Gastroenterology
Volume 140, Issue 1 , Pages 358-360, January 2011
Silvia Tremosini, Jordi Bruix
published online 17 November 2010
Sangiovanni A, Manini MA, Iavarone M, et al. (1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy). The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638–644.
The study by Sangiovanni et al prospectively evaluates the sensitivity, specificity and diagnostic accuracy of contrast-enhanced ultrasound (CEUS), computed tomography (CT), and magnetic resonance (MRI) for the diagnosis of hepatocellular carcinoma (HCC) after detecting de novo liver nodules detected in patients with compensated cirrhosis undergoing surveillance with ultrasound (US). The gold standard for the diagnosis of HCC has been fine needle biopsy and the typical radiologic pattern for the radiologic diagnosis of HCC was hypervascularization in the arterial phase with portal/venous washout.
Sixty-four patients were enrolled in this study, with a total of 67 liver nodules detected under US. The size of the lesions ranged from 0.8 to 2.7 cm (mean, 1.6). All nodules were examined by CEUS-CT-MRI and fine needle biopsy. On histologic examination, 66% were HCC, 3% were intrahepatic cholangiocarcinomas, and 31% were macroregenative nodules or low dysplastic nodules. Biopsies were repeated in all undiagnosed cases; benign lesions underwent an enhanced radiologic follow-up. Nine nodules (26%) had the typical vascular pattern of HCC demonstrated by CE-US, 16 (47%) by CT, and 14 (44%) by MRI. None of the nodules histologically classified as non-HCC showed the typical vascular pattern of HCC. The sensitivity of the combination of 2 imaging techniques (CEUS+CT, CEUS+MRI, CT+MRI) was 21%, 18%, and 26%, respectively, and the specificity was 100%. The rates of positive findings with 2 concordant techniques were comparable in terms of sensitivity, specificity, and accuracy with 3 imaging techniques, in combination. In 1- to 2-cm nodules, the typical radiologic vascular pattern for HCC was more often obtained by CT and MRI alone than CEUS+MRI (P = .027 and P = .031, respectively) or CEUS+CT (P = .038 and P = .043, respectively). CT and MRI had comparable sensitivities for the typical vascular pattern of HCC (44% and 44%), whereas CEUS had a lower sensitivity (26%). The typical vascular pattern of HCC was identified in 65% by a single technique, versus 35% by ≥2 techniques. This finding suggests that a confident diagnosis could be done by a single imaging technique showing the typical vascular pattern. This would significantly reduce the need for fine needle biopsy investigations, without modifying the costs calculated on the basis of the Italian National Health System.
Comment
HCC-related mortality can be reduced by prevention of the acquisition of risk factors (such as viral infection, excessive alcohol intake, or obesity) or by achieving its early detection with application of potentially curative treatment such as resection, liver transplantation, and ablation. In all instances, the smaller the HCC at diagnosis, the higher the likelihood of long-term success after therapy. Accordingly, the goal of screening programs in the population at risk (namely, patients with cirrhosis of any etiology) is to detect and treat HCC at an early stage and, specifically, when it has not grown >2 cm in diameter. Although tumor marker (alfa fetoprotein) determination is not useful for this purpose (Aliment Pharmacol Ther 2009;30:37–47), US is able to detect such small nodules. The critical point at that time is how to confirm diagnosis before treatment indication. Image-guided biopsy is known to have a relevant rate of false negatives and, in addition, is associated with risks of bleeding and potential malignant seeding. As a consequence, HCC diagnosis is frequently established by imaging criteria that may vary across centers. The EASL (J Hepatol 2001;35:421–430) and the American Association for the Study of Liver Diseases (AASLD) guidelines (Hepatology 2005;42:1208–1236) provided a set of definitions that would establish homogeneous definitions to be used for this purpose in patients with cirrhosis, whereas HCC diagnosis in patients without this condition would still require a positive biopsy. Radiologic diagnosis is based on the contrast enhancement pattern at dynamic imaging. Thereby, intense contrast uptake in the arterial phase followed by contrast washout in the venous/delayed phase is considered specific for HCC. In large tumors, imaging characterization is not a major difficulty requiring major expertise, but in nodules <2 cm, the recognition of the specific profile is more challenging. To avoid false-positive diagnoses because of equivocal findings, the AASLD 2005 guidelines allowed HCC >2 cm to be diagnosed with a single dynamic technique, whereas in HCC <2 cm, coincidental findings by 2 of them (CEUS, CT, MRI) were requested. Otherwise, a biopsy would be mandatory. Several studies have validated this diagnostic approach and allowed a refinement of the criteria. In a prospective study (Hepatology 2008;47:97–104) in nodules <2 cm, it was shown that the diagnostic strategy was correct, but that the need to have coincidental findings by 2 techniques significantly reduced the sensitivity of the criteria to around 33%. At the same time, it was shown that using MRI alone the sensitivity would be almost doubled and the specificity would still be almost 100%. In a separate study (Hepatology 2010;51:2010–2029), it was shown that CEUS may incur a false-positive HCC diagnosis in patients with intrahepatic cholangiocarcinoma, a malignancy that is also more frequently observed in patients with cirrhosis and has a completely different treatment strategy. Therefore, some cholangiocarcinomas exhibit the “arterial uptake followed by washout” profile that is ascribed to HCC; fortunately, MRI does not incur in such misdiagnosis (Hepatology 2009;50:791–798).
Finally, the study by Sangiovanni et al shows that the combination of techniques to establish diagnosis increases the economic burden of the clinical process (more imaging techniques and biopsies are needed before therapy), although the diagnostic accuracy that is gained is marginal. Similar findings have been generated in a similar study conducted in Canada (Hepatology 2008;48:362A) and as a whole all this dataset has provided the background to update the AASLD guidelines in 2010 (available from: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf). In them, the recommendation for HCC diagnosis allows a single imaging technique to be used among CT and MRI, and if it is nondiagnostic, the decision has to choose between the second technique or a biopsy is needed. MRI has been extensively validated but according to the specifics of the clinical care setting and profile of the patients, physicians will have to decide whether a negative result by the first of them to be used should prime the use of the second one, or if it is more effective to decide to take a biopsy with all its limitations and risks.
Having exposed the background for the novel strategy for HCC diagnosis, it is worth considering to which extent it will be feasible to establish diagnosis at the ideal size of <2 cm. The transition from low- to high-grade dysplasia and very early HCC usually occurs below this cutoff. Two types of HCC <2 cm can be distinguished: Early HCC and progressed HCC. Early HCC has a vaguely nodular appearance and is well differentiated. It corresponds to the very early HCC stage of the Barcelona Clinic Liver Cancer classification or the carcinoma in situ entity proposed by others (Hepatology 1998;28:1241–12469). Because of the absence of microvascular invasion and the lower proliferative profile, very early HCC has a longer time to recurrence and a higher 5-year survival rate compared with progressed HCC. This has a distinctly nodular pattern and is mostly moderately differentiated, often with evidence of microvascular invasion. On imaging, very early HCC has not yet developed the arterial network that translates into the imaging profile used for diagnosis. Indeed, in a recent study by the same Italian group (Hepatology 2010;52:1723–1730) it has been shown that small, well-differentiated HCC fail to present the imaging diagnostic pattern more frequently than in tumors that have a moderate-to-poor differentiation degree.
Taking into account these comments, it is clear that the target of screening programs that aim to provide long-term survival free of disease recurrence is to detect HCC at the very early stage, but diagnostic confirmation by MRI or CT will remain unmet in a large number of patients. Thus, the nodule will be detected by screening US, but no final imaging diagnosis will be feasible because the same appearance can correspond to a benign condition. Biopsy is to be requested, but again the diagnostic sensitivity is limited in very early HCC because it is composed of well-differentiated hepatocytes that do not easily allow the distinction from nonmalignant nodules. Even within expert pathologists, there is some degree of discrepancy after development of consensus criteria (Hepatology 2009;49:658–664). Immunostaining for different proteins such as Glypican 3, Heat Shock Protein 70, and Glutamyne Synthetase (J Hepatol 2009;50:746–754) may provide some reinforcement for HCC suspicion, but well-established criteria for unequivocal diagnosis need development and validation. Gene signatures have also been proposed to solve the difficulty (Gastroenterology 2006;131:1758–1767); however, validation is lacking. Ultimately, most proposals have been raised using surgical tissues, but in the clinical arena we have only the limited tissue sample obtained by biopsy; in tiny lesions, the puncture may not only sample the nodule, but also—or just—the surrounding tissue. Hopefully, new radiology techniques with organ-specific contrasts will help to overcome the current imitation and the same is expected in the field of tumor markers by the use of proteomics or metabolomics.
It should be stressed that these comments should not be seen as a disappointment or a pessimistic view, but rather the opposite. Some years ago, the usual concept was that HCC was impossible to be diagnosed at a curative stage and that the effort was useless. Now, we are struggling with very small nodules to increase the impact of the treatment options that we have. Facing challenges and framing the difficulties should be seen as the first step for their solution.
PII: S0016-5085(10)01616-1
doi:10.1053/j.gastro.2010.11.012
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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