Hepatocellular carcinoma (HCC) is one of the
worlds most common cancers. The global distribution of HCC
correlates with the geographic prevalence of chronic viral hepatitis
and cirrhosis. Regions with a high incidence of HCC (> 30 cases
per 100,0000 population) include sub-Saharan Africa, Southeast Asia,
and Southern China; North America and Western Europe have a low
incidence (< 2 cases per 100,000). Individuals with persistent
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have 100
times the relative risk of developing HCC as do uninfected persons.
In the United States, both chronic viral hepatitis and HCC are
occurring with increasing frequency. Currently, there are
approximately 3.9 million people infected with HCV and between 1 and
1.25 million infected with HBV in the United States.[4,5] Cirrhosis
is estimated to develop in 20% of patients after 10 years of chronic
HCV infection. Hepatocellular carcinoma occurs at a rate of 1% to 4%
per year after cirrhosis is established. According to a consensus
report by the National Institutes of Health, the annual probabilities
of developing liver cancer are 0.5% among those with chronic HBV and
2.4% after the onset of cirrhosis.
Although the precise mechanism of hepatocarcinogenesis is unknown,
some pathogenetic factors have been defined. Hepatocellular carcinoma
almost always occurs in the setting of chronic hepatocyte injury and
inflammation. The subsequent regenerative response and fibrosis lead
to cirrhosis. This, in turn, may enhance genetic mutations that lead
to the eventual development of carcinoma.
Both HBV and HCV may be involved in multiple steps along this disease
pathway. Through chronic infection, the viral genome may become
incorporated into the hepatocyte DNA and may produce genetic
instability and mutations.
Patients with symptomatic HCC usually present with abdominal pain,
weight loss, jaundice, and abdominal distention resulting from
uncontrollable ascites or tumor mass. Tumors are generally large
and demonstrate extrahepatic spread by the time they become
symptomatic, thus rendering them unresectable. Median survival in
patients with clinically apparent HCC is less than 6 months, and
2-year survival is virtually nonexistent (Table
1). Early detection offers the best potential for curative intervention.
Classification of Nodules
In 1995, the International Working Party developed a nomenclature
system for hepatocellular nodules. The lesions were categorized
according to the presence of dysplasia vs regeneration and according
to the anatomy of the surrounding liver parenchyma.
Regenerative nodules are the result of localized proliferation of
hepatocytes and their supporting stroma. The regenerative nodule
represents a fundamental response to decreased functional liver cell
mass and is presumably the result of increased levels of local growth
factors. When regenerative nodules are distinctly larger than most
cirrhotic nodules in the same liver (generally at least 5 mm or
greater), they may be called large regenerating nodules or
macroregenerative nodules. The cells in a regenerative nodule are
histologically the same as in the adjacent parenchyma.
A dysplastic nodule is a region of hepatocytes with dysplasia but
without definite pathologic criteria of malignancy. These nodules are
usually, but not always, found in cirrhotic livers. Dysplastic
nodules may occur in any size. As the size of the lesions increases,
the prevalence of high-grade or malignant lesions also increases.
Differentiating Nodular Lesions From HCC
Regenerative nodules, dysplastic nodules, and HCC represent a
continuum of the same disease process. Thus, differentiating a large
regenerative nodule from a low-grade dysplastic nodule or a
high-grade dysplastic nodule from HCC is often impossible.
Dysplastic nodules should be diagnosed if there are features
suggestive of a neoplastic process. High-grade dysplastic nodules
should be diagnosed if the neoplastic features are very similar to
those seen in malignancy. The criteria to distinguish high-grade
dysplastic nodules from HCC are arbitrary and depend on how much the
lesion resembles HCC.
The most accurate way to distinguish a regenerative nodule from a
dysplastic nodule and HCC may be through the use of molecular genetic
techniques. Foci of carcinoma are present in approximately 30% of
otherwise benign dysplastic nodules on serial sectioning. Thus, a
diagnosis of HCC cannot be excluded in any dysplastic nodule that is
sampled only with a needle biopsy.
To screen for a disease, asymptomatic people generally undergo a test
or tests in the hope of detecting the disease early in its course.
For a screening program to be effective, it must meet several criteria:
The disease must have a high prevalence and result in significant morbidity.
The natural history of the disease must allow for effective treatment
when it is diagnosed at an asymptomatic stage.
The test must have acceptable sensitivity and specificity.
Since the predictive value of a test depends on the prevalence of the
disease in question, an effective screening program for HCC must
focus on a high-risk population. Mass population screening programs
for HCC are feasible in Asian countries where there is a high
incidence of the disease. In the West, however, where the prevalence
of HCC is low, only patients with chronic viral hepatitis and
compensated cirrhosis require screening.
Most HCC screening protocols use ultrasound and serum
alpha-fetoprotein (AFP), although the use of AFP as a screening test
is complicated by frequent false-negative and false-positive results.
Kang et al reported a sensitivity of 68% and specificity of 20% using
AFP to diagnose early (less than 3 cm) HCC. In another study from
China, serum AFP levels were elevated only in 60% to 70% of patients
with small HCC lesions, and fewer than 20% of the elevated levels of
AFP were due to HCC. Acute-on-chronic hepatitis was the most common
cause of elevated AFP.
There have been several reports of sonographic screening for HCC in
high-risk patients.[14-16] Athough ultrasound is probably a more
sensitive screening tool than AFP, it also produces a high number of
false-positive findings in a multinodular, cirrhotic liver.
Ultrasound is an operator dependent modality, and, as a result,
examination quality may vary widely. Okuda et al reported that only
60% of nodules identified by ultrasound in a cirrhotic liver were
With recent advances in hepatic imaging techniques, small nodular
lesions of undetermined malignant potential are being detected with
increasing frequency in cirrhotic livers. These lesions are also
increasingly noted on liver explant pathology.
In the past, small nodular lesions of undetermined malignant
potential have been classified as adenomatous hyperplasia,
macroregenerative nodules, nodular hyperplasia, dysplastic nodules,
adenomatous hyperplastic nodules, atypical adenomatous hyperplasia,
or adenomatous hyperplasia with malignant foci. These lesions may
vary histologically from benign, large regenerating nodules to
equivocally malignant nodules to nodules containing obvious malignant
foci. Distinguishing benign from malignant or premalignant
disease is clinically important because early surgical intervention
provides the only opportunity for cure.
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