San Francisco—Patients at high risk for liver cancer should undergo surveillance with ultrasound at six-month intervals and any new lesions 1 cm or larger should be evaluated by computed tomography (CT) or magnetic resonance imaging (MRI).

This recommendation was issued by the American Association for the Study of Liver Diseases (AASLD) in its latest guideline on the surveillance of hepatocellular carcinoma (HCC) and was reviewed in a lecture by Tae Kyoung Kim, MD, at the 2012 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

“Proper imaging techniques are crucial for achieving a successful screening program for hepatocellular carcinoma,” said Dr. Kim, of the University of Toronto, in Ontario.

The AASLD practice guideline recommends ultrasound because it is inexpensive, noninvasive, well accepted by patients and can be repeated every six months without risk. Additionally, ultrasound shows high specificity—greater than 90%. However, sensitivity varies from 65% to 80%, Dr. Kim pointed out. “High sensitivity can be only achieved by imposing rigorous operator standards and using proper equipment,” he said.

For new nodules smaller than 1 cm, a repeat ultrasound should be performed in three months. Any new nodule 1 cm or larger detected on the surveillance ultrasound should undergo diagnostic testing according to the updated AASLD guidelines, Dr. Kim said.

“For nodules larger than 2 cm, imaging diagnosis is reliable; for those 1 to 2 cm, imaging diagnosis may be challenging,” he added.

Appropriate diagnostic tests include dynamic contrast-enhanced CT and MRI. If one imaging test is inconclusive, the other imaging test or a biopsy should be performed. Contrast-enhanced ultrasound has proven useful, but is not approved for liver imaging in the United States.

A diagnosis of HCC can be made without biopsy if the imaging shows arterial-phase hyper-vascularity and later washout. “This is diagnostic of HCC,” Dr. Kim said. “With proper imaging techniques, there is no need for biopsy, and the MRI not only shows hypervascularity and washout but other things that can be useful in diagnosis.”

Hemangiomas are frequently detected during HCC surveillance and can be confidently diagnosed by dynamic contrast-enhanced imaging, according to Dr. Kim. Peripheral nodular enhancement, progressive central fill-in and lack of washout are the signs.

Biopsy is needed only if the imaging findings are indeterminate. The biopsy diagnosis of equivocal nodules, such as a high-grade dysplastic nodule or well differentiated HCC, remains a challenge, Dr. Kim said, noting that a small biopsy specimen may not contain portal tracts with stromal invasion and that other features and immunohistochemical markers are prone to sampling error.
Diagnostic imaging tests for HCC are highly specific. Theses tests have moderate sensitivity for small (1-2 cm) nodules. The requirement for two coincident positive imaging exams only decreases the sensitivity; a single exam shows comparable specificity, Dr. Kim noted.

“Dynamic CT/MRI has a high specificity for diagnosing HCC, more than 95%; however, the sensitivity is moderate (50%-70%). Therefore, the development of new diagnostic criteria should focus primarily on improving sensitivity, while maintaining specificity,” he said.

Improving Diagnostic Sensitivity
MRI with a liver-specific contrast agent, such as gadoxetic acid (Gd-EOB-DTPA) or gadobenate dimeglumine (Gd-BOPTA), has been shown to improve the sensitivity of HCC diagnostic imaging.
Dr. Kim led a study of 96 patients evaluated with Gd-BOPTA MRI. Investigators identified 116 nodules of 1 to 2 cm in size; they found 43 HCCs and 73 benign nodules. The investigators assessed MRI findings for signal intensity at each sequence, and several diagnostic criteria were developed.
A univariate analysis revealed four imaging features associated with HCC: arterial phase hyperintensity, portal or delayed phase hypointensity (washout), hyperintensity on T2-weighted images and hepatobiliary phase hypointensity. A multivariable analysis showed that arterial phase hyperintensity and washout were associated with HCC (adjusted odds ratio [OR], 17.1 and 11.7, respectively). The use of these features (fitting AASLD criteria) or the existence of three or more of these findings was associated with a sensitivity of 77% and specificity of 95%. Dr. Kim concluded that the incorporation of these alternative MRI criteria can improve the sensitivity of HCC diagnosis compared with the use of the features recommended in the AASLD practice guideline alone.
Dr. Kim suggested that Gd-EOB-DTPA be added to the diagnostic algorithm for HCC, in particular, to be performed on patients with hypovascularity in the arterial phase or hypervascularity in the arterial phase and no washout.

Norah Terrault, MD, MPH, of the University of California, San Francisco, commented on the need for more widespread surveillance of patients at risk for HCC.
“Overall, surveillance is not done at a level we would like to see. At-risk patients are often not recognized as being at risk.

“Much of the surveillance is dedicated to patients known to have cirrhosis, but a physician may be following a patient with hepatitis C without knowing if that patient has cirrhosis,” she continued. “We have to ask whether patients have cirrhosis, and if we can make that distinction we should initiate surveillance. Although the techniques described by Dr. Kim are not uniformly available, most community gastroenterologists who identify an area of concern can access these imaging studies through referral.”


Dr. Kim has received research funding from Bracco Diagnostics. Dr. Terrault reported no relevant conflicts of interest.