Hepatocellular Carcinoma 

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. Hepatocellular carcinoma is now the third leading cause of cancer deaths worldwide, with over 500,000 people affected. The incidence of hepatocellular carcinoma is highest in Asia and Africa, where the endemic high prevalence of hepatitis B and hepatitis C strongly predisposes to the development of chronic liver disease and subsequent development of hepatocellular carcinoma.

The presentation of hepatocellular carcinoma has evolved significantly over the past few decades. While, in the past, hepatocellular carcinoma generally presented at an advanced stage with right upper quadrant pain, weight loss, and signs of decompensated liver disease, hepatocellular carcinoma is now increasingly recognized at a much earlier stage as a consequence of the routine screening of patients with known cirrhosis, using cross-sectional imaging studies and serum alpha-fetoprotein measurements.

Resection may benefit certain patients, albeit mostly transiently. Many patients are not candidates given the advanced stage of their cancer at diagnosis or their degree of liver disease and, ideally, could be cured by liver transplantation. Globally, only a fraction of all patients have access to transplantation, and, even in the developed world, organ shortage remains a major limiting factor. In these patients, local ablative therapies, including radiofrequency ablation, chemoembolization, and potentially novel chemotherapeutic agents, may extend life and provide palliation.

Hepatocellular carcinoma is a primary cancer of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. The cell of origin is believed to be the hepatic stem cells, although this remains the subject of investigation.^[1] Tumors progress with local expansion, intrahepatic spread, and distant metastases. In general, the tumors are discovered either during routine screening or when symptomatic because of their size or location. Tumors may present as a single mass lesion or as diffuse growth, which can be difficult to differentiate from the surrounding cirrhotic liver tissue and the regenerating liver nodules on imaging studies. The presentation may be caused in part by mass effect that can lead to obstruction of the biliary system or anywhere affecting the liver vasculature. Without aggressive surgical resection, ablative therapy, or liver transplantation, hepatocellular carcinoma results in liver failure and death.

Frequency

In the United States, hepatocellular carcinoma, with its link to the hepatitis C epidemic, represents the fastest growing cause of cancer mortality overall and the second fastest growing cause of cancer deaths among women, based upon data from the Surveillance Epidemiology and End Results (SEER) program.^[2]

Over the past 20 years, the incidence of hepatocellular carcinoma has more than doubled, from 2.6 to 5.2 per 100,000 population. Among African Americans, the increase has been even greater (ie, from 4.7 to 7.5 per 100,000 population overall and to 13.1 per 100,000 population among males). The mortality rate has similarly increased from 2.8 to 4.7 per 100,000 population over the past 5 years alone.

Worldwide, the incidence of hepatocellular carcinoma in developing nations is over twice the incidence of that in developed countries. In 2000, the age-adjusted incidence of hepatocellular carcinoma in men was 17.43 per 100,000 population in developing countries compared with only 8.7 per 100,000 population in the United States. Among women, the disparity was also significant (6.77 vs 2.86 per 100,000 population). The highest incidence of hepatocellular carcinoma is in East Asia, with incidence rates in men of 35 per 100,000 population, followed by Africa and the Pacific Islands.

Mortality rates mirror the incidence rates for hepatocellular carcinoma. In developing countries, the mortality from hepatocellular carcinoma in men is more than double that in developed countries (16.86 vs 8.07 per 100,000 population). In Asia and Africa, the mortality rates are 33.5 and 23.73 per 100,000 population, respectively.

In the United States, the average age at diagnosis is 65 years; 74% of cases occur in men. The racial distribution includes 48% whites, 15% Hispanics, 14% African Americans, and 24% others (primarily Asians). The incidence of hepatocellular carcinoma increases with age, peaking at 70-75 years; however, an increasing number of young patients have been affected, as the demographic shifts from primarily alcoholic liver disease to those in the fifth to sixth decades of life as the consequences of viral hepatitis B and C acquired earlier in life and in conjunction with high-risk behavior. The combination of viral hepatitis and alcohol significantly increases the risk of cirrhosis and subsequent hepatocellular carcinoma.

The major risk factors for developing hepatocellular carcinoma vary by region and degree of national development. See Table 1.

In the United States, the risk factors have historically included alcoholic cirrhosis, hepatitis B (HBV) infection, hemochromatosis, and now hepatitis C (HCV) infection.^[3] However, the obesity epidemic has resulted in a growing population of patients with nonalcoholic fatty liver disease (NAFLD), also referred to as nonalcoholic steatohepatitis (NASH). Patients with NAFLD can progress to fibrosis, cirrhosis, and now hepatocellular carcinoma.^[4] These patients are expected to drive the hepatocellular carcinoma epidemic in the United States and other developed countries. In the developing world, viral hepatitis (primarily hepatitis B), continues to represent the major risk for the development of hepatocellular carcinoma. The impact of hepatitis B vaccination on the eventual rate of hepatocellular carcinoma remains to be determined.^[5] The results of the vaccination of newborns are encouraging.

Temporal trends suggest that the epidemic of hepatocellular carcinoma is likely to continue, reflecting the reservoir of the viral hepatitis endemic in the population. In the United States, the annual incidence of new acute HCV infections appears to have decreased since the mid 1980s. However, the delay between HCV infection and hepatocellular carcinoma development can be up to 30-40 years, leading to the belief that the epidemic of hepatocellular carcinoma is unlikely to begin to decrease until 2015-19.^{[6, 7]} Overall, it is estimated that 1.5% of the US population is infected with HCV, of whom 20-30% may develop cirrhosis. Among patients with cirrhosis, the incidence of hepatocellular carcinoma is 1-6%. This risk is compounded by concurrent alcohol abuse, which increases the risk of cirrhosis and hepatocellular carcinoma in patients with viral hepatitis.

Other trends driving the epidemic include the aging population, obesity, and, perhaps, improved survival of patients with cirrhosis through better management of ascites and portal hypertension. The worldwide burden of hepatocellular carcinoma is also likely to continue. While significant progress has been made worldwide through HBV vaccination as part of the expanded program for vaccination by the World Health Organization (WHO), the prevalence of chronic liver disease remains significant among the older population who is at risk of developing hepatocellular carcinoma.

Table 1. Risk Factors for Primary Liver Cancer and Estimate of Attributable Fractions^[3] (Open Table in a new window)

See Pathophysiology.

The pathophysiology of hepatocellular carcinoma has not been definitively elucidated and is clearly a multifactorial event. In 1981, after Beasley linked HBV infection to hepatocellular carcinoma development, the cause of hepatocellular carcinoma was thought to have been identified.^[7] However, subsequent studies failed to identify HBV infection as a major independent risk factor, and it became apparent that most cases of hepatocellular carcinoma developed in patients with underlying cirrhotic liver disease of various etiologies, including patients with negative markers for HBV infection and who were found to have HBV DNA integrated in the hepatocyte genome.

Inflammation, necrosis, fibrosis, and ongoing regeneration characterize the cirrhotic liver and contribute to hepatocellular carcinoma development. In patients with HBV, in whom hepatocellular carcinoma can develop in livers that are not frankly cirrhotic, underlying fibrosis is usually present, with the suggestion of regeneration. By contrast, in patients with HCV, hepatocellular carcinoma invariably presents, more or less, in the setting of cirrhosis. This difference may relate to the fact that HBV is a DNA virus that integrates in the host genome and produces HBV X protein that may play a key regulatory role in hepatocellular carcinoma development;^[8] an RNA virus replicates in the cytoplasm and does not integrate in the host DNA.

The disease processes, which result in malignant transformation, include a variety of pathways, many of which may be modified by external and environmental factors and eventually lead to genetic changes that delay apoptosis and increase cellular proliferation.

The chart below provides an overview of the pathways and the modifiers that lead to hepatocellular carcinoma.

Recent analysis has sought to elucidate the genetic pathways that are altered during hepatocarcinogenesis.^[9] Among the candidate genes involved, the p53, PIKCA, and ß-catenin genes appear to be the most frequently mutated in patients with hepatocellular carcinoma. Additional investigations are needed to identify the signal pathways that are disrupted, leading to uncontrolled division in hepatocellular carcinoma. Two pathways involved in cellular differentiation (ie, Wnt-ß-catenin, Hedgehog) appear to be frequently altered in hepatocellular carcinoma. Up-regulated WNT signaling appears to be associated with preneoplastic adenomas with a higher rate of malignant transformation.

Additionally, studies of inactivated mutations of the chromatin remodeling gene ARID2 in 4 major subtypes of hepatocellular carcinoma are being performed. A total of 18.2% of individuals with hepatitis C virus–associated hepatocellular carcinoma in the United States and Europe harbored ARID2 inactivation mutations. These findings suggest that ARID2 is a tumor suppressor gene commonly mutated in this tumor subtype.^[10]

While various nodules are frequently found in cirrhotic livers, including dysplastic and regenerative nodules, no clear progression from these lesions to hepatocellular carcinoma occurs. Prospective studies suggest that the presence of small-cell dysplastic nodules conveyed an increased risk of hepatocellular carcinoma, while large-cell dysplastic nodules were not associated with an increased risk of hepatocellular carcinoma. Evidence linking small-cell dysplastic nodules to hepatocellular carcinoma includes the presence of conserved proliferation markers and the presence of nodule-in-nodule on pathologic evaluation. This term describes the presence of a focus of hepatocellular carcinoma in a larger nodule of small dysplastic cells.^[11]

Recent work speculated that hepatocellular carcinoma develops from hepatic stem cells that proliferate in response to chronic regeneration caused by viral injury.^[12] The cells in small dysplastic nodules appear to carry markers consistent with progenitor or stem cells.

See Medical therapy and Surgical therapy.

Because the outcome in patients with advanced hepatocellular carcinoma is uniformly dismal, early diagnosis is crucial in order to provide effective treatment. Early diagnosis of hepatocellular carcinoma is generally the result of routine screening protocols in high-risk patients, including patients with cirrhosis due to viral hepatitis (ie, HBV, HCV), patients with hemochromatosis, patients with alpha-1-antitrypsin deficiency, or patients who abuse alcohol. Among patients with cirrhosis, current recommendations include cross-sectional imaging studies every 6-12 months and serum alpha-fetoprotein (AFP) measurements. With aggressive screening, the rate of resectable hepatocellular carcinoma diagnosed in patients who are at high risk reaches 30-50%, which is nearly twice the rate of unscreened populations.^[13] Despite the significant risk of recurrence, even in treated patients, the screening protocols appear to be cost effective in this population.^[14]

Serum AFP would appear to be an attractive option for screening given its low cost and morbidity. Unfortunately, it is only 40-64% sensitive because many tumors do not produce AFP at all or only at a very advanced stage. AFP levels can be subject to misinterpretation. AFP is principally the result of production by the tumor or by regenerating hepatocytes. Therefore, AFP levels are also frequently elevated in chronic active hepatitis C (levels of 200-300 ng/mL are not uncommon), but they tend to fluctuate and do not progressively increase. AFP levels can also be elevated because of other conditions, such as following liver resection (transient until regeneration complete), recovery following toxic injury, or seroconversion following hepatitis B infection (typically inducing transient exacerbation of inflammation). See Table 2.

When elevated, the AFP is 75-91% specific, and values greater than 400 ng/mL are generally considered diagnostic of hepatocellular carcinoma in the proper clinical context, including appropriate radiologic findings. Better biological markers, including AFP variants, are currently under investigation.^{[15, 16]}

Table 2. Serum Alpha-Fetoprotein (AFP) Determination in Liver Disease^[17] (Open Table in a new window)

The best imaging modality for screening remains the subject of debate. Ultrasonography offers a relatively inexpensive method of screening without the cost of MRI or the exposure to radiation and potentially nephrotoxic contrast agents required for CT scanning.^{[18, 19, 20]} Ultrasound as a screening method is reported to have 60% sensitivity and 97% specificity in the cirrhotic population, and it has been demonstrated to be cost effective.^{[21, 22]} Findings on ultrasound should then be confirmed with further imaging studies and potentially biopsy.

On CT scan, hepatocellular carcinoma generally appears as a focal nodule with early enhancement on the arterial phase with rapid washout of contrast on the portal venous phase of a 3-phase contrast scan. MRI of hepatocellular carcinoma generally demonstrates high signal intensity on T2 imaging. Biopsy is indicated in patients with hepatocellular carcinomas that are greater than 2 cm with low AFP or in whom ablative treatment or transplant is contraindicated. In patients with elevated AFP and consistent imaging characteristics, patients can be treated presumptively for hepatocellular carcinoma without a biopsy. Patients should also undergo evaluation for extrahepatic disease (primarily pulmonary metastasis) with cross-sectional imaging, as this would preclude curative locoregional therapy.

A complete understanding of the surgical and interventional approach to the liver requires a comprehensive understanding of its anatomy and vascular supply.^{[23, 24]} The liver is the largest internal organ, representing 2-3% of the total body weight in an adult. It occupies the right upper quadrant of the abdomen, surrounding the inferior vena cava, and attaches to the diaphragm and parietal peritoneum by various attachments that are commonly referred to as ligaments.

The vascular supply of the liver includes 2 sources of inflow that travel in the hepatoduodenal ligament: the hepatic artery and the portal vein. The hepatic artery is generally derived from the celiac axis, which originates on the ventral aorta at the level of the diaphragm. Common variations include a replaced right hepatic artery, which originates from the superior mesenteric artery, a replaced left hepatic artery, which is derived from the left gastric artery, or a completely replaced common hepatic artery, which can originate from the superior mesenteric artery or aorta. The hepatic artery supplies 30% of the blood flow to the normal liver parenchyma but greater than 90% to hepatic tumors, including both hepatocellular carcinoma and metastatic lesions.

The other major inflow vessel is the portal vein which carries 70-85% of the blood into the liver. The portal vein is confluence of the splenic vein and the superior mesenteric vein, which drain the intestines, pancreas, stomach, and spleen.

The primary venous drainage of the liver is through 3 large hepatic veins that enter the inferior vena cava adjacent to the diaphragm. The right hepatic vein is generally oval in shape, with its long axis in the line of the vena cava. The middle and left hepatic veins enter the inferior vena cava through a single orifice in about 60% of individuals. In addition, there are 10-50 small hepatic veins that drain directly into the vena cava.

The biliary anatomy of the liver generally follows hepatic arterial divisions. The common bile duct gives off the cystic duct and becomes the hepatic duct. The hepatic duct then divides into 2-3 additional ducts draining the liver. There is significant variation in the biliary anatomy, and, thus, careful preoperative imaging is vital prior to embarking on any major hepatic resection.^[24]

The vascular anatomy of the livers defines its functional segments. Bismuth synthesized existing knowledge and new insight into the anatomy of the liver.^[25] Bismuth defined the right and left hemiliver, which is divided by a line connecting the gallbladder fossa and the inferior vena cava, roughly paralleling the middle hepatic vein that is slightly to the left.^[25] The right hemiliver (lobe) is divided into 4 segments (ie, 5, 6, 7, 8), each of which is supplied by a branch of the portal vein. The right lobe drains via the right hepatic vein. The left lobe is composed of 3 segments (ie, 2, 3, 4). Segment 4 is the most medial and is adjacent to the middle hepatic vein. Segments 2 and 3 comprise the left lateral segment, are to the left of the falciform ligament, and drain via the left hepatic vein. Finally, segment 1 (caudate lobe) is located behind the portahepatis and adjacent to the vena cava.

In general, resection of the liver is divided into 2 main categories.^[26] Nonanatomic (wedge) resections are generally limited resections of a small portion of liver without respect to the vascular supply. Anatomic resections involve removing 1 or more of the 8 segments of the liver. Commonly, a right hepatic lobectomy refers to the removal of segments 5-8, an extended right lobectomy (right trisegmentectomy) includes segments 4-8, a left hepatectomy includes segments 2-4, and a left trisegmentectomy includes segments 2, 3, 4, 5, and 8. A left lateral segmentectomy includes only segments 2 and 3. The caudate lobe can be removed as an isolated resection or as a component of one of the more extensive resections noted above. The extent of resection that can be tolerated is based upon the health of the remnant liver, as described in Surgical therapy.

See Medical therapy.