2010-07-06 16:27:18 UTC

Should We Screen for Hepatocellular Carcinoma in Patients with Cirrhosis? If So, in Whom and How?

July 6, 2010

Hashem B. El-Serag, MD, MPH

Hashem B. El-Serag, MD, MPH

Professor of Medicine, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX  



The HCC epidemic

There is an epidemic of hepatocellular carcinoma (HCC) in the U.S., where HCC is currently the fastest growing cause of cancer-related death. As the incidence rates for HCC have tripled in the past two decades,1 the distribution of HCC has shifted towards white Hispanic and non-Hispanic individuals of younger ages (45 and 60 years). This increase is at least partially attributable to a rise in hepatitis C virus-related HCC.
Most patients with HCC are diagnosed at an advanced stage of disease when survival is poor (five-year survival less than 5 percent), except in patients who receive potentially curative therapy (liver transplant, surgical resection or ablation) where a considerable improvement in survival has been observed (five years range between 40 percent and 70 percent). However, population-based studies in the U.S. indicate that only approximately 10 percent of patients with HCC receive these treatments.2 Therefore, HCC surveillance has been advocated to detect HCC at an early stage, when critical treatment can be applied.

Does HCC surveillance work?

Practice guidelines from AASLD have recommended HCC surveillance for high-risk patients.3 In a randomized controlled trial (RCT) of nearly 19,000 hepatitis B virus (HBV)-infected patients in China, it was shown that HCC surveillance with serum alpha fetoprotein (AFP) and abdominal ultrasound at repeated six-monthly intervals improves survival — a 37 percent reduction in HCC-related mortality was reported.4 However, RCT (also in China) reported that surveillance for HCC is not beneficial. Several non-randomized trials, as well as observational studies, have found a survival benefit in those identified with small and early tumors, but these have their unavoidable biases.5 Collectively, the evidence to support the efficacy of HCC surveillance in high-risk groups is reasonable, but not very strong. Given the very low likelihood of new evidence from RCTs, I generally advocate as well as practice HCC surveillance in high-risk groups who have no severe or uncontrolled medical or psychiatric comorbidities.

Who and how?

I recommend HCC surveillance to patients with cirrhosis or advanced hepatic fibrosis irrespective of etiology, and in adult patients (older than 40 to 50 years) with HBV, irrespective of cirrhosis. I use a combination of AFP and liver ultrasound for HCC surveillance every six months, although a one-year interval may be equally effective. Ultrasound has approximately 60 percent to 65 percent sensitivity and greater than 90 percent specificity.6 At a serum cutoff level of 20 ng/mL, AFP has low sensitivity (25 percent to 65 percent) for detecting HCC and is therefore considered inadequate as the sole screening test; this is because only one third of patients with HCC have AFP levels higher than 100 ng/mL. Given the very low rates of HCC surveillance in community practice, I have not abandoned the use or the recommendation of using AFP (in combination with ultrasound), as it is easily used and interpreted and is widely available. Other tests, such as des-gamma carboxy prothrombin (DCP) and lectin-bound AFP (AFP-L3), are available but I have not started using them. In recent U.S. studies, AFP was more sensitive than DCP and AFP-L3 for the diagnosis of early-stage HCC, especially at cutoff of 10.9 ng/mL.7 A combination of these markers only marginally improves surveillance for early HCC (may increase sensitivity, but the specificity drops). CT and MRI — while excellent diagnostic tests — have not been tested for surveillance, and their high cost as well as possible harms (e.g., radiation with CT) are likely prohibitive in most practice settings.

Once a screening test is abnormal, the most reliable diagnostic tests are triple-phase helical CT and triple-phase, dynamic contrast-enhanced MRI; the latter is slightly better in the characterization and diagnosis of HCC. The hallmark of HCC during CT or MRI is the presence of arterial enhancement followed by delayed hypointensity of the tumor in the portal venous and delayed phases. Guidelines state that the diagnosis of HCC in a patient with cirrhosis can be confidently established if a focal hepatic mass greater than 2 cm is identified with a CT or MRI imaging technique that shows typical features for HCC. However, I generally require both tests to be suggestive of HCC if I am to avoid a biopsy. For focal hepatic mass with atypical or discrepant (between CT and MRI) imaging findings, a mass size of 1 to 2 cm or a focal hepatic mass detected in a non-cirrhotic liver should undergo a biopsy. A negative biopsy result does not completely rule out malignant disease, and the nodule should be further studied at three- to six-month intervals until it is seen to disappear, enlarge or display diagnostic characteristics of HCC. Nodules smaller than 1 cm should be followed with ultrasound at three- to six-month intervals. If over a period of two years growth has not been observed, routine surveillance at six-month intervals is suggested.

The extent of utilizing HCC surveillance in clinical practice is low. At least three studies found very low rates of screening among patients diagnosed with HCC. In the largest of these studies, Davila et al. (Hepatology 2010, in press) reported that among 541 patients diagnosed with HCC during 1994 to 2002 and with a prior diagnosis of cirrhosis, only 29 percent received annual surveillance in the three years before HCC diagnosis. The repetitive nature over relatively short periods of HCC surveillance, coupled with the need for prompt recall strategies, somewhat complicated diagnostic evaluation and the limited availability of potentially curative therapy, are likely obstacles in the face of an effective HCC surveillance program.


1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
2. El-Serag HB, Siegel AB, Davila JA, Shaib YH, Cayton-Woody M, McBride R, McGlynn KA. Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol 2006;44:158-66.
3. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-36.
4. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417-22.
5. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008;134:1752-63.
6. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, Marrero JA. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:37-47.
7. Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, Reddy KR, Harnois D, Llovet JM, Normolle D, Dalhgren J, Chia D, Lok AS, Wagner PD, Srivastava S, Schwartz M. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110-8.


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