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Jesly Charlies

Harrison's Internal Medicine > Chapter 88. Tumors of the Liver and Biliary Tree > Hepatocellular Carcinoma >


Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The annual global incidence is about 1 million cases, with a male to female ratio of about 4:1. The incidence rate equals the death rate. In the United States, 19,160 new cases and 16,780 deaths were noted in 2007. The death rate in males in low-incidence countries such as the United States is 1.9 per 100,000 per year; in intermediate-incidence areas such as Austria and South Africa, annual death rates range from 5.120.0 per 100,000; and in high-incidence areas such as in Asia (China and Korea), death rates are as high as 23.1150 per 100,000 per year (Table 88-1). The incidence of HCC in the United States is around 3 per 100,000 persons, with significant sex, ethnic, and geographic variations. These numbers are rapidly increasing and may be an underestimate. Around 4 million persons in the United States are chronic carriers of hepatitis C virus (HCV). About 10% of them, or 400,000, are likely to develop cirrhosis. Around 5% or 20,000 of these may develop HCC annually. Add to this the two other common predisposing factorshepatitis B virus (HBV) and chronic alcohol consumptionand 60,000 new HCC cases annually seem possible. Future advances in HCC survival will likely depend on immunization strategies for HBV and HCV and earlier diagnosis by screening of patients at risk of HCC development.

Jesly Charlies Harrison's Internal Medicine > Chapter 88. Tumors of the Liver and Biliary Tree >


Endemic hot spots occur in areas of China and sub-Saharan Africa, which are associated with both high endemic hepatitis B carrier rates and mycotoxin contamination of foodstuffs, stored grains, drinking water, and soil. Environmental factors are important; Japanese in Japan have a higher incidence than those living in Hawaii, who in turn have a higher incidence than those living in California.

Etiologic Factors

Chemical Carcinogens

Probably the best-studied and most potent ubiquitous natural chemical carcinogen is a product of the Aspergillus fungus, called aflatoxin B 1 . This mold and aflatoxin product can be found in stored grains in hot, humid places, where peanuts and rice are stored in unrefrigerated conditions. Aflatoxin contamination of foodstuffs correlates well with incidence rates in Africa and to some extent in China. In endemic areas of China, even farm animals such as ducks have HCC. The most potent carcinogens appear to be natural products of plants, fungi, and bacteria, such as bush trees containing pyrrollizidine alkaloids as well as tannic acid and safrole. Pollutants such as pesticides and insecticides are known rodent carcinogens.


Both case-control and cohort studies have shown a strong association between chronic hepatitis B carrier rates and increased incidence of HCC. In Taiwanese male postal carriers who were hepatitis B surface antigen (HBsAg)-positive, a 98-fold greater risk for HCC was found compared to HBsAg-negative individuals. The incidence of HCC in Alaskan natives is markedly increased related to a high prevalence of HBV infection. HBV-based HCC may arise from rounds of hepatic destruction with subsequent proliferation and not necessarily from frank cirrhosis. The increase in Japanese HCC incidence rates in the past three decades is thought to be from hepatitis C. A large-scale intervention study sponsored by the World Health Organization (WHO) is currently underway in Asia involving HBV vaccination of the newborn. HCC in African blacks is not associated with severe cirrhosis but is poorly differentiated and very aggressive. Despite uniform HBV carrier rates among the South African Bantu, there is a ninefold difference in HCC incidence between Mozambicans living along the coast and inland. These differences are attributed to the additional exposure to dietary aflatoxin B 1 and other carcinogenic mycotoxins. A typical interval between HCV-associated transfusion and subsequent HCC is ~30 years. HCV-associated HCC patients tend to have more frequent and advanced cirrhosis, but in HBV-associated HCC, only half the patients have cirrhosis; the remainder have chronic active hepatitis (Chap. 300).

Other Etiologic Conditions

The 7585% association of HCC with underlying cirrhosis has long been recognized, more typically with macronodular cirrhosis in Southeast Asia but also with micronodular cirrhosis (alcohol) in Europe and the United States (Chap. 302). It is still not clear whether cirrhosis itself is a predisposing factor to the development of HCC or whether the underlying causes of the cirrhosis are actually the carcinogenic factors. However, ~20 % of U.S. patients with HCC do not have underlying cirrhosis. Several underlying conditions are associated with an increased risk for cirrhosis-associated HCC (Table 88-2), including hepatitis, alcohol abuse, autoimmune chronic active hepatitis, cryptogenic cirrhosis, and nonalcoholic steatohepatitis (NASH). A less common association is with primary biliary cirrhosis and several metabolic diseases, including hemochromatosis, Wilson's disease, α 1 -antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, glycogenesis types 1 and 3, citrullinemia, and orotic aciduria. The etiology of HCC in those 20% of patients who have no cirrhosis is unclear, and their HCC natural history not well-defined.

Other Etiologic Conditions The 75 – 85% association of HCC with underlying cirrhosis has long been

Clinical Features

Symptoms in HCC patients include abdominal pain, weight loss, weakness, abdominal fullness and swelling, jaundice, and nausea (Table 88-3). Presenting signs and symptoms differ somewhat between high- and low-incidence areas. The most common symptom is abdominal pain in high-risk areas, especially in South African blacks; by contrast, only 4050% of Chinese and Japanese patients present with abdominal pain. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor. Occasionally, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. In countries with an active surveillance program, HCC tends to be identified at an earlier stage when symptoms may be due only to the underlying disease. Jaundice is usually due to obstruction of the intrahepatic ducts by the underlying liver disease. Hematemesis may occur due to esophageal varices from the underlying portal hypertension. Bone pain is seen in 312% of patients, but necropsies show bone metastases in ~20% of patients. Patients may be asymptomatic.

Other Etiologic Conditions The 75 – 85% association of HCC with underlying cirrhosis has long been

Physical Signs

Hepatomegaly is the most common physical sign, occurring in 5090% of patients. Abdominal bruits are noted in 625%, and ascites occurs in 3060% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 1050% of patients, from unclear cause. The signs of chronic liver disease may be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins; it should be suspected in patients with tense ascites and a large tender liver (Chap. 302).

Paraneoplastic Syndromes

Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 312% of patients, and hypercholesterolemia in 1040%. A high percentage of patients have thrombocytopenia or leukopenia not caused by cancer infiltration of bone marrow, as in other tumor types.


Although the TNM (primary tumor, regional nodes, metastasis) staging system set up by the American Joint Commission for Cancers (AJCC) is sometimes used, the newer Cancer of the Liver Italian Program (CLIP) system is now popular as it takes cirrhosis into account, as does the Okuda system (Table 88-4). Other staging systems have been proposed and a consensus is needed. The best prognosis is stage I, solitary tumor <2 cm in diameter without vascular invasion. Adverse prognostic features include ascites, vascular invasion, and lymph node spread. Vascular invasion, in particular, has profound effects on prognosis and may be microscopic or macroscopic (visible on CT). Most large tumors have microscopic vascular invasion, so full staging can usually be made only after surgical resection. Stage III disease contains a mixture of lymph nodepositive and negative tumors. Stage III patients with positive lymph node disease have a poor prognosis, and few patients survive 1 year. The prognosis of stage IV is poor after either resection or transplantation, and 1-year survival is rare. A working staging system based entirely on clinical grounds that incorporates the contribution of the underlying liver disease was originally developed by Okuda et al. (Table 88-4). Patients with Okuda stage III have a dire prognosis, because they usually cannot be curatively resected and the condition of their liver typically precludes chemotherapy.

Physical Signs Hepatomegaly is the most common physical sign, occurring in 50 – 90% of patients.

a Extent of liver occupied by tumor.

Note: CLIP, Cancer of the Liver Italian Program

Approach to the Patient: Hepatocellular Carcinoma

History and Physical

The history is important in evaluating putative predisposing factors, including a history of hepatitis or jaundice, blood transfusion, or use of intravenous drugs. A family history of HCC or hepatitis should be sought, and a detailed social history taken to include job descriptions for industrial exposure to possible carcinogenic drugs as well as contraceptive hormones. Physical examination should include assessing stigmata of underlying liver disease such as jaundice, ascites, peripheral edema, spider nevi, palmar erythema, and weight loss. Evaluation of the abdomen for hepatic size, masses or ascites, hepatic nodularity and tenderness, and splenomegaly is needed, as is assessment of overall clinical performance status and psychosocial evaluation.

Serologic Assays

α-Fetoprotein (AFP) is a serum tumor marker in HCC; however, it is only increased in about half of U.S. patients. The other widely used assay is that for des-γ-carboxy prothrombin (DCP), a protein induced by vitamin K absence (PIVKA-2). This protein is increased in as many as 80% of HCC patients but may also be elevated in patients with vitamin K deficiency; it is always elevated after use of warfarin. It may predict for portal vein invasion. In a patient presenting with either a new hepatic mass or other indications of recent hepatic decompensation, carcinoembryonic antigen (CEA), vitamin B 12 , AFP, ferritin, PIVKA-2, and antimitochondrial Ab should be measured, and standard liver function tests should be performed, including prothrombin time (PT), partial thromboplastin time (PTT), albumin, transaminases, γ-glutamyl transpeptidase, and alkaline phosphatase. Decreases in platelet count and white blood cell count may reflect portal hypertension and associated hypersplenism. Hepatitis A, B, and C serology should be measured. If HBV or HCV serology is positive, quantitative measurements of HBV DNA or HCV RNA are needed.


An ultrasound examination of the liver is an excellent screening tool. The two characteristic vascular abnormalities are hypervascularity of the tumor mass (neovascularization or abnormal tumor-feeding arterial vessels) and thrombosis by tumor invasion of otherwise normal portal veins. To determine tumor size and extent and the presence of portal vein invasion accurately, a helical/triphasic CT scan of the abdomen and pelvis with fast contrast bolus technique should be performed to detect the vascular lesions typical of HCC. Portal vein invasion is normally detected as an obstruction and expansion of the vessel. A chest CT is used to exclude metastases. MRI can also provide detailed information, especially with the newer contrast agents. Ethiodol (Lipiodol) is an ethiodized oil emulsion retained by liver tumors that can be delivered by hepatic artery injection (515 mL) for CT imaging 1 week later. For small tumors, ethiodol injection is very helpful before biopsy because its histologic presence constitutes proof that the needle biopsied the mass under suspicion. A prospective comparison of triphasic CT, gadolinium-enhanced MRI, ultrasound, and fluorodeoxyglucose positron emission tomography (FDG-PET) scans demonstrated similar results for CT, MRI, and ultrasound; PET imaging was unsuccessful.

Pathologic Diagnosis

Histologic proof of the presence of HCC is obtained through a core liver biopsy of the mass under ultrasound guidance as well as random biopsy of the underlying liver. Bleeding risk is increased compared to other cancers because (1) the tumors are hypervascular, and (2) patients often have thrombocytopenia and decreased clotting factors. Bleeding risk is further increased in the presence of ascites. Tracking of tumor has been an uncommon problem. Fine-needle aspirates may provide sufficient material for diagnosis of cancer, but core biopsies are preferred. Tissue architecture must be examined to distinguish between HCC and metastatic adenocarcinoma; laparoscopic approaches can also be used. For patients suspected of having portal vein involvement, a core biopsy of the portal vein may be performed safely. If positive, this is regarded as an exclusion criterion for transplantation for HCC.

Screening High-Risk Populations

Screening has not been shown to save lives. Prospective studies in high-risk populations showed that ultrasound was more sensitive than AFP elevations. An Italian study in patients with cirrhosis identified a yearly HCC incidence of 3% but showed no increase in the rate of detection of potentially curable tumors with aggressive screening. Prevention strategies including universal vaccination against hepatitis viruses are more likely to be effective than screening efforts. Despite absence of formal guidelines, most practitioners obtain 6-monthly AFP levels and perform CT (or ultrasound) when following high-risk patients (HBV carriers, HCV cirrhosis, family history of HCC).

Hepatocellular Carcinoma: Treatment

Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. The clinical management choices for HCC can be complex (Fig. 88-1). The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ~4 months, with or without treatment. Treatment results from the literature are difficult to interpret. Survival is not always a measure of the efficacy of therapy because of the adverse effects on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, transplant surgeon, and medical oncologist, is important for the comprehensive management of HCC patients.

Hepatocellular Carcinoma: Treatment Most HCC patients have two liver diseases, cirrhosis and HCC, each of which