Diagnostic Evaluation of Hepatocellular Carcinoma in a Cirrhotic Liver

Hepatocellular carcinoma (HCC) is one of the world’s 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).[1] 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.[2]

In the United States, both chronic viral hepatitis and HCC are occurring with increasing frequency.[3] 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.[6] 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.[7]

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.[8] 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.

Nodular Lesions in a Cirrhotic Liver

Classification of Nodules

In 1995, the International Working Party developed a nomenclature system for hepatocellular nodules.[9] 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.[10] Thus, a diagnosis of HCC cannot be excluded in any dysplastic nodule that is sampled only with a needle biopsy.

Screening for HCC

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:

1. The disease must have a high prevalence and result in significant morbidity.

2. The natural history of the disease must allow for effective treatment when it is diagnosed at an asymptomatic stage.

3. The test must have acceptable sensitivity and specificity.[11]

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.[12] 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.[13]

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.[17] 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 biopsy-positive HCC.[17]

With recent advances in hepatic imaging techniques, small nodular lesions of undetermined malignant potential are being detected with increasing frequency in cirrhotic livers.[18] These lesions are also increasingly noted on liver explant pathology.[19]

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.[20] Distinguishing benign from malignant or premalignant disease is clinically important because early surgical intervention provides the only opportunity for cure.