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 ...
Pediatric GCT: Clinical
Presentation
Depends on primary site:
Ovarian: abdominal pain (may mimic acute
abdomen), palpabl...
Pediatric GCT: Laboratory
Work-up
Alfa fetoprotein (AFP): elevated in yolk sac tumor
and embryonal carcinoma; half-life 5...
Pediatric GCT: Imaging Work-
up
CT scan or MRI of primary: to evaluate the
extent of loco-regional disease
Chest CT: to ...
Pediatric GCT: Staging
Stage Description
I Complete resection with normalization of tumor
markers within expected half-lif...
Histologic Classification
GCT: Pediatric Versus
Adult
Histologically
Children < 4 years age: endodermal sinus tumor
Adolescents: mixed histology ...
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 poo...
Adult GCT
 Introduction of cisplatin-
based therapy curative in
adults
 Einhorn regimen (cisplatin,
vinblastine, bleomyc...
Pediatric GCT: Outcome
Although cisplatin-
based therapy
appeared effective in
small number of
pediatric patients
 Signi...
Pediatric GCT: Treatment
Based on differences between pediatric and
adult tumors, the Pediatric Oncology Group
(POG) and ...
Stage I Testicular: EFS & S
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11
Years
Probability(%)
EFS S
45 37
56 46
 63 patien...
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 1...
Pediatric GCT: Low Stage
Stage II testicular
 17 patients median age
20 months
Ovarian: 57 patients
 Stage I: 41 patie...
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
Etop...
Advanced Pediatric GCT:
Patients
 299 patients diagnosed between February 1990-1996
 Median age 3.4 years (range 3 days-...
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
Probability(%)
HDPEB PEB
132 89
12...
Extragonadal GCT: Prognostic
Factors
Extragonadal GCT typically considered high-risk
 Examine prognostic factors in a la...
GCT: Conclusions
Patients with stage I GCT represent a low-risk group
Patients with stage II-III gonadal GCT appear to b...
Pediatric Liver Tumors
 Rare: ~ 1.1% of malignancies
 100-150 cases/year in US
 0.5-1.5/106
(age < 15 years)
in Western...
Pediatric Liver Tumors
Incidence rates for liver tumors: age-dependent
Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Y...
Hepatoblastoma: Risk Factors
Prematurity and low birth weight
 Disproportionate # of cases with BW < 2500 grams
 RR 15....
Hepatoblastoma: Clinical
Presentation
Asymptomatic abdominal mass
Weight loss, anorexia, emesis, and abdominal pain
(adv...
Hepatoblastoma: Histology
 Derived from undifferentiated embryonal tissue/pluripotent hepatic stem
cells
 Differentiates...
Hepatoblastoma: Relevance
of Histology
Favorable histology defined: “completely
resected tumor with a uniform, well-
diff...
Hepatoblastoma: Work-Up
Diagnostic imaging: important role in
diagnosis, staging and treatment
Ultrasound: usually first...
Hepatoblastoma: Staging
Critical to have agreed-upon staging allowing
comparison between different studies
Early studies...
Surgically-based Staging
 Stage 1 : complete gross
resection with clear margins
 Stage 2 : Gross total resection
with mi...
PRETEXT Staging
PRETEXT I: one sector
involved
PRETEXT II: two
sectors involved
PRETEXT III: two non-
adjoining sectors...
Event-free survival by
PRETEXT stage
EFS by metastases
Hepatoblastoma:
Treatment
Complete surgical resection: mainstay of therapy
Possible at diagnosis: < 50% of patients
Sur...
New Approaches to
Treatment
“New Agents”: attempt to increase response rate
Chemoembolization: Intra-arterial co-
admini...
Hepatic
Chemoembolization
 Normal liver
parenchyma has dual
blood supply:
 75%: portal vein
 25%: hepatic artery
 Live...
Review of World
Experience
Authors collected data on 147 cases
worldwide : 106 had primary LTX, 41 had
rescue LTX
OS 72....
Hepatoblastoma: Conclusions
The addition of cisplatin-based therapy has improved
the outcome for patients with hepatoblas...
Retinoblastoma
 Most frequent eye neoplasm in
childhood
 Third most common intraocular
malignancy in all ages
 Malignan...
Retinoblastoma
Two clinical forms
Bilateral (~40%):
characterized by germline
mutations in Rb1 gene
 Inherited from affe...
Retinoblastoma
 Arises from fetal retinal cells: lost function of both allelic copies
Rb1 gene
 First event germline or ...
Retinoblastoma
Unique tumor: genetic form predisposes to tumor
development in autosomal dominant fashion (85-90%
penetran...
Retinoblastoma: Clinical
Presentation
 Tumor of the young
 Age at presentation
correlates with laterality
 Bilateral < ...
Retinoblastoma: Evaluation
Diagnosis made without pathologic confirmation
 Mass protruding into the vitreous
 Detailed ...
Retinoblastoma: Staging
Reese-Ellsworth (R-E)
grouping system
standard (based on size,
location & number of
lesions)
 Do...
Retinblastoma: Staging
Extra retinal extension: large intraocular
dimension
Metastatic risk & mortality: invasion of ocu...
Retinoblastoma: Treatment
Treatment: aims at preserving life and useful
vision
Factors considered:
Disease: unilateral ...
Retinoblastoma: Treatment
Enucleation: large tumors filling the vitreous with no
likelihood of restoring vision
 Ocular ...
Retinoblastoma: Treatment
Outcome: excellent for unilateral disease treated with
enucleation (85-90% cure)
 Successful c...
Retinoblastoma:
Conclusion
The outcome for patients with retinoblastoma
is excellent
Treatment strategies are aimed at i...
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  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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 &amp;lt; 2 cms
    Stage III: gross residual disease or retroperitoneal lymph nodes &amp;gt; 2 cms without evidence of extra-abdominal or visceral metastases.
    Stage IV: distant metastases.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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 &amp; tetraploid and exhibit gains of chromosome 1q, 3 &amp; 20q along with deletions of 1p &amp;6q. In contrast, adolescent tumors are most commonly aneuploid and exhibit the characteristic isochromosome 12p as well as gains on the X chromosome.
  • &amp;lt;number&amp;gt;
    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%.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    Based on the differences between pediatric and adult germ cell tumors, the POG &amp; 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 &amp; 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 &amp; 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.
  • &amp;lt;number&amp;gt;
    This illustrates the 6-year EFS &amp; 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.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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).
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    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.
  • &amp;lt;number&amp;gt;
    This slide illustrates the 6-year EFS &amp; 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.
  • &amp;lt;number&amp;gt;
    Multivariate Cox proportional hazard regression identified age &amp;gt; 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 &amp;lt; 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 &amp;gt; 12 with thoracic tumors had 5.9 times greater risk of death than patients &amp;lt; 12 years or patients with any other primary
  • &amp;lt;number&amp;gt;
    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 &amp;gt; 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.
  • Hepatoblastoma Retinoblastoma

    1. 1. Germ Cell Tumors, Hepatoblastoma & Retinoblastoma Neyssa Marina, MD Professor of Pediatrics Division of Hematology-Oncology
    2. 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 < 3 years  Extragonadal  Testicular tumors  Peak: adolescence  Gonadal tumors
    3. 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. 4. 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
    5. 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. 6. 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
    7. 7. Histologic Classification
    8. 8. 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
    9. 9. Pediatric GCT: Outcome Survival < 20% before use of chemotherapyKurman Cancer 38: 2404, 1976.
    10. 10. Pediatric GCT: Treatment Cyclophosphamide based therapy: improved outcome  Advanced stage patients continued to have poor outcome Cangir, Cancer 42:1234, 1978.
    11. 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)
    12. 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 63:1657, 1989 Pinkerton, et al. J Clin Oncol, 1986
    13. 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 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. 14. Stage I Testicular: EFS & S 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 Years Probability(%) 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%
    15. 15. 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
    16. 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 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 Years Probability(%) EFS S 69 52 70 536-yr S: 95.7% + 3.1 6-yr EFS: 94.5% + 3.6
    17. 17. 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
    18. 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. 19. 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 Probability(%) 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 Probability(%) 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
    20. 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 > 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
    21. 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 > 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. 22. 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)
    23. 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. 24. 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
    25. 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. 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. 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 alone All other histology is considered unfavorable and if stage II-IV, histology is considered irrelevant Ortega et. al. J Clin Oncology, 2000
    28. 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. 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. 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. 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. 32. Event-free survival by PRETEXT stage
    33. 33. EFS by metastases
    34. 34. 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
    35. 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. 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. 37. Review of World Experience Authors collected data on 147 cases worldwide : 106 had primary LTX, 41 had rescue LTX OS 72.8%
    38. 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. 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 < 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. 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. 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. 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. 43. 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
    44. 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. 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 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
    46. 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 < 10%: prognostic implication
    47. 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. 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. 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. 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
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