Hepatocellular Carcinoma

Updated: Sep 29, 2017
  • Author: Luca Cicalese, MD, FACS; Chief Editor: John Geibel, MD, DSc, MSc, AGAF  more...
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Overview

Background

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. The cell(s) of origin are 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.

HCC is now the third leading cause of cancer deaths worldwide, with over 500,000 people affected. The incidence of HCC 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 HCC.

The presentation of HCC has evolved significantly over the past few decades. Whereas in the past, HCC generally presented at an advanced stage with right-upper-quadrant pain, weight loss, and signs of decompensated liver disease, it 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 (AFP) measurements.

The threat of HCC is expected to continue to grow in the coming years. [2] The peak incidence of HCC associated with hepatitis C virus (HCV) infection has not yet occurred. There is also a growing problem with cirrhosis, which develops in the setting of nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH). NASH typically develops in the setting of obesity, type 2 diabetes, dyslipidemia, and hypertension, and it will undoubtedly remain a significant problem, given the obesity epidemic occurring in the United States. [3] Thus, developing effective and efficient care for patients with end-stage liver disease and HCC must become a significant focus.

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 (RFA), chemoembolization, and potentially novel chemotherapeutic agents, may extend life and provide palliation.

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Anatomy

A complete understanding of the surgical and interventional approach to the liver requires a comprehensive understanding of its anatomy and vascular supply. [4, 5] 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 two sources of inflow that travel in the hepatoduodenal ligament, as follows:

  • Hepatic artery
  • 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 the aorta. The hepatic artery supplies 30% of the blood flow to the normal liver parenchyma but greater than 90% to hepatic tumors, including both HCC 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 three 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 two or three additional ducts draining the liver. There is significant variation in the biliary anatomy, and thus, careful preoperative imaging is vital before any major hepatic resection. [5]

The vascular anatomy of the liver defines its functional segments. Bismuth synthesized existing knowledge and new insight into the anatomy of the liver. [6] Bismuth defined the right and left hemilivers, which are defined by a line connecting the gallbladder fossa and the inferior vena cava, roughly paralleling the middle hepatic vein that is slightly to the left. [6]

The right hemiliver (lobe) is divided into four segments (ie, 5, 6, 7, 8), each of which is supplied by a branch of the portal vein. The right hemiliver drains via the right hepatic vein. The left hemiliver (lobe) is composed of three segments (ie, 2, 3, 4). Segment 4 is the most medial and is adjacent to the middle hepatic vein. Segments 2 and 3 make up the left lateral section, are to the left of the falciform ligament, and drain via the left hepatic vein. Finally, segment 1 (caudate lobe) is located behind the porta hepatis and adjacent to the vena cava.

In general, resection of the liver is divided into the following two main categories [7] :

  • Nonanatomic (wedge) resections are generally limited resections of a small portion of liver, without respect to the vascular supply
  • Anatomic resections involve removing one or more of the eight segments of the liver

Commonly, a right hepatectomy refers to the removal of segments 5-8, an extended right hepatectomy (right trisectionectomy) includes segments 4-8, a left hepatectomy includes segments 2-4, and an extended left hepatectomy (left trisectionectomy) includes segments 2, 3, 4, 5, and 8. A left lateral sectionectomy 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.

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Pathophysiology

The pathophysiology of HCC has not been definitively elucidated and is clearly a multifactorial event. In 1981, after Beasley linked hepatitis B virus (HBV) infection to HCC development, the cause of HCC was thought to have been identified. [8] However, subsequent studies failed to identify HBV infection as a major independent risk factor, and it became apparent that most cases of HCC 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 HCC development. In patients with HBV, in whom HCC can develop in livers that are not frankly cirrhotic, underlying fibrosis is usually present, with the suggestion of regeneration. By contrast, in patients with hepatitis C virus (HCV), HCC 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 HCC development; [9] HCV is an RNA virus that 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 (see the image below).

Hepatocellular carcinoma: pathobiology. Hepatocellular carcinoma: pathobiology.

Efforts have been made to elucidate the genetic pathways that are altered during hepatocarcinogenesis. [10] Among the candidate genes involved, the p53, PIKCA, and β-catenin genes appear to be the most frequently mutated in patients with HCC. Additional investigations are needed to identify the signal pathways that are disrupted, leading to uncontrolled division in HCC. Two pathways involved in cellular differentiation (ie, Wnt-β-catenin, Hedgehog) appear to be frequently altered in HCC. Upregulated 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 four major subtypes of HCC are being performed. A total of 18.2% of individuals with HCV-associated HCC 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. [11]

Whereas various nodules are frequently found in cirrhotic livers, including dysplastic and regenerative nodules, no clear progression from these lesions to HCC occurs. Prospective studies suggest that the presence of small-cell dysplastic nodules conveyed an increased risk of HCC, but large-cell dysplastic nodules were not associated with an increased risk of HCC. Evidence linking small-cell dysplastic nodules to HCC 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 HCC in a larger nodule of small dysplastic cells. [12]

Some investigators have speculated that HCC develops from hepatic stem cells that proliferate in response to chronic regeneration caused by viral injury. [13] The cells in small dysplastic nodules appear to carry markers consistent with progenitor or stem cells.

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Epidemiology

In the United States, HCC, 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, according to data from the Surveillance Epidemiology and End Results (SEER) program. [14]

Over the past 20 years, the incidence of HCC 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). Mortality has similarly increased from 2.8 to 4.7 per 100,000 population over the past decade alone.

Worldwide, the incidence of HCC in developing nations is over twice the incidence of that in developed countries. In 2000, the age-adjusted incidence of HCC 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 HCC is in East Asia, with incidence rates in men of 35 per 100,000 population, followed by Africa and the Pacific Islands.

Mortality figures mirror the incidence figures for HCC. In developing countries, the mortality from HCC 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 figures 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 HCC 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 HCC.

The major risk factors for developing hepatocellular carcinoma vary by region and degree of national development (see Table 1 below). In the United States, the risk factors have historically included alcoholic cirrhosis, HBV infection, hemochromatosis, and now HCV infection. [15] However, the obesity epidemic has resulted in a growing population of patients with NAFLD (ie, NASH). Patients with NAFLD can progress to fibrosis, cirrhosis, and now HCC. [3] These patients are expected to drive the HCC epidemic in the United States and other developed countries.

Table 1. Risk Factors for Primary Liver Cancer and Estimate of Attributable Fractions [15] (Open Table in a new window)

  Europe and United States Japan Africa and Asia
  Estimate Range Estimate Range Estimate Range
HBV 22 4-58 20 18-44 60 40-90
HCV 60 12-72 63 48-94 20 9-56
Alcohol 45 8-57 20 15-33 - 11-41
Tobacco 12 0-14 40 9-51 22 -
OCPs - 10-50 - - 8 -
Aflatoxin Limited exposure Limited exposure Limited exposure
Other < 5 - - - < 5 -

In the developing world, viral hepatitis (primarily hepatitis B), continues to represent the major risk for the development of HCC. The impact of hepatitis B vaccination on the eventual rate of HCC remains to be determined. [16] The results of the vaccination of newborns are encouraging.

Temporal trends suggest that the epidemic of HCC 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 HCC development can be up to 30-40 years, leading to the belief that the epidemic of HCC is unlikely to begin to decrease until 2015-19. [17, 8]

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 HCC is 1-6%. This risk is compounded by concurrent alcohol abuse, which increases the risk of cirrhosis and HCC 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 HCC 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 HCC.

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