Indian J Pediatr (June 2012) 79(6):793–800
DOI 10.1007/s12098-012-0704-1
SYMPOSIUM ON PEDIATRIC ONCOLOGY : MALIGNANT SOLID TUMORS
Primary Malignant Liver Tumors in Children
Sandeep Agarwala
Received: 22 August 2011 / Accepted: 7 February 2012 / Published online: 1 March 2012
# Dr. K C Chaudhuri Foundation 2012
Abstract Liver tumors constitute only 1-4% of all solid
tumors in children. Two-thirds of these are malignant. The
primary malignant tumors are hepatoblastoma (HB), hepa-
tocellular carcinoma (HCC), rhabdomyosarcoma (RMS),
angiosarcoma, rhabdoid tumor, undifferentiated sarcoma
and other rarer tumors. Of these HB is the commonest.
The diagnosis of HB is based on the radiology, elevated
levels of α-fetoprotein (αFP) and the histology/cytology.
Staging is essential for risk categorization, risk adapted
treatment and prognostication. The commonest staging and
risk categorization system used today is PRETEXT system
that is being used by nearly all multicentre trials (American,
European, German, Japanese) in some way. Treatment of
HB is multimodal with surgery and chemotherapy being the
main modalities. Survival is not possible without complete
surgical resection. Majority of tumors are unresectable at
presentation but can be made resectable with chemotherapy,
giving a resection rate of more than 85%. Cisplatin is the
main stay of chemotherapy and is a part of all multidrug
protocols. The 3-y overall survival (OS) today stands at
62%-70% but only 25% patients with metastasis get cured.
Panhepatic tumors and those with local factors causing
unresectability are now dealt with liver transplantation
which has also given a survival rate of nearly 85%. The
overall management of HB and HCC has evolved over the
past 3 decades giving good long term survival rates for HB,
though patients with HCC still do poorly. Successive thera-
peutic trials have focused attention on increasing the effi-
ciency and reducing the toxicity and long term side effects
S. Agarwala (*)
Department of Pediatric Surgery,
All India Institute of Medical Sciences,
New Delhi 110029, India
e-mail: sandpagr@hotmail.com
of the treatment. Among the other uncommon tumors the
rhabdoid tumor and angiosarcoma are chemoresistant and
have a poor outcome while the undifferentiated sarcoma and
rhabdomyosarcoma are now showing better response to the
currently used chemotherapy combinations.
Keywords Primary malignant liver tumors . Children .
Hepatoblastoma . Hepatocellular carcinoma
Introduction
Liver tumors are rare in children and constitute 1-4% of all
solid tumors in children [1]. Two-thirds of these are malig-
nant. Eleven reported series were reviewed by Weinberg and
Finegold [2] (n012560) who reported that 43% of all liver
tumors were HB; 23% hepatocellular carcinoma (HCC);
13% benign vascular tumors; 6% mesenchymal hamarto-
mas; 6% sarcomas; 2% adenomas; 2% focal nodular hyper-
plasia and 5% others. The mean age for HB is 3.2±0.8 y
while that for HCC is 13.1±1.1 y [3]. HB is the commonest
primary liver malignancy in the western countries, with the
incidence being 1.6 to 2 per million children as compared to
0.29 to 0.45 per million for HCC [4, 5]. In some parts of
Eastern Asia (China, Tiwan, Korea, Hong kong and Fiji)
and Sub-Saharan Africa, HCC occurs more frequently and
this is mainly attributed to the high prevalence of hepatitis B
and C infection [6, 7]. In the authors’ experience from 1994
to 2006 of primary malignant liver tumors in children upto
12 y of age, at AIIMS, New Delhi, there were 36 HB, 4
HCC, 2 undiffrentiated sarcomas, 1 rhabdoid tumor and 1
angiosarcoma. The overall management of HB and HCC
has evolved over the past 3 decades, and now long term
survival rates of 70-80% are reported for HB [8–13], though
patients with HCC still do poorly.
794
Hepatoblastoma
HB is an embryonal tumor with slight male preponderance
of 1.7:1 [14] and 70% occuring before 2 y of age [15, 16].
Although a number of genetic alterations have been seen in
association with HB, majority are sporadic. There is a loss
of heterozygosity (LOH) at 11p15.5 locus, high incidence of
trisomy 20, 2 and rarely, 18 [17, 18]. It’s association with
Beckwith Weidman syndrome [19], familial adenomatous
polyposis [20], Gardner’s syndrome are strong enough to
merit regular radiologic surveillance for the development of
HB in these conditions. Other associations have been de-
scribed with hemihypertrophy and adrenal agenesis. Inter-
estingly HB has been associated with extreme prematurity
and very low birth weight(< 1000 g) [21] and in these
groups there is rapid progression and unfavourable outcome
[22].
Pathology
HB is derived from undiffentiated embryonal cells and the
pathology reflects distinct phases of liver cell development
and maturation:(a) undifferentiated small cells which co-
express Cytokeratin and Vimentin reflecting neither epithe-
lial nor stromal differentiation;(b) Embryonal epithelial cells
resembling histology of liver at 6-8 wk of gestation;(c) Well
differentiated fetal hepatocytes indistinguishable in cytolog-
ic and architectural growth pattern from fetal cells. Patho-
logically HB is classified as epithelial with subtypes(fetal/
embryonal/small cell undifferentiated); or mixed epithelial/
mesenchymal with or without teratoid features. Nearly 20%
of epithelial HB show a mixture of fetal and embryonal
subtypes [23]. The tumor is solitary in 80% of the cases
and involves the right lobe in nearly 60% [23, 24]. In one
third both the lobes are involved [25]. Histology may have a
significant prognostic importance with Small cell undiffer-
entiated(SCU) tumors having poor response to chemothera-
py and poorer outcome. Molecular and genetic studies have
attempted to correlate with outcome. In one report high
levels of human telomerase reverse transcriptase(hTERT)
mRNA expression as well as telomerase activity were found
to be independent predictors of prognosis [26]. Another
study showed that loss of heterozygosity on chromosome
15.5 is significantly related to higher recurrence rates [27].
Glycogen content and DNA ploidy of cells has also been
reported to be associated with good outcome [28].
Diagnosis
The diagnosis of HB is based on the radiology, elevated
levels of αFP and the histology/cytology. A dual phase
contrast enhanced CT scan of the abdomen and chest is ideal
for evaluation [29]. αFP is elevated in 90-95% cases of HB
Indian J Pediatr (June 2012) 79(6):793–800
and children with normal or low (< 100ηg/ml) and extreme-
ly high levels have a poorer outcome [30–32]. Twenty
percent of HB have metastasis at presentation and nearly
all of these are to the lungs; therefore CT chest is essential
for staging [2]. For pre-operative histological diagnosis,
needle biopsies or a fine needle aspiration cytology (FNAC)
is adequate in most of the cases [33].
Staging
Correct staging is essential for risk categorization, risk
adapted treatment, prognostication and comparison of
results among various study trials. PRETEXT staging(Pre
Treatment Extent of Disease)(Table 1) [13] was devised by
Liver tumor strategy group (SIOPEL) for their SIOPEL-1
study [34, 35] and has then been used for their subsequent
trials. Further risk grouping is done into a high risk(HR) and
standard risk(SR). All PRETEXT IV, any PRETEXT stage
with either /or E,V,P,C,M + ve, tumors with low αFP <
100ηg/ml and small cell undifferetntiated histology(SCU)
are considered as HR [13, 36]. All other tumors are consid-
ered SR. The Co-operative trials in the North America had
used the traditional (Evans) post-surgical staging system-
now called the COG staging system [37, 38](Table 2). The
German Pediatric Oncology Hematology Study Group
(GPOH) and The Japanese Pediatric Liver Tumor Study
Group (JPLT) have now adopted the PRETEXT staging
system of the SIOPEL for the current and future trials. In
the current ‘Childrens Oncology Group(COG) HB protocol
(AHEP 0731)’, PRETEXT is being used to define surgical
resectability and to identify those tumors that will require
extreme resection or liver transplantation so that these
patients can be referred to appropriate centres and put on
the transplant list at the outset of therapy.
Treatment
Surgical Treatment Complete surgical resection is the corner
stone of treatment and without this, survival is not possible.
Table 1 PRETEXT grouping system (Pre-treatment extent of disease)
PRETEXT I: 3 contiguous sectors tumor free
PRETEXT II: 2 contiguous sectors tumor free
PRETEXT III: 1 sector tumor free
PRETEXT IV: No sector free of tumor
In addition any group may have:
+ V: Ingrowth into venacaval or all three hepatic veins involved
+ P: Ingrowth into portal vein, portal bifurcation involved
+ E: Extrahepatic contiguous tumor
+ C: Involvement of caudate lobe
+ M: Distant metastases
Indian J Pediatr (June 2012) 79(6):793–800
Table 2 Traditional (Evans) COG staging system
Stage I: Complete gross resection at diagnosis with clear margins.
Stage II: Complete gross resection at diagnosis with microscopic
residual disease at margins of resection.
Stage III: Biopsy only at diagnosis, or gross total resection with
nodal involvement or tumor spill orincomplete resection with
gross intrahepatic disease.
Stage IV: metastatic disease at diagnosis.
Before effective chemotherapy was introduced, complete sur-
gical resection, at presentation, was possible in<50% cases
and only half of these survived. Further these primary resec-
tions were associated with significant risk of incomplete
resections, tumor spills, surgical morbidity and mortality.
The COG, GPOH and JPLT have all traditionally recommen-
ded primary resection, whenever feasible, as the initial treat-
ment. In the initial POG/CCG trials only 46% were deemed
resectable at presentation [30]. In the GPOH trials HB-89 and
HB-94, 30% children undergoing primary resection had mac-
roscopic or microscopic residual disease [39], while only 18%
of the more advanced tumors, which received neo-adjuvant
chemotherapy, had macroscopic or microscopic residual dis-
ease. This has prompted the GPOH to adopt the neo-adjuvant
chemotherapy for all its HB patients in the current trials, HB-
99.
The resectability is compromised by multifocality, bilo-
bar involvement, portal vein or inferior venacaval thrombus/
vascular invasion, extension to hepatic hilum, a bulky
lymphadenopathy and distant metastasis. In the central
tumors , involvement of hepatic veins at the confluence with
the IVC may preclude safe complete resection. Liver trans-
plantation has now replaced advanced surgical procedures
that had high morbidity and high incidence of incomplete
resections leading to recurrences.
There has been a debate on the adequacy of surgical
margin in liver resections for HB; 1 cm margin was consid-
ered essential. However, often large liver masses compress
or abut key vascular structures, thereby precluding a 1 cm
margin. Adult studies [40] have reported that margins<1 cm
and upto 4 mm may also be adequate. Reports from SIOPEL
trials have also shown that there was no increase in local
recurrence rates or need for second resections in patients
having a microscopic+ve margin following neodajuvant
chemotherapy and anatomical resection for HB [8, 9].
Therefore, it is now agreed that though one should strive
for achieving a microscopic –ve margin, the presence of
microscopic disease does not portend a poor prognosis with
respect to local tumor recurrence [8, 9, 41, 42].
Multifocal, pan hepatic tumor is another surgical problem
where treatment is controversial. Primary total hepatectomy
with orthotopic liver transplantation is recommended stan-
dard of care for all such patients. This provides a much
795
better cure rate than complex partial hepatectomies [11,
43]. Even in patients having multifocal disease with extra-
hepatic involvement where extrahepatic disease has disap-
peared after initial chemotherapy, the results of liver
transplantation is very good [44–46] and even better than
non-tumor indications for transplant. Neodjuvant chemo-
therapy can down stage such multifocal tumors with com-
plete disappearance of some tumor nodules [47, 48]. For
such cases conventional hepatectomy has also been de-
scribed [49]. This avoids the potential long term complica-
tions of pediatric liver transplant such as impairment of
renal function, dyslipidemia, lymphoproliferative disorders,
and other denovo tumors, infections, chronic and late acute
rejections. Non availability of liver transplantation facility
may be the other reason for conventional hepatectomy in
multifocal cases. Extended resections like extended triseg-
mentectomies [50], central resections [51] and venous grafts
[52, 53] to replace invaded veins have also been advocated
because of shortage or timely non-availability of donor
livers. However, conventional hepatectomies in such situa-
tions have a higher local recurrence rate requiring total
hepatectomy with rescue liver transplant. The cure rate
following such rescue transplants is only 30% as compared
to 69-89% for primary liver transplant [11, 54]. Since 2004,
the recommended treatment for multifocal panhepatic HB
whose residual disease after neoadjuvant chemotherapy is
confined to the liver is total hepatectomy and orthotopic
liver transplant [11]. Liver transplantation (LTx) is a good
modality of treatment for unresectable HB without any
extrahepatic metastatic disease (after neoadjuvant chemo-
therapy and pulmonary metastatectomy). For PRETEXT
IV HB, especially multifocal disease, the long term disease
free survival after LTx is 80% [50, 54]. It has now been
clearly shown that the results of LTx in HB are not as good
when LTx is done as “rescue” procedure after initial inade-
quate resection or relapse [11]. The SIOPEL and COG
criteria for early referral to a centre with transplant facility
are:
1. Multifocal PRETEXT-IV HB
2. Solitary PRETEXT-IV (some of these may get down
staged to PRETEXT-II after neoadjuvant chemotherapy)
3. Unifocal centrally located PRETEXT-II and III tumors
involving main hilar structures (+ P) or all three hepatic
veins (+V).
Chemotherapy In 1971 Memorial Sloan Kettering reported
their 20 y experience with HB and gave a survival rate of
only 13% while survival reported was 35% from the Surgi-
cal Section of American Academy of Pediatrics in 1975.
In1975 it was shown that HBs were chemosensitive and
then on various drugs in combination have been studied.
1982 report from POG [55] on their experience with the use
796
of VCR+DOX+CPM/5FU (Vincristine+Doxorubicin+Cy-
clophosphamide / 5-Fluorouracil) as adjuvant chemotherapy
after resection in HB showed a recurrence rate of 64% when
adjuvant chemotherapy was not used as compared to only
6% when it was. This clearly showed the need for adjuvant
chemotherapy in HB. This report also highlighted that the
combination of VCR+DOX+5FU showed a much better
response than VCR+DOX+CPM when used for unresect-
able tumors. The introduction of cisplatin (CDDP) in mid
80’s dramatically improved the survival rates and the POG
report clearly indicated that CDDP was the most effective
drug against HB [56]. This report of a pilot study using
combination of VCR+5FU+CDDP showed a resolution of
pulmonary secondaries in 80% of cases and 81.8% of the
unresectable tumors could be converted to resectable ones.
Quin et al first described the successful use of combination
of CDDP and Doxorubicin for HB [57]. In 1991 CCG for
the first time described their results with the use of combi-
nation of CDDP+DOX as a continuous infusion [30] and
reported a survival rate of 66%. POG reporting on their
experience with combination of CDDP+5FU +Vincistine
(C5V) [38] showed a survival rate of 90% for resectable
HBs. It also reported that 77% of the unresectable tumors
could be made resectable and in this group the survival rate
was 67%. CCG and POG report in 2000 [58] showed that
only 32% of cases could undergo upfront resection, high-
lighting the need for chemotherapy for the remaining unre-
sectable tumors to make these resectable. This study
reported a 5-y overall survival (OS) and event free survival
(EFS) of 98% and 91% for stage I tumors and 69% and 64%
respectively for stage III tumors. A POG phase II trial on 33
unresectable/metastatic [59] HB using a combination of
Carboplatin + 5FU + VCR showed that this combination
was also effective. At the same time similar developments
were happening across the Atlantic, in Europe. The Interna-
tional Society of Pediatric Oncology Liver Tumor Group
(SIOPEL) was using the combination of CDDP + DOX
(which they had named PLADO) in a neoadjuvant fashion.
The SIOPEL-1 study reported in 2002 [9] showed a 5-y OS
and EFS of 85% and 75% respectively, after the use of
neoadjuvant PLADO as compared to 75% and 66% for all
patients together. This study concluded that preoperative
needle core biopsy of the liver tumor is safe. They also
showed that neoadjuvant chemotherapy made resection eas-
ier and probably gave a better survival. They, for the first
time suggested that with this effective chemotherapy there
may not be any need for re-resection of microscopic positive
margins. SIOPEL-1 also showed that resection of pulmo-
nary metastases can be curative if local control is achieved.
SIOPEL-2 conducted between 1995-98 [12] was a pilot
study for risk adapted therapy (SR and HR) with neoadju-
vant chemotherapy for all patients, using CDDP monother-
apy for standard risk HB (SR-HB) and PLADO for high risk
Indian J Pediatr (June 2012) 79(6):793–800
HB (HR-HB). The study reported a response rate of 90%
and a resection rate of 97% with monotherapy in SR-HB.
The 3-y OS and Progression Free Survival (PFS) for SR-HB
was 91% and 89% and that for HR-HB was 53% and 48%
respectively [12]. As monotherapy with CDDP could com-
pletely eliminate the risk of cardiotoxicity, seen with the use
of DOX, and seemed to have a much lesser hematological
toxicity than the PLADO combination, a randomized con-
trol trial of monotherapy vs. PLADO for SR-HB was
planned to prove this. This multinational, multicentre trial
(SIOPEL-3) conducted between 1998 and 2006, randomly
assigned 126 SR-HB patients to receive CDDP monother-
apy and 129 to receive PLADO [60]. The study reported a
complete resection rate of 95% in monotherapy group
against 93% for PLADO. The 3-y Relapse Free Survival
(RFS) and OS were 83% (95%CI, 77 to 90) and 95% (95%
CI, 91to 95) in monotherapy group and 85% (95%CI 79 to
92) and 93% (95%CI 88 to 98) in PLADO group [60]. The
study conclusively showed that similar resection rate and
survival rates could be achieved with CDDP monotherapy
for SR-HB. The study also showed that CDDP alone had a
significantly lesser hematologic toxicity than PLADO while
the ototoxicity remained same in both groups. JPLT-2 [61]
reported on 212 cases of HB their experience of using
various combinations like CDDP+Pirarubicin or Pirarubi-
cin+Carboplatin and addition of Ifosfamide (ITEC regime).
JPLT-2 in addition used hepatic artery chemoembolization
(HACE) for their HR-HB [61]. They reported a 5-y OS of
100%, 87.1%, 89.7% and 78.3% for PRETEXT I,II,III and
IV respectively. The 5-y OS for metastatic disease in this
study was 49%. JPLT-2 reported a marked improvement
over JPLT-1 for PRETEXT II patients (JPLT-2 92% vs.
JPLT-1 77.8% 3-y OS) and non-metastatic PRETEXT IV
(JPLT-2 78.3% vs. JPLT-1 50.3% 3-y OS). The German
Pediatric Oncology and Hematology group (GPOH) HB
trials HB 89 and HB 94 [39] were similar to the American
trials in terms of upfront resection, whenever feasible. The
HB 99 trial [62] used ifosfamide+CDDP+Dox (IPA) com-
bination for their standard risk tumors and Carboplatin+
Etoposide combination for the HR-HB and reported a 94%
survival for SR and 66% for HR tumors.
The current COG trial, AHEP-0731, the decision for
primary resection or neo-adjuvant chemotherapy is based
on PRETEXT stage. PRETEXT stage –I and II with at least
1 cm margin undergo primary resection while all others
receive neoadjuvant chemotherapy. AHEP-0731 treats all
very low risk patients (stage 1, pure fetal histology[PFH])
with surgery alone. Low risk patients (stage 1 no PFH, stage
1 and 2 non SCU HB) are treated with only 2 courses of
adjuvant C5V. For intermediate risk patients (stage 1 and 2
SCU, any stage 3 HB) the chemotherapy includes DOX
with C5V (C5VD). For high risk tumors drugs like Irinote-
can is being tried. SIOPEL is using CDDP monotherapy for
Indian J Pediatr (June 2012) 79(6):793–800
SR-HB and PLADO for HR-HB and also trying intensified
platinum therapy (SIOPEL-4 trial) for HR-HB. The GPOH
trial HB 99 is using IPA (ifosfamide/cisplatin/Adriamycin)
for SR and combination of Carboplatin and Etoposide in
various dosages for HR tumors [63].
The overall 3-y OS today stands at 62%-70% [39, 58,
63–66] but only 25% patients with metastases get cured.
The outcome for unresectable or metastatic tumors remains
poor even with intensified platinum therapy [64]. Presently,
the aim of all the study groups has been to diminish toxicity
for the low risk, increase survival in intermediate risk
patients and to identify better agents for the high risk
tumors. An international collaboration by the SIOPEL,
COG and GPOH has been started to amalgate all the data
of these three groups so as to identify common data points
for prognostication and risk stratification. This is the CHIC
project (Childhood Hepatic tumors International Collabora-
tion). There are very few reports of Indian experience on
hepatoblastoma. Tata Memorial Hospital, Mumbai reported
on their experience with 18 patients giving a resectability
rate of 88.8% and DFS of 67% [67]. Similar report form
Kidwai Memorial Institute of Oncology, Banglore, on their
experience with 12 cases reported a resection rate of 75%
and a survival rate of 100% for all those who underwent
resection [68]. The authors own experience at AIIMS, New
Delhi, on 36 children showed that 83.3% could undergo
resection with the OS among PRETEXT 2,3 and 4 stages
being 82.6%, 42.9% and 16.7% respectively. The 5 y OS
and EFS for SR was 85% (95CI of 53-78 m) and 80% (95CI
of 51-76 m) and that for HR was 37.5% (95CI of 11-53 m)
and 20% (95CI of 8-45 m) respectively [69].
Hepatocellular Carcinoma
Hepatocellular carcinoma is half as common as HB in the
Western countries but in East Asian countries (Tiwan, Chi-
na, Korea) and the Sub-Saharan Africa it is commoner than
HB. This is because of the high prevalence rate of hepatitis
B and C infections in these regions. Unlike adults where
HCC is usually seen with underlying liver disease, only 20-
35% children with HCC children have underlying liver
disease [70, 71]. Sero-positive rate for Hepatitis B surface
antigen is nearly 100% in children with HCC in Tiwan and
China while almost 80% of HCC in Japan is in children with
chronic active hepatitis C [72]. The underlying liver dis-
eases associated with HCC are tyrosinemia [73], glycogen
storage disease type-1 [74], α1-antitrypsin deficiency [75],
Aligille syndrome [76], Neiman-Pick disease [77], Fanco-
ni’s anemia, Familial polyposis coli and Gardeners syn-
drome, Focal nodular hyperplasia, and hemochromatosis.
Children with severe cholestasis and liver disease related
797
to neonatal hepatitis, biliary atresia and progressive familial
intrahepatic cholestasis are at increased risk for developing
HCC. HCC in children, is now considered to be tumor
family consisting of: (i) HCC adult type and variants; (ii)
fibrolamellar HCC (FL-HCC) and (iii) transitional liver cell
tumor (TLCT) [78]. HCC in children is often multifocal and
bilobar. FL-HC is seen more in the Western world and
occurs mostly in adolescents and young adults [79] and
accounts for<10% of all cases of HCC. FL-HCC are typi-
cally solitary lesions that frequently metastasize to loco-
regional lymphnodes and can have intra-peritoneal spread.
TLCT are usually very large solitary tumors with very
aggressive behaviour. As compared to HB, only 50-70%
of HCC have increased αFP [80]. Nearly 25% cases have
metastatic disease at presentation. HCC is relatively chemo-
resistant, complete resection or transplantation of localized
tumor is the only hope. Relapse is common and disease free
survival of not more than 25-30% has been reported from
the various clinical trials like GPOH HB-89, HB-94 and HB
99 [78]; SIOPEL 1 and 2 [71], SIOPEL- 3 and the COG/
POG study INT 0098 [81]. This has not shown any im-
provement over the years. In the INT-0098 study of POG
and CCG, the 5-y EFS was only 17% [81] and none of stage
IV survived. In the SIOPEL-1 report [71], the overall resec-
tion rate was 36% and the 5 y OS and EFS was 28% and
17% respectively. LTx outcomes in HCC are also not as
good as for HB as metastatic relapse is much more common
after transplantation for HCC. Further the Milan criteria for
LTx in HCC in adults [82] may not be appropriate for
children with HCC who mostly have non-cirrhotic livers.
Undifferentiated Sarcoma of Liver
These are the third most common malignant tumors of the
liver in children and are also called malignant mesanchymal
sarcoma or mesenchymoma. These rare aggressive tumors are
mostly seen in children 5-12 y of age and may sometimes arise
in solitary liver cysts [83]. These are typically large tumors
that appear solid on ultrasound but cystic with solid areas on
CT or MRI scans. !FP is normal. Chemotherapy (like those
for soft tissue sarcoma/ rhabdomyosarcoma- VAC- Vincristin/
Actinomycin D/ Cyclophosphamide) followed by resection
gives the best outcomes but local recurrences are common and
are the main cause for overall poorer outcomes. The reported
survival now is around 70% [84–86].
Rhabdomyosarcoma
Rhabdomyosarcoma of the liver mostly arises from the
extra-hepatic biliary tree in pre-school children. They are
locally invasive and often present with obstructive jaundice
798
and may be misdiagnosed as choledochal cyst unless ultra-
sound clearly demonstrates a solid mass involving the biliary
tree. Histologically, they are embryonal rhabdomyosacroma
and 20% have metastatic disease at presentation. Initial biliary
stenting or external drainage may be required to treat the
obstructive jaundice as there is a high risk for death from
biliary sepsis during chemotherapy. As these are both chemo-
sensitve and radiosensitive, multi-modal therapy with chemo-
therapy, radiation therapy and surgery gives the best outcome
and the reported 5-y overall survival from the intergroup
rhabdomyosarcoma study (IRS) is 66%.
Angiosarcoma
These are rare tumors known to have arisen by malignant
transformation in infantile hemangioms [87, 88]. They are
relatively chemoresistant and have an extremely poor
outcome.
Rhabdoid Tumors
These are rare and very aggressive tumors that have a high
incidence of tumor rupture [89], are chemoresistant and
usually fatal [90]. There are now some reports of response
to chemotherapy with cyclophosphamide/ifosfamide+Acti-
nomycin D and Vincristine [90].
Conflict of Interest None.
Role of Funding Source None.
References
1. Stocker JT. Hepatic tumors in children. In: Suchy FJ, Sokol RJ,
Balistreri WF, eds. Liver disease in children. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 2001. pp. 915.
2. Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood.
Hum Pathol. 1983;14:512–37.
3. Pham TH, Iqbal CW, Grams JM, et al. Outcomes of primary liver
cancer in children: an appraisal of experience. J Pediatr Surg.
2007;42:834–9.
4. Darbari A, Sabin KM, Shapiro CN, et al. Epidemiology of primary
hepatic malignancies in U.S. children. Hepatology. 2003;38:560–
6.
5. Mann JR, Kasthuri N, Raafat F, et al. Malignant hepatic tumours in
children: incidence, clinical features and aetiology. Paediatr Perinat
Epidemiol. 1990;4:276–89.
6. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vacci-
nation in Taiwan and the incidence of hepatocellular carcinoma in
children. N Engl J Med. 1997;336:1855–9.
Indian J Pediatr (June 2012) 79(6):793–800
7. Chen DS. Hepatitis B vaccination: the key toward eradication of
hepatitis B. J Hepatol. 2009;50:805–16.
8. Perilongo G, Shafford E, Plaschkes J. SIOPEL trials using preopera-
tive chemotherapy in hepatoblastoma. Lancet Oncol. 2000;1:94–100.
9. Schnater JM, Aronson DC, Plaschkes J, et al. Surgical view of the
treatment of patients with hepatoblastoma: results from the first
prospective trial of the International Society of Pediatric Oncology
Liver Tumor Study Group. Cancer. 2002;94:1111–20.
10. Aronson DC, Schnater JM, Staalman CR, et al. Predective value of
pretreatment extent of disease system in hepatoblastoma: results
from the International Society of Pediatric Oncology Liver Tumor
Study Group SIOPEL-1 study. J Clin Oncol. 2005;23:1245–52.
11. Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for
hepatoblastoma: results from the International Society of Pediatric
Oncology (SIOP) study SIOPEL-1 and review of the world expe-
rience. Pediatr Blood Cancer. 2004;42:74–83.
12. Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment
for childhood hepatoblastoma. final report of the second study of
the International Society of Paediatric Oncology—SIOPEL 2. Eur
J Cancer. 2004;40:411–21.
13. Roebuck DJ, Aronson D, Clapuyt P, et al. 2005 PRETEXT: a
revised staging system for primary malignant liver tumours of
childhood developed by the SIOPEL group. Pediatr Radiol.
2007;37:123–32.
14. Exelby PR, Filler RM, Grosfeld JL. Liver tumors in children in the
particular reference to hepatoblastoma and hepatocellular carcinoma:
American Academy of Pediatrics Surgical Section Survey, 1974. J
Pediatr Surg. 1975;10:329–37.
15. Ross JA. Hepatoblastoma and birth weight: too little, too big, or
just right? J Pediatr. 1997;130:516–7.
16. Stocker J, Conran R, Selby D. Tumor and pseudo tumors of the
liver. London: Chapman & Hall; 1998.
17. DA De ugrate, Atkinson JB. Liver tumors. In: Grosfeld JL, O’Neill
Jr JA, Fonkalsurd EW, Coran AG, eds. Pediatric surgery. 6th
ed. Philadelphia: Mosby-Elsevier; 2006. pp. 502–14.
18. Albrecht S, von Schweinitz D, Waha A, et al. Loss of maternal
alleles on chromosome arm 11p in hepatoblastoma. Cancer Res.
1994;54:5041–4.
19. Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann
syndrome and hemihyperplasia: a critical review of the evidence
and suggested guidelines for local practice. J Paediatr Child
Health. 2006;42:486–90.
20. Aretz S, Koch A, Uhlhaas S, et al. Should children at risk for familial
adenomatous polyposis be screened for hepatoblastoma and children
with apparently sporadic hepatoblastoma be screened for APC germ-
line mutations? Pediatr Blood Cancer. 2006;47:811–8.
21. McLaughlin CC, Baptiste MS, Schymura MJ, et al. Maternal and
infant birth characteristics and hepatoblastoma. Am J Epidemiol.
2006;163:818–28.
22. Maruyama K, Ikeda H, Koizumi T, et al. Case-control study of
perinatal factors and hepatoblastoma in children with an extremely
low birth weight. Pediatr Int. 2000;42:492–8.
23. Meyers R, Aronson DC, von Schweinitz D, Zimmerman A,
Malogolowkin MH. Pediatric liver tumors. In: Pizzo PA, Pop-
lack DG, eds. Principles and practice of pediatric oncology.
6th ed. Philadelphia: Wolters Kluwer and Lippincott Williams
& Wilkins; 2011. pp. 838–60.
24. Ehrlich P, Greenberg M, Filler RM. Improved long term survival
with preoperative chemotherapy for hepatoblastoma. J Pediatr
Surg. 1997;32:999–1003.
25. Weinblatt M, Siegel S, Siegel M, et al. Preoperative chemotherapy
for unresectable primary hepatic malignancy in children. Cancer.
1982;50:1061–4.
26. Hiyama E, Yamaoka H, Matsunaga T, et al. High expression of
telomerase is an independent prognostic indicator of poor outcome
in hepatoblastoma. Br J Cancer. 2004;91:972–9.
Indian J Pediatr (June 2012) 79(6):793–800
27. Chitraghar S, Iyer VK, Agarwala S, DattaGupta S, Sharma A, Wari
MN. Loss of heterozogosity on chromosome 11p15.5 and relapse
in hepatoblastoma. Eur J Pediatr Surg. 2011;21:50–3.
28. Chopra A, Iyer VK, Agarwala S, et al. Apoptotic protein expression,
glycogen content, DNA ploidy and cell proliferation in hepatoblas-
toma subtyping and their role in prognostication. Pediatr Surg Int.
2010;26:1173–8.
29. Das CJ, Dinghra S, Gupta AK, Iyer VK, Agarwala S. Imaging of
pediatric liver tumors with pathological correlation. Clin Radiol.
2009;64:1015–25.
30. Ortega J, Krailo MD, Haas JE, et al. Effective treatment of unre-
sectable or metastatic hepatoblastoma with cisplatin and continu-
ous infusion doxorubicin chemotherapy: a report from the Children
Cancer Study Group. J Clin Oncol. 1991;9:2167–76.
31. von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D.
Prognostic factors and staging systems in childhood hepatoblas-
toma. Int J Cancer (Paed Oncol). 1997;74:593–9.
32. von Schweinitz D, Wischmeyer P, Leuschner I, et al. Clinico-
pathological criteria with prognostic relevance in hepatoblastoma.
Eur J Cancer. 1994;30A:1052–8.
33. Iyer VK, Kapila K, Agarwala S, Verma K. Fine needle aspiration
cytology of hepatoblastoma: recognition of subtypes on cytomor-
phology. Acta Cytol. 2005;49:355–64.
34. Clatworthy HW, Schiller M, Grosfeld JL. Primary liver tumors in
infancy and childhood. 41 cases variously treated. Arch Surg.
1974;109:143–7.
35. McKinley GA, Pritchard J. A common language for childhood
liver tumors. Pediatr Surg Int. 1992;7:325–6.
36. Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical
treatment of hepatoblastoma in the modern era-recommendtions
from the Childhood liver Tumor Strategy Group of the Interna-
tional Society of Pediatric Oncology (SIOPEL). Eur J Cancer.
2005;41:1031–6.
37. Evans AE, Land VJ, Newton WA, et al. Combination chemotherapy
(Vincristine, Adriamycin, cyclophosphamide and 5-fluorouracil) in
the treatment of children with malignant hepatoma. Cancer.
1982;50:821–6.
38. Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A.
Cisplatin, vincristine and fluorouracil therapy for hepatoblastoma:
a Pediatric Oncology Group study. J Clin Oncol. 1993;11:96–9.
39. Fuchs J, Rydzynski J, vonSchweinitz D, et al. Pretreatment prog-
nostic factors and treatment results in children with hepatoblas-
toma: a report from the German Cooperative Pediatric Liver
Tumor Study HB94. Cancer. 2002;95:172–82.
40. Elias D, Cavalcanti A, Sabourin J-C, et al. Results of 16 curative
hepatectomies with safety margin of less than 10 mm for colorectal
metastases. J Surg Oncol. 1998;69:88–93.
41. Seo T, Ando H, Watnab Y, et al. Treatment of hepatoblastoma
less extensive hepatectomy after effective preoperative chemo-
therapy with cisplatin and Adriamycin. Surgery. 1998;123:407–
14.
42. Dicken BJ, Bigam DL, Lees GM. Association between surgical
margins and long-term outcome in advanced hepatoblastoma. J
Pediatr Surg. 2004;39:721–5.
43. Pimpalwar AP, Sharif K, Ramani P, et al. Strategy for hepatoblas-
toma management: transplant versus nontransplant surgery. J
Pediatr Surg. 2002;37:240–5.
44. Nadalin S, Heuer M, Wallot M, et al. Paediatric acute liver failure
and transplantation: the University of Essen experience. Transpl
Int. 2007;20:519–27.
45. Rhee C, Narsinh K, Venick RS, et al. Predictors of clinical out-
come in children undergoing orthotopic liver transplantation for
acute and chronic liver disease. Liver Transpl. 2006;12:1347–56.
46. Mahadeb P, Gras J, Sokal E, et al. Liver transplantation in children
with fulminant hepatic failure: the UCL experience. Pediatr Trans-
plant. 2009;13:414–20.
799
47. Langevin AM, Pierro A, Liu P, et al. Adriamycin and cis-platinum
administered by continuous infusion preoperatively in hepatoblas-
toma unresectable at presentation. Med Pediatr Oncol. 1990;18:181–
4.
48. von Schweinitz D. Management of liver tumors in childhood.
Semin Pediatr Surg. 2006;15:17–24.
49. Baertschinger RM, Hulya O, Rougemont A, et al. Cure of multi-
focal panhepatic hepatoblastoma: is liver transplantation always
necessary. J Pediatr Surg. 2010;45:1030–6.
50. Tiao GM, Bobey N, Allen S, et al. The current management of
hepatoblastoma: a combination of chemotherapy, conventional
resection, and liver transplantation. J Pediatr. 2005;146:204–11.
51. Hemming AW, Reed AI, Langham Jr MR, et al. Combined resec-
tion of the liver and inferior vena cava for hepatic malignancy. Ann
Surg. 2004;239:712–9.
52. Guerin F, Gauthier F, Martelli H, et al. Outcome of central hepa-
tectomy for hepatoblastomas. J Pediatr Surg. 45:555–63.
53. Hemming AW, Reed AI, Langham MR, Fujita S, van der Werf WJ,
Howard RJ. Hepatic vein reconstruction for resection of hepatic
tumors. Ann Surg. 2002;235:850–8.
54. Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for
hepatoblastoma: indications and contraindications in the modern
era. Pediatr Transplant. 2005;9:557–65.
55. Evans AE, Land VJ, Newton WA, Randolph JG, Sather HN, Tefft
M. Combination chemotherapy (vincristine, adriamycin, cyclo-
phosphamide, and 5-fluorouracil) in the treatment of children with
malignant hepatoma. Cancer. 1982;50:821–6.
56. Douglass EC, Green AA, Wrenn E, Champion J, Shipp M, Pratt
CB. Effective cisplatin (DDP) based chemotherapy in the treat-
ment of hepatoblastoma. Med Pediatr Oncol. 1985;13:187–90.
57. Quin JJ, Altman J, Robinson HT, Cooke RW, Hight DW, Foster
JH. Adriamycin and Cisplatin for hepatoblastoma. Cancer.
1998;56:1926–9.
58. Ortega JA, Douglass EC, Feusner JH, et al. Randomized compar-
ison of cisplatin/vincristine/fluorouracil and cisplatin/continuous
infusion doxorubicin for treatment of pediatric hepatoblastoma: a
report from the Children's Cancer Group and the Pediatric Oncol-
ogy Group. J Clin Oncol. 2000;18:2665–75.
59. Katzenstein HM, London WB, Douglass EC, et al. Treatment of
unresectable and metastatic hepatoblastoma: a pediatric oncology
group phase II study. J Clin Oncol. 2002;20:3438–44.
60. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cis-
platin plus doxorubicin for standard-risk hepatoblastoma. N Engl J
Med. 2009;361:1662–70.
61. Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblasto-
mas treated using the Japanese Study Group for Pediatric Liver
Tumor (JPLT) protocol-2: report from the JPLT. Pediatr Surg Int.
2011;27:1–8.
62. Häberle B, Bode U, von Schweinitz D. Differentiated treatment
protocols for high- and standard-risk hepatoblastoma–an interim
report of the German Liver Tumor Study HB99. Klin Padiatr.
2003;215:159–65.
63. Von Schweinitz D, Haberle B. German liver tumor study: HB 99.
In: First International Symposium Childhood Hepatoblastoma.
Poland: Gdansk; 2007.
64. Malogolowkin MH, Katzenstein HM, Krailo MD, et al. Intensified
platinum therapy is an ineffective strategy for improving outcome
in pediatric patients with advanced hepatoblastoma. J Clin Oncol.
2006;24:2879–84.
65. Casanova M, Zsiros J, Brock P, et al. Metastatic hepatoblastoma—
results of the Siopel 3 study from the International Childhood
Liver Tumour Strategy Group—Siopel. 41st Annual Conference
of the International Society of Paediatric Oncology,SIOP 2009.
Pediatr Blood Cancer. 2009;53:744.
66. Sasaki F, Matsunaga T, Iwafuchi M, et al. Outcome of hepatoblas-
toma treatment with JPLT-1 protocol-1: a report from the Japanese
800
study group for pediatric liver tumor. J Pediatr Surg. 2002;37:851–
6.
67. Shukla PJ, Barreto SG, Qureshi SS, et al. Hepatoblastoma: a single
institutional experience of 18 cases. Pediatr Surg Int. 2008;24:799–
802.
68. Singh T, Satheesh CT, Appaji L, et al. Hepatoblastoma: experience
from single center. Indian J Cancer. 2010;47:314–6.
69. Agarwala S, Bakshi S, Bajpai M, et al. Validation of PRETEXT
staging system and risk categorization for prognostication and
outcome in hepatoblastoma- Results from AIIMS-HB 94 trial.
Pediatr Blood Cancer. 2007;49:401.
70. Hadley GP, Govender D, Landers G. Primary tumors of the liver in
children: an African perspective. Pediatr Surg Int. 2004;20:314–8.
71. Czauderna P, MacKinley G, Perilongo G, et al. Hepatocellular
carcinoma in children: results of the first prospective study of the
International Society of Pediatric Oncology Group. J Clin Oncol.
2002;20:2798–804.
72. Pawlik TM, Scroggins CR, Thomas MB, Vauthey J-N. Advances
in surgical management of liver malignancies. Cancer J.
2004;10:74–87.
73. Van Spronson FJ, Bijleveldem M, van Maldegem BT, Wijburg IA.
Hepatocellular carcinoma in hereditary tyrosinemia type 1 despite
2 (-2 nitro 4-3 trifluoro-methyl-benzenyl) 1-3 cyclohexanedione
therapy. J Pediatr Gastroenterol Nutr. 2005;40:90–3.
74. Bianchi L. Glycogen storage disease I and hepatocellular tumors.
Eur J Pediatr. 1993;152:563–70.
75. Hadzic N, Quaglia A, Mieli-Vergani G. Hepatocellular carcinoma
in a 12 y old child with PiZZ alpha-I-antitrypsin deficiency. Hep-
atology. 2006;43:514–21.
76. Halvorsen RAJ, Garrity S, Kun C, et al. Co-existing hepatocellular
carcinoma in a patient with arteriohepatic dysplasia. Abdom Im-
aging. 1995;20:191–6.
77. Pennington DJ, Sivit CJ, Chandra RS. Hepatocellular carcinoma in
a child with Niemann-Pick disease. Imaging findings Pediatr
Radiol. 1996;26:220–1.
78. Zimmermann A. Hepatoblastoma with cholangioblastic features
(‘cholangioblastic hepatoblastoma’) and other liver tumors with
Indian J Pediatr (June 2012) 79(6):793–800
bimodal differentiation in young patients. Med Pediatr Oncol.
2002;39:487–91.
79. Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Fibrolamellar
hepatocellular carcinoma in children and adolescents. Cancer.
2003;97:2006–12.
80. Grosfeld JL, Otte JB. Liver tumors in children. In: Carcahi R,
Grosfeld JL, Azmy AF,eds. The surgery of childhood tumors. 2nd
ed, Springer:2008. pp. 227-60.
81. Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Hepato-
cellular carcinoma in children and adolescents: results from the
Pediatric Oncology Group and the Children’s Cancer Group inter-
group Study. J Clin Oncol. 2002;20:2789–97.
82. Mazzaferro V, Regalia E, Doci R, et al. Liver transplant for the
treatment of hepatocellular carcinoma in patients with cirrhosis. N
Eng J Med. 1996;334:696–9.
83. Chowdhary SK, Trehan A, Das A, et al. Undifferentiated embry-
onal sarcoma in children: beware of the solitary liver cyst. J Pediatr
Surg. 2004;39:9–12.
84. Bisogno G, Pilz T, Perilongo G, et al. Undifferentiated sarcoma of
the liver in childhood: a curable disease. Cancer. 2002;94:252–7.
85. Kim DY, Kim KH, Jung SE, Lee SC, Park KW, Kim WK. Undif-
ferentiated (embryonal) sarcoma of the liver: combination treat-
ment by surgery and chemotherapy. J Pediatr Surg. 2002;37:1419–
23.
86. Baron PW, Majiessipour F, Bedros AA, et al. Undifferentiated
embryonal sarcoma of theliver successfully treated with chemo-
therapy and liver resection. J Gastrointest Surg. 2007;11:73–5.
87. Awan S, Davenport M, Portmann B, Howard ER. Angiosarcoma
of the liver in children. J Pediatr Surg. 1996;31:1729–32.
88. Nazir Z, Pervez S. Malignant vascular tumors of liver in neonates.
J Pediatr Surg. 2006;41:e49–51.
89. Clairotte A, Ringenbach R, Laithier V, Aubert D, Kantelip B.
Malignant rhabdoid tumor of the liver with spontaneous rupture:
a case report. Ann Pathol. 2006;26:122–5.
90. Ravindra KV, Cullinane C, Lewis IJ, Squire BR, Stringer MD.
Long-term survival after spontaneous ruptureof a malignant rhab-
doid tumor of the liver. J Pediatr Surg. 2002;37:1488–90.