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Hepatocellular Carcinoma

by Steven K. Herrine, MD

Hepatocellular carcinoma (hepatoma) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific. Diagnosis is based on α-fetoprotein (AFP) levels, imaging tests, and sometimes liver biopsy. Screening with periodic AFP measurement and ultrasonography is sometimes recommended for high-risk patients. Prognosis is poor when cancer is advanced, but for small tumors that are confined to the liver, ablative therapies are palliative and surgical resection or liver transplantation is sometimes curative.

Hepatocellular carcinoma is the most common type of primary liver cancer, with an estimated 23,000 new cases and about 14,000 deaths expected in 2012 in the US. However, it is more common outside the US, particularly in East Asia and sub-Saharan Africa; incidence generally parallels geographic prevalence of chronic hepatitis B virus (HBV) infection.

Etiology

Hepatocellular carcinoma is usually a complication of cirrhosis.

The presence of HBV increases risk of hepatocellular carcinoma by > 100-fold among HBV carriers. Incorporation of HBV-DNA into the host’s genome may initiate malignant transformation, even in the absence of chronic hepatitis or cirrhosis.

Other disorders that cause hepatocellular carcinoma include cirrhosis due to chronic hepatitis C virus (HCV) infection, hemochromatosis, and alcoholic cirrhosis. Patients with cirrhosis due to other conditions are also at increased risk.

Environmental carcinogens may play a role; eg, ingestion of food contaminated with fungal aflatoxins is believed to contribute to the high incidence of hepatocellular carcinoma in subtropical regions.

Symptoms and Signs

Most commonly, previously stable patients with cirrhosis present with abdominal pain, weight loss, right upper quadrant mass, and unexplained deterioration. Fever may occur. In a few patients, the first manifestation of hepatocellular carcinoma is bloody ascites, shock, or peritonitis, caused by hemorrhage of the tumor. Occasionally, a hepatic friction rub or bruit develops.

Occasionally, systemic metabolic complications, including hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia, occur. These complications may manifest clinically.

Diagnosis

  • α-Fetoprotein (AFP) measurement

  • Imaging (CT, ultrasonography, or MRI)

Clinicians suspect hepatocellular carcinoma if

  • They feel an enlarged liver.

  • Unexplained decompensation of chronic liver disease develops.

  • An imaging test detects a mass in the right upper quadrant of the abdomen during an examination done for other reasons, especially if patients have cirrhosis.

However, screening programs enable clinicians to detect many hepatocellular carcinomas before symptoms develop.

Diagnosis is based on AFP measurement and an imaging test. In adults, AFP signifies dedifferentiation of hepatocytes, which most often indicates hepatocellular carcinoma; 40 to 65% of patients with the cancer have high AFP levels (> 400 μg/L). High levels are otherwise rare, except in teratocarcinoma of the testis, a much less common tumor. Lower values are less specific and can occur with hepatocellular regeneration (eg, in hepatitis). Other blood tests, such as AFP-L3 (an AFP isoform) and des-γ–carboxyprothrombin, are being studied as markers to be used for early detection of hepatocellular carcinoma.

Depending on local preferences and capabilities, the first imaging test may be contrast-enhanced CT, ultrasonography, or MRI. Hepatic arteriography is occasionally helpful in equivocal cases and can be used to outline the vascular anatomy when ablation or surgery is planned.

If imaging shows characteristic findings and AFP is elevated, the diagnosis is clear. Liver biopsy, often guided by ultrasonography or CT, is sometimes indicated for definitive diagnosis.

Staging

If a hepatocellular carcinoma is diagnosed, evaluation usually includes chest CT without contrast, imaging of the portal vein (if not already done) by MRI or CT with contrast to exclude thrombosis, and sometimes bone scanning.

Various systems can be used to stage hepatocellular carcinoma; none is universally used. One system is the TNM system, based on the following (see Table: Staging Hepatocellular Carcinoma*):

  • T: How many primary tumors, how big they are, and whether the cancer has spread to adjacent organs

  • N: Whether the cancer has spread to nearby lymph nodes

  • M: Whether the cancer has metastasized to other organs of the body

Numbers (0 to 4) are added after T, N, and M to indicate increasing severity.

Staging Hepatocellular Carcinoma*

Stage

Designation

Description

I

T1, N0, M0

Single tumor (any size) with no invasion of blood vessels

II

T2, N0, M0

Single tumor (any size) with invasion of blood vessels

or

Several tumors that are all < 5 cm

IIIA

T3a, N0, M0

Several tumors with at least one > 5 cm

IIIB

T3b, N0, M0

One or more tumors of any size with invasion of a major branch of the portal or hepatic vein

IIIC

T4, N0, M0

Tumor or tumors of any size with invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum

IVA

Any T, N1, M0

Tumor or tumors of any size with spread to nearby (regional) lymph nodes

IVB

Any T, Any N, M1

Tumor or tumors of any size with distant metastasis

*Adapted from the American Joint Committee on Cancer (AJCC): AJCC Cancer Staging Manual, ed. 7. New York, Springer, 2010.

Other scoring systems include the Okuda and the Barcelona-Clinic Liver Cancer staging systems. In addition to tumor size, local extension, and metastases, these systems incorporate information about the severity of liver disease.

The TNM system may predict prognosis better than other systems for patients who are having tumor resection (and possibly transplantation), whereas the Barcelona system may predict prognosis better for patients who are not having surgery (for more information, see Staging systems in hepatocellular carcinoma ).


Screening

An increasing number of hepatocellular carcinomas are being detected through screening programs. Screening patients with cirrhosis is reasonable, although this measure is controversial and has not been shown to reduce mortality. One common screening method is ultrasonography every 6 or 12 mo. Many experts advise screening patients with long-standing hepatitis B even when cirrhosis is absent.


Treatment

  • Transplantation if tumors are small and few

For single tumors < 5 cm or 3 tumors that are all 3 cm and that are limited to the liver, liver transplantation results in as good a prognosis as liver transplantation done for noncancerous disorders. Alternatively, surgical resection may be done; however, the cancer usually recurs.

Ablative treatments (eg, hepatic arterial chemoembolization, yttrium-90 microsphere embolization [selective internal radiation therapy, or SIRT], drug-eluting bead transarterial embolization, radiofrequency ablation) provide palliation and slow tumor growth; they are used when patients are awaiting liver transplantation.

If the tumor is large (> 5 cm), is multifocal, has invaded the portal vein, or is metastatic (ie, stage III or higher), prognosis is much less favorable (eg, 5-yr survival rates of about 5% or less). Radiation therapy is usually ineffective. Sorafenib appears to improve outcomes.

Prevention

Use of vaccine against HBV (see Hepatitis B Vaccine) eventually decreases the incidence, especially in endemic areas. Preventing the development of cirrhosis of any cause (eg, via treatment of chronic hepatitis C, early detection of hemochromatosis, or management of alcoholism) can also have a significant effect.

Key Points

  • Hepatocellular carcinoma is usually a complication of cirrhosis and is most common in parts of the world where hepatitis B is prevalent.

  • Consider the diagnosis if physical examination or an imaging test detects an enlarged liver or if chronic liver disease worsens unexpectedly.

  • Diagnose hepatocellular carcinoma based on the AFP level and liver imaging results, and stage it using chest CT without contrast, portal vein imaging, and sometimes bone scanning.

  • Consider liver transplantation if tumors are small and few.

  • Prevention involves use of the hepatitis B vaccine and management of disorders that can cause cirrhosis.

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