Non-tender. Progressive enlargement. Diameter >2cm. Associated lymphadenopathy. Neurological signs The following should raise suspicion of a brain tumor: \200 \200 Cranial nerve de \201 cits from direct tumor involvement. False localizing signs: ICP). Ce rebellar signs (e.g. ataxia). Visual disturbances or abnormal eye movements: \201 eld and /or acuity defects (optic tract and suprasellar tumors); Parinaud \200\231s syndrome (paral ysis of upward gaze) suggests pineal tumor. Abnormalities of gait. Motor or sensory signs. Behavioral disturbances. Deteriorating school performance or neurodevelopmental milestones. Unexplained focal seizures. Increasing head size (infants). III and VI nerve palsies (mass effect from raised \200 \200 \200 \200 \200 \200 18_McClure_18.indd 654 11/14/2012 3:51:01 PM KEY INVESTIGATIONS 655 Key investigations The most common reason for referral to a specialist is the identi \201 cation of an abnormality on blood \201 lm. Pancytopenia Not all cell lines are equally affected, but the following problems occur as l eukemia or disseminated malignancy displaces normal bone marrow. \200 \200 \200 Pallor, lethargy (low Hb). Bruising and/or petechiae (low platelets). Unexplained fever, recurrent or persistent infection (low WBC). The following tests are used in diagnosis, staging, and assessment for prog- nosis, and as a baseline before starting treatment. Laboratory tests \200 FBC and \201 lm. \200 Coagulation studies. \200 Group and cro ss-match blood. \200 Electrolytes; renal, bone, and liver pro \201 le; urate; lactate de hydrogenase (LDH). CRP, ESR. Ferritin and neuron-speci \201 c enolase (if neuroblastoma li kely). Blood cultures. Thiopurine methyl transferase assay (in case of suspected acute lymp hoblastic leukemia (ALL)). Urine catecholamines (neuroblastoma, phaeochromocytoma). Lumbar puncture for cytospin, cell count, cytology. \200 \200 \200 \200 Imaging Sedation or general anesthetic may be needed in young children when performing thes e procedures. The choice of imaging depends on the likely diagnosis, and may include: \200 \200 \200 \200 \200 \200 CXR. CT scan chest and/or abdomen. MRI scan (better than CT for soft tissue swellings and b rain). Bone marrow aspirate and/or trephine. Technetium ( Meta-iodo-benzylguanidine (MIBG) scan (neuroblastoma, phaeochromocytoma). 99Tc) bone scan. Other investigations These depend on the treatment being planned and may include: \200 gl omerular \201 ltration rate (nephrotoxic chemotherapy, EDTA: nephrectomy). Audiology assessment (platinum chemotherapy, radiotherapy). Echocardiog ram (anthracycline, pulmonary radiotherapy). Lung function (bleomycin, pulmonary radiothera py). Pituitary function (suprasellar tumors, CNS surgery or radiotherapy). \200 \200 \200 18_McClure_18.indd 655 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 656 Acute lymphoblastic leukemia This is the most common malignancy in childhood. It arises fro m malig- nant proliferation of \200\230pre-B \200\231 (common ALL) or T-cell lymphoid prec ursors. The cause is unknown, but in a minority it is associated with chromoso- mal aberrat ions. Possible links to patterns of childhood infection acting as a trigger have been hypot hesized. \200 \200 ALL accounts for 25% of all childhood malignancies. Commonly presents in young children age d 2 \200\2236yrs. Presentation Typically with a short history (days or weeks), and with symptoms and signs re \202 ecting pancytopenia, bone marrow expansion, and lymphadenop- athy. Includes petechia e, bruising, pallor, tiredness, bone/joint pain/swell- ing, limp, lymphadenopathy, airway o bstruction, and pleural effusion. Speci \201 c diagnostic tests \200 \200 \200 \200 Bone CSF Clinical CXR marrow: morphology; immunophenotype; cytogenetics. for cytospin (CNS rarely involved at \201 rst diagnosis). examination of testes in boys for inappropriate swelling. for mediastinal mass. Outline of \200\230standard \200\231 treatment Induction (4wks) \200 \200 \200 Steroids (dexamethasone or prednisolone) throughout induction Weekly IV vincristine IM L-as paraginase (e.g. 9 doses in 3wks or 2 doses of pegylated asparaginase) IV daunorubicin (2 \200\2234 doses, in intermediate and high risk cases) Intrathecal (IT) methotrexate (day 18 ) \200 Note Tumor lysis syndrome (b p.684) is a signi \201 cant risk Consolidation CNS-dir ected therapy \200 Low risk cases: oral mercaptopurine. Higher risk cases: CNS-radiotherapy only for CNS +ve c ases 4-weekly doses of IT methotrexate and continuous \200 add IV cyclophosphamide, cytarabine. Maintenance Continuation treatment for at least 2yrs (3yrs for boys) \200 Daily 6-mercaptopurine (6MP), weekly oral methotrexate (doses titrated according to blood c ount) 4-weekly vincristine IV bolus and 5-day pulses of oral dexamethasone 12-weekly IT met hotrexate \200 Intensive blocks of chemotherapy One or two blocks of 8wks duration, interrupting 1st year of mainte- nance. Combinations of oral steroid, vincristine, doxorubicin, cyclophos- phamid e, cytarabine, and L-asparaginase 18_McClure_18.indd 656 11/14/2012 3:51:01 PM ACUTE LYMPHOBLASTIC leukemia 657 Prognosis Overall survival is approximately 80% with current treatment. Adverse prognostic factors include: \200 \200 \200 \200 Male gender. Age <2yrs or >10yrs. High WCC at diagnosis. Unfavorable cytogenetics: gene rea rrangements (e.g. t(4;11) in infants); AML1 ampli \201 cation; Poor response to induction and failure to remit by day 28. High level of minimal residual disease (MRD) at 28 days. Philadelphia chromosome \200\224t(9;22); MLL \200 Mature B-cell ALL (Burkitt \200\231s type, L3 morphology) Once considered a high-risk group , outlook is similar to that in stand- ard risk ALL now that patients are treated with inte nsive chemotherapy according to strategy for B-cell non-Hodgkins lymphoma (see b p.660). Relapsed ALL Extramedullary relapse (mainly CNS, testes) may present without bone marrow di sease. Treatment is strati \201 ed according to risk factors, which include: \200 \200 \200 Time from \201 rst diagnosis (risk reduces with time). Extramedullary relapse (lower risk , particularly if isolated). Minimal residual disease (MRD) status after re-induction ( \200\223ve status reduces risk). Treatment \200 \200 \200 \200 Intensive re-induction and consolidation for all risk groups. Low risk: High risk: Intermed iate risk: based on minimal residual disease and/or availability of matched donor. Radiothe rapy for extramedullary disease: receiving total body irradiation (TBI) for BMT. 2yrs of continuing conventional chemotherapy. BMT allograft. the role of BMT in this group is unclear; it may be given as a boost for those Prognosis Long-term survival varies: 10 \200\22390% depending on risk (e.g. 90% in those wi th isolated extramedullary relapse more than 2yrs off treatment). 18_McClure_18.indd 657 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 658 Acute myeloid leukemia Acute myeloid leukemia (AML) accounts for 75% of all childhood malig - nancies and <20% of all acute leukaemias. It is also known as acute non- lymphoblastic le ukemia (ANLL). AML results from malignant prolifera- tion of myeloid cell precursors. AML c an be subdivided morphologically using the French \200\223American \200\223British (FAB) cl assi \201 cation system: \200 \200 \200 \200 \200 \200 \200 M1: M2: M3: M4: M5: M6: M7: AML without maturation. AML with maturation. acute promyelocytic leukemia (PML). acute myel omonocytic leukemia with eosinophilia (M4Eo). acute monocytic/monoblastic leukemia. acute e rythroleukaemia. acute megakaryocytic leukemia. Presentation \200 \200 \200 \200 \200 b p.656). Symptoms and signs of bone marrow replacement (see Lymphadenopathy less prominent than in A LL. Intrathoracic extramedullary disease less common than in ALL. M3 may present with coagu lopathy from proteolytic enzyme activity. Solid deposits (chloroma) occasionally seen in M2 , M4, or M5. Cytogenetics Cytogenetic analysis shows characteristic abnormalities: \200 \200 \200 M1 and M2 AML: M3 AML: M4Eo: t(8;21) translocation observed in 15% of all cases. t(15;17) translocation observed in 100% of cases; inv(16) frequently observed. These translocations are regarded as good prognostic indicators. Other complex karyotypes a re associated with poor risk. Treatment In AML prolonged continuation therapy is not used: \200 4 courses intensive myeloablative chemotherapy. The role of the gemtuzumab or Myelotarg (a monoclonal antibody directed against CD33) given alongside chemotherapy is being explored i n the context of clinical trials. PML: improves survival. High risk cases, including those who fail to achieve complete remission after 2 courses, are usually offered BMT in \201 r st remission. all-trans retinoic acid given in induction, before chemotherapy, Prognosis Overall survival is >60%. Relapsed AML All cases require BMT after intensive re-induction, usually in conjunction wit h \200\230FLAG \200\231 or \200\230FLAG-Ida \200\231 regimen (i.e. \202 udarabine, ara- C, and G-CSF sup- port +- idarubicin). 18_McClure_18.indd 658 11/14/2012 3:51:01 PM CHRONIC MYELOID leukemia (ADULT TYPE) 659 Leukemia and Down syndrome The risk of developing acute leukemia is increased 20 \200\22330 times, com- monly either a pre-B (common) ALL or AML (especially M7). Response to chemothe rapy is good and better relapse-free survival is found in those with AML. Children with Dow n syndrome-associated leukemia experi- ence more complications of treatment. Other genetic conditions predisposing to AML \200 \200 \200 \200 \200 \200 \200 \200 \200 Fanconi syndrome. Bloom syndrome. Ataxia telangiectasia. Kostmann \200\231s syndrome. Diamo nd \200\223Blackfan syndrome. Klinefelter \200\231s. Turner \200\231s syndrome. Neuro \201 bromatosis. Incontinentia pigmenti. Chronic myeloid leukemia (adult type) Classically associated with Philadelphia chromosome + ve disease (t(9;22) translocation). It is rare. It has a chronic phase with non-speci \201 c symp- toms (fever, night sweats, and hepatosplenomegaly). During this phase the only cur e is BMT. Some bene \201 t from A-interferon therapy. The chronic phase progresses to a bl ast phase that is similar to acute leukemia. BMT is required. Prognosis is worse if BMT del ayed until blast crisis. Juvenile myelomonocytic leukemia Classi \201 ed with the myelodysplasias, it is also known as juvenile CML. \200 \200 \200 \200 It is rare (<1% of childhood malignancy). Age of onset mostly <2yrs. Associated with monoso my 7, NF1, and Noonan \200\231s syndrome. Response to chemotherapy is poor and only BMT off ers a cure. 18_McClure_18.indd 659 11/14/2012 3:51:01 PM CHAPTER 18 Oncology 660 Lymphoma There are two distinct disease entities that differ in regard to natural his- tory , presentation, and management. Both are more common in boys than girls. Non-Hodgkin \200\231s lymphoma (NHL) The annual incidence of NHL is 10 per million. The maj ority are high-grade tumors that are divided into categories, using histology, immunopheno- type, and cytogenetics (see Box 18.1). Box 18.1 Classi \201 cation of NHL \200 (90% T-cell, 10% pre-B): 30% of all NHL. Most present Lymphoblastic with an anterior medias tinal mass. Disease may be present in bone, bone marrow, skin, CNS, liver, kidneys, and spl een. Cases with >25% blasts in bone marrow are regarded as leukemia (ALL). Terminal deoxynu cleotidyl transferase (TdT) positivity is usually observed. Translocations t(1;14) or t(11; 14) may be observed Mature in the abdomen, head and neck, bone marrow, and CNS. May grow ra pidly. Endemic or African Burkitt \200\231s associated with early EBV infection and frequen tly affects the jaw. Expresses surface immunoglobulin and characteristic translocations t(8 ;14), t(8;22), or t(2;8) Large B cell (BLCL) presents like Burkitt \200\231s; anaplastic la rge cell lymphoma (ALCL) involves extranodal sites (skin and bone). Lymphadenopathy often p eripheral and painful. CNS or bone marrow disease is rare. ALCL is characterized by CD30 ex pression and t(2;5) B cell (Burkitt or Burkitt-like): 30% childhood NHL. Occur cell lymphoma: 15 \200\22320% childhood NHL. Subtypes \200\224diffuse large NHL staging (St Jude system) \200 \200 \200 \200 Stage I: Stage II: Stage III: Stage IV: single site or nodal area (not abdomen or mediastinum). regional nodes, abdominal disease. disease on both sides of the diaphragm. bone marrow or CNS disease. Investigations \200 Tissue: (peritoneal) \202 uid aspirate; exclusional biopsy. Imaging: bone marrow aspirate; lumbar puncture; pleural and abdominal CT and positron emission tomography (PET) scans. Treatment Lymphoblastic (T cell, pre-B cell) lymphoma is treated like ALL. Mature B cell di sease is treated with short series of dose-intensive courses of che- motherapy. Risk of tum or lysis (b p.684) is high. Prognosis Survival is >70% (>90% in those with localized diseas e). 18_McClure_18.indd 660 11/14/2012 3:51:02 PM LYMPHOMA 661 Hodgkin \200\231s Lymphoma The incidence of Hodgkin \200\231s Lymphoma (HL), or Hodgkin \200\231s Disease, is very low before age 5yrs and rises with age. It is more common in pat ients with previous EBV infection. The histology shows Reed \200\223Sternberg cells in an a pparently reactive lymph node in \201 ltrate. Presentation Progressive, painless lymph node enlargement, the most common sites be- ing ce rvical (80%) and mediastinal (60%). Dissemination to extranodal sites is less common, lungs and bone marrow being most frequently involved. Fever, night sweats, weight loss (>10%) co nstitute \200\230B \200\231 symptoms and are common in advanced stages. Subtypes HL is divided into two subtypes, which are then further subdivided by histology. C lassical HL includes nodular sclerosing (most common), mixed cellularity, and lymphocyte-de pleted histology. Nodular lymphocyte \200\223 predominant HL is the other subtype, characte rized by its distinctive his- tology and favorable prognosis. Staging (Ann Arbor system) \200 single site. \200 more than one site and on one side. \200 on both sides of the diaphragm. \200 disseminated disease. Stage I: Stage II: Stage III: Stage IV: Investigations \200 \200 \200 CT of neck, chest, abdomen, and pelvis. FDG PET scan. Bone marrow aspiration and trephine ( if radiological evidence of at least stage III disease). EBV serology and ESR. Isotope bone scan (generally done with stage IV disease, evidence of bone pain, or B symptoms). \200 Treatment National practices differ, in \202 uenced by the balance between cure and ad- ve rse long-term effects. Low stage disease may be cured with involved \201 eld radiotherapy alone, but chemotherapy with low dose involved \201 eld radiotherapy for selected cases is now more commonly employed. Chemotherapy usually includes alkylating agents, vinca alkal oids, anthra- cyclines and steroids, and the addition of radiotherapy is considered es- sen tial at least for bulky mediastinal or stage IV disease. Reductions and augmentations of th ese therapies is being explored in the context of clini- cal trials and the role of PET sca nning is likely to play an increasing role in monitoring of disease and determination of th erapy. Prognosis 5-yr survival >90% (stage IV, 70%; stage I, 97%). Relapse Cure is still possible with second line therapy, including autolo- gous stem cell t ransplant. 18_McClure_18.indd 661 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 662 Central nervous system tumors (1) Brain tumors are the most common solid tumors, accounting for 25% of all childhood malignancies (see Box 18.2 for classi \201 cation). Box 18.2 Classi \201 cation of CNS tumors \200 Infratentorial vomiting, and cerebellar ataxia Supratentorial hypothalamic/pituitary dysfun ction, and visual impairment Primary astrocytomas and ependymomas. They may present with co rd compression CNS tumors (>50%): present with raised ICP, headaches and tumors: present with raised ICP, focal neurology, spinal tumors (rare): differential diagnosis includes metastases: of extracranial tumors (rare) Involvement of the multidisciplinary team is central to management of CNS tumors. The prese nting features vary and may delay the diagnosis. For every childhood brain tumor, there are 75000 children with migraine! Initial management Diagnostic imaging \200 CT is quick and available. It provides essential information for emergency management of hy drocephalus. MRI gives better tumor de \201 nition. Combine with spinal imaging for stagin g of disease. Raised intracranial pressure This requires prompt treatment: \200 \200 Referral and transfer to a pediatric neurosurgical unit. Control tumor swelling with high d ose steroids (usually dexamethasone). CSF drainage: complete resection, depending on locati on and likely diagnosis. initial surgery may involve CSF diversion only, biopsy, or Low grade glioma (grade I, 45% CNS tumors) \200 \200 \200 Most are pilocytic astrocytoma. Cerebellum and optic pathway are most common sites. Outcome depends on site. Posterior fossa lesions can be cured with surgery alone, whereas optic pa thway tumors are relatively inaccessible and morbidity is high. Neuro \201 bromatosis type 1 (NF1) See b pp.531, 946. \200 \200 \200 50% of optic pathway low grade gliomas. Visual outcome better. Radiotherapy contraindicated - increased risk of second tumors. 18_McClure_18.indd 662 11/14/2012 3:51:02 PM CENTRAL NERVOUS SYSTEM tumors (1) 663 High grade glioma (grade III/IV, 10% CNS tumors) \200 \200 \200 Predominantly occur in older children and teenagers. Supratentorial sites predominate. Dif \201 cult to manage since complete resection, essential for good outcome, is dif \201 cul t to achieve. Rarely cured. Treatment usually includes radiotherapy, with the addition of t emozolamide or other agents in the context of clinical trials Diffuse brainstem glioma \200 \200 \200 Glioma in the region of the pons, usually high-grade and inoperable. Radiotherapy is the ma instay of treatment. Median survival <1yr. Primitive neuroectodermal tumors (PNETs, 25% CNS tumors) \200 \200 \200 \200 \200 Most common malignant brain tumors of childhood. Majority occur in the cerebellum (medullob lastoma). Peak incidence is <5yrs. Tumor metastases (mainly via the CSF) in 10 \200\22315%. 70% of localized cases can be cured, but expect signi \201 cant long-term morbidity from radiotherapy. Treatment Treatment includes excision and craniospinal radiotherapy. Additional chemotherap y carries a survival advantage, allowing reduction in drug dose and/or \201 eld of radiot herapy, particularly in younger patients. Chemotherapy regimens include alkylating agents ( e.g., Lomustine (CCNU), cyclophosphamide), platinum drugs (cisplatin, carboplatin), and vin cristine. These are usually given after radiotherapy. 18_McClure_18.indd 663 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 664 Central nervous system tumors (2) Ependymoma (10% of CNS tumors) \200 \200 \200 \200 \200 \200 Periventricular sites. Usually present with obstructive hydrocephalus. 10% metastasize to t he spine. Treated by surgical excision and involved \201 eld radiotherapy. Chemotherapy u sed in younger patients to delay radiotherapy. >70% survival if complete excision. CNS germ cell tumors (5% of CNS tumors) \200 Rare and more commonly seen in teenage males . \200 Midline (suprasellar or pineal): 40% non-germinomatous (secreting) malignant GCTs (GCTs; e.g. embryonal carcinoma, yolk sac tumor, mixed malignant tumors). Mature teratomas seen more in younger patients. Secreting tumors: either serum or CSF. (Biopsy in marker \200\223ve cases). Primary surgery for teratoma: tumor types. Cure in 70% secreting tumors and >90% for germinoma/teratoma. 60% of malignant cases are germinoma, characterized by raised markers (AFP or hCG) in chemotherapy and radiotherapy for other Craniopharyingioma (10% of CNS tumors) \200 Slow-growing midline epithelial tumors in the suprasellar area from \200\230Rathke \200 \231s pouch \200\231. Treatment: radiotherapy in the remainder. Complications include damag e to the hypothalamic \200\223pituitary structures, vision, and behavior. complete resection in 80%, partial resection with focal Retinoblastoma (3% of all tumors) \200 Sporadic or familial (40%) forms that are unilateral or bilateral (30%) on presentation. Pe ak incidence: Presentation: visual deterioration. Treatment: 90% 5-year survival: OS being the most common. \200 unilateral disease, 2 \200\2233yrs; bilateral disease, 0 \200\22312mths. absent or abnormal light re \202 ex (leucocoria), squint, or \200 surgery, chemotherapy, and focal therapy. inherited form at risk of second p malignancy, with 18_McClure_18.indd 664 11/14/2012 3:51:02 PM CENTRAL NERVOUS SYSTEM tumors (2) 665 18_McClure_18.indd 665 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 666 Neuroblastoma A malignant embryonal tumor derived from neural crest tissue with a wide spec trum of behavior. It represents 7% of all childhood malignan- cies. Median age of presentat ion at 2yrs. Sites of involvement include: \200 \200 the adrenal glands (32%); the sympathetic chain: \200 abdomen (28%); \200 thorax (15%); \200 pelvis (6%); \200 neck (2%). May be locally invasive; surrounds, rather than displaces vessels and other structures. Dis tant metastases to bone, bone marrow, liver, CNS, lungs, and skin (especially infants). Presentation Non-speci \201 c and variable. Depends on site, spread, and metabolic effects : \200 \200 Palpable mass (may be painless). Compression of nerves (e.g. Horner \200\231s, spinal cord) , airway, veins, bowel. Bone: Lymphadenopathy and signs of pancytopenia. Sweating, pallor, watery diarrhea, and hypertension. \200 \200 pain and/or limp. Speci \201 c diagnostic tests \200 Urine catecholamine (VMA or homovanillic acid (HVA)) to creatinine ratio, which is raised i n >80% cases. 131 I-MIBG uptake scan: usually +ve. Treatment \200 Biological factors, such as MYCN ampli \201 cation and 17q gain, strongly in \202 uence p rognosis and treatment. Completely resected localized neuroblastoma may need no further tre atment. Incompletely resected, stage 3 tumors require chemotherapy and possibly adjuvant ra diotherapy. Stage 4 (disseminated) and MYCN +ve stage 3 tumors require induction chemothera py, surgery, high dose chemotherapy with autologous stem cell rescue, radiotherapy and diff erentiation therapy with cis-retinoic acid. Targeted antibody treatment is increasingly emp loyed as part of the approach to treatment in the context of clinical trials. Exception: bi ological features receive moderately intensive chemotherapy and surgery only. young (<18 mths old) stage 4 patients with favorable Prognosis Disseminated neuroblastoma only cured in 20 \200\22330%, despite intensive treatm ent. Survival in low risk cases (low stage, infants) is >90%. 18_McClure_18.indd 666 11/14/2012 3:51:02 PM NEUROBLASTOMA 667 Poor prognostic factors in neuroblastoma \200 \200 \200 \200 \200 \200 \200 \200 Age >18mths. Stage 3 and 4 disease. Raised serum ferritin. Raised LDH. Raised neuron-speci \201 c enolase (NSE). Unfavorable histology. MYCN 17q gain/1p loss. oncogene ampli \201 cation. Relapse treatment Options include further surgery, chemotherapy, and/or radiotherapy, depen ding on p treatment. After previous high dose chemotherapy and stem cell transplant, cure i s unrealistic. Treatment aimed at palliation. Infant neuroblastoma (stage IVs) Disseminated disease restricted to bone marrow, liver, and skin. Characteristically resolves spontaneously. Chemotherapy is only for life- threatenin g symptoms. Resection (complete or partial) is usually suf \201 cient for localized diseas e. 18_McClure_18.indd 667 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 668 Wilms \200\231 tumor (nephroblastoma) This is an embryonal tumor of the kidney representing 6 \200\2237% of all child- hood malignancies. Up to 75% present at <4yrs of age (90% <7yrs ). Most causes are sporadic, but 1% have an affected family member. Wilms \200\231 tumor ma y be associated with the following conditions. \200 \200 \200 \200 \200 \200 \200 Genitourinary abnormalities, e.g. horseshoe kidney, hypospadias. Hemihypertrophy syndrome. Aniridia. BWS ( Wilms \200\231, aniridia gonadal dyslasia, retardation (WAGR) complex. Deny s Drash syndrome (nephropathy and genital abnormalities). Perlman syndrome. b p.949). Mutations of the WT1 tumor suppressor gene on chromosome 11p13 detected in Wilms \200\231 t umors; abnormalities of 11p15 are also implicated, associated with BWS. Presentation Mostly as a visible or palpable abdominal mass. Usually painless. Haematuria and hypertension may also be seen. Site Bilateral cases are unusual and more often associated with genetic pre- disposition. E xtrarenal Wilms \200\231 tumors are very rare. Metastases occur in 10% of cases, most commo nly to the lung. Investigations \200 Abdominal US. \200 CT scan of abdomen ( \200\230claw \200\231 sign in involved kidney). \200 CXR or CT. \200 Urine catecholamines to exclude neuroblastoma (prior to anesthetic). \200 Blood count and coagulation studies (a transient acquired vo n Willebrand-like syndrome is recognized and resolves with treatment). Treatment \200 Surgical \200 Chemotherapy resection of tumor without breach of renal ca psule) is curable with vincristine, sometimes including dactinomycin which is also used for stage II disease. In higher-stage disease, doxorubicin is added. In bilateral (stage V) di sease, the aim is to maximize response to chemotherapy prior to performing bilateral nephro n-sparing surgery. Local or abdominal radiotherapy required for incomplete resection (stage III disease). In the presence of metastases (stage IV), surgery to primary tumor is delaye d until resolution of metastases with chemotherapy and radiotherapy is also added. Carbopla tin, cyclophosphamide, and etoposide are usually reserved for unresponsive or recurrent dis ease. excision required. is used for all tumors. In stage I disease (complete Prognosis Overall survival ranges from 770% for stage IV disease to >95% for stage I. 18_McClure_18.indd 668 11/14/2012 3:51:02 PM OTHER RENAL tumors IN CHILDHOOD 669 Relapse \200 Follow-up should include regular CXR as well as abdominal ultrasound as pulmonary relapse i s twice as common as local recurrence. Surgery, second-line chemotherapy, and radiotherapy (if not previously received) may all be applied depending on stage. Cure is achievable foll owing second remission. Nephroblastomatosis Multiple foci of premalignant tissue, also known as nephrogenic rests, characterize this condition. They may be observed on renal US and CT scan. The condition is associated with Wilms \200\231 tumor, but may exist with- out tumor formation (seen on 1% of routine post-mortem examinations). Close monitoring is required due to risk of subsequen t tumor forma- tion. Other renal tumors in childhood Mesoblastic nephroma Occurs in infants and is treated with surgery; chemotherapy is only indicat- ed for incompletely excised cases. Clear cell sarcoma A bone metastasizing renal tumor of childhood. It is more aggressive tha n Wilms \200\231 tumor and accounts for about 6% of cases. Malignant rhabdoid tumor Rare (<2% renal tumors) and occurs mainly in infants. It is associ ated with posterior fossa CNS tumors and has an unfavorable outcome. 18_McClure_18.indd 669 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 670 Bone tumors These tumors are rare in childhood (5% of all pediatric malignancies). \200 I ncidence peaks in teenage years, in which they are the 4th most common group of malignancie s. Majority of cases are osteosarcoma (OS) or Ewing \200\231s sarcoma (ES). They are histol ogically distinct, with different patterns of disease and response to treatment. Sarcomas a re associated with Li \200\223Fraumeni syndrome (familial mutation of p53), and patients cu red of familial retinoblastoma are at a high risk of OS. Osteosarcoma Presentation Localized pain and swelling, pathological fracture, and rarely er ythema. Most affect the long bones around the knee (67%) and humerus. The metaphysis is a m ore common site than mid-shaft. Delay in diagnosis is common. Metastases \200 \200 Seen at diagnosis in 15 \200\22325% of cases Lungs most common site, followed by bones. Diagnostic investigations \200 \200 \200 \200 \200 \200 Plain X-rays of bony lesion. Biopsy (for de \201 nitive diagnosis). Lactate dehydrogenase and alkaline phosphatase. MRI of primary site. CT chest. Isotope bone scan. Treatment Chemotherapy, followed by surgery and then further chemotherapy. The aim is to pe rform limb-preserving surgery whenever possible. Prognosis Adverse outlook is associated with: \200 Inability to resect primary tumor. \200 Poor response to induction chemotherapy. \200 Metastatic disease (especially extrap ulmonary disease). Relapsed osteosarcoma Most recurrences are isolated pulmonary metastases. Surgical resectio n can result in long-term survival in 20 \200\22330% of patients. The role of chemo- therap y for recurrent OS is uncertain. The role of radiotherapy is limited to palliation. Ewing \200\231s sarcoma of bone and soft tissue ES usually occurs in bone, but may also occ ur in soft tissues. ES and pe- ripheral PNETs share a common immunophenotype (CD99 or MIC2) and cytogenetic pro \201 le (t(11;22) in 85% and t(21;22) in 5 \200\22310%). Both tumor c ategories belong to the Ewing \200\231s family of tumors. (Note: Peripheral PNET should not be confused with CNS PNET tumors.) 18_McClure_18.indd 670 11/14/2012 3:51:02 PM BONE tumors 671 Presentation Localized pain and swelling, and sometimes pathological fracture. The diaphysi s of long bones is more commonly affected than metaphysis. The axial skeleton is involved m ore often than in OS with pelvis the most com- mon site. Metastases to lungs and bone are m ore common at diagnosis than in OS. Diagnostic investigations \200 \200 \200 \200 \200 \200 \200 Plain X-rays of bony lesion. Biopsy (for de \201 nitive diagnosis). Lactate dehydrogenase and alkaline phosphatase. MRI of primary site. CT chest. Isotope bone scan. Bone marrow asp irates and trephines (bilateral). Treatment Chemotherapy, followed by surgery and then further chemotherapy. For extremity si tes, limb-preserving surgery is the aim whenever possible. Radiotherapy is an effective adj unct, and an alternative to surgery, partic- ularly at axial sites. Prognosis Adverse outlook associated with: \200 \200 \200 \200 large primaries; axial sites; poor response to induction chemotherapy; metastatic disease. Bony metastases confer a particularly grave prognosis with <20% long- term survivors. Relapsed ES Salvage therapy is rarely successful, and will depend on treatment pre- viously received. Second-line chemotherapy may include combinations involving Etoposide, carboplat in, cyclophosphamide, topotecan and irono- tecan. Surgery and radiotherapy may also have a role in treatment. 18_McClure_18.indd 671 11/14/2012 3:51:02 PM CHAPTER 18 Oncology 672 Rhabdomyosarcoma Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood . It accounts for 6% of all childhood malignancies (commonly aged <10yrs). The majority of cases are sporadic. Most are either embryo- nal or alveolar (more aggressive) subtypes. Bot ryoid (good prognosis) and spindle cell types are also recognized. A small number of cases are associ- ated with Li \200\223Fraumeni syndrome. Presenting features Mass, pain and obstruction of: \200 \200 \200 \200 \200 \200 \200 \200 bladder; pelvis; nasopharynx; parameningeal; paratestis; extremity; orbit; intrathoracic. Lymph node involvement is common. Distant metastases are rare. Diagnosis and staging \200 Imaging of primary site: \200 Biopsy for histological molecu lar and cytogenetic analysis. Alveolar RMS characterized by the presence of t(2;13) or t(1; 13). CT scan of chest. Bone marrow aspirates and trephines. Isotope bone scan. Lumbar punct ure (parameningeal primaries). CT, or MRI. \200 \200 \200 Treatment \200 Chemotherapy (6 \200\2239 courses) with ifosfamide or cyclophosphamide, actinomycin, vincri stine, anthracyclines. Surgery is reserved for accessible sites (paratesticular, peripheral ) after 3 \200\2236 courses of chemotherapy. Radiotherapy after surgery for residual tumor and alveolar histology. Prognosis Ranges from <10% survival for bony metastatic disease to >90% for excised parates ticular tumors. Favorable features are: \200 \200 \200 \200 Younger age at diagnosis. Botryoid or embryonal histology. Paratesticular or super \201 ci al head and neck sites. Absence of nodal involvement or distant metastases. Off treatment monitoring Imaging of primary tumor site by US or MRI and CXRs to screen for pulmonary metastatic recurrence. Relapse \200 \200 \200 Second-line chemotherapy. Radiotherapy may be employed at sites not previously irradiated. Outcome for relapse and recurrence is poor. 18_McClure_18.indd 672 11/14/2012 3:51:03 PM GERM CELL tumors 673 Germ cell tumors Germ cell tumors (GCTs) comprise a heterogeneous group of neo- plasms, oft en with mixed histology. They arise from primordial germ cells in gonads or, following aber rant germ cell migration, in midline extrago- nadal sites, including sacrococcygeal, medias tinal, or CNS sites. GCTs are rare occurring in 3 \200\2235 per million children <15yrs of age, with peak inci- dence seen in children aged <3yrs. 10% of girls with ovarian GCTs are found to have an underlying intersex state. The nomenclature of GCTs is complicated. Mature teratoma is benign. Immature teratoma may d isseminate locally. Malignant GCTs: \200 germinoma totipotent; teratoma, yolk sac tumor ( YST), choriocarcinoma (CHC), and embryonal carcinoma (EC) represent more differentiated for ms. Secreting tumors (YST, CHC, some immature teratomas, and mixed tumors) characterized by secretion of AFP and/or hCG, which may be used for diagnosis, monitoring of treatment resp onse, and detection of recurrence. \200 \200 (or seminoma, dysgerminoma, depending on site) is Presenting symptoms Site-dependent. Testicular masses are usually painless. Ovarian tumors present as either painful or painless abdominal mass. Metastases are rarely present at diag nosis (lungs, the commonest site, bone, and bone mar- row). Diagnosis and staging \200 \200 \200 B-hCG in serum (and CSF for CNS disease). Measurement of AFP and Imaging of primary: Biopsy of unresectable tumors (unless unsafe) an d/or imaging and markers suf \201 cient to make diagnosis. CT scan of chest and abdomen. B one marrow and isotope bone scan to look for metastases. US, CT, or MRI. \200 Treatment of extracranial tumors \200 Surgery followed by observation for low risk tumors (e.g. mature/ immature teratoma and gon adal stage I). Note: Testicular tumors should be removed via an inguinal approach. Sacrococcygeal teratoma s should be removed together with the coccyx to reduce risk of malignant relapse. Chemother apy is reserved for intermedi- ate and high risk disease. Prognosis Survival >90% for malig nant extracranial GCTs. 18_McClure_18.indd 673 11/14/2012 3:51:03 PM CHAPTER 18 Oncology 674 Primary liver tumors \200 Hepatoblastoma (HBL) is the commonest primary pediatric hepatic tumor (<1% all cancers), wi th 2/3 of cases in the \201 rst year of life. Hepatocellular carcinoma (HCC) an embryonal (undifferentiated) sarcoma of the liver are rare in children. Serum AFP levels are raised in >80% HBL. Treatment \200 \200 Chemotherapy including platinum drugs and anthracyclines for HBL. Good surgical result is c ritical for long-term survival. Liver transplant is indicated if local resection not possib le. Treatment is the similar for HCC, although they are less sensitive to chemotherapy. Emb ryonal sarcoma is usually treated on soft tissue sarcomas protocols. Prognosis Long-term survival for HBL is >70%, even in presence of lung metastases. Survival for HCC is signi \201 cantly lower. 18_McClure_18.indd 674 11/14/2012 3:51:03 PM OTHER RARE tumors 675 Other rare tumors Up to 5% of malignancies in childhood are very rare. They include: \200 \200 Epithelial or adult-type tumors, (e.g. carcinomas and melanoma). Embryonal tumors (e.g. rha bdoid tumors). Malignant melanoma Risk factors include: \200 \200 \200 \200 \200 \200 pre-existing conditions; giant congenital naevi; dysplastic naevus syndrome; xeroderma pigm entosum; albinism; immunosuppressive diseases. Most cases arise on healthy skin and may be related to sun exposure. Surgery is the mainsta y of treatment. Survival around 90% for local disease; 25% for metastatic disease. Rhabdoid tumors \200 \200 Highly aggressive tumors that arise in kidneys or CNS. In the CNS, they appear histological ly similar to PNETs, but sometimes associated with tumors outside the CNS. Treatment includ es surgery, chemotherapy, and radiotherapy. Long- term survival is rare. Phaeochromocytoma Tumors in the adrenal medulla and sympathetic ganglia are usually spo- ra dic, but may be associated with von Hippel \200\223Lindau disease and multiple endocrine ne oplasia types 2a and 2b (see b p.440). They present with en- docrine manifestations, (e.g. hypertension, excessive sweating) or a mass. Less than 10% of phaeochromocytomas are malign ant. Investigations Plasma and urine catecholamine levels are usually raised. Treatment Surgery after -adrenergic antagonists to control sympathetic symptoms. Nasopharyngeal carcinoma The commonest epithelial cancer in children. It is found in teenag ers and associated with antibodies to EBV: \200 \200 B interferon. Treatment involves chemotherapy, radiotherapy, and 770%. Overall survival at 5yrs Other carcinomas These carcinomas are rare. \200 (predominantly the papillary variant and associated with Thyroid exposure to radiation). Ma y present with asymmetrical nodular goiter (see b pp.420 \200\223421). Adrenal carcinoma (s een in young adults with occasional occurrences in older children). May present with precoc ious puberty, inappropriate virilization in females (see b p.480). 18_McClure_18.indd 675 11/14/2012 3:51:03 PM CHAPTER 18 Oncology 676 Langerhans cell histiocytosis Langerhans cell histiocytosis (LCH) is a disorder of unknown cause with a wide range of presentations. It is not a malignant condition, but may behave l ike one in its severest forms. Usually managed by pediatric on- cologists. Langerhans cells are normally found in skin, lymph nodes, and airways. LCH results from mon oclonal proliferation and accumulation of histio- cytes, with the characteristics of Langer hans cells, in skin, bone, pituitary, CNS, lungs, intestines, spleen, or bone marrow. It ma y manifest as single- or multisystem disease. Single-system disease is usually con \201 ne d to bone, occasionally to skin, and seen more in older children. The natural history varie s from spontaneous resolution to repeated recurrence, or death.