Anatomic Pathology / PRIMARY LIVER CARCINOMA
Primary Liver Carcinoma Arising in People Younger Than
30 Years
Walter M. Klein, MD,1 Ernesto P. Molmenti, MD,2 Paul M. Colombani, MD,2 Davinder S. Grover,2
Kathleen B. Schwarz, MD,3 John Boitnott, MD,1 and Michael S. Torbenson, MD1
Key Words: Hepatocellular carcinoma; Fibrolamellar carcinoma; Cytokeratin 7; Foci of altered hepatocytes
DOI: 10.1309/TT0R7KAL32228E99
Abstract
Primary liver carcinomas in children and young
adults are uncommon and poorly described. We
examined primary liver carcinomas in people younger
than 30 years and performed immunostains for markers
of biliary (cytokeratin [CK] 7, CK19, CD56) and
hepatocellular (HepPar) differentiation. We found 23
primary liver carcinomas: 13 hepatocellular
carcinomas (HCCs), 9 fibrolamellar carcinomas
(FLCs), and 1 cholangiocarcinoma. Most HCCs
showed compact (n = 7) or trabecular (n = 4) growth
patterns. The Edmondson grades were as follows: 1, 3
tumors; 2, 8 tumors; and 3, 2 tumors. All HCCs and
FLCs were HepPar+. All FLCs and 7 of 9 HCCs were
CK7+. In contrast, a control group of 65 adult HCCs
showed less CK7 positivity (24 [37%];
P = .03). CK19 was positive in 2 HCCs and CD56 in 1
HCC. No chronic background liver disease was seen,
although 3 cases showed foci of altered hepatocytes.
HCCs are the most common primary liver carcinoma in
children and young adults, followed by FLCs. They are
morphologically similar to adult HCC, but more likely
to be CK7+.
512 Am J Clin Pathol 2005;124:512-518
512 DOI: 10.1309/TT0R7KAL32228E99
Primary hepatic carcinomas are rare in children and
young adults, accounting for approximately 1% of tumors
in people younger than 20 years.1 Of these, approximately
two thirds are hepatoblastomas, whereas most of the
remainder are primary hepatocellular carcinomas (HCCs).1
Unlike HCC in adults, the risk factors for pediatric HCC are
poorly understood. Although case reports have described
pediatric HCC in association with a wide variety of con-
genital anomalies and metabolic diseases, a recent, large,
epidemiologic study found that underlying liver or meta-
bolic disease was absent in most cases of pediatric HCC.1
Furthermore, epidemiologic evidence strongly suggests
that risk factors for HCC in children and young adults are
different from those in adults.1
It is unclear, however, whether histologic differences
can be found between HCC arising in children and young
adults and those arising in adults. Thus, we undertook a ret-
rospective study to examine the histologic features of these
tumors. In addition, we carefully examined sections of
background nonneoplastic liver samples for evidence of
chronic liver disease. We anecdotally had noted immuno-
phenotypic differences in pediatric HCC, with pediatric
cases frequently showing strong cytokeratin (CK) 7 pos-
itivity, and further studied these tumors with immuno-
stains for CK7, CK19, CD56, and HepPar. CK7 and
CK19 are well-recognized markers of biliary differentia-
tion, but numerous studies also have demonstrated posi-
tivity in a modest proportion of adult HCCs.2-5 CD56 is
expressed in biliary epithelium in some biliary tract dis-
eases6 and in approximately 25% of cholangiocarcino-
mas7 but not in hepatocytes. HepPar is a marker of hepa-
tocyte differentiation.
© American Society for Clinical Pathology

Materials and Methods
Tissue Sample Selection
All available cases of primary liver carcinoma from
January 1984 to January 2003 at the Johns Hopkins Hospital,
Baltimore, MD, in persons younger than 30 years were exam-
ined. We decided to include all people younger than 30 years
based on epidemiologic findings that demonstrate a steady
baseline incidence of liver carcinoma before age 40, when the
incidence increases dramatically as a consequence of chronic
liver disease.8 Hepatoblastomas were excluded.
H&E-stained sections and multiple 5-µm unstained sec-
tions for subsequent immunohistochemical analysis were cut
from formalin-fixed, paraffin-embedded sections. The morpho-
logic features of the HCCs were determined by using the World
Health Organization classification (trabecular/macrotrabecular,
pseudoglandular/acinar, compact, and scirrhous), and the
tumors were graded using the modified Edmondson nuclear
grading system.9 Nonneoplastic liver tissue samples were eval-
uated for underlying liver disease. Reticulin stains were per-
formed on cases with H&E findings that suggested nodular
regenerative hyperplasia. The medical records and laboratory
findings also were reviewed for causes of chronic liver disease.
Immunohistochemical Analysis
Antigen retrieval was performed for 5 minutes in 0.01
mol/L of sodium citrate buffer. Sections then were treated with
monoclonal antibodies against CK7 (dilution 1:500; DAKO,
Carpinteria, CA), CK19 (dilution 1:10; DAKO), CD56 (dilution
1:100; Zymed, San Francisco, CA), and HepPar (dilution
1:100; DAKO). Ki-67 immunostains also were performed on
selected sections (dilution 1:1,000; DAKO). The Envision kit
(DAKO) was used according to the manufacturer’s instructions.
The sections stained for CK7, CK19, and CD56 were evaluated
in a semiquantitative scoring system of 0 to 3 based on the per-
centage of tumor cells labeled: 0, no labeling or focal positivity
less than 5%; 1+, 5% to 33% of cells; 2+, 34% to 66% of cells;
and 3+, greater than 66% of cells. Intensity of staining was
scored as weak (1+), moderate (2+), and strong (3+).
Control Groups
As a control group for the frequency of CK7 staining, tissue
arrays containing 65 HCCs from adults older than 40 years also
were stained for CK7 as described. The tissue arrays were con-
structed at Johns Hopkins from formalin-fixed, paraffin-embed-
ded tissue samples from the surgical pathology archives. The
average ± SD age at resection for these adult cases was 63 ± 13
years (range, 40-85 years). The distribution of the modified
Edmondson nuclear grades was as follows: 1, 12 (18%); 2, 24
(37%); 3, 25 (38%); and 4, 4 (6%). Fibrolamellar carcinomas
(FLCs) were excluded from this control group.
© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
When studying the background liver samples of cases
with HCC, we noted discrete foci of altered hepatocytes
(FAH). To betters understand these FAH, we examined 4 sep-
arate control groups for the presence of FAH: colon carcino-
ma metastatic to the liver with no underlying liver disease (n
= 25), HCCs in adults older than 40 years with cirrhotic back-
ground liver samples (n = 25), HCCs in adults older than 40
with background liver samples showing no significant fibrosis
(n = 25), and hepatoblastomas (n = 15).
Results
We identified 23 cases of primary liver carcinoma,
including 13 HCCs (57%), 9 FLCs (39%), and 1 intrahepatic
cholangiocarcinoma (4%). There was a slight male pre-
dominance (13 males, 10 females). No cases were associ-
ated with congenital anomalies or metabolic or other
recognized inherited diseases. At the initial examination,
the serum α-fetoprotein level was elevated in 6 (46%) of 13
cases ❚Table 1❚. Three patients with typical HCC had
known chronic hepatitis B virus (HBV) infection (Table 1),
whereas none of the remaining patients had identifiable
chronic liver disease at the clinical or histologic level. In 1
case (case 11), the HCC was associated with and seemed to
arise out of a hepatic adenoma. The available records for
this case did not indicate use of oral contraceptive pills or
other exposure to exogenous estrogens or androgens.
Histologic Features of HCC
The 13 patients with HCC included 8 males and 5 females
with a mean age of 19.3 years (range, 4-27 years). Of these 13
cases, 10 specimens were obtained from resections and 3 from
needle biopsies. The architectural growth patterns were compact
(n = 7), trabecular (n = 4), macrotrabecular (n = 1), and com-
bined trabecular/compact (n = 1). The modified Edmondson
grades were as follows: 1, 3; 2, 8; and 3, 2. Three HCCs had
areas of tumor composed of small, round-to-oval clusters of
hepatocytes embedded in fibrous stroma somewhat resembling
biliary-type differentiation ❚Image 1A❚. Extensive necrosis was
seen in 4 cases and angiolymphatic invasion in 4 cases.
Histologic Features of Cholangiocarcinoma
The 1 intrahepatic cholangiocarcinoma was from a resec-
tion specimen from a 25-year-old man with no evidence of
chronic biliary tract disease. The histologic findings were
those of a typical cholangiocarcinoma. Tumor necrosis and
angiolymphatic invasion were present.
Immunohistochemical Findings in HCC
Sufficient tissue for immunohistochemical analysis was
present in 9 of 13 HCC cases. All 9 HCCs were strongly (3+)
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Klein et al / PRIMARY LIVER CARCINOMA

❚Table 1❚
Histologic and Immunohistochemical Findings in 13 HCCs and 1 Cholangiocarcinoma

Case No./ Specimen Growth Nuclear Serum AFP HBV CK7 CK19
Sex/Age (y) Type Pattern Grade (ng/mL)* Test Result Other Findings (I/D) (I/D)

Hepatocellular carcinoma
1/F/4 Resection Compact 2 500,000 – Fatty change in nonneoplastic 2+/2+ 0/0
liver; s/p embolization
2/M/10 Resection Compact 2 78,000 – Fatty change in nonneoplastic 0/0 0/0
liver; tumor necrosis, s/p
radiation and chemotherapy, ALI
3/M/13 Resection Compact 2 Normal – Nonneoplastic liver with nodular NA NA
regenerative hyperplasia; tumor
with necrosis, ALI
4/M/13 Needle biopsy Macrotrabecular 1 2,202,600 HBsAg+;HBeAg–; — NA NA
HBeAb+
5/M/16 Resection Trabecular 2 437,015 – Tumor with necrosis, ALI 0/0 0/0
6/F/22 Resection Compact 1 ND ND — 3+/2+ 0/0
7/M/22 Needle biopsy Compact 1 380,000 HBsAg+; HBeAg+; Cirrhosis NA NA
HBeAb–
8/F/23 Resection Trabecular and 3 644,000 HBsAg+; HBeAg–; FAH in nonneoplastic liver; s/p 3+/3+ 1+/1+
compact HBeAb+ radiation and chemotherapy
9/M/25 Resection Compact 2 Normal – Tumor CD56+ 1+/1+ 1+/1+
10/F/25 Resection Trabecular 2 Normal – — 3+/2+ 0/0
11/F/25 Resection Trabecular 3 Normal – Tumor seems to have developed 3+/3+ 0/0
out of hepatic adenoma
12/M/26 Resection Compact 2 Normal – s/p chemoembolization 1+/1+ 0/0
13/M/27 Needle biopsy Trabecular 2 ND – s/p chemotherapy NA NA
Cholangiocarcinoma
14/M/25 Resection Cholangio- — Normal – FAH in nonneoplastic liver; tumor 3+/3+ 2+/1+
carcinoma necrosis, ALI

ALI, angiolymphatic invasion; AFP, α-fetoprotein; CK, cytokeratin; FAH, focus of altered hepatocytes; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAg
hepatitis B surface antigen; HBV, hepatitis B virus; I/D, intensity/distribution (see text); NA, no tissue available for immunohistochemical analysis; ND, not done; s/p, status
post; +, positive; –, negative.
* Results are given in conventional units; to convert to Système International units (µg/L), multiply by 1.0.

and diffusely positive for HepPar. Of the 9 typical HCCs, 7
(78%) were positive for CK7 ❚Image 1B❚. Immunohistochemical
staining for CK7 was weak (n = 2 cases), moderate (n = 1
case), and strong (n = 4 cases). In contrast, CK7 positivity
was less common in control adult HCCs, 24 of 65 (37%; P
= .03; Yates-corrected χ2). In the adult samples, CK7 stain-
ing did not correlate with the degree of background liver
fibrosis. CK7 was positive in 15 (38%) of 39 with advanced
fibrosis or cirrhosis and 9 (35%) of 26 without significant
fibrosis (P = .11).
Immunohistochemical staining for CK19 was positive in
2 (22%) of 9 HCCs with weak intensity ❚Image 1C❚. One HCC
was strongly and diffusely positive for CD56 in a membra-
nous manner ❚Image 1D❚.
Immunohistochemical Findings in Cholangiocarcinoma
The intrahepatic cholangiocarcinoma was negative for
HepPar and CD56 but was strongly positive for CK7 in a dif-
fuse distribution and moderately positive for CK19 in a
patchy distribution.
Fibrolamellar Carcinoma
We identified 9 FLCs ❚Image 1E❚ in 4 males and 5
females with a mean age of 20.0 years (range, 12-29 years).
Of these 9 cases, 4 were obtained from resection specimens, 4
from wedge biopsies, and 1 from a needle biopsy. Significant
necrosis was seen in 2 of 9 cases.
All FLCs were strongly and diffusely positive for HepPar.
CK7 was moderately to strongly positive in all 9 cases (100%)
of FLC ❚Image 1F❚. Immunohistochemical staining for CK19
and CD56 was negative in all cases.
Histologic Features of the Background Liver Samples
Sections were available to review the background liver
samples in 7 of 14 HCC cases, the cholangiocarcinoma
case, and 3 of 9 FLC cases. Three cases of typical HCC
were known to arise in the setting of chronic HBV infection
(Table 1). Sections of background liver were available in 2
of 3 of the HBV-associated cases and showed minimal
chronic inflammation and no fibrosis. In the third HBV-
associated case (case 7), the surgical pathology report indi-
cated that the background liver was cirrhotic, although
slides and blocks were not available for confirmation. An
additional 2 cases showed patchy mild fatty change in the
nonneoplastic liver samples. The background liver samples
showed mild nodular regenerative hyperplasia in 1 case of
HCC and 2 cases of FLC. None of the remaining cases
showed chronic hepatitis or fibrosis.

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514 DOI: 10.1309/TT0R7KAL32228E99
 Anatomic Pathology / ORIGINAL ARTICLE

A B

C D

E F

❚Image 1❚ A, Hepatocellular carcinoma (HCC) with a trabecular growth pattern (H&E, ×100); inset from the same case shows a
focus with a biliary-like growth pattern (H&E, ×200). B, HCC positive for cytokeratin (CK) 7 in a 3+/3+ manner; inset with more focal
CK7 staining, 2+/1+ (×200). C, HCC positive for CK19 in a 2+/1+ manner (×200). D, HCC with CD56 staining in a membranous
manner (×200). E, Typical fibrolamellar carcinoma (H&E, ×200). F, Fibrolamellar carcinoma positive for CK7 in a 3+/3+ manner.
Adjacent nonneoplastic bile ducts also are positive (×200). See the text for an explanation of the scoring for staining.

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515 DOI: 10.1309/TT0R7KAL32228E99 515
Klein et al / PRIMARY LIVER CARCINOMA

Despite the lack of chronic hepatitis and fibrosis, the
background nonneoplastic liver samples showed discrete FAH
in 1 of the 7 HCC cases, 1 of 3 FLC cases, and the intrahe-
patic cholangiocarcinoma. FAH were microscopically of 2
types: The first (found in the cholangiocarcinoma case)
showed large, pale hepatocytes without fatty change ❚Image
2A❚, essentially identical to those described by Su et al10 as
“glycogen storing foci” (FAH-GS). The second (found in the
HCC and FLC cases) was characterized by circumscribed,
nodular foci of smaller hepatocytes with an increased
nuclear/cytoplasmic ratio, fatty change, and occasional
extramedullary hematopoiesis ❚Image 2B❚ and ❚Image 2C❚.
Both types were demarcated sharply from the surrounding liver
and were readily apparent at scanning power magnification. In
the HCC and intrahepatic cholangiocarcinoma cases, multiple
FAH were found that varied from 0.3 to 0.6 mm. The FLC
case revealed a single focus measuring approximately 6 mm.
None of these FAH were identified during original gross pro-
cessing of the specimens.
Tissue blocks were available for immunohistochemical
analysis for 2 of 3 cases with FAH (HCC and FLC cases). The
FLC case demonstrated moderate 2+ staining for CK7 and an
increase in proliferation with Ki-67: there was 5% staining in
the FAH compared with less than 1% staining of hepatocytes
in the background liver ❚Image 2D❚. The other FAH was CK7–
with no increased proliferation.
In the 4 control groups, no cases were seen of the second
type of foci (with fatty change and smaller hepatocytes).

A B

C D

❚Image 2❚ A, Glycogen-storing foci of altered hepatocytes (FAH) are demarcated sharply from the adjacent normal liver tissue
(H&E, ×40). B, A second type of FAH from a case of fibrolamellar carcinoma demonstrates smaller hepatocytes, an increased
nuclear/cytoplasmic ratio, and fatty change (H&E, ×100). C, Higher magnification (H&E, ×200) of the FAH from B. D, Focal 2+
cytokeratin 7 staining in the FAH from B (×200). See the text for an explanation of the scoring for staining.

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However, the FAH-GS were found in the background liver tis-
sue samples in 1 (7%) of 15 cases of hepatoblastoma, 2 (8%)
of 25 cases of adult HCC arising in the setting of cirrhosis, 5
(20%) of 25 cases of adult HCCs arising in livers with no sig-
nificant fibrosis, and 5 (20%) of 25 livers resected for meta-
static colon carcinoma.
Discussion
HCC is common in adults, with a worldwide incidence of
450,000 and approximately 10,000 cases diagnosed annually
in the United States. The majority of adult cases are due to
chronic liver injury from chronic viral hepatitis B or C or other
chronic liver disease such as fatty liver disease.11 In contrast,
the risk factors for pediatric HCC are not well characterized.
Despite the case reports of HCCs found in association with
congenital and metabolic diseases, epidemiologic findings
indicate that most individuals in the United States do not have
a clinically recognized underlying liver disease.1 Our findings
strongly support these epidemiologic observations and show
that most HCCs in children and young adults do not arise in the
setting of histologically recognizable liver disease. In other
nations, however, underlying liver disease is more commonly
present. In a study from Poland, 15 (39%) of 39 children had
cirrhosis, mostly from chronic HBV infection,12 as did 68% of
55 children in a study from Taiwan.13
At the histologic level, HCCs were more common than
FLCs, and 1 intrahepatic cholangiocarcinoma was found. The
HCCs generally were moderately differentiated with compact
or trabecular growth patterns. CK7 was present in 7 (78%) of
9 HCCs. In this regard, HCCs in children and young adults are
more similar to FLCs, which are also positive for CK7, com-
pared with adult HCCs that have a lower frequency of CK7
positivity. Strong expression of CK7 has been reported in 2
cases of FLC.14
The normal hepatocyte has a limited CK expression pattern,
composed of CK8 and CK18. Biliary epithelium, in contrast,
expresses CK7 and CK19 in addition to CK8 and CK18.15
However, CK7 also has been used in some studies as a marker
of hepatic stem cells.16 We do not have sufficient data in the pres-
ent study to explore whether the CK7 expression is more reflec-
tive of biliary differentiation or indicative of stem cell features.
Despite the presence of CK7 expression in most cases
and focal areas of biliary-type morphologic features in some
cases, the HCCs in the present study are distinct from those
that we would classify as combined hepatocholangiocarcino-
mas: combined hepatocholangiocarcinomas lack the diffuse
and strong HepPar positivity in the cholangiocarcinoma com-
ponent, demonstrate areas of true gland formation, and also
have dual positivity for CK7 and CK19 in the cholangiocarci-
noma component.
© American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
Several cases in the present study contained FAH in the
background liver that were morphologically discrete from the
adjacent hepatocytes. These FAH are similar to those
described by others in diseased human livers10,17 and animal
models.18,19 Our findings extend our understanding of these
interesting foci by demonstrating their presence in the non-
neoplastic and nondiseased livers of children and young adults
in whom primary liver carcinoma developed. Although addi-
tional studies are needed, the findings from animal and human
studies suggest that these foci are a logical place to search for
precursor lesions to HCC. Because FAH-GS were found in the
background liver samples of all control groups, including the
partial hepatectomy specimens resected for metastatic colon
carcinoma, these FAH might be less likely to represent direct
precursor lesions than the FAH characterized by fatty changes
and smaller hepatocytes. These latter FAH have similar mor-
phologic features to some of the HCCs, and 1 of 2 also
demonstrated CK7 and a slightly higher proliferative rate.
Nevertheless, FAH-GS might still have a role because others
have shown that the size and frequency of FAH-GS correlate
with neoplasia in the liver.20 We suspect more cases in the
present study also might have demonstrated FAH if the back-
ground livers had been sampled more extensively. However,
the specimens all were processed in a routine manner for diag-
nostic purposes and typically had only 1 or 2 sections of non-
neoplastic liver.
One potential explanation for the development of HCC in
young people when no underlying liver disease is identifiable
would be the presence of germline mutations in 1 copy of a
tumor suppressor gene, as described in a child with adenoma-
tous polyposis.21 Although no recognizable inherited disease
syndromes were evident in the cases described herein, these
atypical foci might have added significance as a potential
source for identifying early genetic changes in HCC, includ-
ing tumor suppressor genes.
HCCs in children and young adults typically were mod-
erately differentiated and demonstrated compact or trabecular
growth patterns. They frequently showed CK7 positivity, and
FLCs were uniformly CK7+. In addition, FAH can be identi-
fied in the nondiseased background liver samples in some
cases and might represent precursor lesions.
From the Departments of 1Pathology, 2Surgery, and 3Pediatrics,
the Johns Hopkins University School of Medicine, Baltimore, MD.
Address reprint requests to Dr Torbenson: the Johns Hopkins
University School of Medicine, Room B314, 1503 E Jefferson,
Baltimore, MD 21231.
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© American Society for Clinical Pathology