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com/esps/ World J Gastroenterol 2014 November 21; 20(43): 15955-15964

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DOI: 10.3748/wjg.v20.i43.15955 © 2014 Baishideng Publishing Group Inc. All rights reserved.

TOPIC HIGHLIGHT

WJG 20th Anniversary Special Issues (1): Hepatocellular carcinoma

Histopathology of hepatocellular carcinoma

Manuel Schlageter, Luigi Maria Terracciano, Salvatore D’Angelo, Paolo Sorrentino

Manuel Schlageter, Luigi Maria Terracciano, Department of marizes recent developments and tries to put new HCC
Pathology, University Hospital Basel, 4031 Basel, Switzerland biomarkers in context with the WHOs reclassification.
Salvatore D’Angelo, Paolo Sorrentino, Liver Unit, Clinical and Furthermore it also addresses the group of tumors
Experimental Hepatology, S.G. Moscati General Hospital, 83100 known as combined hepatocellular-cholangiocellular
Avellino, Italy
carcinomas.
Author contributions: Schlageter M conceived and wrote the
article; Terracciano LM conceived and wrote the article; D’
Angelo S conceived and supervised the article; Sorrentino P con- © 2014 Baishideng Publishing Group Inc. All rights reserved.
ceived and supervised the article.
Correspondence to: Paolo Sorrentino, MD, PhD, Liver Unit, Key words: Histology; Pathology; Hepatocellular cari-
Clinical and Experimental Hepatology, S.G. Moscati General noma
Hospital, Via Otranto 2, 83100 Avellino,
Italy. paolosorrmed@tin.it Core tip: Hepatocellular carcinoma (HCC) is currently
Telephone: +39-347-5888993 the sixth most common type of cancer with a high
Received: January 17, 2014 Revised: May 9, 2014
mortality rate and an increasing incidence worldwide.
Accepted: July 22, 2014
Published online: November 21, 2014 HCC most commonly occurs on ground of a cirrhotic
liver but interestingly an increasing proportion of HCCs
develop in the non-fibrotic or minimal fibrotic. Although
this process is yet to be completely understood, this
changing scenario also has impact on the material
Abstract seen by pathologists, presenting them with new di-
Hepatocellular carcinoma (HCC) is currently the sixth agnostic dilemmas. This review summarizes recent
most common type of cancer with a high mortality developments and tries to put new HCC biomarkers in
rate and an increasing incidence worldwide. Its etiol- context with the WHOs reclassification.
ogy is usually linked to environmental, dietary or life-
style factors. HCC most commonly arises in a cirrhotic
liver but interestingly an increasing proportion of Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P. His-
HCCs develop in the non-fibrotic or minimal fibrotic topathology of hepatocellular carcinoma. World J Gastroenterol
liver and a shift in the underlying etiology can be ob- 2014; 20(43): 15955-15964 Available from: URL: http://www.
served. Although this process is yet to be completely wjgnet.com/1007-9327/full/v20/i43/15955.htm DOI: http://
understood, this changing scenario also has impact dx.doi.org/10.3748/wjg.v20.i43.15955
on the material seen by pathologists, presenting them
with new diagnostic dilemmas. Histopathologic crite-
ria for diagnosing classical, progressed HCC are well
established and known, but with an increase in detec- INTRODUCTION
tion of small and early HCCs due to routine screening
programs, the diagnosis of these small lesions in core Hepatocellular carcinoma (HCC) is the sixth most com-
needle biopsies poses a difficult challenge. These le- mon type of cancer and with about 9.2% of all deaths it
sions can be far more difficult to distinguish from one is the third most common cause of cancer death[1]. HCC
another than progressed HCC, which is usually a clear is more common in males than in females and mostly
cut hematoxylin and eosin diagnosis. Furthermore le- occurs in developing countries. The increasing trend is
sions thought to derive from progenitor cells have re- mainly due to a cohort effect related to infection with
cently been reclassified in the WHO. This review sum- hepatitis B and C viruses (HBV and HCV), the incidence

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 Schlageter M et al . Histopathology of HCC

of which peaked in the 1950s to 1980s. By contrast, in Dysplastic foci

North America, Europe, and Japan, HCV infection is the Dysplastic foci are uniform lesions and their morphology,
main risk factor, together with alcohol use. Time trends cytoplasmatic staining, nuclear size and cellular atypia
in incidence of hepatocellular carcinoma of developed discriminates them from the surrounding liver tissue. By
countries parallel the timing of HCV spread. In Japan definition, these clusters are < 1 mm in size and do not
and Europe, where HCV infection spread earlier than in fulfill criteria for malignancy i.e. invasive growth[9]. A simi-
the United States, the incidence of hepatocellular carci- lar and hard to distinguish lesion is small cell dysplasia.
noma has almost reached a plateau and in some areas it These are round foci of small dysplastic cells with an in-
is declining; however, in the United States, incidence is creased nuclear/cytoplasmatic ratio. They are usually seen
still increasing and the infection could have a synergistic in cirrhotic livers and are also considered premalignant
effect with other risk factors, such as non-alcoholic fatty lesions due to their increased proliferation index and low
liver disease. rate of apoptosis[10].
In most cases, HCC is a multistage disease whose
occurrence is linked to environmental, dietary and life- Dysplastic nodules
style factors[2]. Unlike other cancers, HCC usually arises In contrast to dysplastic foci, dysplastic nodules are de-
on a previously damaged organ, mostly in the setting of fined as being larger than 1mm in size. These lesions are
chronic hepatopathy, cirrhosis[3,4], or in association with usually found in cirrhosis and are generally subdivided
hereditary diseases such as hemochromatosis, Wilson’s into low-grade and high-grade lesions. Both subtypes
disease and a-1-antitrypsin deficiency. However, in about have been described as possible progenitor lesions to
15%-20% of cases HCC may occur in the non-fibrotic HCC but regression has also been described in literature.
liver or in livers with minimal portal fibrosis without any Low-grade dysplastic nodules only present minimal ab-
septal fibrosis[5]. normality with a normal to slightly increased nuclear/cy-
Although histopathologic criteria for diagnosing toplasmatic ratio, minimal atypia, no mitoses and one to
classical, progressed hepatocellular carcinoma have not two cells wide cell plates. Portal tracts and the reticulin
recently changed, diagnosis of small and early lesions network are still present. The borders of the lesions can
has gained of importance due to the increased detection be rounded but usually do not show compression of the
rate of these early lesions in routine screening programs. adjacent liver tissue. In addition, high-grade dysplastic
These lesions can be far more difficult to distinguish nodules may display the following histological features:
from one another than progressed HCC. Furthermore increased nuclear/cytoplasmatic ratio, nuclear hyperchro-
lesions thought to derive from progenitor cells have re- masia, irregular nuclear borders, peripheral location of
cently been reclassified in the WHO. the nucleus, occasional mitoses, cell plates > 2 cells, baso-
philic cytoplasm, pseudo gland formation and resistance
to iron accumulation. Occasional unpaired arteries have
Precursor lesions also been described in high-grade dysplastic nodules[9,11,12].
HCC
Although a typical adenoma-carcinoma sequence does
not represent a frequent pathway in hepatic carcinogen- Gross Pathology
esis, hepatocellular adenoma (HCA) may rarely act as a Up until only two decades ago, it was unknown how
precursor lesion of HCC[4]. It occurs predominantly in fe- HCC arose and how it evolved from early to advanced
male patients using oral contraceptives, but has also been cancer in humans. With the remarkable advances of vari-
described female patients with maturity onset diabetes ous diagnostic imaging techniques and the establishment
of the young type 3[6]. In males it is described in patients of a follow-up system for the high-risk population, the
with glycogen storage disease or androgen treatment. numbers of surgically resected cases of early stage small
This type is usually beta-catenin mutated and is reported HCCs and the amount of biopsy material form minute
to have a higher risk of malignant transformation[7]. HCCs has increased. Extensive morphologic studies
Metabolic syndrome has recently also been described as of this material have revealed that many HCCs arise in
an emerging risk factor for HCA[6]. Obesity and alcohol equivocal nodular lesions, such as dysplastic nodules
mostly lead to an inflammatory HCA, which express pro- in the cirrhotic liver and are highly differentiated in the
teins such as Amyloid A and CRP. Generally, malignant early stages. At the same time, it has been established that
transformation has been described in 4%-8% of patients. well-differentiated HCC in the early stages evolves to
In some cases no etiology for the development of a he- advanced and dedifferentiated tumor in a multistep fash-
patocellular adenoma can be determined. The differential ion[13,14]. This is particularly true for patients with chronic
diagnosis between HCA and well-differentiated HCC HBV and hcv infections.
arising in non-cirrhotic liver can be challenging, especially An additional characteristic feature of HCC is its
when tumors histologically similar to HCA occur in un- frequent occurrence in the form of multiple nodules[15].
usual clinico-pathological settings, such as in a man or an In HCC, the simultaneous occurrence of multiple HCCs
older woman and/or display cytological or architectural may reflect either the dissemination of malignant cells
atypia[8]. from a single primary tumor to form satellite tumor nod-

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 Schlageter M et al . Histopathology of HCC

ules (intrahepatic metastasis), or the synchronous devel- (> 3 cells), prominent acinar pattern, small cell changes,
opment of several independent tumors. The two possible cytologic atypia, mitotic activity, vascular invasion, ab-
mechanisms of development of multiple HCCs reflect sence of Kupffer cells and the loss of the reticulin net-
important differences in pathogenesis that appear to have work[23]. The most common histologic growth patterns
an impact on treatment and prognosis[16]. Differences in are: trabecular-resembling normal liver tissue, pseudo-
prognosis between these two categories probably result glandular or acinar with possible bile or fibrin content
from the fact that multiple HCCs developing from intra- and the compact or solid pattern (Figure 1). Bile produc-
hepatic metastasis are more aggressive and more poorly tion can frequently be observed. Within the tumor cells
differentiated than multiple HCCs that are composed of Mallory-bodies and pale bodies can be also present[22].
several independent tumours that emerge more or less si- Histomorphologic appearance of hepatocellular car-
multaneously. Molecular analysis of the HBV integration cinoma varies greatly from patient to patient and even in
patterns and genetic changes has indicated independent a single patient, different stages of intratumoral differen-
multicentric development of these nodules[15,17-20]. tiation and growths patterns can be observed. Some au-
During histological assessment, small and early HCCs thors postulate a step-wise dedifferentiation of an initially
should be distinguished from advanced disease. While the well differentiated small lesion into a larger, less differenti-
diagnosis is mostly clear in advanced stage cases, small, ated tumor which leads to intratumoral heterogeneity. The
early and therefore mostly well-differentiated lesions can well differentiated lesion is usually replaced by tissue of
be problematic. Due to established screening programs in the dedifferentiated component in advanced disease and
cirrhotic patients, biopsies of these lesions problematic therefore leads to a nodule in nodule appearance. Espe-
lesions have increased in number. cially in very advanced stage, but sometimes also in small
The international consensus group for hepatocellular tumors, the initial well-differentiated tumor component
carcinoma[21] and the WHO[22] propose the following clas- may not be discernible[13,14,24,25].
sification: (1) early HCC: a: well differentiated; b: small In contrast, progressed HCC shows an expansive and
size (< 2 cm); and c: poorly defined margins, vaguely infiltrative histologic growth pattern with complete neo-
nodular type; and (2) progressed HCC: a: > 2 cm; b: vascularization with unpaired arteries and possible vas-
small size (< 2 cm), but moderately differentiated, dis- cular infiltration. There are no portal tracts seen within
tinctly nodular type. the tumor and all the classical histologic patterns (i.e.,
HCCs of the vaguely nodular type occur more often trabecular/sinusoidal, pseudoglandular, solid and undif-
in cirrhosis, are usually smaller in size and less often show ferentiated) are usually present (Figure 1). The tumors are
portal vein invasion than the distinctly nodular type. Fur- mostly encapsulated and septae are detected. Encapsula-
thermore they are hypovascular and almost never show tion is reported to be more frequent in tumor arising in
intrahepatic metastasis. In resected specimens, they are a cirrhotic liver than in non-cirrhotic livers[11]. Most of
sometimes difficult to localize, because their margins to these tumors show satellite nodules within 2 cm of the
the surrounding liver tissue are not well defined and por- primary tumor nodule as well as metastasis in the liver.
tal tracts are retained within the tumor[11]. The distinctly In HCC, angioarchitecture plays a very important role
nodular subtype has a discernible capsule and usually oc- during tumor growth and is also essential part of mod-
curs in a cirrhotic liver. ern imaging modalities. Progressed HCC has classical
Progressed hepatocellular carcinoma can grossly be unpaired arteries positive for SMA and CD34. These ar-
classified into the following macroscopic groups: nodular, teries are not associated with a portal tract and therefore
massive and diffuse. The nodular type can either consist have no contact to bile ducts. They also show less elastic
of a single or multiple nodules. Single nodules are usually fibers compared to normal intrahepatic arteries. Early
encapsulated and may show extracapsular growth in the HCC of the vaguely nodular type has a reduced density
vicinity of the primary nodule. The multinodular type is of unpaired arteries compared to progressed HCC and
an aggregation of a varying amount of small nodules. therefore appears hypovascular in imaging. Due to the
The massive type is defined as a large tumor with irregu- presence of portal tracts within tumor, although less in
lar demarcation. This morphologic appearance can also number than in normal liver tissue, these lesions also re-
been seen in advanced stage nodular HCC. The diffuse ceive blood from the portal vein[26,27]. Early HCC of the
type is described to have many small nodules in a liver distinctly nodular type as well as progressed-HCC appear
lobe or the whole organ[11]. hypervascular because of earlier neovascularization with
Rarely a pedunculated or protruded growth can be unpaired arteries.
observed. If the HCC grows extrahepatically with a pe-
duncle, this should be termed “pedunculated”. If a pe-
duncle is absent the term “protruding” is adequate[11]. Histologic grade
Although some authors suggest using a conventional
3-scale system, the most widely used grading system in
Histopathology HCC remains the 4-scale Edmondson and Steiner sys-
The classical histomorphologic features of HCC are the tem[28,29]. Grade Ⅰ consists of small tumor cells, arranged
following: well vascularized tumors with wide trabeculae in trabeculae, with abundant cytoplasm and minimal

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 Schlageter M et al . Histopathology of HCC

than grade Ⅱ and have angulated nuclei. Grade Ⅳ has

A
prominent pleomorphism and often anaplastic giant cells.
Since HCC is usually quite heterogeneous the eligibility
of tumor grading in biopsy specimens is unclear. A study
done by Pawlik et al[30] demonstrates that needle core
biopsies, especially of progressed HCCs tend to under-
grade tumors compared to following surgical resection
specimens.

Histologic variants
20 mm
Fibrolamellar HCC
Fibrolamellar HCC is a rare subtype first described by
B
Edmondson accounting for less than 1% of all tumors[31].
This subtype is seen in young patients without liver cir-
rhosis and with no other known predisposing factors and
has a better prognosis than classical HCC[32,33]. Grossly it
shows many fibrous septae and may have a central scared
zone with possible calcification, therefore mimicking fo-
cal nodular hyperplasia (Figure 2D). Histologically the tu-
mor cells grow in sheets and trabeculae that are separated
by collagen fibers which are often hyalinized and show
50 mm
a characteristic lamellar pattern[11]. Cytoplasmatic inclu-
sions such as ground glass pale bodies and cytoplasmatic
C globules which are PAS-positive and immunoreactive to
anti fibrinogen are often seen. Van Eyken and colleagues
report an abundant CK7 and a focal CK19 expression in
this subtype[34].

Sarcomatous HCC
Sarcomatous HCC is another subtype which can occur by
itself, but also within classical HCC. The tumor cells are
spindle-shaped and show bizarre anaplastic figures. Gi-
ant cells are often present, but they can also been seen in
20 mm other types of HCC. In cases where there is no adjacent
classical HCC, these tumor can be difficult to distinguish
D from leiomyosarcoma and fibrosarcoma[35,36].

Scirrhous HCC
Scirrhous HCC shows diffuse fibrotic change which can
occur after various antitumoral treatments and seldom in
untreated tumors. These fibrotic changes often lead to
misdiagnosis as cholangiocellular carcinoma or metastasis
in preoperative imaging. This type of tumor histologically
shows fibrosis along the sinusoid-like blood spaces, with
atrophy of the trabeculae. In immunohistochemistry He-
20 mm Par-1 and CK7 (65%) can be positive[37]. Kojiro[11] reports
a marked CD8+ predominant lymphocyte infiltrate in
Figure 1 Growth patterns of progressed hepatocellular carcinoma. A: 84% of the cases. In his series he also describes a unique
Hepatocellular carcinoma (HCC) with trabecular growth pattern [hematoxylin directly subcapsular location of most of these tumors
and eosin (HE), × 300]; B: HCC with pseudoglandular growth pattern (HE, × which leads to a possible pedunculated macroscopy.
100); C: HCC with solid growth pattern (HE, × 200); D: HCC with giant cell for-
mation (HE, × 200).
clear-cell variant of HCC
The clear-cell variant of HCC is usually arranged in a
nuclear irregularity that are almost indistinguishable from trabecular pattern and is characterized by clear cytoplasm
normal liver tissue. Grade Ⅱ tumors have prominent that contains glycogen and a variable amount of fat
nucleoli, hyperchromatism and some degree of nuclear vesicles[38]. Mostly only parts of the tumor show these
irregularity. Grade Ⅲ tumors show more pleomorphism clear-cell changes (Figure 2A). A male predominance of

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 Schlageter M et al . Histopathology of HCC

ance of > 5% of the tumor, presence of Mallory-bodies,

A
fibrosis, inflammation and ballooning of the hepatocytes
as in steatohepatitis (Figure 2C). The inflammatory in-
filtrate usually consists of neutrophils, plasma cells and
lymphocytes. Fibrosis usually appears in a pericellular and
trabecular form. These patients often suffer from non-
alcoholic steatohepatitis but this phenotype of carcinoma
is also seen in patients without steatohepatitic changes in
the non-neoplastic liver tissue[40].

HCC with lymphoid stroma

HCC with lymphoid stroma is an entity only described in
a few case reports. This is a tumor consisting of a mas-
B
sive inflammatory infiltrate, often with very few identifi-
able tumor cells in HE stain (Figure 2B). Most of the
cells are lymphocytes, some macrophages, giant cells,
plasma cells and neutrophils can also be detected. Immu-
nohistochemical subtyping of the lymphoid cells show
more CD3+ T-Cells than CD20+ B-Cells. The T-Cells
are mostly of the CD4+ subtype[41,42]. It is still unclear if
this is a regression phenomenon or an entity by its own.

Immunohistochemistry and
C Differential diagnosis
Especially in early stage and therefore mostly well differ-
entiated hepatocellular carcinoma immunohistochemistry
can be helpful for distinguishing adenoma, focal nodular
hyperplasia and dysplastic nodules from HCC[23].

Adenoma vs well-differentiated HCC

In conventional histology hepatocellular adenoma re-
sembles normal liver tissue but may show pseudoglandu-
lar architecture, especially when arising in a patient with
20 mm anabolic use. The tumor cells often have an increased
cell size due to increased intracellular glycogen or fat ac-
D cumulation but show regular nuclei without atypia. The
cell sheets are 2 layers thick. HCC arising from trans-
formed adenoma is usually well- to moderately-differ-
entiated and only few cases showed vascular invasion or
satellite nodules[43].
Beta-catenin mutations are reported in 20% of all
HCCs, with a higher rate in HCC developing from livers
with chronic hepatitis C[44]. Hepatocellular adenoma can
also be beta-catenin activated in 10%-15% of the cases.
The beta-catenin mutation leads to a series of upregulat-
20 mm
ed genes which are important for cell proliferation. One
of these genes is glutamine-synthetase, which is therefore
Figure 2 Histologic variants of hepatocellular carcinoma. A: Hepatocellular diffusely positive in beta-catenin mutated tumors. Normal
carcinoma (HCC), clear cell variant [hematoxylin and eosin (HE), × 100]; B: liver tissue shows glutamine-synthetase expression in the
HCC with lymphoid stroma (HE, × 100/× 200). C: HCC, steatohepatic variant
pericentral hepatocytes but not in periportal or midzonal
(HE, × 200); D: HCC, fibrolamellar variant (HE, × 50).
localized hepatocytes. In hepatic adenoma, glutamine-
synthetase can either be completely negative, localized
variable degree is reported of this particular subtype of in the pericentral area as in normal liver, or show patch-
HCC[11,39]. like expression with no particular pattern. In beta-catenin
mutated hepatic adenoma diffuse and strong expression
Steatohepatic HCC is seen[45].
Steatohepatic HCC is characterized by a steatotic appear- Glypican-3 is a proteoglycan which is a histochemi-

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 Schlageter M et al . Histopathology of HCC

High-grade dysplastic nodule vs well-differentiated HCC

A
Although these criteria are still controversial, in cases
where cell plates are thick (> 3 cells), there is a focal
pseudoglandular growth pattern and a loss of the re-
ticulin network, HCC can possibly be diagnosed with
conventional histology. Unfortunately not all HCCs show
these patterns and high-grade dysplastic nodules can
mimic similar histological features[12].
High-grade dysplastic nodules can either be of the
distinctly or vaguely nodular type in a cirrhotic liver.
These lesions show atypia which is insufficient for the
diagnosis of HCC, usually have an increased cell density
compared to the surrounding liver tissue and show an
B
irregular trabecular pattern. The most common form
of cytological atypia is small cell change/dysplasia char-
acterized by small cells with decreased cytoplasma and
moderately enlarged nuclei[50]. Unpaired arteries have
also been described in these lesions. The best criterion
to differentiate these lesions from early HCC is stromal
invasion, but this can be very difficult to assess, especially
in biopsy specimens. In a cirrhotic liver, this feature can
be difficult to distinguish from small groups of hepato-
cytes entrapped within fibrous septae. In these cases, a
CK7/19 stain can be helpful to highlight the ductular re-
action around these foci, since these non-neoplastic intra-
C
septal hepatocytes and the adjacent ductular reaction in
dysplastic nodules are thought to derive from a common
progenitor cell. This ductular reaction should be pres-
ent around 50% of the circumference of a nodule and is
mostly absent in HCC[21,51-53].
Furthermore high-grade dysplastic nodules may show
peripheral and focal staining for CD34, whereas diffuse
sinusoidal staining is typically seen in nodular HCC. Some
authors suggest using CD34 combined with Glypican-3
to achieve a higher sensitivity. Numbers on Glypican-3
expression in dysplastic nodules vary widely (3%-76%).
CD34 in combination with SMA also marks unpaired
D
muscularised arteries. Unfortunately neovascularization is
rarely complete in early HCC[46,54,55].
Gluthamine-synthetase (GS) expression is seen more
frequently in HCC than in high-grade dysplastic nodules
(69.8% vs 13.6%). In these positive dysplastic nodules GS
was expressed in less than 50% of the cells whereas in
HCC it was reported positive in over 50% of the cells[56].
In addition to Glypican-3 and GS, Di Tommaso and
colleagues also reported heat shock protein 70 (HSP70)
to be positive in 73.5% of HCCs while only a single case
of dysplastic nodule was positive. They therefore suggest
using the combination of HSP70, GS and Glypican-3 for
Figure 3 Immunohistochemistry. A: well-differentiated hepatocellular carci- discriminating HCC from high-grade dysplastic nodule.
noma (HCC) [hematoxylin and eosin (HE), × 20]; B: Glypican-3 (HE, × 10/× When using these three markers they could achieve a sen-
200); C: Heat-shock-protein 70 (HE, × 10/× 200); D: Gluthamine-synthetase
(HE, × 10/× 200).
sitivity of 72% and a specificity of 100% for the detection
of malignancy with a cut-off of any two positive markers
in resection specimens (Figure 3). In biopsy specimens the
cal and serological marker for HCC. In normal liver it markers are less sensitive due to unequal distribution of
is not expressed but it occurs in fetal liver and the pla- positive cells. It is therefore recommended to use clathrin
centa. Glypican-3 has been reported in 70%-90% of all heavy chain as an additional marker in small biopsy speci-
HCCs[46-49]. mens to increase sensitivity[57,58].

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 Schlageter M et al . Histopathology of HCC

In conclusion the loss of the reticulin fiberwork, stro- patocellular-cholangiocarcinoma. In contrast to classical
mal invasion and a positivity of at least 2 out of 3 mark- HCC which is thought to develop from mature hepato-
ers (HSP70, GS, Glypican 3) are considered the strongest cytes in a multistep carcinogenesis, recent studies suggest
parameters in the diagnosis of early HCC in resection a common progenitor cell capable of differentiating into
specimens[55]. hepatocytes and cholangiocytes that is activated when liv-
Molecular analysis can be useful for proving clonal- er damage occurs and therefore leads to various types of
ity of a lesion, but since well differentiated HCC and combined carcinomas[61,62]. These combined carcinomas
high-grade dysplastic nodules can both have monoclonal usually show a staining for CK7/19 although this has also
growth patterns this analysis is not particularly helpful in been described in classical HCC. The expression of these
this differential diagnosis[11]. markers can either be interpreted as transdifferentiation
into cholangiocytes or dedifferentiation in a common
HCC vs metastasis progenitor cell[63]. The WHO subclassifies these carcino-
The differential diagnosis of HCC varies greatly depend- mas into the classical subtype and the subtype with stem
ing on the underlying liver disease. In hepatitic/cirrhotic cell features. The latter is the case when the stem cell fea-
livers, HCC, its precursor lesions and cholangiocellular tures predominate and is then subdivided into the typical,
carcinoma occur more frequently than malignant lesions intermediate and cholangiolocellular subtype[22].
of non-hepatic origin. In patients without underlying In the classical subtype the hepatocellular and biliary
liver disease, HCC accounts only for about 2% of malig- component have the typical morphology of HCC and
nant liver neoplasms. The most common primary sites biliary adenocarcinoma respectively and may have any dif-
that metastasize into the liver are lung, colon, pancreas ferentiation. The hepatocellular component can be high-
and breast[59]. In some cases metastasis can mimic he- lighted with a Hep Par-1, CD10 or pCEA staining, the
patocellular carcinoma. The primary tumors resembling biliary component with a D-PAS or mucicarmine stain
HCC include clear-cell renal cell carcinoma, clear-cell to show mucin production and immunohistochemically
adenocarcinoma of the female genital organs, adrenal with CK7/19 and epithelial membrane antigen (EMA). A
carcinoma and hepatoid adenocarcinoma of the stom- low expression of Hep Par-1, CD56, c-KIT and epithelial
ach. Sometimes metastatic neuroendocrine tumors of the cell adhesion molecule (EpCAM) has also been reported.
gastrointestinal tract, especially with trabecular growth CD133 and vimentin are usually negative. The biliary
pattern can also be difficult to distinguish from HCC. component often shows abundant desmoplastic stroma.
In cases where the hepatic origin of a tumor is un- The hepatocellular component may also stain positive for
clear, polyclonal CEA (pCEA) or Hepatocyte Paraffin 1 CK7/19. In the zone where these components intersect,
antigen (Hep Par-1) can be useful to prove the hepatic cells often have phenotypical and/or immunohistochemi-
origin while the latter is considered the most sensitive cal properties of stem/-progenitor cells[64-67].
and specific marker. These markers are also positive in Since it remains unclear if the subtypes with stem-
normal liver tissue and Hep Par-1 positivity has also cell features are all distinctive entities, they are, for the
been described in adenocarcinoma of the lung, pancreas, time, according to the WHO, subsumed under the term
stomach, esophagus, gall bladder, small intestine, adrenal “combined hepatocellular-cholangiocarcinoma with stem
gland, melanoma, paraganglioma and the urinary bladder. cell features”. In contrast to the classical type, the follow-
Hep Par-1 shows a cytoplasmatic granular positivity in ing subtypes are not mucin-producing. While Hep Par-1
almost all well-differentiated HCCs, but this number di- expression is less frequent in these subtypes with stem
minishes to < 50% in poorly differentiated HCC. pCEA cell features than in the classical subtype, expression of
shows diffuse cytoplasmatic expression in most adeno- CD133, EpCAM and vimentin is significantly higher[67].
carcinomas, but in HCC there is a distinct “chicken-wire These subtypes are often intermixed but their major
fence” pattern around the canaliculi. As with Hep Par-1, components are defined as follows:
the sensitivity and specificity of pCEA decline with de- The typical subtype shows mature hepatocytes with
differentiation of the tumor[11,59,60]. In the adult, alpha- peripheral aggregates of small cells with a high nuclear/
fetoprotein (AFP) is positive in HCC and germ cell tu- cytoplasmatic ratio and hyperchromatic nuclei. These
mors while normal liver tissue does not stain for AFP. In peripheral cells are positive for CK7/19, EMA, CD56,
contrast to the previous two markers, the percentage of c-KIT and EpCAM and don’t show any mucin produc-
AFP-positive tumor cells increases with dedifferentiation. tion. Adjacent to these cells abundant stroma can be
In HCC CD10 shows a similar staining pattern as pCEA, observed.
but is negative in adenocarcinomas. MOC-31 is a marker The intermediate cell subtype is composed of cells
which is expressed in glandular epithelia of various sites, with intermediate features of both hepatocytes and chol-
but is negative in HCC, melanoma and lymphoma. HCC angiocytes. The cells are gathered in stands, solid nests or
is usually positive for CK8 and CK18 and negative for trabeculae. The cells are small and have scant cytoplasm
CK7, CK19 and CK20 in about 70% of the cases[59]. with an increased nuclear/cytoplasmatic ratio and are usu-
ally embedded within less stroma than the typical subtype.
Combined hepatocellular-cholangiocarcinoma Expression of CK7/19 and EMA is frequent, while posi-
Less than 1% of all liver carcinomas are combined he- tivity for HePar-1, CD56, CD133, EpCAM is observed

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 Schlageter M et al . Histopathology of HCC

less often. Liver Transpl 2004; 10: S9-S15 [PMID: 14762832 DOI: 10.1002/
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P- Reviewer: Bayraktar Y, Iwasaki Y, Watanabe T

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