Lancet 2003;362:1907; Postgrad Med J 2000;76:4

Cause: (Nejm 1999;340:798) The vast majority of cases of hepatocellular carcinoma (HCC) are due to chronic hep B or chronic hep C infection (RR = 100-200). In the U.S., where infection rates are lower, viral hepatitis still accounts for 71% of HCC (Hepatology 1993;18:1326). Cirrhosis of any cause is a risk. The cirrhosis of hep B, hep C, or hemochromatosis is associated with a RR of > 100. Other causes of cirrhosis (eg, alcohol, PBC, Wilson’s, α₁-AT deficiency, autoimmune disorders) are associated with a much lower RR of 2-5. Glycogen storage disease, tyrosinemia, and porphyria cutanea tarda are causative. Aflatoxin (a toxin from Aspergillus found in a variety of stored foods like peanuts, corn, and rice), anabolic steroids, and thorium dioxide (an obsolete radiographic contrast medium) are apparent toxic causes. The fibrolamellar variant occurs in younger pts lacking chronic liver disease (Am J Gastro 2009;104:2617).

Epidem: The incidence of HCC varies widely by region and correlates with chronic hep B infection. The highest rates are in Asia and sub-Saharan Africa, where 10-25% of the population is infected by hep B and the HCC incidence is 30-120/100,000 per yr in men. In Japan, HCC is the third-leading cause of cancer death, largely due to hep C (Nejm 1993;328:1797). Incidence in southern Europe is 5-10/100,000 per yr (Brit J Surg 1998;85:1319). The incidence in the U.S. has risen over the past 3 decades from 1.4/100,000 to 2.4/100,000 per yr, and the disease is occurring at a younger age. This is probably a result of the increasing incidence of hep C infection. Blacks are affected twice as often as whites, and men 3 times as often as women (Nejm 1999;340:745).

Pathophys: The mechanisms by which viral hepatitis causes HCC are unknown. Chronic inflammation and increased hepatocyte turnover are probably important. There may be direct oncogenic effects of the viruses as well. Aflatoxin induces p 53 mutations, allowing unrestrained cell proliferation (Lancet 1991;338:1356).

Sx: Weight loss, RUQ pain, malaise, and jaundice are the typical sx of advanced disease. Sudden clinical decompensation in a pt with established cirrhosis is a second common presentation. With the advent of detection by screening, many pts are asymptomatic.

Si: RUQ mass, hepatomegaly, irregular liver edge, bruit over the liver, stigmata of chronic liver disease (p 26), tumor-induced fever.

Crs: The tumor grows locally, compromises hepatic function, invades blood vessels, and spreads to lungs and then to distant sites. Median survival without rx is 3-6 months after the onset of sx. Five-yr survival of pts treated with transplant for small lesions is similar to the survival of pts undergoing transplant for any reason. Five-yr survival for those undergoing successful resection may be as high as 50% (see Rx). Five-yr survival in the fibrolamellar variant is better, as these pts do notgenerally have chronic liver disease and can have wide resections (66%).

Cmplc: Paraneoplastic syndromes are frequent. These include hypercholesterolemia (11%), hypoglycemia (2.8%), hypercalcemia (1.8%), and erythrocytosis (2.5%) (Cancer 1999;86:799).

Diff Dx: The differential is that of a hepatic mass (p 250). The suggested approach to dx varies with the size of the lesion, and guidelines have been developed based on this (Hepatology 2005;42:1208). Nodules found on US <1 cm should be followed at 3- to 6-month intervals for 2 yr, and if stable routine surveillance is done. Nodules of 1-2 cm found on US are investigated with 2 dynamic contrast studies such as MRI and CT scan. If both scans show a typical appearance for HCC (hypervascular with washout in the portal venous phase), then the pt can be treated as HCC. If both scans do notshow this appearance, then the lesion is biopsied. If the nodule is greater than 2 cm at the initial dx and has typical HCC features on 1 dynamic imaging test or an AFP >200 ng/mL, then bx is notneeded. If the imaging is nondiagnostic or the liver is notcirrhotic, bx is done. A cavernous hemangioma should be ruled out prior to bx by MRI or by tagged rbc scan if the initial imaging study suggests that possibility. The dx should always be considered when a pt with cirrhosis has a clinical deterioration.