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

Incidence
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 consumption
and 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.

Epidemiology
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 B1. 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.

Hepatitis
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 B1 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, 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.

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.
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.

Staging

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.

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

-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--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, -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.

Radiology

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.