Received: 15 February 2018 Revised: 13 May 2018 Accepted: 30 May 2018

DOI: 10.1002/pbc.27293

Pediatric
RESEARCH ARTICLE Blood &
The American Society of
Cancer Pediatric Hematology/Oncology

Surgical management of children and adolescents with upfront

completely resected hepatocellular carcinoma

Amber M. D'Souza1 ∗ Rachana Shah1 ∗ Anita Gupta2 Alexander J. Towbin3

Maria Alonso4 Jaimie D. Nathan4 Alex Bondoc4 Greg Tiao4 James I. Geller1

1 Division of Oncology, Cincinnati Children's

Hospital Medical Center, Cincinnati, Ohio Abstract

2 Division of Pathology and Laboratory Medicine,
Cincinnati Children's Hospital Medical Center,
Cincinnati, Ohio
3 Department of Radiology, Cincinnati Children's
Hospital Medical Center, Cincinnati, Ohio
4 Division of Pediatric General and Thoracic
Surgery, Cincinnati Children's Hospital Medical
Center, Cincinnati, Ohio
Correspondence
James I. Geller, Division of Oncology, Cincinnati
Children's Hospital Medical Center, 3333 Burnet
Avenue, MLC 7018, Cincinnati, Ohio-45229.
Email: james.geller@cchmc.org
∗ Amber M. D'Souza and Rachana Shah have
contributed equally to this work.
Background: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often
chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver
transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for
stage I disease.
Methods: A retrospective review of patients < 18 years of age with completely resected HCC
treated with surgical intervention alone at our institution from 2004 to 2015 was conducted.
Results: Twelve patients with a median age of 12 years (range = 1–17; number of females = 7)
with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identi-
fiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-
differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic
shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moder-
ate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intra-
hepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven
patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imag-
ing. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten
patients received no adjuvant chemotherapy. All patients are alive without evidence of disease
with a median follow-up of 54.1 months (range = 28.1–157.7 months).

Conclusions: Pediatric and adolescent patients with upfront, completely resected HCC can be
effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, espe-
cially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Dis-
tinct pediatric selection criteria are needed to identify patients most suitable for LT.

KEYWORDS
adolescent, hepatocellular carcinoma, liver transplant, Milan criteria, pediatric

1 INTRODUCTION intake, or autoimmune and nonalcoholic steatohepatitis.2 In children

Hepatocellular carcinoma (HCC) represents the second most common
type of malignant hepatic neoplasm in children, though only 0.5–1%
of all HCC manifest before 20 years of age.1 In adults, HCC typically
occurs in the setting of pre-existing chronic liver disease induced cir-
rhosis, triggered most commonly by viral hepatitis, excessive alcohol
ABBREVIATIONS: A1AT, alpha-1 antitrypsin deficiency; CCG, Children's Cancer Group;
COG, Children's Oncology Group; EFS, event-free survival; HCC, hepatocellular carcinoma;
LT, liver transplantation; MC, Milan criteria; MELD, Model for End-Stage Liver Disease; OS,
overall survival; PELD, pediatric end-stage liver disease; PFIC2, progressive familial
intrahepatic cholestasis type-2; POG, Pediatric Oncology Group
and adolescents within the Western world, only 30% of HCC occurs in
the context of an identifiable pre-existing chronic liver disease, includ-
ing anatomic abnormalities (Abernethy, Fontan procedure, and biliary
atresia), and genetic predispositions (Alagille syndrome, progressive
familial intrahepatic cholestasis type-2 [PFIC2]).
The mainstay of treatment for HCC in children and adolescents
remains complete surgical resection. However, HCC is often invasive
or multifocal at diagnosis, rendering less than 30% amenable to sur-
gical resection.3,4 Historically, as an adjunct to surgery, children and
adolescents with HCC have been treated with intensive multi-agent
chemotherapy regimens,5,6 with approximately 40% of children with

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c 2018 Wiley Periodicals, Inc. 1 of 8
https://doi.org/10.1002/pbc.27293
2 of 8
HCC demonstrating chemotherapy response. The 5-year event-free
survival (EFS) for pediatric HCC remains suboptimal at 20%, with
a 5-year overall survival (OS) ranging from 13 to 28%.7–9 However,
the prognosis is favorable in patients with Evans stage I HCC. While
international cooperative group protocols have all included adjuvant
chemotherapy for stage I HCC, its role remains unknown.8
Liver transplantation (LT) is an option for pediatric patients with
unresectable localized disease or HCC in the setting of end-stage liver
disease.10–14 The Milan criteria (MC) for transplant selection were
originally defined for adults with HCC in the setting of cirrhosis, to
identify the subset of patients who were likely to have favorable trans-
plant outcomes. Unfortunately, there are no prospectively validated
patient selection criteria for LT in the pediatric population. Most pedi-
atric cases fall outside of MC at diagnosis; several retrospective stud-
ies have shown favorable outcomes in children with HCC that exceed
MC.13,15–17
We conducted a single institution, retrospective review to improve
our understanding of upfront, completely resected (Evans stage I) HCC
in children and adolescents treated without adjuvant chemotherapy.
2 METHODS
Following institutional review board approval, a retrospective analysis
was performed of patients < 18 years of age with upfront, completely
resected HCC treated at our institution between January 1, 2004 and
December 31, 2015. Evans stage I HCC was defined as completely
upfront resected tumors, without macroscopic or microscopic residual
disease, lymph node involvement, or metastatic disease. Patients with
localized disease who underwent LT upfront were considered to also
be Evan's stage I.8 TNM staging was also obtained as per the Amer-
ican Joint Committee on Cancer (AJCC) for HCC.18 Demographics,
pre-existing conditions, treatment, therapy-related morbidity, and out-
comes were reviewed. Histopathology, radiographic, and surgical data
were reviewed by a pathologist (A.G.), radiologist (A.J.T.), and surgeons
(A.B., J.D.N., M.A., and G.T.) for accuracy and completeness.
Histopathology was classified according to WHO Classification of
Tumors of the Digestive System.19 Computed tomography scan and/or
magnetic resonance imaging obtained at diagnosis were reviewed
to determine the size and number of liver lesions as well as the
overall PRETEXT score, based on Children's Oncology Group (COG)
modifications to the 2005 PRETEXT guidelines.20 The Child–Pugh
score,21 pediatric end-stage liver disease (PELD) score (for chil-
dren < 12 years),22 and Model for End-Stage Liver Disease (MELD)
score (for children ≥ 12 years)23 were collected. MC were assessed for
each patient who underwent LT.24
3 RESULTS
3.1 Patient characteristics
We identified 32 patients < 20 years of age diagnosed with HCC at our
institution from 2004 to 2015. Sixteen underwent resection at diagno-
sis, of which thirteen had negative margins and were classified as Evans
D'SOUZA ET AL .
stage I. Of these 13 patients, one had Fanconi anemia and required
reduced-intensity conditioning allogeneic stem cell transplantation
for myelodysplastic syndrome 2 months after HCC tumor resection,
leading to nononcologic death. The remaining 12 patients were
included in subsequent analysis (Table 1). The median age was 12 years
(range = 1–17); seven were female. Ten patients did not receive
any chemotherapy. One patient (Patient #10) received two cycles of
adjuvant cisplatin and 5-flououracil based on the discretion of the
primary oncologist for suboptimal negative margins (3 mm). Another
had biliary and lymphovascular invasion and received six cycles of
sorafenib (Patient #12). Four patients had de novo HCC; four had
HCC in the context of genetic predisposition and cirrhosis—PFIC2 = 2,
alpha-1 antitrypsin deficiency (A1AT) = 1, and Alagille syndrome = 1;
and four had HCC in the context of anatomic predisposition without
cirrhosis—Abernethy syndrome (congenital portosystemic shunt = 2
and portal vein thrombosis treated with a mesocaval shunt = 2).
3.2 Histopathology and molecular features
Pathology review showed four patients with a cirrhotic liver (PFIC-
2 = 2, A1AT = 1, and Alagille = 1), with moderate to well-differentiated
(wd) HCC arising in dysplastic nodules (Figure 1). One of the six
patients with a noncirrhotic liver had a 0.7 cm early HCC arising within
a focal nodular hyperplasia-like lesion and another had multifocal wd-
HCC developing within hepatic adenoma. There were two patients
with fibrolamellar HCC and the remaining four cases had early to wd-
HCC arising within adenomas in a background of Abernathy or por-
tal venous thrombosis (Figure 1). Six patients had multifocal disease
histologically.
3.3 Staging and risk factors
PRETEXT stages were I (2), II (8), and IV (2) (Table 1). One patient's
portal vein was compressed by the tumor (P2) and five patients had a
tumor within 1 cm of the intrahepatic inferior vena cava or all three
hepatic veins (V0). One patient had intrabiliary and lymphovascular
invasion (Patient #12). None had caudate lobe, lymphatic, or extrahep-
atic involvement. The median serum alpha-fetoprotein level at diagno-
sis was 2.1 ng/ml (range = 1–17,043.3). Child–Pugh scores were Class
A = 6, Class B = 4, and Class C = 1. The median MELD/PELD score was
10 (range = 5.4–47.6). One patient (Patient #10) did not have any lab-
oratory data available.
3.4 Surgical treatment
Two patients underwent hepatic segmentectomy and three underwent
hemihepatectomy. One patient with PFIC2 (Patient #3) was provision-
ally treated with radiofrequency ablation at biopsy. Seven patients
were treated with LT. In four patients (Patients #1, 2, 3, and 5), LT was
performed due to the development of HCC with a cirrhotic background
liver, in the context of a pre-existing genetic condition. These four
patients were suffering from complications of their pre-existing liver
disease, including coagulopathy, ascites, and/or hyperammonemia. Of
the remaining three patients transplanted, Patient #4 had Turner
TA B L E 1 Characteristics and outcomes of patients with upfront, completely resected HCC

Patient
Pre-existing disease De novo Fibrolamellar
a a a
Patient characteristics 1 2 3 4 5 6 7 8 9 10 11 12
D'SOUZA ET AL .

Age at diagnosis (years) 1 6 1 11 13 17 10 13 10 18 16 17

Gender Male Female Female Female Male Male Male Female Female Male Female Female
Background liver disease PFIC2 A1AT PFIC2 Abernethy Alagille syndrome Mesocaval Abernethy Mesocaval Normal Normal Normal Normal
shunt, PVT shunt, PVT
Other nodules Low and High grade None Adenomatosis Dysplastic nodules Adenomatosis Adenomas Adenomatosis FNH Adenoma None None
high grade
dysplastic dysplastic Macrodegenerative
nodules nodules nodule
Cirrhosis (Ishak score) Cirrhosis Cirrhosis Cirrhosis (F1) Noncirrhotic Cirrhosis (F1) Noncirrhotic Noncirrhotic Noncirrhotic Noncirrhotic Noncirrhotic Noncirrhotic Noncirrhotic
(F1) (F1)
Histology md-HCC wd-HCC HCC wd-HCC wd-HCC wd-HCC wd-HCC Early HCC ×5 arising Early HCC wd-HCC md- Fibrolamellar
within adenomas fibrolamellar
HCC
Edmondson grade II–III I I–II I–II I I I – – I II II
Extratumoral vascular and Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Present
lymphatic invasion (microscopic)
Disease site(s) Bilateral Right lobe Hilum Bilateral Dome Bilateral Left lobe Bilateral Right lobe Right lobe Right Lobe Right lobe
Focality (by pathology) Multifocal Solitary Solitary Multifocal Multifocal Multifocal Solitary Multifocal Solitary Multifocal Solitary Solitary
Maximum diameter of 1.2 cm 6.5 cm 3 cm 4.5 cm 3.8 cm 10 cm 13 cm 9.1 cm adenoma with 0.7 cm 10 cm 7 cm 8.5 cm
largest focib foci of early HCC
Marginsc – – – – – – 1.5 cm – 1.5 cm 3 mm 2 cm 1 cme
PRETEXT II II II IV II II II IV I I II II
PRETEXT annotation – F2 – V0F4 V0F2 V0 P2V0F2 V0F6 – – – –
factors
Evans/COG stage I I I I I I I I I I I I
TNM stage T2N0Mx T1N0Mx T1NxMx T2N0Mx T2N0Mx T3aNxMx T1N0Mx T3aN0Mx T2NxM0 T2N0Mx T1NxMx T2N0Mx
AFP at diagnosis (ng/ml) 17,403.3 2.2 11,899.2 1 2.1 1.1 2 3.1 4.2 Unknown 1.8 1.5
Child–Pugh score Class B Class B Class C Class A Class B Class A Class A Class B Class A Unknown Class A Class A
d
MELD/PELD score 38.9 26.2 47.6 18.3 11 10 7.3 8 5.4 Unknown 8 6
Treatment LT LT Radioablative LT LT LT Left LT Right hemi- Right Right hemi- Right hemi-
therapy; LT hepatectomy hepatectomy hepatectomy hepatectomy hepatectomy
Response CR CR CR CR CR CR CR CR CR CR CR CR
Vital status Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive
EFS/OS (months) 49.3 87.3 64 56.1 47.2 66 105.5 46 28.1 157.7 52.2 33.5
a
Patient diagnosed with HCC postoperatively.
b
Measured by pathology.
c
Margins for patients who underwent hepatic resection.
d
MELD (Model for End-Stage Liver Disease): age ≥ 12 years, PELD (pediatric end-stage liver disease): age < 12 years.
e
Parenchymal margin = 1 cm. Patient did have lymphovascular and bile duct invasion.
A1AT, alpha-1 antitrypsin deficiency; AFP, alpha-fetoprotein; CR, complete response; EFS, event-free survival; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; LT, liver transplant; md, moderately
3 of 8

differentiated; OS, overall survival; PFIC2, progressive familial intrahepatic cholestasis type-2; PVT, portal vein thrombosis; wd, well differentiated.
4 of 8 D'SOUZA ET AL .

F I G U R E 1 Pathology of stage I HCC. (A) 6-year-old male with PFIC2 had a 1.2 cm, well-demarcated yellow–green mass, discrete from the
green cirrhotic background liver. Histology demonstrated an encapsulated lesion with moderate differentiation, with large areas devoid of reti-
culin framework that on high power (B) in the center (left half) is composed of small neoplastic hepatocytes with eosinophilic hyaline globules,
and conspicuous nucleoli surrounded by areas (right half) similar to the background with the exception of more pleomorphism, prominent nucle-
oli, and eosinophilic globules (Patient #1, hematoxylin and eosin [H&E], 400× [right and left]). (C) Compared to the histology in (B), this moder-
ately differentiated hepatocellular carcinoma arose in a noncirrhotic background. The tumor cells have more eosinophilic cytoplasm secondary to
increased mitochondria, and the islands of tumor cells are separated by fibrous bands. These histology findings are consistent with fibrolamellar
HCC (Patient #11, H&E 400×). (D) Patient #8 had multiple ß-catenin activated and HNF1 inactivated adenomas arising in a noncirrhotic liver, of
which five lesions showed stromal invasion (E) consistent with early HCC (H&E at 400×). (F) Glutamine synthetase does not only show diffuse
brown cytoplasmic expression within several of the neoplasms indicative of ß-catenin activation, but also highlights stromal invading tumor cells
(Patient #10, glutamine synthetase immunostain, 400×)

syndrome and Shone's complex with advanced liver disease with
hyperammonemia and subsequent variceal bleeding. Patient #6 had
previously undergone right hemihepatectomy for adenoma, rendering
a left hepatic resection for the neoplastic lesion difficult. Patient #8
had noncirrhotic liver disease and a previous mesocaval shunt along
with portal hypertension, idiopathic fibrosis, and ascites. These three
patients had previous biopsies showing a wd-hepatocellular neoplasm
but were only diagnosed with HCC after LT.
The median time to transplant from listing was 103 days
(range = 17–713 days). The patient listed for 713 days (Patient
#8) had careful monitoring of very slow growing liver lesions, which
were initially thought to be wd-hepatocellular adenomas, prior to
ultimate transplantation.
3.5 MC and the transplant cohort
Five of the seven patients who underwent LT exceeded MC by imaging
(Table 2). Specifically, one patient had a solitary lesion > 5 cm and four
others had more than three foci with the largest foci being greater than
3 cm. The rationale to transplant outside of MC varied among patients.
In two cases (Patient #2 and 5), there was concern for impending liver
failure in the setting of a cirrhotic background liver secondary to pre-
existing liver disease. One of those two patients had biopsy-proven
HCC prior to transplant, whereas the other had high-grade dysplas-
tic nodules at biopsy but confirmed HCC at transplant. Patients #4,
6, and 8 were transplanted for aforementioned reasons. All three of
these patients exceeded MC; however, in all three, HCC was only con-
firmed at the time of transplant, and each was previously diagnosed
with hepatic adenomas (ß-catenin activated subtype) from pretrans-
plant biopsies.
3.6 Treatment-related morbidity and outcomes
There were no complications related to nontransplant HCC resections
(n = 5). Of those who underwent LT, two patients had postoperative bil-
iary complications, both requiring re-operation. Patient #3, due to her
age and size, received a deceased donor, left lateral section allograft
procured during an in situ split. Despite performing an on-table cholan-
giogram to delineate biliary anatomy, the segmental duct was not iden-
tified and therefore not reconstructed at the time of transplant. As a
result, a second surgery was needed to place this duct into continu-
ity with the patient's dominant biliary reconstruction. Patient #5 likely
developed a contained leak from the transplant hepaticojejunostomy,
which created an inflammatory pseudocyst which then created a mass
effect. The subsequent biliary obstruction required removal of the rind
and revision of the biliary anastomosis.
D'SOUZA ET AL . 5 of 8

TA B L E 2 Milan criteria of patients with upfront completely resected HCC treated with liver transplantation

Milan criteria
Up to three lesions Vascular or
One lesion with each with extrahepatic Exceeded Milan Reason for exceeding Milan
Patient (n = 7) diameter ≤ 5 cm diameter ≤ = 3 cm involvement criteria criteria
1 n/a + Absent No –
2 − n/a Absent Yes Solitary lesion > 5 cm
3 + n/a Absent No –
4 n/a − Absent Yes >3 foci with largest
focus > 3 cm
5 n/a − Absent Yes >3 foci with largest
focus > 3 cm
6 n/a − Absent Yes >3 foci with largest
focus > 3 cm
8 n/a − Absent Yes >3 foci with largest
focus > 3 cm
HCC, hepatocellular carcinoma; n/a, not applicable.

Additional transplant-associated morbidities included acute
cellular rejection (n = 2) successfully treated with a steroid pulse,
immunosuppression-related Epstein–Barr virus viremia (n = 2), one of
whom required treatment with rituximab, and immunosuppression-
related recurrent Clostridium difficile infections and cytomegalovirus
viremia (n = 1). In regard to chronic transplant-related sequelae,
Patient #8 developed hepatic venous outflow obstruction and even-
tually developed severe antibody mediated rejection leading to
end-stage renal disease and is now listed for a kidney transplant.
All twelve patients are alive at the time of this publication, with
no evidence of disease recurrence, with a median follow-up of 54.1
months (range = 28.1–157.7).
4 DISCUSSION
HCC is an aggressive hepatic neoplasm that is often chemoresistant,
with a response rate of ∼20% in adults and 40% in children, sug-
gesting underlying biological differences between pediatric and adult
HCC.7 Prior cooperative group studies included chemotherapy for
stage I pediatric and adolescent HCC, though standard of care in adult
patients with HCC does not include such adjunctive treatment.
The Pediatric Oncology Group (POG) and Children's Cancer Group
(CCG) conducted an intergroup clinical trial (INT-0098) that aimed
at comparing surgical resectability, EFS, and toxicity for children with
HCC, postoperatively treated with either a combination of cisplatin,
5-fluorouracil, and vincristine (C5V, Regimen A) versus cisplatin and
continuous-infusion doxorubicin (Regimen B). Eight patients in the
cohort had stage I disease; three patients received Regimen A; and five
patients received Regimen B in a postoperative setting. The 5-year EFS
and OS was 88% for all patients with stage I HCC. Given the absence
of a control arm (no chemotherapy), there remains no conclusive evi-
dence that adjuvant chemotherapy offers additional benefit in children
and adolescents with resectable localized HCC.8
The Group for Epithelial Liver Tumors of the International Society of
Pediatric Oncology (SIOPEL) conducted its first clinical trial (SIOPEL
1) that aimed at reducing surgical morbidity/mortality and improv-
ing survival outcomes in children with primary epithelial liver tumors
by administering a combination of cisplatin and doxorubicin (PLADO)
in a neoadjuvant setting.7 Subsequently, SIOPEL 2 and 3 evaluated
whether therapy intensification with platinum- and doxorubicin-based
chemotherapy would improve tumor resectability.25 Upfront surgery
was not used in these SIOPEL studies, making it impossible to assess
for any impact of chemotherapy for otherwise initially resectable
HCC.
Complete surgical resection, when possible, remains the corner-
stone of HCC therapy and the best chance for cure regardless of age
at diagnosis. The main goal of surgical resection is to remove all sites
of disease while preserving liver function. In adults, the presence of
cirrhosis makes complete hepatic resection harder in terms of pre-
serving liver function and minimizing the risk of perioperative compli-
cations from portal hypertension.26 Additionally, two-thirds of pedi-
atric patients with HCC present with unresectable disease, and use
of chemotherapy to improve resectability is often not successful.4 In
our cohort, using traditional POG/CCG/COG surgical standards that
include upfront surgery for initially resectable HCC when feasible,
two patients underwent hepatic segmentectomy and three underwent
hemihepatectomy (Table 1). All five patients had a successful gross
total resection, with negative margins, and remain disease free.
Despite extensive studies, the optimal liver resection margin
remains controversial. Some studies have shown a resection margin
of ≥2 cm to improve OS and recurrence27,28 while others have shown
similar outcomes with a narrow margin of <1 cm or even <5 mm.29,30
In our cohort, one patient with 3 mm margins (Patient #10) received
two cycles of adjuvant chemotherapy based on the discretion of the
primary oncologist, and another with a 1 cm margin received six cycles
of sorafenib due to intrabiliary and lymphovascular invasion (Patient
#12). The other three patients who underwent conventional resection
had 1.5–2 cm margins. With relatively small numbers, it is impossible to
make conclusions on how to define adequate margins; however, we do
note that all five patients, including two with ≤1 cm margins, are alive
without recurrence.
6 of 8
LT in adult patients with HCC in whom surgical resection is
not feasible has been shown to improve survival.24,31 In children
with HCC, LT has been associated with improved disease-free
survival (range = 63–89%) compared to conventional treatment with
chemotherapy and resection, particularly in children with advanced-
stage tumors or chronic underlying liver disease.10–15,32 The Pediatric
Liver Unresectable Tumor Observatory registry was initiated to collect
prospective data on pediatric patients (age < 18 years) undergoing
LT for treatment of unresectable primary malignant liver tumors.33
An interim report from 2015 included 53 patients with HCC who
received an LT (29 with underlying genetic predisposition and 24 in
the setting of a normal background liver).34 The majority of patients
with HCC in the setting of a diseased liver had PRETEXT I or II disease
and did not receive chemotherapy, compared to those with HCC in an
otherwise normal liver, in which the majority had PRETEXT IV disease
and received chemotherapy either neoadjuvantly or both pre- and
post-transplant. This analysis reportedly demonstrated long-term
survival in all pediatric patients with HCC in the setting of chronic
underlying disease treated with LT without chemotherapy (n = 29;
median follow-up = 799 days).34 In pediatric patients who developed
unresectable HCC without any chronic underlying disease, the results
of LT were less favorable but cure was still observed in two-thirds of
the cases (n = 24, median follow-up = 799 days).34
In 1996, a prospective series of 48 adult patients with HCC with
relatively small tumor masses (defined by size and number) and no
extrahepatic or vascular extension demonstrated good transplant out-
comes, leading to the generation of the MC,24 a tool that has since
been validated both retrospectively and prospectively.24,35 Using this
criteria, long-term recurrence-free survival after LT in adult recipients
with HCC has improved from 30% to 75%.24,35,36 However, the MC
have been criticized as being too strict; several studies have demon-
strated good outcomes with more liberal criteria.37–40 The role of
MC in the pediatric population has not been validated. A retrospec-
tive review of pediatric patients with HCC treated with LT (n = 11)
reported an OS of 73% in the transplant group compared to 50% of
patients in the conventional group (n = 8) who were treated with liver
resection ± chemotherapy (excluding two patients in the conventional
group who had disseminated disease and did not receive any therapy
due to poor general condition). Eight (73%) patients in the transplant
group exceeded MC.11 Another single-institution experience with LT in
10 children with HCC, in which 70% exceeded MC, demonstrated a
5-year OS of 83.3%.15 Several additional studies have continued to
demonstrate good transplant outcomes in children with HCC who
exceed MC, highlighting the need for distinct pediatric criteria.13,17,32
In our study, 71% (5/7) of patients that were transplanted exceeded
the original MC (Table 2), and all seven remain alive and cancer free.
A consideration in interpreting these data is that three of the patients
exceeding MC were not known to have HCC at the time of transplant.
One reason why MC may not help appropriately select the
best pediatric transplant candidates perhaps relates to underlying
liver pathology. Specifically, MC were defined in adult patients with
cirrhosis-associated HCC, whereas about 60–70% of pediatric HCC
are reported to occur within a noncirrhotic liver.2 Interestingly, a
review of 105 adults who received an LT for noncirrhotic HCC demon-
D'SOUZA ET AL .
strated that, in contrast to HCC in cirrhosis, tumor size was not pre-
dictive of survival.41 Secondly, the application of adult MC to children
and adolescents undermines tumor biologic differences between the
groups. As evidenced in the cohort presented herein, the biological
heterogeneity of pediatric HCC is substantial. Of note, our cohort did
have a higher number of patients with a predisposition to HCC (67%)
compared to the typical incidence in North America (30%). For these
reasons and based on evolving survival data, recent critical reviews of
the management of advanced pediatric liver tumors advocate that LT
should be offered to children with any size or number of HCC, provided
there is no satisfactory surgical alternative and that the tumor remains
confined to the liver.17,42
This retrospective case series is limited by its representation of a
single institution with a quaternary hepatology and liver transplant
program, thereby restricting its generalizability. Additionally, patient
selection protocols may vary from one transplant center to another,
which may lead to notable differences in outcomes. Given the small
number of patients and absence of any events, we were unable to
perform any analysis to identify risk factors associated with tumor
recurrence.
In conclusion, complete tumor resection is essential for cure of
pediatric and adolescent HCC. When complete upfront resection is
achieved, especially for patients with underlying conditions predispos-
ing to HCC, adjuvant chemotherapy can likely be omitted. Early con-
sideration of LT may be beneficial to children and adolescents with
unresectable localized disease, possibly independent of MC, provided
that the disease remains confined to the liver. Given the rarity of these
tumors in children and adolescents, national and international collabo-
ration is essential to prospectively validate our results on a larger scale,
to facilitate evaluation of novel therapeutic approaches, to improve our
understanding of biological differences between pediatric and adult
HCC, and to further define distinct algorithmic care specific for pedi-
atric and adolescent HCC.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
ORCID
Amber M. D'Souza http://orcid.org/0000-0002-0552-6947
James I. Geller http://orcid.org/0000-0001-5181-116X
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Surgical management of children and adolescents with upfront
completely resected hepatocellular carcinoma. Pediatr Blood
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