.

      * Morphologic subtypes similar to the T-cell–rich or anaplastic variants of large-cell lymphoma have been reported.

      * Rare examples of precursor B-cell or T-cell lymphoma have also been reported.

      * Other types of PCNSL are also identified in children:

        * ALCL (including T-cell and null-cell tumors): 21 % of cases

        * Precur sor B-cell and T-cell lymphoblastic lymphomas (Figs. 37.6, 37.7, 37.8, and 37.9): 16 %

        * Burkitt's lymphoma: 12 %

        * Histiocytic lymphoma: 5 %

        * Less common variants: 6 %

Fig. 37.6

Diffuse neoplasti c lymphoid infiltrate in a 5-year-old boy

Fig. 37.7

Tumor from patient in Fig. 37.6 demonstrating membranous positivity for leukocyte com mon antigen

Fig. 37.8

Same tumor as in Fig. 37.6 demonstrating diffuse immunopositivity for CD3 consistent with a T-cell phenotype. Analysis for CD20 expression was negative

Fig. 37.9

Same tumor as in Fig. 37.6 demonstrating immunopositivity for terminal deoxynucleotide transferase (Tdt), consistent with a precursor T-cell lymphoblastic lymphoma

    * Lymphomatoid granulomatosis represents a polymorphous, angiocentric and invasive infiltrate including atypical T lymphocytes, plasmacytoid lymphocytes, and macrophages

      * May be associated with demonstrable EBV genome

      * May occur as CNS disease alone or in combination with pulmonary manifestations

      * May occur in the setting of AIDS

    * Intravascular lymphomatosis represents CNS involvement by a primarily systemic, intravascular (often large-B-cell) lymphoma, or (rarely) a T-cell lymphoma

      * Multifocal infarcts associated with vascular occlusion are common.

Fig. 37.4

Diffuse larg e-cell lymphoma. This tumor shows immunopositivity for CD20 consistent with a B-cell phenotype

Fig. 37.5

Perivascular arrangement of cells represents a characteristic histologic feature of PCNSL.

## 37.5 Immunohistochemistry

  * When a lympho ma is suspected and sufficient tissue is available, tissue should be submitted for flow cytometry.

  * Diffuse large-B-cell lymphomas show positivity for pan-B-cell markers such as CD19 and CD20 (Fig. 37.10A), although an often variable infiltrating T-cell component is always present (Fig. 37.10B).

Fig. 37.10

(A) CD20 immunopositivity in a diffuse large-B-cell lymphoma. (B) Infiltrating T cells (CD3-positive) represent a minor component of another example of diffuse large-B-cell lymph oma. (C) In situ hybridization demonstrates EBV genome in the viable region of the same diffuse large-B-cell lymphoma

  * The presence of EBV genome is often demonstrable by in situ hybridization (Fig. 37.10C)

  * Most tumors express BCL-2 and BCL-6.

  * MZBCL expresses CD19, CD20, CD79a, and occasionally CD5. CD3 and CD10 are usually negative.

## 37.6 Molecular Pathology

  * Loss of chromosome 6q is a ssociated with poorer outcome.

  * Copy gain of 18q21, which includes loci for MALT1 and BCL2, is common.

  * Clonal abnormalities including t(1;14), t(6;14), and t(13;18) translocations have been reported.

  * Global gene expression profiling of diffuse large-B-cell lymphomas has allowed the identification of three distinct subsets with differing profiles and prognostic differences:

    * The germinal center B-cell–like diffuse large-B-cell lymphomas characterized by the expression of genes of the normal germinal center B cells, including BCL-6, CD10, and CD38, with a more favorable clinical outcome

    * The activated B-cell–like diffuse large-B-cell lymphomas characterized by the high levels of expression of genes that are normally induced during in vitro activation of peripheral blood B cells, including a gene that is translocated in lymphoid malignancies, IRF4 (MUM1/LSIRF), anti-apoptotic genes such as FLIP and bcl2, and a subset of the genes that are characteristic of plasma cells

    * Type 3 diffuse large-B-cell lymphomas, which express neither of these sets of genes at a high level

## 37.7 Prognosis

  * Most primary CN S lymphomas do not show systemic dissemination and yet show poor survival of only about 1½ years.

Suggested Reading

Abla O, Weitzman S. Primary central nervous system lymphoma in children. Neurosurg Focus. 2006;21:E8.CrossRefPubMed

al-Ghamdi H, Sabbah R, Martin J, Patay Z. Primary T-cell lymphoma of the brain in children: a case report and literature review. Pediatr Hematol Oncol. 2000;17:341–3.CrossRefPubMed

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.CrossRefPubMed

Brennan KC, Lowe LH, Yeaney GA. Pediatric central nervous system posttransplant lymphoproliferative disorder. AJNR Am J Neuroradiol. 2005;26:1695–7.PubMed

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© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_38

# 38. Histiocytic Tumors

Abir Mukherjee1 and Adekunle M. Adesina2

(1)

Department of Pathology and Laboratory Medicine, Temple University Hospital and School of Medicine, 3401 North Broad Street, Out Patient Building Room B339, Philadelphia, PA 19140, USA

(2)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Langerhans cell histiocytosisLCHRosai-Dorfman diseaseRDDErdheim-Chester diseaseHemophagocytic lymphohistiocytosisJuvenile xanthogranulomaCD1a, CD207 (Langerin)S-100 proteinBirbeck granule

## 38.1 Overview

  * Histiocytic tumors are a heterogeneous group of tumors and tumorlike masses commonly associated with histologically identical extracranial lesions.

  * They are broadly cla ssified into three groups:

    * Dendritic cell disorders:

      * Langerhans cell histiocytosis (LCH)

      * Juvenile xanthogranuloma (JXG)

      * Erdheim-Chester disease (ECD)

    * Macrophage cell disorders:

      * Rosai-Dorfman disease (RDD)

      * Hemophagocytic lymphohistiocytosis (HLH)

    * Malignant histiocytosis

  * LCH resu lts from clonal proliferation of dendritic cells with Langerhans cell characteristics.

    * LCH was previously known as histiocytosis X, which included entities such as eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease.

    * LCH as currently defined may present as unifocal, multifocal (usually polyostotic), or disseminated disease.

    * The estimated annual incidence of LCH ranges from 0.5 to 5.4 cases per million persons per year, with a male-to-female ratio of 2:1.

    * The etiology of LCH is unknown. Putative triggers of the clonal proliferation include viral infections, a defect in intercellular communication (T cell–macrophage interaction), and/or a cytokine-driven process mediated by tumor necrosis factor, interleukin 11, and leukemia inhibitory factor.

    * Over 50 % of cases show oncogenic BRAFV600E mutation.

  * Non-LCH assoc iated lesions encompass a varied group.

    * The most common examples are Rosai-Dorfman disease (RDD), hemophagocytic lymphohistiocytosis (HLH), Erdheim-Chester disease (ECD), and juvenile xanthogranuloma (JXG).

    * A high prevalence of BRAFV600E mutation has been demonstrated in ECD but not in other non–Langerhans cell histiocytosis.

    * RDD has an estimated annual incidence of approximately 100 cases per year in the United States, with CNS involvement in less than 5 % of these cases.

  * True histiocyti c malignant tumors of the CNS are extremely rare and include histiocytic sarcoma and follicular dendritic cell sarcoma.

    * Rare examples of primary CNS histiocytic sarcoma and intracranial follicular dendritic cell sarcoma have been described.

## 38.2 Clinical Features

  * LCH typic ally occurs in children, with a mean age of onset of 12 years.

    * Diabetes insi pidus, with or without associated signs of hypothalamic dysfunction including obesity, hypogonadism, and growth retardation, is the usual clinical presentation.

    * Signs of increased intracranial pressure, cranial nerve palsies, seizures, visual disturbances, and ataxia also occur.

  * RDD in th e CNS shows a predilection for males and typically presents during the fourth to fifth decade.

    * In contrast, nod al-based RDD has a mean age of presentation of 20.6 years.

    * CNS forms usually present as an intracranial space-occupying mass.

    * Cervical lymphadenopathy and systemic symptoms may be absent.

  * JXG occur s in young children, primarily as cutaneous nodules.

    * Dural and parenchymal lesions can occur with or without skin lesions.

    * Xanthoma disseminatum occurs in young adults, typically involving the hypothalamus, pituitary gland, and dura in addition to extracranial involvement.

  * ECD typical ly affects adults. Systemic involvement of bo ne, viscera, and adipose tissue is usual but may not be evident.

    * CNS involvement usually affects the cerebellum, spinal cord, pituitary, meninges, or orbit.

  * HLH is a ra re autosomal recessive multisystem disease of early infancy.

    * Clinical symptom s are fever, hepatosplenomegaly, and cytopenias.

    * Diffuse leptomeningeal and multifocal parenchymal brain involvement is seen in almost all cases.

## 38.3 Neuroimaging

  * In LCH, MRI lesions include craniofacial bone and skull base lesions in 56 % (Fig. 38.1), hypothala mic–pituitary region lesions in 29 %, choroid plexus lesions in 6 %, intraaxial gray and white matter lesions in 36 %, and cerebral atrophy in 8 %.

Fig. 38.1

Langerhans cell histiocytosis (LCH). Coronal (A) and axial (B) T2-weighted MR images show an orbital mass extending into the anterior cranial fossa and having heterogeneous signal intensity. Coronal (C) and sagittal (D) T1-weighted postcontrast images show heterogeneous moderate enhancement. An apparent diffusion coefficient (ADC) map (E) shows increased diffusion

    * With diabetes insipid us, there is loss of the posterior pituitary bright spot.

    * The MRI lesions in LCH can range from sharply demarcated tumorlike lesions to punctate lesions in the cerebral parenchyma.

    * Hyperintensi ties in the cerebellar dentate nucleus and basal ganglia also may be seen on T1-wei ghted MR images.

  * In RDD, MRI u sually shows solitary or multiple dura-based masses, mimicking meningioma.

    * Parenchymal and intrasellar lesions, as well as extension from an orbital/nasal/sinus lesion, have also been described.

    * Intramedullary spinal cord lesions also have been reported.

  * HLH is characterized by diffuse abnormal T2 signal intensity in the white matter.

## 38.4 Pathology

  * Gross pathology

    * LCH lesions can be yellow or white, dura-based nodules or granular, well-delineated or ill-defined parenchymal infiltrates.

    * RDD can be single or multiple, dura-based, intracranial or intraspinal masses. The indurated lesions can be simultaneously intradural and extradural.

  * Intraoperative cytology smear

    * Aspirat es in LCH are cellular, with a dominant population of round to oval histiocytes with ovoid to lobated, reniform nuclei containing pale chromatin and prominent longitudinal grooves or folds.

      * The c ytoplasm is abundant and frequently vacuolated. The background contains a variable number of inflammatory cells including eosinophils, lymphocytes, and neutrophils.

    * Aspirates of RDD contain phagocytic histiocytes, admixed with small lympho cytes, transformed lymphocytes, plasmacytoid lympho cytes, and immunoblasts.

      * Phagocytic histiocytes are very large cells with macronuclei, enlarged nucleoli, and abundant cytoplasm; they often contain phagocytosed lymphocytes, which are thought to traffic back and forth through the cytoplasm of these histiocytes (emperipolesis).

      * Lymphocytes should be present in the same plane of focus as the histiocytic cytoplasm, to be certain of emperipolesis.

  * Histopathology

    * LCH has a poly morphic infiltrate composed of Langerhans cells, macrophages, lymphocytes, plasma cells, and a va riable number of eosinophils (Fig. 38.2).

      * The nuclei of Langerhans cells are typically slightly eccentric, ovoid, reniform, or convoluted, with linear grooves and inconspicuous nucleoli.

      * The cytoplasm is abundant and pale to eosinophilic.

      * LCH can occasionally present with demyelination and a sparse infiltrate of Langerhans cells.

      * A paraneoplastic encephalitis-like presentation involving the cerebellum and brainstem, characterized by infiltrating CD8-reactive lymphocytes, axonal destruction, and secondary demyelination, microglia activation, and gliosis is rarely associated with LCH.

    * RDD shows sheets of histiocytes with vacuolated cytoplasm, admixed with lymphocyte s and plasma cells.

      * Emperipolesis is pathognomonic but may not be seen in 30 % of cases presenting as leptomeningeal disease.

    * JXG or xanthoma disseminatum shows histiocytes with scattered Touton giant cells, lymphocytes, and eosinophils.

    * EC D shows lipid-laden histiocytes with small nuclei, Touton-like multinucleate giant cells, and scant lymphocytes and eosinophils, along with fibrosis.

    * HLH shows diffuse infiltrations of lymphocytes and macrophages with hemophagocytosis.

    * Histiocytic sarcoma shows a malignant histiocytic infiltrate.

    * Follic ular dendritic cell sarcoma may show spindle cells with vesicular nuclei and whorl formation.

Fig. 38.2

Histology o f LCH: A heterogeneous inflammatory infiltrate including histioc ytes, eosinophils, lymphocytes, and plasma cells (A) with a variable amount of multinucleated giant cells (B)

## 38.5 Immunohistochemistry

  * Immunohistochemistry is critical in defining these lesions, which are often histologically similar.

  * In LCH:

    * Langerhans cells express S-100 protein, vimentin, CD1a (Fig. 38.3A), langerin (CD207) (Fig. 38.3B) and HLA-DR.

    * They almost never express CD45, CD15, or lysozyme.

    * Ki67/MIB-1 proliferation indices range from 4 % to 16 %.

Fig. 38.3

(A) CD1 a immunopositivity is seen in the proliferating dendritic cells of LCH. (B) CD207 (langerin) immunopositivity is seen in the proliferating dendritic cells of LCH

  * Histiocytes in RDD are positive for S-100 protein, CD11c, CD68, and MAC387. They are negati ve for CD1a and may or may not express lysozyme.

  * Histiocytes in JXG or xanthoma disseminatum are negative for CD1a, lysozyme, and S-100 protein but positive for CD 11c, CD68, and factor XIIIa. They may be either positive or negative for MAC387.

  * Histiocytes in ECD are negative for CD1a and S-100 protein but positive for CD68.

  * Macrophag es in HLH are positive for CD11c and CD68 but may be either positive or negative for CD1a and S-100 protein.

  * Histiocytic sarcoma tumor cells are positive for CD68, CD11c, lysozyme, and CD14. Lymphoid, myeloid, and dendritic markers are negative.

  * Follicular dend ritic cell sarcoma may be positive for vimentin and epithelial membrane antigen (EMA), thus mimicking meningioma, but these cells are also positive for dendritic cell markers such as CD21, CD23, and CD35.

## 38.6 Electron Microscopy

  * The ult rastructural hallmark of Langerhans cells is Birbeck granules, which are 34-nm intracytoplasmic pentalaminar structures that are shaped like a rod or tennis racket, with cross-striation and a zipper-like central core (Fig. 38.4).

Fig. 38.4

The classic ultrastructural diagnostic feature of LCH is the Birbeck granule, an intracytoplasmic pentalaminar s tructure shaped like a rod or tennis racket, with cross-striation and a zipper-like central core

## 38.7 Molecular Pathology

  * LCH is a monoclonal proliferation.

    * Oncogenic BRAF V600E mutation has been demonstrated in over 50 % of LCH cases, showing no association with disease site or stage. A high prevalence of recurrent BRAF mutations in LCH indicates that it is a neoplastic process that may respond to MEK pathway inhibitors.

    * p53 positivity has been noted in the Langerhans cell nuclei, but mutations of the p53 gene rarely have been documented.

  * Molecular stu dies using polymorphic regions of human androgen receptor locus have demonstrated that RDD is a polyclonal disorder.

    * The etiology of RDD is unknown, but molecular and immunophenotypic studies suggest derivation from activated macrophages, shown to produce interleukin-1β and TNFα.

  * HLH is a rare autosomal recessive, multisystem disease of early infancy.

    * Associated genetic defects include mutations of PRF-1, UNCI3D, STX11, and STXBP2.

## 38.8 Differential Diagnosis

  * A major diagnostic dilemma is distinguishing LCH from non-LCH lesions.

    * An unequi vocal diagnosis of LCH can be achieved using an appropriate panel of immunostains including CD1a and langerin, or el ectron microscopy to determine the presence of Birbeck granules.

  * LCH and non-LCH lesions must be distinguished from granulomas induced by infectious organisms.

    * Parasitic infections may be associated with granulomas having a prominent eosinophilic infiltrate.

    * Excluding an infection is critical in ensuring accurate diagnosis and appropriate managemen t.

## 38.9 Prognosis

  * The ove rall survival of LCH is 88 % at 5 years and 15 years, and 77 % at 20 years.

    * Spontaneous recovery may be seen in unifocal LCH.

    * Poorer prognosis, with a mortality rate of up to 20 %, has been observed in multifocal, multisystem LCH with organ dysfunction.

    * No prognostic significance has been associated with cytologic atypia and mitotic activity in LCH.

  * RDD has excellent prognosis with no evidenc e of disease progression following surgery.

  * HLH is leth al without bone marrow transplantation.

Suggested Reading

Andriko JA, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman disease isolated to the central nervous system: a report of 11 cases. Mod Pathol. 2001;14:172–8.CrossRefPubMed

Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919–23.CrossRefPubMedPubMedCentral

Beverley PC, Egeler RM, Arceci RJ, Pritchard J. The Nikolas Symposia and histiocytosis. Nat Rev Cancer. 2005;5:488–94.CrossRefPubMed

Fillipovitch AH, Chandrakasan S. Pathogenesis of hemophagocytic histiocytosis. Hematol Oncol Clin North Am. 2015;29:895–902.CrossRef

Grois N, Prayer D, Prosch H, Lassmann H. Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain. 2005;128:829–38.CrossRefPubMed

Haroche J, Charlotte F, Arnaud L, von Deimling A, Hélias-Rodzewicz Z, Hervier B, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 2012;120:2700–3.CrossRefPubMed

Hasselblatt M, Sepehrnia A, von Falkenhausen M, Paulus W. Intracranial follicular dendritic cell sarcoma. Case report. J Neurosurg. 2003;99:1089–90.CrossRefPubMed

Lesniak MS, Viglione MP, Weingart J. Multicentric parenchymal xanthogranuloma in a child: case report and review of literature. Neurosurgery. 2002;51:1493–8.PubMed

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumors of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2007. p. 193–6.

Paulli M, Bergamaschi G, Tonon L, Viglio A, Rosso R, Facchetti F, Geerts ML. Evidence of polyclonal nature of the cell infiltrate in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Br J Hematol. 1995;91:415–8.CrossRef

Prayer D, Grois N, Prosch H, Gadner H, Barkovich AJ. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol. 2004;25:880–91.PubMed

Shinoda J, Murase S, Takenaka K, Sakai N. Isolated central nervous system hemophagocytic lymphohistiocytosis: case report. Neurosurgery. 2005;56:187.CrossRefPubMed

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Weidauer S, von Stuckrad-Barre S, Dettmann E, Zanella FE, Lanfermann H. Cerebral Erdheim-Chester disease: case report and review of literature. Neuroradiology. 2003;45:241–5.CrossRefPubMed

Weintraub M, Bhatia KG, Chandra RS, Magrath IT, Ladisch S. p53 expression in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 1998;20:7–12.CrossRef

Willis B, Abin A, Weinberg V, Zoger S, Wara WM, Matthay KK. Disease course and late sequelae of Langerhans cell histiocytosis: 25 year experience at University of California, San Francisco. J Clin Oncol. 1996;14:2073–82.PubMed

# Part XIII
Interesting or Challenging Cases and Exercises in Pattern Recognition
© Springer International Publishing AG 2016

Adekunle M. Adesina, Tarik Tihan, Christine E. Fuller and Tina Young Poussaint (eds.)Atlas of Pediatric Brain Tumors10.1007/978-3-319-33432-5_39

# 39. Case Studies

Adekunle M. Adesina1  , Christine E. Fuller2 and Lucy Balian Rorke-Adams3

(1)

Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, RM 286A, Houston, TX 77030, USA

(2)

Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 1035, Cincinnati, OH 45229-3026, USA

(3)

Department of Pathology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

Adekunle M. Adesina

Email: aadesina@bcm.tmc.edu

Keywords

Case studiesPediatric brain tumorsHistoryPathologyMRI

## 39.1 Case Study A

### 39.1.1 History Summary

  * A 2½-year-old girl presented with signs and symptoms of increased intracranial pressure.

  * MRI studies disclosed a large, partially cystic mass involving the right cerebellar hemisphere and right cerebellopontine angle with hydrocephalus. The lesion was isointense on T1-weighted images, and showed heterogeneous contrast enhancement.

  * Additional imaging studies revealed multiple drop metastases along the spinal cord.

### 39.1.2 Pathology Findings

  * Figures 39.1, 39.2, and 39.3 show different areas from the tumor tissue retrieved at the time of s urgical debulking. Representative images of some immunohistochemical studies are also provided, including epithelial membrane antigen ( EMA) (Fig. 39.4 ), smooth muscle actin (SMA) (Fig. 39.5), and BAF47/INI1 (Fig. 39.6).

Fig. 39.1

Tumor tissue from surgical de bulking

Fig. 39.2

Tumor tissue from surgi cal debulking

Fig. 39.3

Tumor tissue from s urgical debulking

Fig. 39.4

Immunohistochemical study: epithelial membrane antigen (EMA)

Fig. 39.5

Immunohis tochemical study: smooth muscle actin (SMA)

Fig. 39.6

Imm unohistochemical study: BAF47/INI1

What is the diagnosis?

## 39.2 Case Study B

### 39.2.1 History Summary

  * An 8-year-old boy presented with headache, vomiting, and decreased visual acuity.

  * MRI studies disclosed a large, solid intracerebral lesion involving the right temporoparietal region. The lesion had a minor cystic component, focal necrosis, was isointense to gray matter on both T1- and T2-weighted images, and enhanced with contrast. There was some peritumoral edema and mass effect. The lesion was not in close proximity to the ventricular system.

### 39.2.2 Pathology Findings

  * Figures 39.7 and 39.8 are representative photomicrographs of routine H&E stained sections of tumo r from partial surgical excision. Immunohistochemical studies for glial fibrillary acidic protein (GFAP) and ep ithelial membrane antigen (EMA) are depicted in Figs. 39.9 and 39.10.

Fig. 39.7

Photo micrograph from partial surgical excision (H&E stain)

Fig. 39.8

Photo micrograph from partial surgical excision (H&E stain)

Fig. 39.9

Imm unohistochemical study: glial fibrillary acidic protein (GFAP)

Fig. 39.10

Imm unohistochemical study: epithelial membrane antigen (EMA)

What is the diagnosis?

## 39.3 Case Study C

### 39.3.1 History Summary

  * A 10-year-old boy presented with headaches and "clumsiness." According to his parents, these symptoms have been slowly progressive over the course of a year.

  * MRI studies rev ealed a large posterior fossa lesion; Figure 39.11 shows a representative T1-weighted postcontrast image.

Fig. 39.11

T1-weighted postcontrast MR image

### 39.3.2 Pathology Findings

  * Figures 39.12, 39.13, 39.14, and 39.15 are representative photomicrographs of routine H&E stained sections from tissu e obtained at gross total resection of this lesion. No additional stains were performed.

Fig. 39.12

Pho tomicrograph showing tissue from gross total resection (H&E stain)

Fig. 39.13

Phot omicrograph showing tissue from gross total resection (H&E stain)

Fig. 39.14

Photom icrograph showing tissue from gross total resection (H&E stain)

Fig. 39.15

Photomicro graph showing tissue from gross total resection (H&E stain)

What is the diagnosis?

## 39.4 Case Study D

### 39.4.1 History Summary

  * A 16-year-old boy presented with headaches, nausea, and vomiting.

  * A large, right post erior parasagittal lesion was detected on MR imaging studies. A representative T1-weighted postcontrast image is shown in Fig. 39.16. Of note, a smaller lesion was present more anteriorly (not shown); this lesion was also parasagittal and was solid with diffuse contrast enhancement.

Fig. 39.16

T1-weighted postcontrast MR image

### 39.4.2 Pathology Findings

  * Figures 39.17–39.19 are representative photomicrographs of routine H&E stained sections from tissue obtained at gross total resection of this lesion. The features depicted in Figs. 39.17 and 39.18 made up the majority of the lesion, while the findings in Fig. 39.19 were seen only focally.

Fig. 39.17

Photom icrograph showing typical tissue from gross total resection (H&E stain)

Fig. 39.18

Photomic rograph showing typical tissue from gross total resection (H&E stain)

Fig. 39.19

Photomic rograph showing tissue from limited area of gross total resection (H&E stain)

  * Examples of epithe lial membrane antigen (EMA) and INI1 are shown in Figs. 39.20 and 39.21.

Fig. 39.20

Immunoh istochemical study: epithelial membrane antigen (EMA)

Fig. 39.21

Immunohi stochemical study: INI1

What is the diagnosis?

## 39.5 Case Study E

### 39.5.1 History Summary

  * A 16-year-old boy pre sented with headache and blurred vision.

  * MRI (Fig. 39.22A) shows a mass that is slightly heterogeneous but predominantly hypointense on T1-weighted imaging and hyperintense with T2 weighting (Fig. 39.22B). The mass is eccentrically placed to the right of midline, occupying the suprasellar cistern and apparently arising from the region of the sella.

Fig. 39.22

MRI: T1-w eighted (A), T2-weighted (B), and diffusion-weighted (C) imaging

    * Following the administration of gadolinium, there is enhancement of the more solid-appearing superior aspect of the tumor, with more heterogeneous enhancement of the right-sided suprasellar mass.

    * There is evidence for a left-to-right downward sloping of the pituitary fossa.

    * There is increased diffusion (Fig. 39.22C).

  * The patient underwent a biopsy and partial resection of the tumor.

### 39.5.2 Pathology

  * Intraoperative smear shows a hypocellular myxoid lesion (Fig. 39.23A).

Fig. 39.23

(A) Intrao perative smear. (B–E) Additional microscopic images

  * Additional microscopic images show a chondroid lesion with variable cellularity (Fig. 39.23B–E) and surrounding reactive bone changes (Fig. 39E.2E).

  * Immunostains include S-100 (Fig. 39.24A), epithelial membrane antigen (EMA) (Fig. 39.24B), and Ki67 (Fig. 39.24C).

Fig. 39.24

Immunos tains: S-100 (A), EMA (B), and Ki67 (C)

What is the diagnosis?

## 39.6 Case Study F

### 39.6.1 History Summary

  * A 15-year-old boy pre sented with headache and blurred vision.

  * MRI and CT scans showed the presence of a clival mass.

  * The patient had surgery for biopsy and partial resection.

### 39.6.2 Pathology

  * Microscopy shows a mo derately cellular and pleomorphic tumor with variably vacuolated cells in a myxoid matrix (Fig. 39.25).

Fig. 39.25

(A–E) Micros copic images

  * There are frequent mitoses, as well as diffuse positivity for S-100 (not shown) and cytokeratin (Fig. 39.26).

Fig. 39.26

Immunohistoche mical study: cytokeratin

What is the diagnosis?

## 39.7 Case Study G

### 39.7.1 History Summary

  * A 17-year-old girl presente d with upper extremity weakness.

  * MRI and CT studies show the presence of an extraaxial, dura-attached mass in the right posterior frontal lobe.

  * The patient underwent a gross total surgical resection.

### 39.7.2 Pathology

  * Microscopy sections show a highly cellular, small blue cell tumor (Figs. 39.27 and 39.28) with a prominent myxoid component (Fig. 39.29), chondroid differentiation (Fig. 39.30), and regional spindle cells, sometimes arranged in a herringbone pattern (Figs. 39.31 and 39.32).

Fig. 39.27

Micros copic image: highly cellular, small blue cell tumor (H&E stain)

Fig. 39.28

Micros copic image: highly cellular, small blue cell tumor (H&E stain)

Fig. 39.29

Micro scopic image: prominent myxoid component (H&E stain)

Fig. 39.30

Microsco pic image: chondroid differentiation (H&E stain)

Fig. 39.31

Micros copic image: regional spindle cells (H&E stain)

Fig. 39.32

Microsc opic image: regional spindle cells (H&E stain)

  * Tumor cells show a diffuse membranous immunopositivity for CD99 and focal positivity for S-100 in the chondroid regions. EMA, synaptophysin, cytokeratin, desmin, myogenin, and myoD are negative (not shown) .

What is the diagnosis?

## 39.8 Case Study H

### 39.8.1 History Summary

  * A boy 4 years and 4 months of age presented with multiple cranial nerve deficits, dysarthria, and motor weakness, more severe on the left side than on the right.

  * MRI and CT studies d isclosed a tumor in the brainstem. A biopsy was not done.

### 39.8.2 Treatment

  * The child was treated with radiation therapy.

  * The child was treated with Thiotepa.

  * The child had an autologous bone marrow transplant.

  * Nevertheless, there was inexorable growth of tumor, and he died 18 months later.

### 39.8.3 Autopsy

  * Postmortem e xamination disclosed a hemorrhagic tumor extending from the right cerebral peduncle in the midbrain caudally into the most caudal portion of the pons.

    * The tumor was largest at the level of the locus ceruleus (Fig. 39.33).

Fig. 39.33

Autops y specimen

    * In addition, multiple metastases were found in leptomeninges at all levels, along with parenchymal, hemorrhagic tumor in th e temporal lobe (Figs. 39.34 and 39.35).

Fig. 39.34

Autop sy specimen

Fig. 39.35

Auto psy specimen

    * Figure 39.36 shows microscopic images.

Fig. 39.36

(A, B) Microscopic images

What is the diagnosis?

## 39.9 Case Study I

### 39.9.1 History Summary

  * A 9-ye ar-old boy presented with recent onset of seizures and headache.

  * MRI studies (Fig. 39.37) disclosed a left hemispheric mass that was isointense on T1-weighted imaging and hyperintense on T2-weighted imaging, with slight postcontrast enhancement.

Fig. 39.37

MRI showi ng a left hemispheric mass. (A) T1-weighted image. (B) T2-weighted image. (C, D) Postcontrast enhancement

  * Patient underwent a near gross-total resection.

  * The patient is alive 10 years after the resection.

### 39.9.2 Histology

  * The tumor is c omposed of oval to spindle cells in a fibrillary matrix (Fig. 39.38A and B).

Fig. 39.38

(A–D) Histologic sp ecimens

  * There is a distinct perivascular pseudorosette-like arrangement of tumor cells, which is florid in some regions (Fig. 39.38C), and less florid at the infiltrative edge (Fig. 39.38D).

  * There is associated diffuse immunopositivity for glial fibrillary acidic protein (GFAP) (Fig. 39.39A).

Fig. 39.39

Immunoh istochemical studies: (A) GFAP. (B) Ki67

  * Immunostain for Ki67 shows a low proliferation index (Fig. 39.39B).

What is the diagnosis?

## 39.10 Case Study J

### 39.10.1 History Summary

  * A 5-month-old boy presented with vomiting and altered sensorium.

  * MRI studies (Fig. 39.40) revealed a left hemispheric mass that was heterogeneous on T1-weighted imaging and hyperintense on T2-weighted imaging, associated with extensive peritumoral edema. There was marked contrast enhancement and associated diffusion restriction on the ADC map.

Fig. 39.40

MRI showin g a left hemispheric mass. (A) T1-weighted image. (B) T2-weighted image. (C) Postcontrast enhancement. (D) ADC map

  * The patient underwent biopsy followed by a limited resection.

### 39.10.2 Pathology

  * Intraoperative smears and frozen sections are shown in Fig. 39.41.

Fig. 39.41

(A–E) Intrao perative smears and frozen sections

  * Microscopic images from the permanent sections are shown in Fig. 39.42.

Fig. 39.42

(A, B) Micr oscopic images from permanent sections

  * Immunostains include GFAP, p53, and Ki67 (Fig. 39.43).

Fig. 39.43

Immunohistochem ical studies: (A) GFAP. (B) p53. (C) Ki67

  * Synaptophysin and neurofilament immuno stains are negative.

What is the diagnosis?

## 39.11 ANSWERS: Case Study A

### 39.11.1 Diagnosis

  * Atypical teratoid rhab doid tumor (AT/RT)

### 39.11.2 Other Findings

  * Additional immunohistochemical stains that were positive include glial fibrillary acidic protein (GFAP), pancytokeratin (in the epithelial islands and rare individual cells), synaptophysin, and CD99.

### 39.11.3 Comment

  * This case teaches several lessons:

    * Not all cerebellar tumors with a predominance of small blue cells are medulloblastomas. AT/RT should be suspected in cases occurring in the very young (age <3 years) and in cases with cells or components divergent from the typical "small blue cell" appearance.

    * Judicious utilization of multiple immunohistochemical stains, to include especially EMA and SMA, together with neuronal and glial markers, is essential in assessment of polyphenotypia characteristic of AT/RT.

    * Immunohistochemical assessment for INI1 status (BAF47 stain—Note that the tumor cells have lost expression for this marker in the current case) is confirmatory of AT/RT status, and is helpful in differentiating this tumor from other lesions that may contain cells with a rhabdoid morphology (glioblastoma, choroid plexus tumors, meningioma). In the latter tumors, nuclear positivity for BAF47 /INI1 would be retained.

## 39.12 ANSWERS: Case Study B

### 39.12.1 Diagnosis

  * Clear cell ependymoma

### 39.12.2 Comment

  * This case teaches several lessons:

    * Not all ependymomas arise in association with ventricles; they also may be intraparenchymal.

    * The presence of perivascular pseudorosettes should always raise the suspicion for ependymoma, particularly in the setting of a clear cell tumor.

    * Clear cell ependymoma may closely mimic a variety of other clear cell tumors, including oligodendroglioma, neurocytoma, hemangioblastoma, meningioma, and metastatic renal cell carcinoma. As noted above, the finding of perivascular pseudorosettes is an important clue; GFAP positivity and a dotlike pattern by EMA effectively rule out the other listed possibilities. Ultrastructural analysis may be needed only in rare cases.

## 39.13 ANSWERS: Case Study C

### 39.13.1 Diagnosis

  * Pilocytic astrocyt oma

### 39.13.2 Comment

  * This case teaches several lessons:

    * Review of available radioimaging studies is critical in the pathologic workup of tumors of the C NS, and often provides very helpful clues to diagnosis in cases where tissue is limited or unusual or uncommon histologic patterns of otherwise readily recognizable tumors are detected. In this case, the enhancing cyst with mural nodule configuration found in this child's cerebellum should alert the pathologist to be on the lookout for features of low-grade tumors, especially pilocytic astrocytoma.

    * Pilocytic astrocytoma is a "great mimicker" among the pediatric CNS tumors. It may exhibit a wi de array of histologic features, including (for example) areas that look like oligodendroglioma or perivascular pseudorosettes, as in ependymoma. In the context of more typical features of pilocytic astrocytoma (as seen in this case), including biphasic loose and compact architecture and numerous eosinophilic granular bodies, the diagnosis of pilocytic astrocytoma is more readily apparent.

    * Pleomorphism does not always connote malignancy; degenerative nuclear atypia is not uncommonly found in slow-growing, low-grade tumors. Often these bizarre nuclei may have intranuclear cytoplasmic invaginations instead of prominent nucleoli. Diagnostic features of malignancy or benignity are found in the tissue surrounding these pleomorphic nuclei .

## 39.14 ANSWERS: Case Study D

### 39.14.1 Diagnosis

  * Anaplastic meningioma with papill ary and rhabdoid components

### 39.14.2 Comment

  * This case teaches several lessons:

    * Parasagittal lesions that appear to have dural attachment or involvement, whether they are so lid or have a cystic component, should raise a suspicion for dura-based tumors, most commonly meningioma. The finding of a dural tail is particularly helpful in confirming the dura-based nature of a lesion.

    * WHO grade II and grade III meningioma variants are more frequent in children. Lesions exhibiting a prominent papillary architecture (with or without concomitant rhabdoid cells) should prompt a careful search for more classic features of meningioma, including a more spindle-cell morphology, as seen in Fig. 39D.4. Unfortunately, well-formed whorl arrangements are infrequent in high-grade meningiomas, necessitating the application of immunohistochemical stains. EMA staining is characteristic of meningiomas, whereas choroid plexus carcinomas should be positive for pancytokeratin. Nuclear positivity for INI1/BAF47 should be retained in rhabdoid meningiomas, but this is not true of AT/RT.

    * The finding of multiple meningiomas should prompt a workup for NF2.

## 39.15 ANSWERS: Case Study E

### 39.15.1 Diagnosis

  * Chondrosarcoma, int ermediate grade

### 39.15.2 Comment

  * Chondrosarcoma mimicking a pituitary adenoma is unusual.

  * This tumor probably is arising from bone of the skull base.

  * An important differential diagnosis is chondroid chordoma.

## 39.16 ANSWERS: Case Study F

### 39.16.1 Diagnosis

  * Chordoma with malignant transformation.

### 39.16.2 Comment

  * Malignant transformation is infrequent in chordoma.

  * The presence of malignant transformation portends a poor prognosis.

  * An important differential diagnosis is chondrosarcoma.

## 39.17 ANSWERS: Case Study G

### 39.17.1 Diagnosis

  * Extraskeletal mesenchymal chondro sarcoma

### 39.17.2 Comment

  * This tumor is rare in the CNS.

  * H&E histologic features as illustrated are characteristic.

  * The presence of chondroid differentiation is a major distinguishing feature from hemangiopericytoma.

  * Small biopsies without a distinct chondroid component may be problematic.

## 39.18 ANSWERS: Case Study H

### 39.18.1 Diagnosis

  * Medulloepitheli oma (Note: The neoplastic cells did not express any antigen except for a few fields showing histological features of glial differentiation).

### 39.18.2 Comment

  * This case teaches several lessons:

    * Not all brainstem tumors are astrocytomas.

    * Although most medulloepitheliomas arise in the cerebrum, they also occur in other CNS sites.

    * Antigen expression may be inconsistent.

## 39.19 ANSWERS: Case Study I

### 39.19.1 Diagnosis

  * Angiocentric glioma

### 39.19.2 Comment

  * Perivascular pseudorosette-like arrangements, though characteristic for ependymoma, may occur in tumors other than ependymomas.

## 39.20 ANSWERS: Case Study J

### 39.20.1 Diagnosis

  * Congenital gliobl astoma

### 39.20.2 Comment

  * Congenital glioblastoma is uncommon.

  * In this infant, the clinical and neuroradiologic profile suggested differential diagnoses that included supratentorial primitive neuroectodermal tumor (PNET), medulloepithelioma, atypical teratoid rhabdoid tumor (AT/RT), choroid plexus carcinoma, and anaplastic epend ymoma.

Index

A

Adamantinomatous craniopharyngioma

clinical features

frozen section

immunohistochemistry

intraoperative smears

macroscopic features

microscopic features

necrotic-appearing

papillary craniopharyngioma

pilocytic astrocytoma

squamous cell carcinoma

stellate reticulum

wet keratin

molecular pathology

neuroimaging

overview

prognosis

Adenohypophysis

Adrenocorticotropic hormone (ACTH)

Anaplastic ependymoma

SeeEpendymoma

Anaplastic meningioma

Anaplastic mixed oligoastrocytoma

SeeOligodendroglial tumor

Atypical meningioma

Atypical teratoid/rhabdoid tumors (AT/RTs)

CPA

cytologic preparation

definition

differential diagnosis

electron microscopy

gross pathology

histology

immunostaining

infratentorial mass

molecular pathology

necrosis

prognosis

spinal cord mass lesion

supratentorial mass

symptoms

B

Biphasic medulloblastoma

Brain tumor

analysis

classification

grading system

neuroradiologic findings

C

Central nervous system (CNS)

Central neurocytoma

clinical features

differential diagnosis

electron microscopy

histologic features

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Chordoid meningiomas

Choroid plexus carcinoma (CPC)

autopsy brains

clinical features

hemorrhage and necrosis

histology

atypical choroid plexus papillomas

differential diagnosis

electron microscopy

fibrovascular papillary projections

immunohistochemistry

molecular pathology

pleomorphic epithelioid cells

prognosis

rhabdoid morphology

small cell morphology

intraoperative cytologic imprints

neuroimaging

overview

surgical specimens

Choroid plexus papillomas (CPPs)

Classic medulloblastomas

Clear cell ependymoma

SeeEpendymoma

Clumsiness

Cowden disease (CD)

association

clinical features

molecular pathology

overview

Cranial nerve deficits

D

Desmoplastic infantile astrocytomas (DIA)

clinical features

differential diagnosis

immunohistochemistry

neuroimaging

overview

pathology

prognosis

Desmoplastic infantile ganglioglioma (DIG)

clinical features

differential diagnosis

immunohistochemistry

neuroimaging

overview

pathology

prognosis

Diffuse astrocytoma

Diffuse intrinsic pontine glioma (DIPG)

Dysembryoplastic neuroepithelial tumors (DNETs)

clinical features

differential diagnosis

gangliocytoma

immunohistochemistry

neuroimaging

CT scan

diffusion images

enhancement

MR spectroscopy

primary superficial cortical location

T1-weighted image

overview

pathology

BRAF V600E mutations

calcification

cortical dysplasia

diffuse microcystic pattern

floating neurons

glial nodules

macrogyri

nonspecific histologic variants

oligodendroglia-like cells

oligodendroglioma

pilocytic astrocytoma

prognosis

RGNT

E

Embryonal neuroepithelial tumors

clinical features

differential diagnosis

electron microscopy

gross specimen

histology

immunohistochemistry

intraoperative smears

molecular pathology

neuroimaging

prognosis

Embryonal tumor with abundant neuropil and true rosettes (ETANTR)

SeeEmbryonal neuroepithelial tumors

Endolymphatic sac tumors

Ependymoma

clinical features

differential diagnosis

electron microscopy

gross pathology

histology

immunohistochemistry

intraoperative cytologic imprints

molecular pathology

neuroimaging

overview

prognosis

Ependymomas

Epithelial membrane antigen (EMA)

Epstein-Barr virus (EBV)

Erdheim-Chester disease (ECD)

Extraventricular neurocytoma

clinical features

differential diagnosis

electron microscopy

histologic features

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

F

Fibrous meningioma

Flexner-Wintersteiner rosettes

G

Gangliocytoma

clinical features

differential diagnosis

electron microscopy

histology

anaplastic ganglioglioma

binucleated ganglion cell

dysmorphism

florid subarachnoid tumor

ganglioid cells

microcystic and vacuolated stroma

perivascular pattern

pilocytic pattern

reticulin and collagen-rich stroma

tumor cells

immunohistochemistry

intraoperative smear preparations

molecular pathology

mural nodule

neuroimaging

CT scans

enhancement

mural nodule

T1-weighted images

T2-weighted image

overview

prognosis

Ganglioglioma

SeeGangliocytoma

Germ cell tumors

choriocarcinoma

definition

histopathology

immunohistochemistry

clinical features

diagnosis

embryonal carcinoma

definition

histopathology

immunohistochemistry

endodermal sinus

definition

histopathology

immunohistochemistry

germinoma

definition

histopathology

immunohistochemistry

mixed germ cell tumor

molecular pathology

neuroimaging

prognosis

teratomas

definition

histopathology

immunohistochemistry

Glial fibrillary acidic protein (GFAP)

Granular cell tumor

clinical features

histopathology

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

H

Headache

and blurred vision

and decreased visual acuity

nausea

vomiting

Hemangioblastoma

clinical features

diagnosis

germline mutations

histology

immunohistochemistry

intraoperative smears and samples

neuroimaging

surgical resection

tumor embolization

ultrastructural level

vascular spaces

VHL syndrome

Hemangiopericytoma (HPC)

clinical signs and symptoms

cytologic smears

definition

differential diagnosis

histology

immunohistochemical profile

molecular pathology

neuroimaging

prognosis

ultrastructural findings

Hemophagocytic lymphohistiocytosis (HLH)

High-grade astrocytoma

Histiocytic tumors

classification

ECD

electron microscopy

follicular dendritic cell sarcoma

HLH

JXG

LCH

characteristics

clinical features

differential diagnosis

immunohistochemistry

monoclonal proliferation

neuroimaging

pathology

prognosis

malignant tumors

non-LCH

RDD

clinical features

immunohistochemistry

neuroimaging

pathology

prognosis

I

Infiltrative astrocytomas

clinical features

differential diagnosis

electron microscopy

gross pathology

histology

immunohistochemistry

intraoperative cytologic smears

molecular pathology

morphologic variants

neuroimaging

overview

prognosis

Intracranial pressure

J

Juvenile xanthogranuloma (JXG)

L

Langerhans cell histiocytosis (LCH)

characteristics

clinical features

differential diagnosis

immunohistochemistry

monoclonal proliferation

neuroimaging

pathology

Lhermitte-Duclos disease (LDD)

association

clinical features

differential diagnosis

histopathology

immunohistochemistry

molecular pathology

neuroimaging

overview

Lymphomatoid granulomatosis

Lymphoplasmacyte-rich meningioma

M

Malignant epithelioid glioneuronal tumor (MEGNT)

clinical features

differential diagnosis

electron microscopy

intermediate filaments

microtubules and dense-core neurosecretory granules

synaptic junction

histology

epithelioid cell

pseudopallisading necrosis

rhabdoid/ganglioid appearance

spindle cells

undifferentiated cells

immunohistochemistry

desmin

epithelial membrane antigen

GFAP

INI1 protein expression

MIB-1

neuromarkers

vimentin

intraoperative smear preparation

molecular pathology

neuroimaging

overview

pathology

prognosis

Malignant lymphoma

B-cell lymphoma

clinical features

EBV

histopathology

diffuse large-cell lymphoma

diffuse neoplastic lymphoid

leukocyte common antigen

perivascular arrangement

T-cell phenotype

terminal deoxynucleotide transferase

immunohistochemistry

immunosuppression

incidence

intraoperative cytologic smears

molecular pathology

neuroimaging

prognosis

Malignant melanomas

Malignant peripheral nerve sheath tumors (MPNSTs)

cellularity and collagenous

clinical features

definition

differential diagnosis

grading

hemangiopericytoma

hemorrhagic/necrotic foci

immunohistochemistry

intraoperative smears

molecular pathology

myxoid pattern

neuroimaging

PNET

prognosis

radiographic features

ultrastructural features

Medulloblastoma

characteristics

clinical features

definition

differential diagnosis

diffuse leptomeningeal enhancement

electron microscopy

Gorlin's syndrome

histologic features

immunohistochemistry

intraoperative cytologic imprints/smears

midline vermian mass

molecular pathology

NAA peak

neuroimaging

prognosis

thecal sac drop metastases

Melanocytic lesions

clinical features

cytology findings

diagnosis

electron microscopy

histology

immunohistochemical staining

leptomeningeal melanocytes

molecular pathology

neuroimaging

prognosis

Melanocytomas

Meningiomas

clinical features

cytologic smears

diagnosis

electron microscopy

EMA

histologic variants

immunohistochemical/molecular determination

melanocytoma

molecular pathology

neurofibromatosis type 2

neuroimaging

prognosis

renal cell carcinoma

round/lobulated tan-yellow mass

spindle-cell lesions

vimentin

Meningothelial meningioma

Microcystic meningioma

Mixed oligoastrocytomas (MOAs)

SeeOligodendroglial tumor

Myxopapillary ependymoma

SeeEpendymoma

N

N-acetyl aspartase (NAA)

National Institutes of Health (NIH)

Neurofibromas

cell types

characteristics

clinical features

collagenous

differential diagnosis

immunohistochemistry

malignant transformation

neurofilament antibody

neuroimaging

NF1 gene

smear preparation

traumatic neuroma

variants

Wavy nuclei

Neurofibromatosis 1 (NF1)

clinical features

histopathological features

astrocytoma

central nervous system

MPNSTs

neurofibroma

immunohistochemistry

incidence

molecular pathology

neuroimaging

NIH

prognosis

Neurofibromatosis 2 (NF2)

clinical features

diagnosis of

histological features

immunohistochemistry

incidence

molecular pathology

neuroimaging

prognosis

schwannoma

Nodular medulloblastoma

O

Oligodendroglial tumor

autopsy

clinical features

cytological squash/smear

differential diagnosis

histology

immunohistochemical marker

molecular pathology

necrosis

neuroimaging

overview

prognosis

ultrastructural examination

Opsoclonus-myoclonus-ataxia syndrome (OMA)

P

Papillary ependymoma

SeeEpendymoma

Papillary glioneuronal tumor (PGNT)

clinical features

differential diagnosis

diffusion weighted imaging

electron microscopy

enhancement

histology

glial component

minigemistocytes

mitotic activity

necrosis and microvascular proliferation

neurocytic cells

neuronal component

tumor infiltration

immunohistochemistry

molecular pathology

neuroimaging

MRI

T1-weighted imaging

overview

prognosis

smear preparations

Papillary meningioma

Paraganglioma

clinical features

differential diagnosis

electron microscopy

histology

chief cells

diffuse pigmentation

fibrovascular septa

immunopositivity

immunostain

intraoperative touch preparation

Ki-67

melanotic paraganglioma

reticulin stains

Zellballen pattern

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

sausage-shape appearance

Paraneoplastic cerebellar degeneration (PCD)

Paraneoplastic disorders

clinical features

CNS

differential diagnosis

electron microscopy

ganglia

immunohistochemistry

neuroimaging

OMA

pathology

PCD

PEM

prognosis

Paraneoplastic encephalomyelitis (PEM)

Pheochromocytomas

Pilocytic astrocytomas (PAs)

clinical features

differential diagnosis

EGBs

electron microscopy

histologic heterogeneity

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Rosenthal fibers

Pilomyxoid astrocytoma (PMA)

clinical features

differential diagnosis

EGBs

electron microscopy

histologic findings

histologic heterogeneity

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Rosenthal fibers

Pineal parenchymal tumor of intermediate differentiation (PPTID)

histopathology

immunohistochemistry

neuroimaging

overview

Pineal parenchymal tumors

neuroimaging

pineoblastoma

clinical features

histopathology

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

pineocytoma

immunohistochemistry

clinical features

histopathology

neuroimaging

overview

PPTID

clinical features

histopathology

immunohistochemistry

neuroimaging

overview

Pituicytoma

clinical features

histopathology

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Pituitary adenomas

atypical pituitary adenoma

cell of origin

clinical features

differential diagnosis

electron microscopy

frozen section

functional definitions

histology

immunohistochemistry

intraoperative smears

molecular pathology

neuroimaging

prognosis

size/radiological features

WHO classification

Pleomorphic xanthoastrocytoma (PXA)

clinical features

cytologic samples

differential diagnosis

electron microscopy

gross pathology

histology

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Primary central nervous system lymphoma (PCNSL)

SeeMalignant lymphoma

Primitive neuroectodermal tumors (PNETs)

SeeEmbryonal neuroepithelial tumors

Psammomatous meningioma

R

Renal cell car (RCC)

Retinal angiomas

Rhabdoid meningioma

Rhabdoid predisposition syndrome (RPS)

Rosai-Dorfman disease (RDD)

clinical features

immunohistochemistry

neuroimaging

pathology

polyclonal disorder

prognosis

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT)

clinical features

differential diagnosis

electron microscopy

histology

immunohistochemistry

molecular pathology

neuroimaging

prognosis

smear preparations

WHO classification

S

Schwannoma

bony erosion

clinical features

differential diagnosis

histopathological features

immunohistochemical staining

microscopic features

molecular biology

nuclear freezing

T2-weighted images

treatment

ultrastructural features

Verocay body formation

Seizures and headache

Solitary fibrous tumor (SFT)

clinical signs and symptoms

definition

differential diagnosis

histology

immunohistochemical profile

molecular pathology

neuroimaging

prognosis

Spindle cell oncocytoma

clinical features

histopathology

immunohistochemistry

molecular pathology

neuroimaging

overview

prognosis

Subependymal giant cell astrocytoma (SEGA)

Subependymoma

SeeEpendymoma

T

Transitional meningiomas

Tuberous sclerosis complex (TSC)

causative mutations

clinical features

cortical tubers

definitive diagnosis

electron microscopy

hamartomas and neoplasms

immunohistochemistry

molecular pathology

neuroimaging

prognosis

SEGA

subependymal nodules

U

Upper extremity weakness

V

Vomiting and altered sensorium

Von Hippel-Lindau (vHL) disease

clinical features

diagnosis

functions

germline mutation

hemangioblastomas

histopathological features

immunohistochemistry

molecular pathology

neuroimaging

prognosis

retinal angiomatosis

Von Hippel-Lindau (VHL) syndrome

W

Weibel-Palade body

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