Hepatocellular carcinoma is the fifth most common malignant tumor in men and the eighth in women, but is among the three most common tumors in many of the most populous regions of the world. Approximately 550 000 new cases of hepatocellular carcinoma occur globally each year, constituting 5.6% of all new cancers. Hepatocellular carcinoma ranks third in annual cancer mortality rates.
High incidences of the tumor occur in eastern and southeastern Asia, some of the western Pacific Islands, and sub-Saharan Africa, but the tumor is rare or uncommon in most industrialized countries. Intermediate incidences occur in some European and South American countries. Hepatocellular carcinoma is increasing in incidence in a number of industrialized countries, especially in Japan but to a lesser extent in parts of North America and Europe.
Gender Distribution
Men are generally more susceptible to hepatocellular carcinoma. Male predominance is, however, more obvious in populations at high risk for the tumor (mean ratio 3.7:1.0) than in those at low or intermediate risk (2.4:1.0).
The main determinant of this difference is the higher rate of chronic hepatitis B virus infection (the most important cause of hepatocellular carcinoma in countries with a high incidence of the tumor) and exposure to the fungal toxin, aflatoxin (another important cause of the tumor in countries with a high incidence of hepatocellular carcinoma) in males than females in populations at high risk for hepatocellular carcinoma. In industrialized countries, patients with hepatocellular carcinoma in the absence of cirrhosis have an approximately equal sex distribution.
Age Distribution
The incidence of hepatocellular carcinoma increases progressively with advancing age in all populations, although it tends to level off in the oldest age groups. However, in Chinese and even more in Black African populations, the age distribution is skewed toward a younger age. This phenomenon is most striking in Mozambique, where more than 50% of Shangaan men with the tumor are younger than 30 years of age. Hepatocellular carcinoma is rare in children.
Clinical Presentation
Patients with hepatocellular carcinoma are often unaware of its presence until the tumor has reached an advanced stage. Black Africans, in particular, usually seek treatment late in the illness. When far advanced, hepatocellular carcinoma generally presents with typical symptoms and physical signs, and diagnosis is then relatively easy. Before this late stage is reached, however, clinical recognition is often difficult. The tumor frequently coexists with longstanding cirrhosis, more so in industrialized countries. In these countries, the cirrhosis is usually symptomatic and when hepatocellular carcinoma supervenes the patient has few, if any, symptoms attributable to the tumor. If, in addition, the tumor is small (as it often is in the presence of cirrhosis), it may not be obvious on physical examination. One circumstance that should alert the clinician to the possibility that hepatocellular carcinoma has developed is a sudden and unexplained change in the patient’s condition: He or she may complain of abdominal pain or weight loss; ascites may worsen or become blood-stained or intractable; the liver may enlarge rapidly or develop a bruit or hepatic failure may supervene. In contrast, in Chinese and Black African populations at high risk of hepatocellular carcinoma, the symptoms, if any, of the coexisting cirrhosis are overshadowed by those of the tumor. Hepatocellular carcinomas are generally considerably larger in these populations and the patient’s symptoms and signs are accordingly more florid, and this facilitates clinical diagnosis.
The most common symptom is upper abdominal pain, which is usually a dull ache but may become intense in the later stages of the illness. Pain is usually accompanied by weakness, anorexia, and loss of weight. Jaundice is infrequent. Physical findings depend upon the stage of the disease at the time the patient is first seen. Early on there may be no abnormal findings or only evidence of cirrhosis. More often the tumor is advanced at the first visit. The liver is then almost always enlarged, sometimes massively so, especially in Black African and Chinese patients, and may be tender. The surface may be smooth or obviously nodular, and the texture is stony-hard or firm. An arterial bruit (or rarely a friction rub) may be heard over the liver. Ascites may be present and increases in severity with progression of the tumor and the spleen is sometimes slightly enlarged. Slight or moderate wasting may be evident at the time of the first visit. Thereafter, progressive wasting is the rule. Jaundice is unusual and mild early on but may appear or deepen with progression of the disease. Physical evidence of cirrhosis is common in patients in industrialized countries.
Atypical presentations of hepatocellular carcinoma are with obstructive jaundice; an acute abdominal crisis when the tumor ruptures causing acute hemoperitoneum; Budd-Chiari syndrome when it invades the hepatic veins and severe pitting edema of the lower limbs when the inferior venal cava is blocked by tumor; superior mediastinal syndrome when the superior vena cava is compressed by malignant lymph nodes in the mediastinum; bone pain in the presence of bony metastases; and respiratory symptoms when the right hemidiaphragm is markedly elevated or pulmonary metastases or a large pleural effusion are present. Hepatocellular carcinoma may also present with one or more of a number of paraneoplastic syndromes, including most often hypoglycemia, polycythemia, or hypercalcemia.
Diagnosis
Conventional tests of hepatic function do not distinguish hepatocellular carcinoma from other hepatic masses or from cirrhosis. Accordingly, they contribute little to the diagnosis of the tumor.
a-Fetoprotein is an a1-globulin that is normally present in high concentration in fetal serum but in only minute amounts thereafter. Reappearance of high concentrations of the globulin in the serum strongly suggests the diagnosis of hepatocellular carcinoma (or hepatoblastoma). This finding is especially true in populations with a high incidence of hepatocellular carcinoma: Approximately 90% of Chinese and Black African patients have raised serum levels and roughly 75% have diagnostically raised levels (greater than 500 ng/ml). These percentages are appreciably lower in populations with low or intermediate incidences of the tumor, and a-fetoprotein is consequently a less useful tumor marker in these populations. Raised serum levels range over six orders of magnitude, although figures of greater than 1 million are rare. Synthesis of a-fetoprotein by a tumor is permanent and age-related: The younger the patient, the more likely the serum value is to be raised and the higher the level attained. There is no gender difference in afetoprotein production provided the patients are matched for age. No obvious correlation exists between the serum concentration of a-fetoprotein and any of the clinical or biochemical features of the tumor or the survival time of the patient. Small, asymptomatic tumors are accompanied by appreciably lower serum levels of a-fetoprotein than are symptomatic tumors.
The reason why 500 ng/ml is taken as a diagnostic level of a-fetoprotein is that serum concentrations up to this level may be found in patients with acute and chronic hepatitis and cirrhosis. False-positive results may also occur in patients with tumors of endodermal origin and nonseminomatous tumors of the ovary or testis.
Pulmonary metastases may be seen on plain chest radiography, particularly often in Black African and Chinese patients. They are almost always multiple. The right hemidiaphragm may be abnormally raised and may lose its normally crescentic outline.
Ultrasonography detects the majority of hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver. Its advantages include safety, availability, and cost effectiveness, although it has the drawbacks of being nonstandardized and observerdependent. Approximately two-thirds of hepatocellular carcinomas are uniformly hyperechoic, with the remainder being partly hyperechoic and partly hypoechoic; small, early tumors are hypoechoic. Tumors located immediately under the right hemidiaphragm may be difficult to visualize. Ultrasonography with Doppler is useful for assessing the patency of the inferior vena cava, portal vein and its larger branches, and hepatic veins. Dynamic contrast-enhanced Doppler ultrasonography with intraarterial infusion of carbon dioxide microbubbles and intravenous-enhanced color Doppler ultrasonography, by characterizing hepatic arterial and portal venous flow in hepatic nodules, facilitates the differentiation between malignant and benign hepatic nodules.
Spiral (helical) computerized tomography and computerized tomography during arterial portography have greatly improved imaging of hepatocellular carcinoma. The images obtained are, however, not specific. Computerized tomography is particularly useful in defining the extent of the tumor within and beyond the liver, and showing the course, caliber, and patency of blood vessels. Because iodized poppy seed oil (Lipiodol) is concentrated and retained in hepatocellular carcinoma tissue, injection of this material at the end of hepatic arteriography can be used in conjunction with computerized tomography, performed after a suitable delay, to detect very small tumors.
Magnetic resonance imaging provides another means of distinguishing hepatocellular carcinoma from normal liver tissue. Many tumors have a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images. Gradient echo sequences and turbo spin-echo sequences have greatly reduced the time needed for magnetic resonance imaging. Furthermore, use of a contrast agent, such as gadopentetate dimeglumine and superparamagnetic iron oxide, increases the accuracy of magnetic resonance imaging, especially in detecting small hepatocellular carcinomas in cirrhotic livers and distinguishing small hepatocellular carcinomas from hemangiomas or dysplastic nodules uncovered in surveillance programs.
Hepatic digital subtraction angiography is helpful in recognizing small hypervascular hepatocellular carcinomas, but may miss early well-differentiated hypovascular tumors. Angiography is also essential in delineating the hepatic arterial anatomy when planning surgical resection, transplantation, bland or chemoembolization of the tumor, or infusion of cytotoxic drugs into the hepatic artery or its branches. Angiography with recirculation will also determine the patency of the hepatic veins.
Laparoscopy can be used to detect peritoneal and other extrahepatic spread, ascertain whether the nontumorous part of the liver is cirrhotic, and obtain a biopsy of the liver under direct vision.
Pathology
Definitive diagnosis of hepatocellular carcinoma depends upon demonstrating the typical histological features of the tumor. Samples suitable for diagnosis can usually be obtained by either percutaneous needle biopsy or fine-needle aspiration. Because there is a risk of local, regional, or systemic dissemination of the tumor cells by needling the liver, these procedures should be avoided as long as the tumor is thought to be operable.
Gross Appearance
Hepatocellular carcinoma may take three forms: nodular, massive, or diffuse. The nodular variety accounts for 75% of tumors and usually coexists with cirrhosis. It is characterized by numerous round or irregular nodules scattered throughout the liver, many of which are confluent. The massive type is more common in younger patients without cirrhosis. It is the type most likely to rupture. The diffusely infiltrating variety is rare: A large part of the liver is infiltrated homogeneously by indistinct tumor nodules, which may be difficult to distinguish from the cirrhotic nodules that are almost invariably present.
The portal vein and its branches are infiltrated by tumor in approximately 70% of cases seen at necropsy. The hepatic veins and bile ducts are invaded less often.
Microscopic Appearance
Hepatocellular carcinoma is classified histologically into well-differentiated, moderately differentiated, and undifferentiated (pleomorphic) varieties.
Well-differentiated Despite the aggressive nature and poor prognosis of the great majority of hepatocellular carcinomas, most tumors are well-differentiated. Trabecular and acinar (pseudoglandular) varieties occur. In the trabecular variety the malignant hepatocytes grow in irregular anastomosing plates separated by sinusoids lined by flat epithelial cells. The trabeculae resemble those of normal adult liver, although they are often thicker and are composed of several layers of cells. The malignant hepatocytes are polygonal with abundant slightly granular cytoplasm that is less eosinophilic than that of normal hepatocytes. The nuclei are large and hyperchromatic with prominent nucleoli. Bile production is the hallmark of hepatocellular carcinoma, regardless of the pattern. A variety of gland-like structures are present in the acinar variety. They are composed of layers of malignant hepatocytes surrounding the lumen of a bile canaliculus, which may contain impissated bile. The individual cells may be more elongated and cylindrical than in the trabecular variety.
Moderately differentiated Solid, scirrhous and clear-cell varieties occur. In the solid type, the cells are usually small. Pleomorphic multinucleated giant cells are occasionally present. The tumor grows in solid masses or cell nests. Central ischemic necrosis is common in the larger tumors. In the scirrhous type, the malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma. Duct-like structures are occasionally present.
In most tumors, the cells resemble hepatocytes, although occasionally the cells are clear cells.
Undifferentiated The cells are pleomorphic, varying greatly in size and shape. The nuclei are also extremely variable. Large numbers of bizarre-looking giant cells are present. Occasionally, the cells may be spindle-shaped, resembling sarcoma cells.
Extrahepatic metastases are present at necropsy in 40–57% of patients with hepatocellular carcinoma. They are more common (roughly 70%) in patients without coexisting cirrhosis than in those with cirrhosis (approximately 30%). The most frequent sites are the lungs (up to 50%) and regional lymph nodes (approximately 20%).
Fibrolamellar hepatocellular carcinoma typically occurs in young patients, has an approximately equal sex distribution, does not produce a-fetoprotein, is not caused by chronic hepatitis B or C viruses, and almost always arises in a noncirrhotic liver. It is more often amenable to surgical treatment and therefore generally has a better prognosis than typical hepatocellular carcinoma. It does not, however, respond to chemotherapy any better than other forms of the tumor. The hepatocytes are characteristically plump and deeply eosinophilic and are encompassed by abundant fibrous stroma composed of thin parallel fibrous strands that separate the cells into trabeculae or nodules. The cytoplasm is packed with swollen mitochondria, and in approximately half of the tumors contains pale or hyaline bodies. Nuclei are prominent and mitoses are rare.
Etiology And Pathogenesis
Hepatocellular carcinoma is multifactorial in etiology and complex in pathogenesis. A number of risk factors for the tumor have been identified. Chronic necroinflammatory hepatic disease, especially cirrhosis, is the most common causal association, especially in industrialized countries. All forms of cirrhosis may be complicated by tumor formation, although not with the same frequency. Constitutive proliferation of hepatocytes triggered by continuous cycles of hepatocyte necrosis and regeneration and DNA damage resulting from the generation of oxidative stress by the chronic necroinflammation are the main pathogenetic mechanisms.
The most common environmental risk factor for hepatocellular carcinoma is chronic hepatitis B virus infection. It is implicated in about 80% of the hepatocellular carcinoma that occurs at high frequency in eastern and southeastern Asia, the Pacific islands, and subSaharan Africa. Approximately 54% of patients with the tumor globally are infected with the virus. Chronic carriers of the virus are infected very early in life, either by perinatal or horizontal infection, and they are at very high risk of developing the tumor later in life. The virus is thought to be both directly and indirectly hepatocarcinogenic. Many of the patients who develop hepatocellular carcinoma have cirrhosis and this contributes to the carcinogenic process. However, hepatitis B virus DNA becomes integrated into host DNA and is thought to be directly oncogenic. The hepatitis B virus x gene appears to play a central role in the direct hepatocarcinogenicity of this virus. Possible mechanisms include direct disruption of cellular DNA, generation of chromosomal instability, suppression of the function of tumor suppressor genes, and increased transactivation of protooncogenes.
Chronic hepatitis C virus infection is an important risk factor in industrialized countries. Together with hepatitis B virus, it is estimated to be responsible for more than 80% of global hepatocellular carcinoma. Virtually every patient with hepatitis C virus-induced hepatocellular carcinoma has cirrhosis and this is thought to be the major contributor to hepatocarcinogenesis. However, evidence is accumulating that the core and NS5A proteins of the virus may be directly carcinogenic. Hepatitis B and C viruses have synergistic hepatocarcinogenic effects.
A fungal toxin, aflatoxin B1, is an important cause of the tumor in sub-Saharan Africa, China, and Taiwan. It contaminates certain staple foodstuffs, such as maize and ground nuts. High levels of dietary intake result in the accumulation of an electrophilic metabolite, aflatoxin B1-8,9-exo-epoxide that, together with its metabolite, forms adducts with host DNA that result in the inactivation of the p53 tumor suppressor gene and other genotoxic effects. Aflatoxin B1 and chronic hepatitis B virus infection have synergistic hepatocarcinogenic effects.
Iron overload of the liver is a cause of hepatocellular carcinoma in patients with one of two diseases. The first is an inherited disease, known as hereditary hemochromatosis, in which the iron overload results from an inherited predisposition to absorb too much iron from a diet with a normal iron content. The second disease, dietary iron overload in the African, results from the consumption of large quantities of a traditional beer, which is homebrewed in cast iron drums or pots and which therefore contains a high iron content. Excess hepatic iron in these conditions causes cirrhosis, but is also directly hepatocarcinogenic by producing oxygen reactive species and oxidative damage to cellular DNA and other organelles.
Recently, it has been realized that nonalcoholic steatohepatitis with its associated metabolic abnormalities of hyperglycemia, insulin resistance, hypertriglyceridemia as well as obesity and arterial hypertension, is a risk factor for hepatocellular carcinoma. The resulting cirrhosis contributes to the carcinogenic process, but in addition oxidative damage and other changes are incriminated.
A number of rare inherited abnormalities may be complicated by hepatocellular carcinoma. These are a1-;antitrypsin deficiency, glycogen storage disease, hereditary tyrosinemia, hereditary hypercitrullinemia, and acute intermittent porphyria.
Natural History And Prognosis
Symptomatic hepatocellular carcinoma carries a grave prognosis. The main reasons for this are the advanced stage of the disease when the patient is first seen and the presence of coexisting cirrhosis. The natural history of hepatocellular carcinoma in its florid form is one of rapid progression with increasing hepatomegaly, abdominal pain, wasting, and deepening jaundice. In Black African and Chinese populations, death often ensues within 4 months, although in industrialized countries the tumor generally runs a more indolent course with longer survival times.
Treatment
The treatment of hepatocellular carcinoma depends on the burden of disease, the presence or absence of cirrhosis, and the degree of hepatic dysfunction.
Surgical Resection
Surgical intervention offers the only chance of cure. For resection to be considered, the tumor must be confined to one hepatic lobe and be favorably located in that lobe, and ideally the nontumorous tissue should not be cirrhotic. Resection can, however, be considered if the cirrhosis is not severe and the tumor is either confined to the left lobe or, if present in both lobes, allows the surgeon to perform a segmentectomy or limited nonanatomic resection. The number of patients with resectable tumors is small in countries with a high incidence of hepatocellular carcinoma. Even after successful resection, there is a high recurrence rate of the tumor.
Transplantation
Transplantation can be performed in patients in whom the tumor is not resectable but is confined to the liver, or in whom advanced cirrhosis and poor liver function preclude resection. Even patients with reasonably good liver function may be better served by transplantation. Because of undetected spread before surgery, the rate of tumor recurrence is high.
Nonoperative Treatments
Small tumors not amenable to resection because they are multiple or inaccessible or because of severe liver dysfunction have been treated with a variety of intralesional techniques. Alcohol injection was used initially, but more recently radiofrequency ablation has been preferred. Arterial embolization or chemoembolization are additional palliative methods in selected patients. They are also used to reduce the size of the tumor in an attempt to make resection possible or to allow a more conservative resection.
Chemotherapy
A large number of anticancer drugs, including alkylating agents, antitumor antibiotics, antimetabolites, plant alkaloids, platinum derivatives, and procarbazine, have been tried alone and in various combinations, and by different routes of administration, in the treatment of hepatocellular carcinoma, but response rates have invariably been less than 20%. Because single agents have limited value in treating hepatocellular carcinoma, it is not surprising that combinations of these agents are also disappointing. Multidrug resistance is an important factor in the poor outcomes, and the development and testing of drugs that reverse this resistance is in progress. Biologic response modifiers tested to date have not proved to be of value.
Screening For Small Presymptomatic Tumors
Because symptomatic hepatocellular carcinoma is seldom amenable to surgical intervention and responds poorly to conservative modalities of treatment, there is a pressing need either to prevent the tumor or to diagnose it at a presymptomatic stage when surgical intervention is still possible. Mass screening of populations at high risk for the tumor is a daunting and expensive task with a relatively low yield. Long-term surveillance of individuals known to be at high risk (particularly those chronically infected with hepatitis B or C viruses) is more effective and can be costeffective. Ultrasound examination is used as the initial imaging screen in association with measurement of serum a-fetoprotein levels, usually performed at 6-month intervals.
Prevention
The only very effective means of preventing hepatocellular carcinoma at present is the use of hepatitis B virus vaccination. Universal incorporation of this vaccine into the Expanded Program of Immunization in countries in which infection with this virus is endemic and hepatocellular carcinoma common has already resulted in a more than tenfold decrease in viral carrier rates and a more than 70% reduction in the occurrence of hepatitis B-virus-induced hepatocellular carcinoma in the age cohorts that have received the vaccine.
Cholangiocarcinoma
Cholangiocarcinomas may originate from small intrahepatic bile ducts (peripheral cholangiocarcinoma), larger or hilar intrahepatic ducts (hilar cholangiocarcinoma) (when located at the bifurcation of the right and left main intrahepatic bile ducts, referred to as Klatskin tumor), or extrahepatic bile ducts (bile duct carcinoma).