Screening for hepatocellular carcinoma has become part of the standard of care for the management of patients with cirrhosis.
1
This practice is endorsed by the American Association for Study of Liver Disease (AASLD)1
and the European Association for Study of the Liver (EASL).2
In this issue of The American Journal of Medicine Stravitz et al3
address the performance of hepatocellular carcinoma screening in their area and find it lacking.The majority of gastroenterologists in the US provide hepatocellular carcinoma screening for their patients.
4
However the data from Stravitz et al3
and others4
suggest that surveillance is not widely undertaken outside of gastroenterology practices. They examined the effect of screening for hepatocellular carcinoma on access to liver transplantation. Patients with hepatocellular carcinoma were stratified into a “standard of care” group who received at least 1 imaging study in the year prior to diagnosis of hepatocellular carcinoma. A second group was known to be cirrhotic, but did not receive any imaging in the preceding year, and the third group was not known to be cirrhotic prior to presentation. Nearly 70% of those in the “standard of care” group had hepatocellular carcinoma that was suitable for liver transplantation, compared to only 35% of those without prior imaging and 18% of those not known to be cirrhotic. Despite this, only 32% of the “standard of care” group actually received a new liver, compared with 13% in the no imaging group and 7% of the third group. Only 9% of tumors in this study were diagnosed as single lesions.The study highlighted some glaring deficiencies in the care of patients with liver disease. Only 61% of those with hepatocellular carcinoma had received any form of surveillance. Seventeen percent of the patients were known to be cirrhotic, yet did not receive surveillance. Eighteen percent were not even known to be cirrhotic.
There have now been several studies showing that surveillance is underutilized in the US.
5
, 6
Leykum et al5
and Davila et al6
have shown that no more than 28% of patients diagnosed with hepatocellular carcinoma underwent regular surveillance prior to diagnosis, and that patients who were screened regularly had a 10-fold greater chance of being offered curative therapy, with an associated improvement in survival.The AASLD has endorsed hepatocellular carcinoma surveillance using ultrasound as the only surveillance test.
1
α-Fetoprotein is seldom diagnostically elevated in lesions smaller than 2 cm, and therefore is of limited use as a surveillance test. Yet El Serag et al7
showed that most patients who receive some form of surveillance receive only α-fetoprotein testing. Not only is surveillance underutilized, but appropriate treatment of hepatocellular carcinoma is not offered as frequently as it should be.7
Compared with results obtained elsewhere, even the “standard of care” group had disappointing results. In Europe and Japan, 50-60% of hepatocellular carcinomas are single lesions at presentation, usually smaller than 2 cm.
8
It is not really clear why the US lags behind the rest of the world in this aspect of the management of cirrhosis. Possible explanations include that the hepatitis C epidemic hit the US about 20 years later than Japan and Europe, where they have had to cope with high hepatocellular carcinoma incidence rates for many years, whereas in the US, although rates are rising, they are still quite low. Another possibility lies in the distrust of the value of ultrasound in cirrhosis. The AASLD practice guidelines
1
suggest that surveillance should be performed at 6-month intervals using ultrasound. This has recently been validated.9
Many centers in the US believe that detection of small hepatocellular carcinoma in a cirrhotic liver is not possible using ultrasound. Our experience in Toronto, and experience in Europe and Japan, shows that it is possible to diagnose early hepatocellular carcinoma on ultrasound despite cirrhosis, and that this can be achieved in the majority of patients.Many liver transplant centers prefer computed tomography (CT) scanning for surveillance. It is not practical to provide CT surveillance for the large numbers of patients with cirrhosis who are not on transplant waiting lists. In addition, exposure to the high levels of radiation associated with CT scans might be acceptable for patients with a life-threatening condition, ie, those on the transplant waiting list, but it might not be acceptable for patients who might have to undergo many years of screening with no certainty that hepatocellular carcinoma will ever develop. Finally, there can be a sense of futility, because historically hepatocellular carcinoma has had such a poor outcome.
The final issue raised by Stravitz et al
3
is the poor recognition of cirrhosis in patients at risk for this complication. The risk of hepatocellular carcinoma is increased long before ascites or variceal bleeding develops, before the liver function tests become abnormal, and before radiological changes are evident. However, there are a number of noninvasive ways of determining the severity of fibrosis and of suspecting that cirrhosis might be present; these include inversion of the aspartate aminotransferase/alanine aminotransferase ratio.10
The platelet count falls, initially within the normal range, but subsequently to below normal.11
A number of indices have been developed based on readily available blood tests that can predict a high likelihood of cirrhosis being present, including the AST-to-Platelet Ratio Index,11
and proprietary panels such as Fibrotest and Fibrosure.12
Within the last decade hepatocellular carcinoma has gone from a largely incurable disease to one in which cure is possible, at least theoretically, in the majority of patients. However, for this to happen several factors have to be in place. Patients at risk need to be identified and to undergo regular surveillance to identify small liver lesions. A diagnostic algorithm to determine whether these lesions are hepatocellular carcinoma or not has been devised
1
and should be followed. It is no longer acceptable to simply monitor lesions that are larger than 1 cm to see whether they develop characteristics of hepatocellular carcinoma. The larger the hepatocellular carcinoma when diagnosed, the lower the likelihood of cure.13
Decision analysis has demonstrated that the strategy of observation to determine growth of the lesion is inferior to a strategy of biopsy with appropriate management of hepatocellular carcinoma or appropriate follow-up if hepatocellular carcinoma cannot be diagnosed.14
Lesions that are not classical need to be investigated with biopsy, but the pathologist should be attuned to the use of markers to demonstrate the earliest stages of hepatocellular carcinoma. This might not be possible on morphology alone. Finally potentially curative therapy is available for small lesions and needs to be applied.Thus, regular surveillance should play a crucial role in reducing mortality from hepatocellular carcinoma. It should be widely instituted and its results aggressively acted upon. The tools to do this are available and are not expensive. In 2008, presentation with a hepatocellular carcinoma larger than 3 cm should not happen and represents a failure of medical management. Given the current state of knowledge, failure to provide surveillance for patients with identified risk factors for hepatocellular carcinoma who develop hepatocellular carcinoma is likely a cause for legal action.
References
- Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236
- Clinical management of hepatocellular carcinoma.J Hepatol. 2001; 35: 421-430
- Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome.Am J Med. 2008; 121: 119-126
- Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey.Am J Gastroenterol. 1999; 94: 2224-2229
- Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival.Clin Gastroenterol Hepatol. 2007; 5: 508-512
- Utilization of screening for hepatocellular carcinoma in the United States.J Clin Gastroenterol. 2007; 41: 777-782
- Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study.J Hepatol. 2006; 44: 158-166
- Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival.Liver Int. 2006; 26: 543-551
- Semiannual surveillance for hepatocellular carcinoma improved patient survival compared to annual surveillance (Korean experience).Hepatology. 2004; 6: 368
- Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease.Arch Intern Med. 2003; 163: 218-224
- APRI: an easy and validated predictor of hepatic fibrosis in chronic hepatitis C.J Clin Gastroenterol. 2006; 40: 535-542
- Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease.BMC Gastroenterol. 2006; 6: 6
- Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360
- Management of solitary 1 cm to 2 cm liver nodules in patients with compensated cirrhosis: a decision analysis.Can J Gastroenterol. 2007; 21: 491-500
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© 2008 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
