Germ Cell Tumors, Hepatoblastoma & Retinoblastoma

1. Germ Cell Tumors, Hepatoblastoma & Retinoblastoma Neyssa Marina, MD Professor of Pediatrics Division of Hematology-Oncology

2. Pediatric GCT • Rare: 2-3% of childhood malignancies • Arise from pluripotent cells & composed of tissues foreign to site of origin • Occur at gonadal & extragonadal sites • Bimodal age distribution • Peak < 3 years • Extragonadal • Testicular tumors • Peak: adolescence • Gonadal tumors

3. Pediatric GCT: Clinical Presentation • Depends on primary site: • Ovarian: abdominal pain (may mimic acute abdomen), palpable abdominal mass • Testicular: Irregular, non-tender masses • Extragonadal tumors: depends on tumor location • Constipation & urinary retention for sacrococcygeal tumors • Respiratory distress for mediastinal tumors

4. Pediatric GCT: Laboratory Work-up • Alfa fetoprotein (AFP): elevated in yolk sac tumor and embryonal carcinoma; half-life 5-7 days • β-Human chorionic gonadotropin (β-HCG): usually synthesized during pregnancy & elevated in choriocarcinoma, embryonal carcinoma and germinomas; half-life 24-36 hours • Lactic dehydrogenase (LDH): correlate with tumor burden in patients with dysgerminoma • Placental alkaline phosphatase (PLAP): elevated in patients with dysgerminoma

5. Pediatric GCT: Imaging Work-up • CT scan or MRI of primary: to evaluate the extent of loco-regional disease • Chest CT: to evaluate presence of metastases • Bone scan: to evaluate for distant metastases

6. Pediatric GCT: Staging

7. Histologic Classification

8. GCT: Pediatric Versus Adult • Histologically • Children < 4 years age: endodermal sinus tumor • Adolescents: mixed histology tumors • Genetically(Schneider, Genes, Chromosomes & Cancer 34:115, 2001) • Childhood tumors: diploid & tetraploid • Gains of chromosomes (1q, 3 & 20q) & deletions 1p & 6q • Adolescent tumors: aneuploid • Isochromosome 12p

9. Pediatric GCT: Outcome • Survival < 20% before use of chemotherapy Kurman Cancer 38: 2404, 1976.

10. Pediatric GCT: Treatment • Cyclophosphamide based therapy: improved outcome • Advanced stage patients continued to have poor outcome Cangir, Cancer 42:1234, 1978.

11. Adult GCT • Introduction of cisplatin-based therapy curative in adults • Einhorn regimen (cisplatin, vinblastine, bleomycin): high-complete remission rate (Einhorn, Ann Int Med 87:293, 1977) • Increasing cisplatin dose-intensity: increased toxicity without improving outcome (Nichols, J Clin Oncol 9:1163, 1991)

12. Pediatric GCT: Outcome • Although cisplatin-based therapy appeared effective in small number of pediatric patients • Significant concerns regarding pulmonary and ototoxicity prevented widespread use of this therapy Mann, Cancer 63:1657, 1989 Pinkerton, et al. J Clin Oncol, 1986

13. Pediatric GCT: Treatment • Based on differences between pediatric and adult tumors, the Pediatric Oncology Group (POG) and the Children’s Cancer Group (CCG) designed two prospective studies • Localized gonadal GCT: • Stage I testicular: evaluate the event-free survival & overall survival following surgical resection. • Stage I/II malignant GCT: evaluate the role of surgery + PEB • Advanced GCT: • Stage III/IV gonadal & stage I-IV extragonadal: evaluate the role of cisplatin dose-intensity in a randomized trial

14. Stage I Testicular: EFS & S • 63 patients stage I testicular tumors treated with surgery & observation • Age: 1 mo.-5 years • Histology: 57 yolk sac carcinoma • Failures: 13 patients (median 4 mo. range, 2-18 mo.) • Disease recurrence (n=7); median 3 mo. (2-18 mo.) • Markers never normalized (n=6); median 4.5 mo. (2-10 mo.) 6-yr S 100% 6-yr EFS 81.8% + 6.6

15. Treatment Schema

16. Pediatric GCT: Low Stage • Stage II testicular • 17 patients median age 20 months • Ovarian: 57 patients • Stage I: 41 patients median age 11.9 years • Stage II: 16 patients median age 10.7 years • Treatment: surgery + 4-6 cycles PEB 6-yr S: 95.7% + 3.1 6-yr EFS: 94.5% + 3.6

17. Advanced GCT Study Design Cisplatin 100 mg/m2 Etoposide Bleomycin PEB RANDOMIZE Diagnosis Cisplatin 200 mg/m2 Etoposide Bleomycin HD-PEB

18. Advanced Pediatric GCT: Patients • 299 patients diagnosed between February 1990-1996 • Median age 3.4 years (range 3 days-20 years) • 183 female • Primary sites • 165 extragonadal tumors • 134 gonadal tumors • Stage distribution: • 30 stage I/II • 136 stage III • 133 stage IV • Following surgery patients randomized • 150 patients (PEB): 67 gonadal tumors; 83 extragonadal • 149 patients (HD-PEB): 67 gonadal; 82 extragonadal

19. Advanced GCT: EFS & S by Treatment 6-yr S:91.7% + 3.3 6-yr EFS: 89.6% + 3.6 6-yr S: 86% + 4.1 6-yr EFS: 80.5% + 4.8 P=0.05 P=0.176 P=0.0284

20. Extragonadal GCT: Prognostic Factors • Extragonadal GCT typically considered high-risk • Examine prognostic factors in a large group of patients • By multivariate Cox regression for EFS • Age > 12 years: only significant prognostic factor (p=0.002) • Relative Risk 3.8 • After adjusting for age, treatment was borderline significant (p=0.064) • In multivariate Cox regression for OS, the interaction of age & primary site was highly significant (p<0.0001) • Patients > 12 years with thoracic tumors 5.9 times greater risk of death than patients < 12 years or patients with any other primary

21. GCT: Conclusions • Patients with stage I GCT represent a low-risk group • Patients with stage II-III gonadal GCT appear to be an intermediate risk group • Patients with advanced extragonadal tumors represent a high-risk group • Age > 12 years is the factor most predictive for EFS in these patients • There is a significant interaction between age and primary site. • This suggests that patients over 12 years with thoracic tumors are biologically different.

22. Pediatric Liver Tumors • Rare: ~ 1.1% of malignancies • 100-150 cases/year in US • 0.5-1.5/106 (age < 15 years) in Western countries • Affects infants and young children (6 mo – 3yrs; mean age 19 months) • Third most common intra-abdominal neoplasm (67% hepatic malignancies < 20 yrs but 91% < 5 years) • Hepatocellular carcinoma more frequent than hepatoblastoma in Asia and Africa (hepatitis B infection endemic)

23. Pediatric Liver Tumors • Incidence rates for liver tumors: age-dependent Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999.

24. Hepatoblastoma: Risk Factors • Prematurity and low birth weight • Disproportionate # of cases with BW < 2500 grams • RR 15.64 for BW <1000g, 2.53 for BW 1000-1499g, 1.21 for BW 1500-2499g • Association with overgrowth syndromes: • Beckwith-Wiedemann (LOH 11p15) • Familial adenomatous polyposis (FAP; inactivation of tumor suppressor gene on chromosome 5) • Estimated that 1:20 cases of hepatoblastoma have FAP • Lifetime risk of hepatoblastoma for children of FAP families: 1/250 compared to 1/100,000 in general population

25. Hepatoblastoma: Clinical Presentation • Asymptomatic abdominal mass • Weight loss, anorexia, emesis, and abdominal pain (advanced disease) • Distant metastases ~ 20% of cases mostly to lung • Intraperitoneal, lymph node, brain, and local tumor thrombus • Thrombocytosis is common • HB cells secrete IL-1B: induces fibroblasts/endothelial cells to produce IL-6  hepatocyte growth factor secretion and thrombopoeitin secretion • 90% of patients have elevated alpha-fetoprotein • Rare: hypertension in cases of renin-secreting mixed HB or precocious puberty in HB secreting human chorionic gonadotropin

26. Hepatoblastoma: Histology • Derived from undifferentiated embryonal tissue/pluripotent hepatic stem cells • Differentiates into hepatocytes, biliary epithelial cells • Originally, 2 subtypes recognized • Epithelial (mixture of embryonal and fetal) • Mixed epithelial and mesenchymal • Later classification based on degree of differentiation • Embryonal (30%) : tubular or glandular; rosettes of elongated cells • Fetal (54%) : highly differentiated; resemble normal hepatocytes with rare mitoses; lack normal lobular architecture • Anaplastic/small cell undifferentiated type (6%) : small cells with densely stained nuclei and scant cytoplasm • Macrotrabecular (10%) : features similar to hepatocellular carcinoma

27. Hepatoblastoma: Relevance of Histology • Favorable histology defined: “completely resected tumor with a uniform, well-differentiated fetal component exhibiting < 2 mitoses per 10 HPF” • Patients treated with surgical resection alone • All other histology is considered unfavorable and if stage II-IV, histology is considered irrelevant Ortega et. al. J Clin Oncology, 2000

28. Hepatoblastoma: Work-Up • Diagnostic imaging: important role in diagnosis, staging and treatment • Ultrasound: usually first test performed • Helps evaluate cystic versus solid masses • CT scan or MRI: defines the tumor extent, vascular supply, operability and distant extent of tumor • Laboratory work-up: • Alfa Fetoprotein: most valuable test • Elevated in 80-90% of patients & useful for monitoring • Biologic half-life: 5-7 days

29. Hepatoblastoma: Staging • Critical to have agreed-upon staging allowing comparison between different studies • Early studies of hepatoblastoma showed that surgical resection is the mainstay of therapy and required for cure • Staging based on surgical criteria (currently used by German Cooperative Group, CCG, POG) • Investigators at SIOP began using preoperative chemotherapy for all patients and thus devised alternative staging system (PRETEXT)

30. Surgically-based Staging • Stage 1 : complete gross resection with clear margins • Stage 2 : Gross total resection with microscopic residual disease at margins • Stage 3 : Gross total resection with nodal involvement or tumor spill during resection OR incomplete resection with gross residual intrahepatic disease • Stage 4 : Metastatic disease with complete or incomplete resection

31. PRETEXT Staging • PRETEXT I: one sector involved • PRETEXT II: two sectors involved • PRETEXT III: two non-adjoining sectors free or 3 sectors involved • PRETEXT IV: all four sectors involved

32. Event-free survival by PRETEXT stage

33. EFS by metastases

34. Hepatoblastoma: Treatment • Complete surgical resection: mainstay of therapy • Possible at diagnosis: < 50% of patients • Surgery: curative > 90% of purely fetal hepatoblastomas • 5-year survival with surgery: < 10% other histologies • Chemotherapy: used to convert inoperable tumors into resectable tumors • Current 5-year survival rate 75% • Current objective: improve the prognosis for the 25% of patients who die of disease

35. New Approaches to Treatment • “New Agents”: attempt to increase response rate • Chemoembolization: Intra-arterial co-administration of chemotherapeutic and vascular occlusive agents to treat malignant diseases. • Liver Transplant: an alternativepatients with unresectable disease following chemotherapy

36. Hepatic Chemoembolization • Normal liver parenchyma has dual blood supply: • 75%: portal vein • 25%: hepatic artery • Liver tumors: receive their blood supply almost exclusively from hepatic artery • 10% of normal parenchyma: sufficient to maintain metabolic activity

37. Review of World Experience • Authors collected data on 147 cases worldwide : 106 had primary LTX, 41 had rescue LTX • OS 72.8%

38. Hepatoblastoma: Conclusions • The addition of cisplatin-based therapy has improved the outcome for patients with hepatoblastoma • Increasing the proportion of patients who can undergo resection • Prognosis: sub-optimal for patients with unresectable tumors (following chemotherapy) and for patients with metastases • Chemo-embolization and liver transplantation appear to be promising in this subset of patients • Identification of new active agents important to attempt to decrease the number of patients with unresectable tumors following chemotherapy

39. Retinoblastoma • Most frequent eye neoplasm in childhood • Third most common intraocular malignancy in all ages • Malignant melanoma and metastatic carcinoma • 2.5-4% of all pediatric cancer • 11% of all cancer in children < 1 year of age • Two-thirds of cases before 2 years and 95% before 5 years • Average age-adjusted incidence rate 2-5/106 children • 300 children develop retinoblastoma each year

40. Retinoblastoma Two clinical forms • Bilateral (~40%): characterized by germline mutations in Rb1 gene • Inherited from affected survivor (25%) • New germline mutation (75%) • 10% unilateral • Impossible to tell whether hereditary • Unilateral (~ 60% of cases)

41. Retinoblastoma • Arises from fetal retinal cells: lost function of both allelic copies Rb1 gene • First event germline or somatic • Second event always somatic • Mutations in Rb1 detected in 90% cases • Another gene or alternate mechanism of inactivation

42. Retinoblastoma • Unique tumor: genetic form predisposes to tumor development in autosomal dominant fashion (85-90% penetrance) • Majority of children acquire new mutation (15-25% positive family history) • Risk of retinoblastoma in offspring of retinoblastoma survivors • Bilateral disease: 45% • Unilateral disease: 2.5% • Risk of retinoblastoma in siblings: • Bilateral disease: 45% • Unilateral disease: 30%

43. Retinoblastoma: Clinical Presentation • Tumor of the young • Age at presentation correlates with laterality • Bilateral < 1 year of age • Unilateral: 2nd or 3rd year of life • Half of cases diagnosed under 1 year: bilateral compared to <10% of cases diagnosed after 1 year • Most common presentation leukocoria followed by strabismus

44. Retinoblastoma: Evaluation • Diagnosis made without pathologic confirmation • Mass protruding into the vitreous • Detailed documentation of number, location & size of tumors as well as retinal detachment, sub-retinal fluid & vitreous, sub-retinal seeds • Imaging studies aid diagnosis • CT, ultrasound & MRI: important to evaluate extraocular extension • Metastases: 10-15% of patients associated with choroidal, scleral invasion or involvement of iris-ciliary body or optic nerve • Bone marrow aspirate, CSF & bone scintigraphy to evaluate patients with these findings

45. Retinoblastoma: Staging • Reese-Ellsworth (R-E) grouping system standard (based on size, location & number of lesions) • Does not predict eye salvage • New staging systems developed • Pathologic staging: features influence treatment & prognosis

46. Retinblastoma: Staging • Extra retinal extension: large intraocular dimension • Metastatic risk & mortality: invasion of ocular coats and optic nerve • Optic nerve involvement common (25-45%): impact on outcome limited to involvement beyond lamina cribosa • Choroidal involvement: up to 40% patients • Extensive < 10%: prognostic implication

47. Retinoblastoma: Treatment • Treatment: aims at preserving life and useful vision • Factors considered: • Disease: unilateral vs. bilateral • Potential for vision • Staging: intra & extra ocular

48. Retinoblastoma: Treatment • Enucleation: large tumors filling the vitreous with no likelihood of restoring vision • Ocular implant usually placed • Focal treatments: small tumors in patients with bilateral disease combined with chemotherapy • Chemotherapy: extraocular disease, intraocular disease with high-risk features and patients with bilateral disease (combined with focal therapies) • Radiotherapy: combined with focal treatment provides excellent local control • Radiation predisposes to second malignancies: avoid or delay its use

49. Retinoblastoma: Treatment • Outcome: excellent for unilateral disease treated with enucleation (85-90% cure) • Successful chemoreduction has led to attempts at salvaging eyes in very young children with unilateral disease • Bilateral disease: treated enucleation of eyes with advanced disease and radiation for remaining eyes • Up-front chemotherapy to achieve chemoreduction followed by aggressive focal therapy • Increase in eye salvage rate & decrease and delay of radiotherapy • Best results with carboplatin, vincristine and etoposide

50. Retinoblastoma: Conclusion • The outcome for patients with retinoblastoma is excellent • Treatment strategies are aimed at increasing eye salvage rate and decreasing late effects • Patients with bilateral disease are at risk for second malignancies • The use of radiotherapy increases that risk • Genetic counseling is an essential part of treatment for patients with bilateral disease