Germ Cell Tumors, Hepatoblastoma &

Retinoblastoma

Neyssa Marina, MDProfessor of Pediatrics

Division of Hematology-Oncology

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

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

location Constipation & urinary retention for

sacrococcygeal tumors Respiratory distress for mediastinal tumors

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

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

Pediatric GCT: StagingStage

Description

I Complete resection with normalization of tumor markers within expected half-life.

II Microscopic residual disease: persistent marker elevation; lymph nodes < 2 cms

III Gross residual disease: retroperitoneal lymph nodes > 2 cms; no extra-abdominal or visceral metastases

IV Distant metastases

Histologic Classification

GCT: Pediatric Versus Adult

HistologicallyChildren < 4 years age: endodermal sinus

tumorAdolescents: 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

Pediatric GCT: Outcome

Survival < 20% before use of chemotherapyKurman Cancer 38: 2404, 1976.

Pediatric GCT: Treatment

Cyclophosphamide based therapy: improved outcome

Advanced stage patients continued to have poor outcome

Cangir, Cancer 42:1234, 1978.

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)

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

Pediatric GCT: TreatmentBased 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 + PEB

Advanced GCT: Stage III/IV gonadal & stage I-IV extragonadal:

evaluate the role of cisplatin dose-intensity in a randomized trial

Stage I Testicular: EFS & S

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11

Years

Prob

abilit

y (%

)

EFS S

45 37

56 46

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% + 6.6

6-yr S 100%

Treatment Schema

Drug Standard PEB High-dose PEB

Cisplatin

20 mg/m 2/d x 5

40 mg/m 2/d x 5

Etoposide

100 mg/m 2/d x 5

100 mg/m 2/d x 5

Bleomycin 15 U/m 2 IV day 1 15 U /m 2 IV day 1

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

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11

Years

Probab

ility (

%)

EFS S

69 52

70 536-yr S: 95.7% + 3.1

6-yr EFS: 94.5% + 3.6

Advanced GCT Study Design

Diagnosis

RANDOMIZE

Cisplatin 100 mg/m2EtoposideBleomycinPEB

Cisplatin 200 mg/m2

EtoposideBleomycinHD-PEB

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

Advanced GCT: EFS & S by Treatment

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Years

Proba

bility

(%)

HDPEB PEB

132 89

122 72

P=0.0284

6-yr EFS: 89.6% + 3.6

6-yr EFS: 80.5% + 4.8

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Years

Proba

bility

(%)

HDPEB PEB

134 91

134 80

6-yr S:91.7% + 3.3

6-yr S: 86% + 4.1

P=0.176

P=0.05

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

GCT: ConclusionsPatients 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.

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)

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.

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

Hepatoblastoma: Clinical Presentation

Asymptomatic abdominal massWeight 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-fetoproteinRare: hypertension in cases of renin-secreting mixed

HB or precocious puberty in HB secreting human chorionic gonadotropin

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

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

Hepatoblastoma: Work-Up

Diagnostic imaging: important role in diagnosis, staging and treatmentUltrasound: 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

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 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)

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

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

Event-free survival by PRETEXT stage

EFS by metastases

Hepatoblastoma: Treatment

Complete surgical resection: mainstay of therapyPossible at diagnosis: < 50% of patientsSurgery: 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

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

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

Review of World Experience

Authors collected data on 147 cases worldwide : 106 had primary LTX, 41 had rescue LTX

OS 72.8%

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

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

Retinoblastoma

Two clinical formsBilateral (~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)

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

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%

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

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 extensionMetastases: 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

Retinoblastoma: StagingReese-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

Group Definition

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

Retinblastoma: Staging

Extra retinal extension: large intraocular dimensionMetastatic 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% patientsExtensive < 10%: prognostic implication

Retinoblastoma: Treatment

Treatment: aims at preserving life and useful vision

Factors considered:Disease: unilateral vs. bilateralPotential for visionStaging: intra & extra ocular

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

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

Retinoblastoma: Conclusion

The outcome for patients with retinoblastoma is excellent

Treatment strategies are aimed at increasing eye salvage rate and decreasing late effectsPatients 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