Germ Cell Tumors, Hepatoblastoma

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 lt 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
  
• ß-Human chorionic gonadotropin (ß-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 lt 4 years age endodermal sinus tumor
• Adolescents mixed histology tumors
• Genetically (Schneider, Genes, Chromosomes
  Cancer 34115, 2001)
• Childhood tumors diploid tetraploid
• Gains of chromosomes (1q, 3 20q) deletions 1p
  6q
• Adolescent tumors aneuploid
• Isochromosome 12p

9
Pediatric GCT Outcome

• Survival lt 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 421234, 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 87293, 1977)
• Increasing cisplatin dose-intensity increased
  toxicity without improving outcome (Nichols, J
  Clin Oncol 91163, 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 631657, 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 Childrens 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 (n7) median 3 mo. (2-18 mo.)
• Markers never normalized (n6) 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 S91.7 3.3
6-yr EFS 89.6 3.6
6-yr S 86 4.1
6-yr EFS 80.5 4.8
P0.05
P0.176
P0.0284
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 gt 12 years only significant prognostic
  factor (p0.002)
• Relative Risk 3.8
• After adjusting for age, treatment was borderline
  significant (p0.064)
• In multivariate Cox regression for OS, the
  interaction of age primary site was highly
  significant (plt0.0001)
• Patients gt 12 years with thoracic tumors 5.9
  times greater risk of death than patients lt 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 gt 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 lt 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 lt 20 yrs but 91 lt 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 lt 2500 grams
• RR 15.64 for BW lt1000g, 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 120 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 lt 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 lt 50 of patients
• Surgery curative gt 90 of purely fetal
  hepatoblastomas
• 5-year survival with surgery lt 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 lt 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 lt 1 year of age
• Unilateral 2nd or 3rd year of life
• Half of cases diagnosed under 1 year bilateral
  compared to lt10 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 lt 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