High-risk patients
Individuals at high risk should be screened for hepatocellular carcinoma using ultrasonography and serum α-fetoprotein levels. Screening increases the proportion of cancers that are resectable. However, a study comparing 6-month and 12-month survival intervals in a cohort of HCV-infected patients with hemophilia showed no substantial benefit to more frequent screening.

PATHOLOGY

Three morphologic patterns of hepatocellular carcinoma have been described: nodular, diffuse, and massive. Diffuse and massive types account for > 90% of cases. The nodular type usually has multiple lesions in both lobes.

Histologic arrangements
Several histologic arrangements have been identified: trabecular, compact, pseudoglandular or acinar, clear cell, and a fibrolamellar variant, which is associated with a relatively favorable prognosis and a younger age at diagnosis. The fibrolamellar variant is more commonly resectable and is not usually associated with infection and cirrhosis.

Staging and prognosis

The staging system for hepatocellular cancer is based on the number and size of lesions and the presence or absence of vascular invasion (Table 1). The Okuda staging system accounts for the degree of liver dysfunction and may better predict prognosis than the TNM staging system. However, the Okuda staging system does not adequately predict resectability and primarily predicts end-stage disease. Child-Pugh System and MELD scores measure liver function, and are not cancer staging systems. Because of the limited value of standard staging, the most important factors determining survival are technical resectability of lesions and degree of dysfunction of the normal liver. Groups in Spain, Italy, and China have created prognostic indices that may prove useful for making treatment decisions. The Barcelona Clinic Liver Cancer staging system was designed to be a diagnostic and treatment strategy to compare tumor stage, liver-function status, and performance status in its schema. Surgical resection is considered to be the best treatment for patients with solitary tumors and normal bilirubin levels who do not have portal hypertension. According to the Barcelona schema, patients may be considered for liver transplantation if the above criteria are not met or for ablation if the disease is at an early stage (solitary tumors < 5 cm or up to three nodules with no single nodule > 3 cm). Such patients will have a 5-year survival of 50% to 75%. Chemoembolization is appropriate for patients with intermediate-stage disease who are asymptomatic and have preserved liver function, with a bilirubin level < 3 mg/dL; their 3-year survival will be 50% or better. For patients with advanced disease, there are fewer established therapeutic options; enrollment in a research study may be the best of these.

Of the roughly 20% of patients who can undergo resection, factors associated with improved survival include curative resection, small tumor size, well differentiated tumors, and normal performance status. Cirrhosis, nodal metastases, and an elevated prothrombin time are indicative of a poor prognosis, as are male sex, age > 50 years, poor performance status, duration of symptoms < 3 months, tumor rupture, aneuploidy, high DNA synthesis rate, hypocalcemia, vascular invasion, and a high serum α-fetoprotein level.

Treatment

Surgery
Surgery is the form of treatment that offers the greatest potential for cure even though only a small minority of patients will actually be cured. Unfortunately, many patients whose disease is thought to be resectable are clinically understaged preoperatively.

Only stage I or II tumors have a significant likelihood of being resectable for cure. Resectability is limited by the functioning liver tissue at the completion of a negative margin operation. Therefore, even a large tumor may still be potentially resectable for cure. Moreover, contiguous involvement of large vessels (including the portal vein and inferior vena cava) or bile ducts does not automatically mitigate against a resection. Resection is contraindicated in patients with metastatic disease to non-portal nodes and in extrahepatic locations. The use of the Child-Pugh score and volumetric evaluation aids in assessment of resectability. For cirrhotic patients in whom less than 30%–35% of the liver remains at the completion of resection, operative treatment is contraindicated. Likewise, this is true for noncirrhotic patients where less than 25%–30% remains.