Reply to: “Non-invasive diagnosis of small nodules in cirrhosis”
Authors: Massimo Iavarone, Fabio Piscaglia
Journal: Journal of Hepatology (2013)

Non-invasive diagnosis of small nodules in cirrhosisJournal of HepatologyVol. 59Issue 6PreviewIn the recent issue of the Journal of Hepatology, Iavarone and colleagues [1] 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. Full-Text PDF Open AccessContrast 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 We 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]Iavarone M. Piscaglia F. Vavassori S. Galassi M. Sangiovanni A. Venerandi L. et al.Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis.J Hepatol. 2013; 58: 1188-1193Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. 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. We could not agree more on this remark, which is in agreement, and not in contrast, with our article. Indeed, we also previously reported that the radiological contrast imaging hallmark of HCC occurs in less than 25% of small well differentiated HCCs [[2]Iavarone M. Sangiovanni A. Forzenigo L.V. Massironi S. Fraquelli M. Aghemo A. et al.Diagnosis of hepatocellular carcinoma in cirrhosis by dynamic contrast imaging: the importance of tumor cell differentiation.Hepatology. 2010; 52: 1723-1730Crossref PubMed Scopus (56) Google Scholar]. To limit the rates of false negative diagnosis and thus the need for biopsies, we therefore suggested the sequential application of contrast imaging techniques, i.e., contrast enhanced CT-scan (CT), magnetic resonance (MRI) or ultrasound (CEUS), accompanied by histological characterization of the nodule whenever radiology fails to provide a diagnosis [[3]Sangiovanni A. Manini M.A. Iavarone M. Romeo R. Forzenigo L.V. Fraquelli M. et al.The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.Gut. 2010; 59: 638-644Crossref PubMed Scopus (307) Google Scholar]. As a matter of fact, this algorithm with CT and MRI as imaging techniques has been endorsed by the American Association for the Study of Liver Disease [[4]Bruix J. Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6473) Google Scholar] and partially by the European Association for the Study of the Liver [[5]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. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4445) Google Scholar]. With the addition of CEUS, the algorithm has been adopted in Italy [[6]Italian Association for the Study of the Liver (AISF) Position paper of the Italian Association for the Study of the Liver (AISF): the multidisciplinary clinical approach to hepatocellular carcinoma.Dig Liver Dis. 2013; ([epub ahead of print])Google Scholar] and in Asia [7Omata M. Lesmana L.A. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.Hepatol Int. 2010; 4: 439-474Crossref PubMed Scopus (820) Google Scholar, 8Kudo M. Izumi N. Kokudo N. Matsui O. Sakamoto M. Nakashima O. et al.Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.Dig Dis. 2011; 29: 339-364Crossref PubMed Scopus (619) Google Scholar]. Additionally, Dr. Fujita points out that the similar behavior of ICC smaller or larger than 3 cm is somehow unexpected. What is important to note is that most of our ICC were discovered during surveillance of cirrhotic patients, which means that even those beyond 3 cm (a minority of cases, less than 40%) were actually only rarely large (>5 cm), which could explain the possible discrepancy with previous reports in which tumors >3 cm were most often very large, implying a higher rate of intratumoral necrosis leading to atypical patterns. Moreover, we disagree on Dr. Fujita comments on the interpretation of the discrepancies in the diagnostic accuracy of contrast CT scan between ours and the study by Kim et al. concerning nodules less than 3 cm in size [[9]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.AJR Am J Roentgenol. 2007; 189: 1428-1434Crossref PubMed Scopus (104) Google Scholar]. We would like to think that such discrepancies reflect a misinterpretation of the study results, possibly owing to the adoption of different CT-scan techniques and application of different protocols of image acquisition, specifically, the lack of a delayed venous phase analysis in Kim study, i.e., the absence of an overview of all phases of CT-scan. Another problem with that study could relate to the small sample size of the study which included 8 ICCs smaller than 3 cm only, of which only 2 had central and peripheral enhancement pattern in the arterial phase, still in the absence of any detail regarding the corresponding venous pattern. Further complicating the interpretation of Kim and colleagues data, are the 5 nodules with a wash-out in the venous phase lacking any description of the arterial phase. Thus, we strongly believe that without an accurate description of the enhancement pattern of the nodules throughout the three vascular phases of contrast imaging, as we did in our study, it is rather impossible to establish a diagnosis of HCC ruling out ICC in cirrhosis [[1]Iavarone M. Piscaglia F. Vavassori S. Galassi M. Sangiovanni A. Venerandi L. et al.Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis.J Hepatol. 2013; 58: 1188-1193Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. In other words, our conclusion was that CT-scan poorly suffers from the risk of misdiagnosis of ICC for HCC, but also that ICC cannot be diagnosed by imaging and requires a biopsy. Therefore, we are in keeping with the comment of Dr. Fujita that HCC and ICC with atypical imaging features are likely difficult to be distinguished from other non-malignant lesions by the dynamic vascular enhancement pattern on CT-scan alone, which means that a biopsy is required. On practical ground, we also previously commented on the role of CEUS in this setting, which leads to the possibility of using ultrasonography to the same end [[10]Barreiros A.P. Piscaglia F. Dietrich C.F. Contrast enhanced ultrasound for the diagnosis of hepatocellular carcinoma (HCC): comments on AASLD guidelines.J Hepatol. 2012; 57: 930-932Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar], with the well-known limits of CEUS in terms of staging. In this connection, let us also elaborate on Dr. Fujita comment regarding the diagnostic role of Kupffer cell-specific contrast agent Sonazoid® in CEUS, which may be used for the non-invasive diagnosis of small nodules in cirrhosis. While it is well recognized that the diagnostic ability of this contrast medium relies on the lack of Kupffer cells in the mesenchymal meshwork of the malignant lesions, at variance with normal and cirrhotic liver parenchyma and most solid benign liver nodule, thereby resulting in a filling defect of the contrast during the post-vascular phase, yet, this CEUS fails to distinguish between the two different malignant tumors ICC and HCC [[11]Claudon M. Dietrich C.F. Choi B.I. Cosgrove D.O. Kudo M. Nolsøe C.P. et al.Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver-update 2012: a WFUMB–EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.Ultraschall Med. 2013; 34: 11-29Crossref PubMed Scopus (517) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.