Download HEPATOBLASTOMA

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
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 Workup
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
Histologic Classification
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
Pediatric GCT: Outcome
 Survival < 20% before use of chemotherapy
Kurman 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 cisplatinbased 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 cisplatinbased 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: 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
Stage I Testicular: EFS & S
6-yr S 100%
100
Probability (%)
 63 patients stage I testicular
tumors treated with surgery
& observation
56
46
 Age: 1 mo.-5 years
80
 Histology: 57 yolk sac
45
37
6-yr
EFS 81.8% + 6.6
carcinoma
 Failures: 13 patients
(median 4 mo. range, 2-18
mo.)
60
EFS
40
S
20

0

0
1
2
3
4
5
6
Years
7
8
9
10
11
Disease recurrence (n=7);
median 3 mo. (2-18 mo.)
Markers never normalized
(n=6); median 4.5 mo. (210 mo.)
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
100
 Ovarian: 57 patients
 Stage I: 41 patients
median age 11.9 years
 Stage II: 16 patients
median age 10.7 years
Probability (%)
20 months
 Treatment: surgery + 46 cycles PEB
6-yr S: 95.7% + 3.1
70
53
69
52
80
6-yr EFS: 94.5% + 3.6
60
EFS
S
7
8
40
20
0
0
1
2
3
4
5
6
Years
9
10
11
Advanced GCT Study Design
Diagnosis
R
A
N
D
O
M
I
Z
E
Cisplatin 100 mg/m2
Etoposide
Bleomycin
PEB
Cisplatin 200 mg/m2
Etoposide
Bleomycin
HD-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
132
89
80
72
122
60
HDPEB
40
Probability (%)
Probability (%)
100
6-yr EFS: 89.6% + 3.6
6-yr EFS: 80.5% + 4.8
P=0.05
PEB
100
134
91
80
134
80
40
20
0
0
1
2
3
4
5
6
Years
7
8
9
10
11
12
6-yr S: 86% + 4.1
60
20
0
6-yr S:91.7% + 3.3
HDPEB
PEB
P=0.176
P=0.0284
0
1
2
3
4
5
6
Years
7
8
9
10
11
12
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: 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 highrisk 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 intraabdominal 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, welldifferentiated 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 nonadjoining 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 coadministration 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
Ia
Ib
Definition
IIa
IIb
IIIa
IIIb
Solitary tumor 4-10 dd
IVa
IVb
Multiple tumors, some >
10 dd
Va
Massive tumor involving
> half retina
Vb
Vitreous seeding
Solitary tumor < 4 dd
Multiple tumors, none >
4 dd
Multiple tumors 4-10 dd
Any lesion anterior to
equator
Solitary lesion > 10 dd
behind equator
Any tumor extending
anterior to ora serrata
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