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Hepatocellular Carcinoma
Epidemiology and Etiology
Hepatocellular carcinoma (HCC) is the sixth most common malignancy in the world and the fastest growing cause of cancer-related death. This is in part due to endemic viral hepatitis in developing countries and the epidemic of obesity in the Western world. Currently, 84% of patients with HCC live in Asia and Africa, but the incidence of HCC in the United States has been steadily increasing since 1975, and HCC is projected to be the third leading cause of cancer death by 2030. More common among men, the incidence of HCC in the United States has increased since 1975 to 2000 from 1.4 to more than 5 per 100,000, respectively. Of the 600,000 deaths per annum worldwide, 50% occur in China.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are both strongly associated with the development of HCC. This association increases significantly with coinfection of both of these viruses. Hepatitis B has a higher prevalence in Asia and Africa, whereas hepatitis C is more prevalent in Japan, Europe, and the United States. The incidence of HCC has actually been decreasing recently in China and Korea, likely demonstrating successful HBV vaccination programs. This is in stark contrast to the increasing incidence in the United States, the Middle East, and Japan, driven by HCV- and obesity-related liver disease.
The average age at the time of diagnosis of HCC in the United States is 65 years, with a 75% male predominance. In the United States, hepatitis C and B and alcohol consumption are the commonest causes of HCC. The rise of HCC in Western countries was previously fueled by the increase in the prevalence of hepatitis C. The greatest incidence of hepatitis C infection was during the late 1970s and early 1980s, with a dramatic drop in incidence in the late 1980s ( Fig. 132.1 ). Because of the time necessary for cancer to develop in infected patients and the increased risk in older patients, the number of patients with HCC has risen rapidly as this bolus of patients infected many years ago matures ( Fig. 132.2 ). Current estimate of the prevalence of HCV in the US population is 3.5 million (1.1%). With the advent of direct-acting antiviral medications many patients will be cured of the virus, but the risk of developing HCC is still 5.1% over 10 years after sustained viral response.
Steatohepatitis
With the explosion of obesity in many parts of the world, it is clear that a large proportion of patients suffering from obesity have steatohepatitis, and many will progress to cirrhosis, putting them at risk for HCC. Approximately 20% of adults in the United States have metabolic syndrome, and the incidence of nonalcoholic steatohepatitis (NASH) is estimated to be 12.2%. The yearly incidence of the development of HCC in patients with NASH is similar to patients suffering from HCV (2.6% vs. 4.0% per year), but the worldwide burden of NASH is projected to be much greater than that of HCV. The potential magnitude of the disease burden of NASH can be realized by the facts that 1.1% of the US population has HCV and 25% of liver transplants are done for HCV-related HCC while 12.2% of the population has steatohepatitis and the annual risk of development of HCC in the two populations appears to be similar. The main reason NASH-related liver disease has not reached its zenith is that the epidemic of obesity is a relatively recent event.
Other Risk Factors
In sub-Saharan Africa, Southeast Asia, and China, aflatoxin, a contaminant in maize and nuts, produced by the fungi Aspergillus , is a potent carcinogen. The carcinogenic potential increases 30-fold in the presence of chronic HBV infection ( Table 132.1 ). The estimate of the percentage of HCC related to aflatoxin ranges between 5% and 28%. Programs to reduce exposure to aflatoxins, in combination with HBV vaccination efforts, have been effective.
TABLE 132.1
Major Risk Factors for Hepatocellular Carcinoma
| Infection | Hepatitis B |
| Hepatitis C | |
| Toxin/drug | Alcoholic cirrhosis |
| Aflatoxins | |
| Anabolic steroids | |
| Genetic | Hemochromatosis |
| α 1 -Antitrypsin deficiency | |
| Immunologic | Autoimmune chronic active hepatitis |
| Primary biliary cirrhosis | |
| Other | Obesity |
| Nonalcoholic steatohepatitis | |
| Cirrhosis (other causes and idiopathic) |
Pathogenesis
Hepatitis B, a DNA virus, integrates itself into hepatocyte DNA and is thought to increase the rate of oncogene transcription. Hepatitis C, an RNA virus, does not incorporate into DNA of the hepatocytes, and its relationship with HCC is thought to be through chronic inflammation. After cirrhosis develops, HCV continues to replicate, which sustains inflammation and a rapid cell turnover, resulting in mutation and dysplastic changes that lead to neoplastic growth. The pathogenesis in steatohepatitis is poorly understood, although the associated chronic inflammation is thought to contribute to the development of HCC. Termed the immune-metabolic interface, the influences of altered insulin signaling and nuclear factor κB are still being elucidated.
Pathophysiology
Understanding the pathophysiology of HCC is critical when considering diagnosis and treatment for this relatively unique malignancy. The three most important clinical aspects of the pathophysiology of HCC are (1) its relationship to cirrhosis and chronic inflammation, (2) arterial angiogenesis, and (3) portal vein invasion.
Cirrhosis
Traditionally, more than 90% of patients who developed HCC had liver fibrosis. In patients with hepatitis C, almost all the patients with HCC have cirrhosis, and the risk of developing HCC after cirrhosis is established is approximately 3% to 5% per year. Increasingly, patients without cirrhosis are developing HCC. This shifting trend is not completely understood, but it is clear that most of these patients have a significant amount of chronic inflammation from HBV or NASH.
The cirrhotic liver consists of regenerative nodules surrounded by fibrosis. It appears that because of chronic inflammation, progression from regenerative nodules to dysplasia and finally to HCC occurs. This is a multistep process of a precancerous lesion progressing from a dysplastic foci to a low-grade dysplastic nodule, then high-grade dysplastic nodule, and eventually to HCC. Dysplastic nodules generally range from 1 to 2 cm and contain areas of dysplasia or carcinoma in situ. The risk of liver cancer is not localized to one specific site in the liver but rather is uniform across all the hepatocytes, so the resulting carcinogenic potential is termed a field defect . This field defect is responsible for the high rate of recurrence after resection of HCC because the remaining liver contains oncogenic potential. This is why recurrence after resection most commonly takes the form of a second primary lesion rather than a recurrence of the resected lesion itself. This powerful field defect is why a patient's response to locoregional therapy prior to liver resection does not predict the likelihood of recurrence. The field defect is why the greatest risk factor for the development of HCC is a previous HCC, with the risk in the HCV cirrhotic patient increasing from 3% to 5% per year to 20% per year after a diagnosis of HCC.
Arterial Angiogenesis
The normal and cirrhotic liver both are supplied by a unique dual blood flow, dominated by portal venous inflow. Dysplastic nodules are predominantly supplied by the portal vein, but HCC derives its blood supply primarily from the hepatic artery. This clinically useful feature of HCC is due to the dysregulation of angiogenesis and lack of a basement membrane that occurs with malignant tumors. This propensity for HCC to undergo neoangiogenesis and hepatic arterial hyperperfusion allows characterization of lesions and diagnosis of typical appearing lesions as HCC via imaging without requiring a biopsy. On computed tomography (CT) and magnetic resonance imaging (MRI), the HCC lesion will be hyperdense during the arterial phase compared with the surrounding liver parenchyma. HCC will then “washout” during the portal venous phase, as the predominantly arterial blood supply has already passed through the lesion by the time the portal venous contrast phase is peaking. The arterial blood vessels supplying the tumor have a characteristic appearance of both vessel size and branch density. This abnormal arterial perfusion allows for treatment of HCC via embolization of the predominant artery(ies) supplying the tumor.
Portal Vein Invasion
Another characteristic of HCC is its propensity to invade the portal vein. Tumors measuring more than 2 cm have an increased risk of portal vein invasion, which can be assessed on imaging.
Predictably, the risk of local or remote recurrence of HCC in patients with microscopic or macroscopic portal venous invasion is higher following liver resection or transplantation. Macroscopic portal vein invasion is a contraindication to transplantation and, in many cases, to liver resection as well. It is likely that portal venous invasion is either a mechanism for dissemination of the tumor and/or a marker that the metastatic cells are able to invade and survive in other organs, such as the lung or bone.
It is well recognized that the recurrence of HCC after transplantation is related to the total tumor burden. This finding is likely a reflection of the increased probability of vascular invasion and/or cellular dedifferentiation when the tumor is large or multifocal.
Combined Hepatocellular-Cholangiocarcinoma
Approximately 1% of liver tumors in patients with cirrhosis are found to be combined hepatocellular-cholangiocarcinoma. These mixed lesions do not seem to follow the traditional multistep sequence of HCC carcinogenesis, but possibly result from malignant transformation of a progenitor cell that retains the ability to differentiate into either cell type. Biopsy of HCC prior to resection or transplant is rarely indicated, so these mixed lesions are frequently presumed to be HCC until the explant pathology is available. The outcome of patients with mixed tumors undergoing transplant is not frequently described, but a multicenter, retrospective matched cohort study found that patients with combined lesions have the same 1-, 3- and 5-year actuarial survival when compared with patients with pure HCC (93%, 78%, and 78% vs. 97%, 86%, and 86%, respectively; P = .9). The results, derived from data including only 15 patients with mixed tumors compared with 30 controls, needs to be replicated.
Clinical Presentation of HCC
HCC can present in varying ways: as an incidental finding during ultrasound for right upper quadrant pain, abdominal mass, weight loss, anorexia, or onset of ascites or while screening for patients at risk for HCC, with or without evidence of cirrhosis.
A patient with known cirrhosis who develops any of the symptoms previously mentioned should be suspected of having developed HCC. The finding of small asymptomatic liver lesions during the radiologic evaluation for liver transplantation is another common presentation, particularly in patients with hepatitis C or NASH.
Physical examination is most often dominated by the signs of cirrhosis, such as jaundice, ascites, cachexia, splenomegaly, hepatomegaly, spider angiomata, or palmar erythema. Conversely, the physical exam may be normal in patients with HBV or NASH who can experience HCC prior to the development of cirrhosis.
Laboratory Findings
Due to the limited success of treatment of advanced HCC, early detection is critical. Blood tests can reveal abnormal liver function and elevated liver enzymes, again, most often driven by the underlying cirrhosis. Viral serologies including hepatitis B surface antigen and hepatitis C antibody tests are also necessary. Patients with cirrhosis may also demonstrate thrombocytopenia, which is a marker of portal hypertension. α-Fetoprotein (AFP) may be elevated in patients with HCC; however, this is neither highly sensitive nor specific. The American Association for the Study of Liver Disease (AASLD) updated their guidelines for screening patients at risk of developing HCC in 2010, recommending liver ultrasound and serum AFP measurement every 6 months. The evidence for screening patients with risk factors other than HBV is somewhat controversial.
AFP can be used as a confirmatory test in cases in patients with cirrhosis and a liver mass. A level greater than 400 ng/mL is diagnostic when there is a liver mass greater than 2 cm with arterial hyperenhancement. It is important to remember that serum AFP can be less than 20 ng/mL in more than 40% of patients with HCC, and the AFP can be elevated in patients with active viral hepatitis without cancer.
The des-carboxyprothrombin (DCP) and the lens culinaris agglutinin-reactive fraction of AFP, termed AFP-L3, are candidate biomarkers that may increase the specificity for HCC when used with serum AFP screening. DCP is elevated in approximately 40% of patients with HCC smaller than 2 cm. There is no correlation between serum DCP and AFP levels.
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