Non-invasive diagnosis of small nodules in cirrhosis

Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosisJournal of HepatologyVol. 58Issue 6PreviewContrast enhanced computed tomography (CT-scan) is a standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. This technique, however, is not validated to exclude intrahepatic cholangiocarcinoma (ICC) which may develop in patients with cirrhosis, as well. Full-Text PDF Reply to: “Non-invasive diagnosis of small nodules in cirrhosis”Journal of HepatologyVol. 59Issue 6PreviewWe appreciate Dr. Fujita comments on our study on the diagnostic accuracy of contrast enhanced CT-scan to evaluate the dynamic vascular enhancement pattern of intrahepatic cholangiocarcinoma (ICC) in cirrhotic patients [1]. One comment is that lack of the radiological hallmark of hepatocellular carcinoma (HCC, wash-in followed by wash-out) does not preclude the diagnosis of an HCC with an atypical vascular behavior and that the typical hallmark is less often found in small and well differentiated tumors. Full-Text PDF Open Access In the recent issue of the Journal of Hepatology, Iavarone and colleagues [[1]Iavarone M. Piscaglia F. Vavassori S. Galassi M. Sangiovanni A. Venerandi L. et al.Contrast enhancement CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis.J Hepatol. 2013; 58: 1188-1193Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar] report the dynamic vascular enhancement pattern of mass-forming intrahepatic cholangiocarcinoma (ICC) on helical CT in patients with cirrhosis. The authors conclude that contrast enhanced CT-scan may be able to be used as a sole imaging technique for non-invasive diagnosis of nodules developing in cirrhosis irrespective of nodule size, because the radiological hallmark of early homogenous enhancement in the arterial phase and wash-out in the delayed phase in hepatocellular carcinoma (HCC) was not observed in any of the ICCs. The absence of contrast wash-out in delayed phases in ICCs has been shown also in a study using magnetic resonance imaging (MRI) for 25 patients with cirrhosis [[2]Rimola J. Forner A. Reig M. Vilana R. de Lope C.R. Ayuso C. et al.Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma.Hepatology. 2008; 50: 791-798Crossref Scopus (217) Google Scholar]. These findings do not mean that a nodule not having the radiological hallmark of HCC is not HCC. In a prospective study that evaluated small nodules (1–3 cm) in cirrhosis, using enhanced helical CT-scan and contrast enhanced ultrasonography (CEUS) in accordance with the 2001 European Association for the Study of the Liver (EASL) guidelines, among 72 nodules, 14 were hypovascular on both CT-scan and CEUS, which were all less than 2 cm in diameter, and 5 of which proved to be HCC by biopsy [[3]Bolondi L. Gaiani S. Celli N. Golfieri R. Francesco Grigioni W. Leoni S. et al.Characteristics of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma.Hepatology. 2005; 42: 27-34Crossref PubMed Scopus (362) Google Scholar]. Of 63 well-differentiated HCCs with a mean size of 1.57 cm, only 8 (13%) had the radiological hallmark of HCC on multi-detector CT [[4]Yoon S.H. Lee J.M. So Y.H. Hong S.H. Kim S.J. Han J.K. et al.Multiphasic MDCT enhancement pattern of hepatocellular carcinoma smaller than 3 cm in diameter: tumor size and cellular differentiation.Am J Roentogenol. 2009; 193: W482-W489Crossref PubMed Scopus (98) Google Scholar]. Thus, the radiological hallmark of large HCCs is not necessarily that of small HCCs. In the study by Iavarone and colleagues, tumor size did not significantly affect CT-scan appearance of ICC, which is not in keeping with a previous study, where for tumors smaller than 3 cm in diameter, there was no significant difference between the enhancement pattern of ICC and that of HCC [[5]Kim S.J. Lee J.M. Han J.K. Kim K.H. Lee J.Y. Choi B.I. Peripheral mass-forming cholangiocarcinoma in cirrhotic liver.Am J Roentogenol. 2007; 189: 1428-1434Crossref PubMed Scopus (104) Google Scholar]. The discrepancy between the studies might be attributable to the different characteristics of ICCs registered and/or different techniques for contrast enhanced CT-scan. It should be noted that smaller nodules have lesser risk of malignancy, leading to the recommendation of follow-up of a nodule smaller than 1 cm in the guidelines. Following the publication of a study showing that early enhancement in the arterial phase followed by wash-out in the delayed phase on CEUS did not discriminate between HCC and ICC [[6]Vilana R. Forner A. Bianchi L. Garcia-Criado A. Rimola J. Rodriguez de Lope C. et al.Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.Hepatology. 2010; 51: 2020-2029Crossref PubMed Scopus (237) Google Scholar], the American Association for Study of Liver Diseases (AASLD) updated the guidelines, in which one imaging technique (CT-scan or MRI) excluding CEUS is advocated for diagnosing even small liver nodules. Another reason for withdrawal of CEUS from the diagnostic algorithm in the AASLD guidelines is unavailability of specific contrast agents producing microbubbles for ultrasonography in the United States, but which are available in Europe, Canada, and Asia [[7]Tan C.H. Low S.C. Thng C.H. APASL and AASLD consensus guidelines on imaging diagnosis of hepatocellular carcinoma: a review.Int J Hepatol. 2011; 2011: 519783Crossref PubMed Google Scholar]. In the updated EASL guidelines, two imaging techniques are recommended for diagnosing small liver nodules although one imaging technique is also acceptable, and the role of CEUS is controversial in non-invasive diagnosis of HCC in cirrhosis [[8]European Association for the Study of the Liver European Organisation for Research and Treatment of Cancer EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2013; 56: 908-943Abstract Full Text Full Text PDF Scopus (4508) Google Scholar]. In the Asian Pacific Association for the Study of the Liver guidelines, CEUS on its own is an accepted imaging modality for HCC diagnosis [[7]Tan C.H. Low S.C. Thng C.H. APASL and AASLD consensus guidelines on imaging diagnosis of hepatocellular carcinoma: a review.Int J Hepatol. 2011; 2011: 519783Crossref PubMed Google Scholar]. The vascular enhancement pattern shown by contrast enhanced CT-scan appears to be dependent on tumor activity and the amount of interstitial space in the fibrous stroma of an individual ICC [[9]Chung Y.E. Kim M.J. Park Y.N. Choi J.Y. Pyo J.Y. Kim Y.C. et al.Varying appearances of cholangiocarcinoma: radiologic pathologic correlation.Radiographics. 2009; 29: 683-700Crossref PubMed Scopus (277) Google Scholar], implying varying appearances of ICC. In fact, in the study by Iavarone and colleagues [[1]Iavarone M. Piscaglia F. Vavassori S. Galassi M. Sangiovanni A. Venerandi L. et al.Contrast enhancement CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis.J Hepatol. 2013; 58: 1188-1193Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar], variable vascular patterns of ICC in early and delayed phases were observed. Other than HCCs and ICCs, a variety of non-neoplastic, preneoplastic, and neoplastic lesions develop in the cirrhotic liver, such as focal fatty infiltration, arterioportal shunt, immature abscesses, macro-regenerative nodules, hepatic tuberculosis, focal nodular hyperplasia, dysplastic nodules, hemangiomas, and metastatic nodules from other sites [9Chung Y.E. Kim M.J. Park Y.N. Choi J.Y. Pyo J.Y. Kim Y.C. et al.Varying appearances of cholangiocarcinoma: radiologic pathologic correlation.Radiographics. 2009; 29: 683-700Crossref PubMed Scopus (277) Google Scholar, 10Dietrich C.F. Liver tumor characterization – comments and illustrations regarding guidelines.Ultraschall Med. 2012; 33: S22-S30Crossref PubMed Scopus (47) Google Scholar]. HCC and ICC with atypical imaging features are likely difficult to be distinguished from such lesions by the dynamic vascular enhancement pattern on CT-scan alone. Using Kupffer cell-specific and/or hepatocyte-specific contrast agents, additional CEUS or MRI may be warranted for non-invasive diagnosis of small nodules in cirrhosis. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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