This document summarizes information about hepatoblastoma, a rare type of liver cancer that mostly affects young children. It discusses the history and terminology of hepatoblastoma. Key points include: hepatoblastoma typically affects children under 3 years old and accounts for about 1% of childhood cancers. Complete surgical resection is the main treatment when possible but less than 50% of patients are resectable at diagnosis. The addition of cisplatin-based chemotherapy has improved outcomes by increasing resectability. Prognosis remains suboptimal for patients with unresectable or metastatic disease after chemotherapy. Chemoembolization and liver transplantation are promising alternative treatments in these cases.

1. ARJUN MANDADE
COORDINATOR: DR. RASMI P.

2.  1898, the first case.
 6-week-old boy.
 Autopsy - large tumor.
 Described as a teratoma.
 1962, the term “hepatoblastoma”.

3. • Hepatoblastoma: WHO
• As malignant tumor with divergent patterns of
differentiation, ranging from cells resembling
fetal epithelial hepatocytes to embryonal cells,
and with differentiated tissues including osteoid-
like material, fibrous connective tissue, and
striated muscle fibers.
• Usually does not spread outside the liver.
• Younger than 3 years old.

4.  Primarily - infancy to about 5 years, most cases -
during the first 18 months.
 Most common primary hepatic malignancies in
childhood- 27.6% ; but relatively rare, accounting
for approximately 1% of all childhood
malignancies.
 White > black children and boys > girls up to about age
5, when the gender difference disappears.
 Overall incidence - increased by 7.4%/year and,
specifically, by 6.5% among males.
 prematurely born with VLBW.

5. Exact cause - unknown, there are a number of genetic
conditions:
 Beckwith-Wiedemann syndrome
 Familial adenomatous polyposis (FAP)
 Li- Fraumeni syndrome
 Hemihypertrophy
 Hepatitis B Infection
 Others
 Medications
 Familial cases

6.  Differentiates into hepatocytes & biliary epithelial cells
 Originally, 2 subtypes recognized:
 Epithelial (mixture of embryonal and fetal)
 Mixed epithelial and mesenchymal.
Favorable :
“completely resected tumor with a uniform,
well- differentiated fetal component
exhibiting < 2 mitoses per 10 HPF”
Patients treated with surgical resection

8. Asymptomatic right upper quadrant abdominal mass.
 Weight loss, anorexia, emesis, and abdominal pain
(advanced disease).
 Rarely - abdominal pain and hemorrhage after
posttraumatic or “spontaneous” rupture of a
previously occult tumor
Distant metastases ~ 20% of cases mostly to lung
 Intraperitoneal, lymph node, brain, and local tumor
thrombus
Thrombocytosis is common.

9. Diagnosis

10. Association with a variety of malignancies or benign diseases.
To monitor response to therapy.
To detect tumor recurrence after treatment.
Reliable predictor of outcome.
<100 ng/ml are aggressive and associated with a poor
prognosis.
b-catenin, E-cadherin, and cyclin D1, are being evaluated.

12. Abdominal ultrasound +/- Doppler.
CT (Contrast-enhanced CT with arterial and
portal venous phase ).

13.  USG: hyperechoic with
hypoechoic septae.
 CT: hypodense to liver in
pre contrast and all phases
of postcontrast study.

14.  MRI: vascular anatomy
& more precise margin
– T1: hypointense
– T2: hyperintense
– T1& T2
hypointense
septae.
 New imaging modality
- Gadoxetate disodium
(Gd-EOB-DTPA), a
hepatocyte-specific
MRI contrast agent.

15. STAGING

17. COG STAGING

18. RISK STRATIFICATION

19. Chemotherapy
• SURGERY
• Chemo-embolisation
• LIVER TRANSPLANT

20.  Introduced the concept of preoperative chemotherapy
in hepatoblastoma.
 SIOPEL 1 – 1990-1994
 SIOPEL 2 – 1994-1998
 Phase II study on High dose Cyclophosphamide –
1996-2001
 SIOPEL3 - 1998-2005 A prospective randomised
clinical trial on standard risk hepatoblastoma.
 SIOPEL4- 2005-2009

21. Four courses of cisplatin (80 mg/m2 d.1 in 24
hrs i.v. infusion) and doxorubicin (30
mg/m2/day d.1 and 2 in 24 hrs i.v. infusion)
given 3 weekly, called PLADO.
Postoperatively two additional chemotherapy
courses were given.
 overall response rate of 82%
 5-year overall survival (OS) of 75%
 event-freesurvival (EFS) of 66%

22.  SR- Resectable + No mets
 HR- Unresectable +/- Mets or Low AFP
 Division into standard and high risk tumors has been
validated.
 Also - first time an important concept of monotherapy
based on cisplatin only.
 Different strategies - SR and HR.
• SR - 6 cisplatin x 2weekly @ 80 mg/m2 in 24-hrs i.v. infusion,.
• HR - intensified by addition of carboplatin and decrease of
chemotherapy interval from 3 to 2 weeks.

23. RESPONSE
RATE
3 yrs
PFS
3 yrs
OS
Corresponding
resection Rate
SR 90% 91% 89% 97%
HR 78% 53% 48% 67%
Metastases and low AFP(<100ng/ml)- Poor prognostic factors

24. Remained stratified :
SR and HR, however HR definition was modified
by –
• low AFP tumors
• Ruptured at diagnosis.

28. CONCLUDED :
• SIOPEL 3 SR arm study has documented that a
simple monotherapy regimen based on CDDP
alone is non inferior to the combination
CDDP/DOXO (PLADO) for standard risk
hepatoblastoma and, as predicted, clearly less
toxic.

29. HR- SIOPEL 3 trial - results - slightly
superior to SIOPEL 2, probably due to
• Cisplatin intensification (4 preoperative courses
instead of 3) and
• progress in liver surgery (liver transplantation).

30.  For HR tumors.
 As a single-arm trial.
 Not randomized, but outcomes were far superior to
historical controls.
 (CYCLE A) Cisplatin 80mg/m2 D1 f/by 70mg/m2 on
D8,15,29,36,43,57,64.+ Doxorubicin 30mg/m2 on
D8,9,36,37,57,58 f/by Sx.
 Remained unresectable - received additional
preoperative chemotherapy (CYCLE B: doxorubicin 25
mg/m(2)/d on days 1-3 and 22-24, and carboplatin AUC
10·6 mg/mL/min/day IV in 1 h on days 1 and 22)

31.  Postop. chemotherapy was given (CYCLE C:
doxorubicin 20 mg/m(2)/day on d 1, 2, 22, 23, 43,
and 44, and carboplatin AUC 6·6 mg/mL/min/day in
1 h on d1, 22, and 43) to patients who did not
receive cycle B.
 3-year EFS - 76%.
 3-year OS was 83%.
 Conclusion : feasible and efficacious for complete
remission at the end of treatment for patients with
HR HB.

32.  Standard-risk HB-
• Cisplatin monotherapy arm of the SIOPEL-3 study.
• 4 # NACT f/by SX f/by 2 #Adj. chemo .
 High-risk HB-
• Dose intensive “super PLADO” arm of the SIOPEL-3
study.
• Super PLADO (cisplatin alternating with carboplatin-
doxorubicin).
 Very high-risk HB-
• SIOPEL-4 protocol with dose-intensive weekly
cisplatin/doxorubicin induction therapy.

33. Current SIOPEL recommendations for
consideration of liver transplantation in
hepatoblastoma include:
1. Multifocal PRETEXT4 tumors.
2. Large solitary PRETEXT 4 tumors.
3. Some PRETEXT 3 centrally located unifocal tumors.
4. Tumor extension/invasion into all 3 hepatic veins,
inferior vena cava, main portal vein or its both
branches.

34.  PRETEXT I - treated with primary resection f/by
low doses of cisplatin–pirarubicin.
 Otherwise, patients received preoperative
cisplatin–pirarubicin (CITA), f/by surgery and
postoperative chemotherapy.
 Ifosfamide, pirarubicin, etoposide, and carboplatin
(ITEC) were given as a salvage treatment.
 (SCT) - reserved for patients with metastatic
diseases.

35. JPLT-2 - two approaches :
• 1- Unresectable and/or metastatic cases- ITEC
was administered for tumors that did not show at
least PR to the first-line regimen CITA .
• 2- For tumors with metastases, the standard
protocol includes high-dose chemotherapy with
hematopoietic SCT for postoperative
consolidation.

37. JPLT 1 JPLT2
5 Yr OS 3 yrs OS 3 yrs OS
PRETEXT I 100% -
PRETEXT II 87.1% -
PRETEXT III 89.7% 77.8%
EFS- 67.5%
92.0%
EFS- 81.6%
PRETEXT IV 78.3% 50.3%
EFS- 47.1
78.3%
EFS- 50.3%
Metastatic
disease
43.9% ALMOST SAME
43.9% 44.0%
SX R1 - 87.7%
SX R2 - 55.8%

38.  PRETEXT - radiographically stages – before Sx,
whereas COG stage employs the results of
surgical resection prior to the administration of
systemic therapy.
 In current SIOPEL studies, PRETEXT is one of a
handful of prognostic factors – SR or HR V/S in
COG, metastatic disease has historically been
the single criteria for inclusion in the HR
category, Stage IV.

39.  All patients except those with pure fetal
histology, were randomized to receive
cisplatin/doxorubicin (CD) or
cisplatin/5FU/vincristin (C5V).
 Outcomes - were not significantly different
but less toxicity in the C5V.

40.  Conclusions—
• PRETEXT, COG stage, SCU histology, and AFP<100, as
assessed at diagnosis, are important determinants.
STAGE PRETEXT
5 Yr OS
COG
5 Yr OS
I 88.9% Pure fetal histology (PFH) 100%,
PFH Unfavorable Hiso: 100%
II 84.5% 97.5%
III 71.6% 70.2%
IV 30.9% 39.3%

44. Chemotherapy
• Surgery
• Chemo-embolisation
• Liver Transplant
#

45. 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

46. 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.

47. M/C Primary liver cancer in childhood.
Annual incidence 0.5-1.5/million
Peak incidence – first 2 yrs
Highly sensitive to chemo.
Unresectable to resectable.
Sx- 1st line treatment.
Unresectable without distant mets- Rescued
with Transplant; survival is excellent.

48. 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.

49. THANK YOU…!!