1 Germ Cell Tumors, Hepatoblastoma & Retinoblastoma Neyssa Marina, MDProfessor of PediatricsDivision of Hematology-Oncology
2 Pediatric GCT Rare: 2-3% of childhood malignancies Arise from pluripotent cells & composed of tissues foreign to site of originOccur at gonadal & extragonadal sitesBimodal age distributionPeak < 3 yearsExtragonadalTesticular tumorsPeak: adolescenceGonadal tumorsPediatric germ cell tumors are rare representing only 2-3% of childhood malignancies. They arise from pluripotent stem cells and are usually composed of tissues foreign to the original site of origin. Tumors can arise in both gonadal and extragonadal sites.During the rest of the time, I will be discussing extracranial germ cell tumors since their intracranial counterparts are usually discussed in the context of brain tumors.
3 Pediatric GCT: Clinical Presentation Depends on primary site:Ovarian: abdominal pain (may mimic acute abdomen), palpable abdominal massTesticular: Irregular, non-tender massesExtragonadal tumors: depends on tumor locationConstipation & urinary retention for sacrococcygeal tumorsRespiratory 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 daysβ-Human chorionic gonadotropin (β-HCG): usually synthesized during pregnancy & elevated in choriocarcinoma, embryonal carcinoma and germinomas; half-life hoursLactic dehydrogenase (LDH): correlate with tumor burden in patients with dysgerminomaPlacental 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 diseaseChest CT: to evaluate presence of metastasesBone scan: to evaluate for distant metastases
6 Pediatric GCT: Staging StageDescriptionIComplete resection with normalization of tumor markers within expected half-life.IIMicroscopic residual disease: persistent marker elevation; lymph nodes < 2 cmsIIIGross residual disease: retroperitoneal lymph nodes > 2 cms; no extra-abdominal or visceral metastasesIVDistant metastasesStaging: the staging systems for germ cell tumors includes a combination of clinical presentation and the extent of surgical resection at the time of diagnosis. As illustrated:Stage I: completely resected with normalization of markers according to half-lifeStage II: microscopic residual as evidenced by persistent marker elevation or retroperitoneal lymph nodes < 2 cmsStage III: gross residual disease or retroperitoneal lymph nodes > 2 cms without evidence of extra-abdominal or visceral metastases.Stage IV: distant metastases.
7 Histologic Classification There are at least 6 histologic sub-types of germ cell tumors as illustrated in the table on the left abstracted from a recent paper by J. Mann. This include germinomas, teratomas, which can be further classified as mature, immature or frankly malignant. In addition, the tumor can include yolk sac carcinoma, embryonal carcinoma or choriocarcinoma.
8 GCT: Pediatric Versus Adult HistologicallyChildren < 4 years age: endodermal sinus tumorAdolescents: mixed histology tumorsGenetically (Schneider, Genes, Chromosomes & Cancer 34:115, 2001)Childhood tumors: diploid & tetraploidGains of chromosomes (1q, 3 & 20q) & deletions 1p & 6qAdolescent tumors: aneuploidIsochromosome 12pWhen one compares pediatric and adult germ cell tumor patients, several differences become apparent. First, in children less than 4 years of age, the most common histologic sub-type is endodermal sinus tumors, whereas in adolescents and young adults the most common sub-type are mixed germ cell tumors.In addition to the histologic differences, cytogenetically tumors in these two age groups are also different. For instance, pediatric tumors (illustrated in the top panel) are commonly diploid & tetraploid and exhibit gains of chromosome 1q, 3 & 20q along with deletions of 1p &6q. In contrast, adolescent tumors are most commonly aneuploid and exhibit the characteristic isochromosome 12p as well as gains on the X chromosome.
9 Pediatric GCT: Outcome The survival of pediatric germ cell tumors was poor before the consistent use of effective chemotherapy with survival in the 20% range as illustrated in this slide from a paper describing outcome of 63 patients with endodermal sinus tumor of the ovary. In that series, the actuarial survival at 3 years was 13%.Survival < 20% before use of chemotherapyKurman Cancer 38: 2404, 1976.
10 Pediatric GCT: Treatment Cyclophosphamide based therapy: improved outcomeAdvanced stage patients continued to have poor outcomeThe introduction of chemotherapy including cyclophosphamide at 10 mg/kg/d x 5 days every 6 weeks improved the prognosis for pediatric patients with germ cell tumors as illustrated in this slide. However, the outcome for patients with advanced disease especially stage IV continued to be poor.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)The introduction of the Einhorn regimen revolutionized the treatment of testicular tumors in adults since it produced high-remission rates.A subsequent study by Nichols evaluated the role of cisplatin dose intensifications in these patients. In this study, patients received etoposide 100 mg/m2/d x 5 days and weekly bleomycin and were assigned to either cisplatin 20 mg/m2/d x 5 days or 40 mg/m2/day x 5 days. Survival for both groups was 74% and the high-dose regimen was significantly more toxic. The authors concluded that the use of high-dose cisplatin in these patients was not warranted.
12 Pediatric GCT: Outcome Although cisplatin-based therapy appeared effective in small number of pediatric patientsSignificant concerns regarding pulmonary and ototoxicity prevented widespread use of this therapyAlthough preliminary results from St. Jude and the United Kingdom suggested that cisplatin-based therapy was effective in children with 67-84% survival at 5 years.Pediatricians continued to have significant concerns regarding the toxicity of this combination. This included concerns regarding both the pulmonary toxicity of bleomycin as well as hearing loss with cisplatin.Mann, Cancer 63:1657, 1989Pinkerton, 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 studiesLocalized 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 + PEBAdvanced GCT:Stage III/IV gonadal & stage I-IV extragonadal: evaluate the role of cisplatin dose-intensity in a randomized trialBased on the differences between pediatric and adult germ cell tumors, the POG & CCG designed two prospective studies in pediatric patients with germ cell tumors.The first study for patients with localized germ cell tumors (May 1990-March 1995) had three objectives:1. Evaluate the event-free and overall survival of pediatric patients with testicular tumors following surgical resection & observation.2. Evaluate the role of surgery and PEB in the treatment of patients with stage II testicular and stage I-II ovarian tumors.3. Evaluate survival for patients with immature teratomas following complete surgical resection & observation.The second study for patients with advanced germ cell tumors (February 1990-February 1996) defined as stage III/IV gonadal and all extragonadal tumors evaluated the role of cisplatin dose intensity.
14 Stage I Testicular: EFS & S 63 patients stage I testicular tumors treated with surgery & observationAge: 1 mo.-5 yearsHistology: 57 yolk sac carcinomaFailures: 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% + 6.6This illustrates the 6-year EFS & OS, respectively of 81.8% and 100%.We can conclude that surgical resection followed by observation is effective treatment for these patients and avoids the use of chemotherapy in 80% of the patients.
15 Treatment SchemaThis slide illustrates the treatment schema for all patients. Patients with localized disease received standard PEB with cisplatin at a dose of 20 mg/m2/day x 5 days. The advanced stage patients were randomly assigned to standard or HD-PEB. As you can see, the only difference between these two arms is the cisplatin dose.
16 Pediatric GCT: Low Stage Stage II testicular17 patients median age 20 monthsOvarian: 57 patientsStage I: 41 patients median age 11.9 yearsStage II: 16 patients median age 10.7 yearsTreatment: surgery cycles PEB6-yr S: 95.7% + 3.16-yr EFS: 94.5% + 3.6There were 74 patients with stage II testicular and stage I-II ovarian tumors enrolled on the localized study and treated with surgical resection followed by 4-6 cycles of PEB.This included 17 patients (median age of 20 months) with stage II testicular tumors, 41 patients with stage I ovarian tumors (median age 11.9 years) and 16 patients with stage II ovarian tumors (median age 10.7 years).
17 Advanced GCT Study Design Cisplatin 100 mg/m2EtoposideBleomycinPEBRANDOMIZEDiagnosisCisplatin 200 mg/m2EtoposideBleomycinHD-PEBThis slide reviews the study design for patients with advanced germ cell tumors. That is following diagnosis, patients were randomized to standard of dose-intensive PEB.
18 Advanced Pediatric GCT: Patients 299 patients diagnosed between FebruaryMedian age 3.4 years (range 3 days-20 years)183 femalePrimary sites165 extragonadal tumors134 gonadal tumorsStage distribution:30 stage I/II136 stage III133 stage IVFollowing surgery patients randomized150 patients (PEB): 67 gonadal tumors; 83 extragonadal149 patients (HD-PEB): 67 gonadal; 82 extragonadal299 patients with extracranial, advanced GCT were eligible for participation in the high-risk study. The patients were diagnosed between FEB , had a median age of 3.4 years were female and there were 134 gonadal and 165 extragonadal tumors. The stage distribution included a 269 patients with stage III or IV disease.Following surgery 150 patients were randomized to PEB while 149 were randomized to HD-PEB. There was an equal distribution of primary sites by treatment.
19 Advanced GCT: EFS & S by Treatment 6-yr S:91.7% + 3.36-yr EFS: 89.6% + 3.66-yr S: 86% + 4.16-yr EFS: 80.5% + 4.8P=0.05P=0.176P=0.0284This slide illustrates the 6-year EFS & OS by assigned treatment. As you can see, there is a clear EFS advantage of HD-PEB with a p-value of However, there is no significant difference in survival between treatment arms.When assessing the causes of events in the two arms, it is clear that more patients suffer disease recurrence in the standard PEB, while there is an increased incidence of toxic events in patients receiving HD-PEB.
20 Extragonadal GCT: Prognostic Factors Extragonadal GCT typically considered high-riskExamine prognostic factors in a large group of patientsBy multivariate Cox regression for EFSAge > 12 years: only significant prognostic factor (p=0.002)Relative Risk 3.8After 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 primaryMultivariate Cox proportional hazard regression identified age > 12 years as the only significant prognostic factor for EFS with a risk of death 3.8 times higher in these patients as compared to patients < 12 years of age. After adjusting for age, treatment was borderline significant for EFS.In multivariate COX PH model for OS, the interaction of age and primary site was highly significant. Patients > 12 with thoracic tumors had 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 groupPatients with advanced extragonadal tumors represent a high-risk groupAge > 12 years is the factor most predictive for EFS in these patientsThere is a significant interaction between age and primary site.This suggests that patients over 12 years with thoracic tumors are biologically different.In conclusion, patients with stage I germ cell tumors represent a low-risk group.Patients with stage II-IV gonadal tumors appear to be an intermediate risk group with an excellent outcome following PEB.Patients with advanced extragonadal germ cell tumors are a higher-risk group.In this group, age > 12 years is the most predictive factor for EFS. There is a significant interaction between age and primary site suggesting that patients over 12 years with thoracic tumors are biologically different.
22 Pediatric Liver Tumors Rare: ~ 1.1% of malignanciescases/year in US/106 (age < 15 years) in Western countriesAffects 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-dependentRies 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 weightDisproportionate # of cases with BW < 2500 gramsRR for BW <1000g, 2.53 for BW g, 1.21 for BW gAssociation 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 FAPLifetime risk of hepatoblastoma for children of FAP families: 1/250 compared to 1/100,000 in general population
25 Hepatoblastoma: Clinical Presentation Asymptomatic abdominal massWeight loss, anorexia, emesis, and abdominal pain (advanced disease)Distant metastases ~ 20% of cases mostly to lungIntraperitoneal, lymph node, brain, and local tumor thrombusThrombocytosis is commonHB cells secrete IL-1B: induces fibroblasts/endothelial cells to produce IL-6 hepatocyte growth factor secretion and thrombopoeitin secretion90% of patients have elevated alpha-fetoproteinRare: 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 cellsDifferentiates into hepatocytes, biliary epithelial cellsOriginally, 2 subtypes recognizedEpithelial (mixture of embryonal and fetal)Mixed epithelial and mesenchymalLater classification based on degree of differentiationEmbryonal (30%) : tubular or glandular; rosettes of elongated cellsFetal (54%) : highly differentiated; resemble normal hepatocytes with rare mitoses; lack normal lobular architectureAnaplastic/small cell undifferentiated type (6%) : small cells with densely stained nuclei and scant cytoplasmMacrotrabecular (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 aloneAll other histology is considered unfavorable and if stage II-IV, histology is considered irrelevantOrtega et. al. J Clin Oncology, 2000
28 Hepatoblastoma: Work-Up Diagnostic imaging: important role in diagnosis, staging and treatmentUltrasound: usually first test performedHelps evaluate cystic versus solid massesCT scan or MRI: defines the tumor extent, vascular supply, operability and distant extent of tumorLaboratory work-up:Alfa Fetoprotein: most valuable testElevated in 80-90% of patients & useful for monitoringBiologic half-life: 5-7 days
29 Hepatoblastoma: Staging Critical to have agreed-upon staging allowing comparison between different studiesEarly studies of hepatoblastoma showed that surgical resection is the mainstay of therapy and required for cureStaging 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 marginsStage 2 : Gross total resection with microscopic residual disease at marginsStage 3 : Gross total resection with nodal involvement or tumor spill during resection OR incomplete resection with gross residual intrahepatic diseaseStage 4 : Metastatic disease with complete or incomplete resection
31 PRETEXT Staging PRETEXT I: one sector involved PRETEXT II: two sectors involvedPRETEXT III: two non-adjoining sectors free or 3 sectors involvedPRETEXT IV: all four sectors involved
34 Hepatoblastoma: Treatment Complete surgical resection: mainstay of therapyPossible at diagnosis: < 50% of patientsSurgery: curative > 90% of purely fetal hepatoblastomas5-year survival with surgery: < 10% other histologiesChemotherapy: used to convert inoperable tumors into resectable tumorsCurrent 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 rateChemoembolization: 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 vein25%: hepatic arteryLiver tumors: receive their blood supply almost exclusively from hepatic artery10% 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 LTXOS 72.8%
38 Hepatoblastoma: Conclusions The addition of cisplatin-based therapy has improved the outcome for patients with hepatoblastomaIncreasing the proportion of patients who can undergo resectionPrognosis: sub-optimal for patients with unresectable tumors (following chemotherapy) and for patients with metastasesChemo-embolization and liver transplantation appear to be promising in this subset of patientsIdentification 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 agesMalignant melanoma and metastatic carcinoma2.5-4% of all pediatric cancer11% of all cancer in children < 1 year of ageTwo-thirds of cases before 2 years and 95% before 5 yearsAverage age-adjusted incidence rate 2-5/106 children300 children develop retinoblastoma each year
40 Retinoblastoma Two clinical forms Bilateral (~40%): characterized by germline mutations in Rb1 geneInherited from affected survivor (25%)New germline mutation (75%)10% unilateralImpossible to tell whether hereditaryUnilateral (~ 60% of cases)
41 RetinoblastomaArises from fetal retinal cells: lost function of both allelic copies Rb1 geneFirst event germline or somaticSecond event always somaticMutations in Rb1 detected in 90% casesAnother gene or alternate mechanism of inactivation
42 RetinoblastomaUnique 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 survivorsBilateral disease: 45%Unilateral disease: 2.5%Risk of retinoblastoma in siblings:Unilateral disease: 30%
43 Retinoblastoma: Clinical Presentation Tumor of the youngAge at presentation correlates with lateralityBilateral < 1 year of ageUnilateral: 2nd or 3rd year of lifeHalf of cases diagnosed under 1 year: bilateral compared to <10% of cases diagnosed after 1 yearMost common presentation leukocoria followed by strabismus
44 Retinoblastoma: Evaluation Diagnosis made without pathologic confirmationMass protruding into the vitreousDetailed documentation of number, location & size of tumors as well as retinal detachment, sub-retinal fluid & vitreous, sub-retinal seedsImaging studies aid diagnosisCT, ultrasound & MRI: important to evaluate extraocular extensionMetastases: 10-15% of patients associated with choroidal, scleral invasion or involvement of iris-ciliary body or optic nerveBone marrow aspirate, CSF & bone scintigraphy to evaluate patients with these findings
45 Retinoblastoma: Staging GroupDefinitionIaSolitary tumor < 4 ddIbMultiple tumors, none > 4 ddIIaSolitary tumor 4-10 ddIIbMultiple tumors 4-10 ddIIIaAny lesion anterior to equatorIIIbSolitary lesion > 10 dd behind equatorIVaMultiple tumors, some > 10 ddIVbAny tumor extending anterior to ora serrataVaMassive tumor involving > half retinaVbVitreous seedingReese-Ellsworth (R-E) grouping system standard (based on size, location & number of lesions)Does not predict eye salvageNew staging systems developedPathologic staging: features influence treatment & prognosis
46 Retinblastoma: Staging Extra retinal extension: large intraocular dimensionMetastatic risk & mortality: invasion of ocular coats and optic nerveOptic nerve involvement common (25-45%): impact on outcome limited to involvement beyond lamina cribosaChoroidal involvement: up to 40% patientsExtensive < 10%: prognostic implication
47 Retinoblastoma: Treatment Treatment: aims at preserving life and useful visionFactors considered:Disease: unilateral vs. bilateralPotential for visionStaging: intra & extra ocular
48 Retinoblastoma: Treatment Enucleation: large tumors filling the vitreous with no likelihood of restoring visionOcular implant usually placedFocal treatments: small tumors in patients with bilateral disease combined with chemotherapyChemotherapy: 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 controlRadiation 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 diseaseBilateral disease: treated enucleation of eyes with advanced disease and radiation for remaining eyesUp-front chemotherapy to achieve chemoreduction followed by aggressive focal therapyIncrease in eye salvage rate & decrease and delay of radiotherapyBest results with carboplatin, vincristine and etoposide
50 Retinoblastoma: Conclusion The outcome for patients with retinoblastoma is excellentTreatment strategies are aimed at increasing eye salvage rate and decreasing late effectsPatients with bilateral disease are at risk for second malignanciesThe use of radiotherapy increases that riskGenetic counseling is an essential part of treatment for patients with bilateral disease