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

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Presentation on theme: "Germ Cell Tumors, Hepatoblastoma & Retinoblastoma Neyssa Marina, MD Professor of Pediatrics Division of Hematology-Oncology."— Presentation transcript:

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 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 StageDescription IComplete resection with normalization of tumor markers within expected half-life. IIMicroscopic residual disease: persistent marker elevation; lymph nodes < 2 cms IIIGross residual disease: retroperitoneal lymph nodes > 2 cms; no extra-abdominal or visceral metastases IVDistant metastases

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 EFS 81.8% yr S 100%

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 cycles PEB 6-yr S: 95.7% yr EFS: 94.5% + 3.6

17 Advanced GCT Study Design Diagnosis RANDOMIZERANDOMIZE Cisplatin 100 mg/m2 Etoposide Bleomycin PEB Cisplatin 200 mg/m 2 Etoposide Bleomycin HD-PEB

18 Advanced Pediatric GCT: Patients  299 patients d iagnosed between February 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 P= yr EFS: 89.6% yr EFS: 80.5% yr S:91.7% yr S: 86% P=0.176 P=0.05

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 cases/year in US /10 6 (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 , National Cancer Institute, SEER Program. NIH Pub. No Bethesda, MD, 1999.

24 Hepatoblastoma: Risk Factors  Prematurity and low birth weight Disproportionate # of cases with BW < 2500 grams RR for BW <1000g, 2.53 for BW g, 1.21 for BW g  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 alternative patients 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 2-5/10 6 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: 2 nd or 3 rd 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 GroupDefinition Ia Solitary tumor < 4 dd Ib Multiple tumors, none > 4 dd IIa Solitary tumor 4-10 dd IIb Multiple tumors 4-10 dd IIIa Any lesion anterior to equator IIIb Solitary lesion > 10 dd behind equator IVa Multiple tumors, some > 10 dd IVb Any tumor extending anterior to ora serrata Va Massive tumor involving > half retina Vb Vitreous seeding

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


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