Reply to: ‘‘Poor contrast enhanced ultrasonography! There is no limit to its decline in the diagnosis of hepatocellular carcinoma on cirrhosis!’’
Authors: Alejandro Forner, Ramón Vilana, Manel Solé, Jordi Bruix
Journal: Journal of Hepatology (2015)

Poor contrast enhanced ultrasonography! There is no limit to its decline in the diagnosis of hepatocellular carcinoma on cirrhosis!Journal of HepatologyVol. 62Issue 6PreviewWe have read with great interest the article by Forner and co-workers, who described the use of contrast-enhanced ultrasound (CEUS) to define the priority for diagnostic work-up of hepatocellular carcinoma (HCC) nodules <2 cm arising in cirrhotic livers during ultrasound (US) surveillance [1]. Full-Text PDF Open AccessLack of arterial hypervascularity at contrast-enhanced ultrasound should not define the priority for diagnostic work-up of nodules <2 cmJournal of HepatologyVol. 62Issue 1PreviewCurrent guidelines recommend diagnostic work-up for nodules >1 cm detected during screening for hepatocellular carcinoma (HCC). This implies that patients with benign conditions may undergo unnecessary evaluation and those with small nodules may be intervened too early, leading to overdiagnosis. Since increased arterial vascularization is the hallmark of malignancy, its detection by contrast-enhanced ultrasound (CEUS) could become the signal to proceed with diagnosis confirmation. The aim was to assess if HCCs <2 cm without arterial hyperenhancement by baseline CEUS have a benign evolutionary profile, suggesting that diagnosis and invasive treatment could be delayed until detection of an overt malignant profile, associated with increased vascularization. Full-Text PDF We would like to thank Giorgio et al. for their interest in our recent study about the role of contrast-enhanced ultrasound (CEUS) in the diagnostic process of small nodules detected during screening US [[1]Forner A. Vilana R. Bianchi L. Rodríguez-Lope C. Reig M. García-Criado M.Á. et al.Lack of arterial hypervascularity at contrast-enhanced ultrasound should not define the priority for diagnostic work-up of nodules <2 cm.J Hepatol. 2015; 62: 150-155Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. In this study, the main conclusion was that the absence of contrast hyperenhancement during the arterial phase at CEUS does not predict a less malignant profile and thus, priority for diagnostic work-up and treatment should not differ according to contrast profile at CEUS. The letter by Giorgio et al. criticised some methodological aspects of our study and they claim that CEUS still has an important role in the diagnostic recall strategy upon the detection of a nodule by screening US. The first concern raised in the letter was the use of the non-invasive diagnostic criteria by MRI after 2007 as gold standard for HCC conclusive diagnosis. Since the non-invasive HCC diagnosis by imaging has been extensively and prospectively validated, and fully accepted by the main scientific societies [2Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6721) Google Scholar, 3EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4656) Google Scholar] and the Spanish guidelines for HCC management [[4]Forner A. Ayuso C. Isabel Real M. Sastre J. Robles R. Sangro B. et al.Diagnosis and treatment of hepatocellular carcinoma.Med Clin (Barc). 2009; 132: 272-287Crossref PubMed Scopus (68) Google Scholar], Giorgio et al. will surely agree with us that delaying the HCC diagnosis and treatment until histological confirmation is ethically questionable. In addition, we would like to highlight that in only 14 out of 119 (11.7%) HCC lesions the final diagnosis was based only on imaging criteria, and all 18 HCC lesions with absence of arterial contrast hyperenhancement detection at CEUS were histologically confirmed. Moreover, Giorgio et al. summarize some studies aimed to evaluate the diagnostic accuracy of CEUS alone or associated to CT/MRI for HCC diagnosis, emphasizing that CEUS showed the best diagnostic accuracy. This is not surprising since the combination of imaging techniques is always associated with better specificity than when just only one imaging technique, whatever one is used. Furthermore, Giorgio et al. questioned the feasibility of cytology for diagnosing intrahepatic cholangiocarcinoma and dysplastic nodules. However, the samples were processed in cell-block; this allows the assessment of cyto-histological findings and the use of immunohistochemistry markers, which permits the diagnosis of both entities [5Sempoux C. Jibara G. Ward S.C. Fan C. Qin L. Roayaie S. et al.Intrahepatic cholangiocarcinoma: new insights in pathology.Semin Liver Dis. 2011; 31: 49-60Crossref PubMed Scopus (149) Google Scholar, 6Kojiro Masamichi Alves Venancio Badve Sunil Balabaud Charles Bedosa Pierre Bhathal Prithi et al.International Consensus Group for Hepatocellular NeoplasiaThe International Consensus Group for Hepatocellular Neoplasia consists ofPathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2008; 49: 658-664Crossref Scopus (637) Google Scholar]. Regarding the feasibility of CEUS, in the 5 cases (3%) mentioned the nodule was deeply located with a poor sonographic window and despite that the nodule was previously visualized by US, a reliable CEUS was not possible. This is not surprising since our study was prospective and the inclusion criteria was the identification of a solitary nodule smaller than 2 cm by screening US and not by CEUS exploration, and expert radiologists will agree that not all US visible nodules can be explored by CEUS. Giorgio et al. also claim data regarding the diagnostic accuracy of MRI. We would like to stress that our study is not aimed to assess the diagnostic accuracy of MRI, or compared it with CEUS, since this information has been previously reported [7Forner A. Vilana R. Ayuso C. Bianchi L. Solé M. Ayuso J.R. et al.Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.Hepatology. 2008; 47: 97-104Crossref PubMed Scopus (818) Google Scholar, 8Rimola J. Forner A. Tremosini S. Reig M. Vilana R. Bianchi L. et al.Non-invasive diagnosis of hepatocellular carcinoma ⩽2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI.J Hepatol. 2012; 56: 1317-1323Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. As requested, in our cohort of patients, MRI did not identify the target nodule in 25 out of 168 patients (14.8%), but only 3 of these nodules were HCC. Contrarily, MRI identified other nodules in 39 patients, 7 of them being additional HCC focus unidentified by CEUS. Finally, Giorgio et al. suggest that most recurrence might be due to de novo HCC arising from an oncogenic cirrhotic liver. However, 2 out of 3 recurrences after resection and 2 distal recurrence after ablation were detected within the first 6 months, and 2 recurrences in ablated patients appeared in the treated nodule (and in one case also associated with distal recurrence). These 6 cases (out of 10 cases of recurrence) reflect a malignant nature with invasive potential. In summary, we hope that these comments help to clarify some of the controversies raised by Giorgio et al., while also exposing that the evaluation and management of the patients as per risk of cancer progression and death, should not be different from the process with CEUS positive patients. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.