# Presentation: 205909

## Germ Cell Tumors, Hepatoblastoma & Retinoblastoma

- Neyssa Marina, MD
- Professor 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

**Notes:**
Pediatric 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.

## 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

## 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: Staging

| Stage | 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 |

**Notes:**
Staging: 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-life
Stage II: microscopic residual as evidenced by persistent marker elevation or retroperitoneal lymph nodes < 2 cms
Stage III: gross residual disease or retroperitoneal lymph nodes > 2 cms without evidence of extra-abdominal or visceral metastases.
Stage IV: distant metastases.

## Histologic Classification

**Notes:**
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.

## 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

**Notes:**
When 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.

## Pediatric GCT: Outcome

- Survival < 20%  before use of chemotherapy

- Kurman Cancer 38: 2404, 1976.

**Notes:**
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%.

## Pediatric GCT: Treatment

- Cyclophosphamide based therapy: improved outcome
- Advanced stage patients continued to have poor outcome

- Cangir, Cancer 42:1234, 1978.

**Notes:**
The 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.

## 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)

**Notes:**
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.

## 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

**Notes:**
Although 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.

## 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

**Notes:**
Based 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.    

## 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% _+_ 6.6

- 6-yr S 100%

**Notes:**
This 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.

## Treatment Schema

**Notes:**
This 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.

## 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

**Notes:**
There 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).

## Advanced GCT Study Design 

**Diagnosis**

**RANDOMIZE**

**Cisplatin 100 mg/m2**
**Etoposide**
**Bleomycin**
**PEB**

**Cisplatin 200 mg/m****2**
**Etoposide**
**Bleomycin**
**HD-PEB**

**Notes:**
This 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.

## 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

**Notes:**
299 patients with extracranial, advanced GCT were eligible for participation in the high-risk study.  The patients were diagnosed between FEB 1990-96, had a median age of 3.4 years.  183 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.

## Advanced GCT: EFS & S by  Treatment

- P=0.0284

- 6-yr EFS: 89.6% _+_ 3.6

- 6-yr EFS: 80.5% _+_ 4.8

- 6-yr S:91.7% + 3.3

- 6-yr S: 86% _+_ 4.1

- P=0.176

- P=0.05

**Notes:**
This 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 0.054.  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. 

## 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

**Notes:**
Multivariate 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 

## 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.

**Notes:**
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.

## 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 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

## 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 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

## 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)

## 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 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

## 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 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)

## 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 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

## 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

| 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 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

## Retinoblastoma: Treatment

- Treatment: aims at preserving life and useful vision
- Factors considered:
- Disease: unilateral vs. bilateral
- Potential for vision
- Staging: 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 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