Diagnostic Cytology
Hepatocellular Carcinoma
Hepatocellular carcinoma accounts for 500 000 to a million
cases per year. It is responsible for 20-40% of cancer deaths in
high-incidence regions such as sub-Saharan Africa, China, and
Japan, and 0.5-2% of cancer deaths in low-incidence regions,
such as western Europe and North America.38,39 However, in
recent years the incidence is rising in the United States,40 largely
due to chronic hepatitis C virus infection from transfusion of
blood and blood products unscreened for hepatitis C virus until
1992. The incidence of hepatitis B virus and hepatitis C surface
antigenemia in patients with hepatocellular carcinoma is > 90%
both in North America and in other countries.40,41 Reports from
Taiwan show that 80% of patients with hepatocellular carci-
noma have a chronic form of hepatitis B, and the tumor devel-
ops in HBsAg carriers.41 The incorporation of hepatitis B42,43 and
hepatitis C44,45 viral DNA into the DNA of neoplastic cells of
hepatocellular carcinoma has been detected.
Hepatocellular carcinoma is less likely to develop in patients
with alcoholic cirrhosis ofthe liver. In the United States, only about
4% of patients with alcoholic cirrhosis develop hepatocellular
carcinoma. Because alcoholic cirrhosis is much more common
in the West than in the East, it plays an important role in the
etiology of hepatocellular carcinoma in North America.
In some African countries, ingestion of aflatoxins, metabolic
products of the growth of
Aspergillus flavus,
may be involved in
the etiology of hepatocellular carcinoma.38 Studies show that
aflatoxin B1, the most toxic of the aflatoxins, is highly carcino-
genic for some animal species. In Mozambique, the incidence of
hepatocellular carcinoma is the highest in the world and the per
capita intake of aflatoxins is also the highest.46
Grossly, hepatocellular carcinoma may present as a soli-
tary mass, as multiple nodules, or as diffuse liver involvement.
Hepatocellular carcinoma may permeate the liver through the
portal venous system. The growth of carcinoma in the branches
of the portal vein may lead to a tumor thrombus of the portal
trunk and sudden increase in portal hypertension. Metastases
to regional lymph nodes and distant spread may also occur.
However, hepatocellular carcinomas tend to remain localized
in the liver without metastases. Improved imaging techniques
combined with the use of aspiration biopsy may provide time to
establish the diagnosis before it is too late for surgical excision.
Morphologic differences among different cases of hepatocel-
lular carcinoma are well recognized in histologic sections. As can
be expected, FNA smears of the tumors from different patients
exhibit various cytomorphologic appearances. Many histologic
patterns of hepatocellular carcinoma have been described in the
literature. They often cannot be appreciated and distinguished
from one another in FNA smears. The increasing use of FNA
biopsy in the 1980s prompted the description of such cytomor-
phologic features and cytologic diagnostic criteria of different
cytologic types of hepatocellular carcinoma,47,48 which are help-
ful in accurately diagnosing this tumor and differentiating it
from secondary cancers.
On the basis of cytomorphologic features of hepatocellu-
lar carcinoma observed in aspirate smears in correlation with
histopathology, the tumors can be classified into four types: well-
differentiated, moderately differentiated, poorly differentiated,
and pleomorphic large-cell type.19,47 The first author diagnosed
234 cases of hepatocellular carcinoma, including 71 of the
well-differentiated cell type, 41 of the moderately differentiated
cell type, 21 of the poorly differentiated cell type, and 7 of the
pleomorphic large-cell type (4 cases of fibrolamellar variant).19
The cytomorphologic features of these four types of hepato-
cellular carcinoma are summarized as follows.
W ell-Differentiated Cell Type
The neoplastic hepatocytes of well-differentiated hepatocellu-
lar carcinoma have minimal nuclear atypia and possess intact
cell membranes that can survive the force of smearing. The
microtrabecular and microacinar variants37 of well-differentiated
hepatocellular carcinoma are the major source of false-negative
diagnosis as atypical or reactive hepatocytes. However, the aspirates
are easily smeared into granular smear.25 Reticulin stain on cell
block49 can then confirm the malignant nature of the small bland
hepatocytes by demonstrating the absence or marked decrease of
reticulin fibers and the loss of single cell plate architecture.
Fine-needle aspiration smears are usually highly cellular and
contain solitary tumor cells and tumor cells in loose groupings
as well as many fragments of neoplastic tissue and tightly packed
tissue fragments with narrowest regions less than or equal to
three cells in thickness, wrapped by peripheral endothelium.
The neoplastic cells are often arranged in a trabecular fashion or
in thick cords, papillae, or cell balls (Fig. 28.31). The neoplastic
cells are monotonous and are composed of small hepatocytes
with high N/C ratio and have regular, uniform, centrally located
round nuclei with a finely granular chromatin pattern. The cyto-
plasm is reduced and cell borders are less polygonal than those
of benign hepatocytes seen in the same specimen, and nucleoli
are usually distinct (Fig. 28.32). This tumor can be recognized
at low-power examination by cytomorphology alone in a well-
prepared smear (Fig. 28.31). The histology on cell block shows
trabecular arrangement.
M icrotrabecular Variant19,37
The aspirates present as granular smears containing numerous
thin trabeculae (Fig. 28.33) with the narrowest region only one
or two cells in thickness (Fig. 28.34) with or without peripheral
Fig. 28.31 Hepatocellular carcinoma, well-differentiated cell
type, classic. Granular smear containing sharply outlined trabecular
groupings, a useful low power clue for hepatocellular carcinoma. FNA smear
(Papanicolaou x LP).
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