Eleonora Terzi

Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma.

The aim of this review is to present the similarities and differences between the latest guidelines for noninvasive diagnosis of hepatocelullar carcinoma (HCC) of American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), and Japanese Society of Hepatology. All the four guidelines defined a typical HCC vascular pattern as the homogeneous hyperenhancement (wash-in) in the arterial phase followed by wash-out in the venous or late phase. The AASLD and EASL guidelines accept only four-phase computed tomography and dynamic contrast magnetic resonance imaging (MRI) for HCC diagnosis, whereas the APASL and Japanese guidelines also accept contrast-enhanced ultrasound (CEUS). Regarding CEUS, the APASL guidelines accept the use of Levovist or Sonazoid as contrast agents, whereas the Japanese guidelines accept only the use of Sonazoid. The AASLD and EASL guidelines recommend using only extracellular contrast agents such as gadolinium for MRI, whereas the APASL guidelines also included the use of super paramagnetic iron oxid-MRI, and the Japanese guidelines recommended the use of gadolinium-ethoxybenzyl-diethylentriamine pentaacetic acid-MRI. The AASLD and EASL guidelines propos a diagnostic algorithm starting from the tumor size, whereas the APASL and Japanese guidelines recommend an algorithm starting from arterial tumor vascularity (hyper- or hypovascular in the arterial phase). In conclusion, important differences exist among the Western and Eastern guidelines for noninvasive HCC diagnosis.

Conditional Survival after Hepatic Resection for Hepatocellular Carcinoma in Cirrhotic Patients

Purpose: Survival estimates are commonly reported as actuarial survival after the first observation, but future survival probabilities can change over time. Conditional survival is a measure of prognosis for patients who have sometimes already survived several years since diagnosis; however, data on conditional survival for cirrhotic patients, resected for hepatocellular carcinoma (HCC), are lacking. Experimental Design: Clinical data from 300 consecutive cirrhotic patients who underwent HCC resection were reviewed and the actuarial survival estimated. The 5-year conditional survival was calculated as CS = S(x + 5)/S(x) and represents the probability of surviving an additional 5 years, given that the patient has already survived x years. Results: The 3-, 5-, and 10-year survival rates were, respectively, 69.0%, 57.7%, and 25.3% and were lower in cases of portal hypertension, Model for End-stage Liver Disease (MELD) score ≥9, United Network for Organ-Sharing T3 tumor, GIII–GIV tumors, and microscopic vascular invasion. However, the 5-year conditional survival calculation showed that patients resected for more advanced (T3) tumors or with adverse histologic features will experience the same survival probabilities as patients with less advanced tumors or favorable histology from the third year after surgery onward, as they had probably escaped recurrence from intrahepatic metastases. Patients who underwent repeated hepatectomy for recurrence presented higher conditional survival. Conclusions: Conditional survival showed that the impact of different variables influencing survival is not linear over time after hepatic resection. Information derived from conditional survival can be used to better manage patients with HCCs, including the potential future setting of adjuvant therapies and the choice of listing, or not, for transplantation resected patients not recurring within 2 years. Clin Cancer Res; 18(16); 4397–405. ©2012 AACR.

Characterization of primary and recurrent nodules in liver cirrhosis using contrast-enhanced ultrasound: which vascular criteria should be adopted?

PURPOSE To assess the impact of different vascular patterns at contrast-enhanced ultrasound (CEUS) on the characterization of small liver nodules (10-30 mm) in cirrhosis and to determine whether primary nodules and recurrent nodules (after a previously treated hepatocellular carcinoma) display variations in enhancement pattern. MATERIALS AND METHODS A total of 135 cirrhotic patients were evaluated. A diagnosis of hepatocellular carcinoma (HCC) was established according to AASLD Guidelines, based on imaging (computed tomography and/or magnetic resonance) or liver biopsy. All patients underwent CEUS. Different CEUS patterns were evaluated in terms of diagnostic accuracy: HYPER-HYPO: Arterial hyperenhancement followed by washout (hypoechoic appearance compared with surrounding parenchyma) in late phase; HYPER-ISO: Arterial hyperenhancement followed by isoenhancement (isoechoic appearance) in late phase; ISO-ISO: Isoenhancement in all vascular phases. RESULTS A total of 155 consecutive primary (n = 90) or recurrent (n = 65) nodules were detected. HCC was diagnosed in 127 nodules (71 primary, 56 recurrent). A characteristic HYPER-HYPO CEUS pattern was revealed in 52/127 (40.9%) HCCs (31 primary, 21 recurrent) giving a positive predictive value (PPV) of 98% (97% primary, 100% recurrent) and an accuracy of 51% (54% primary, 46% recurrent). A HYPER-ISO pattern was noted in 46 HCCs (31 primary, 15 recurrent). Assuming this pattern to also be indicative of HCC, the PPV and accuracy were 94% (93% primary, 97% recurrent) and 77% (84% primary, 68% recurrent), respectively. An ISO-ISO pattern was present in 29 HCCs (9 primary, 20 recurrent) and 22 non-HCCs (14 primary, 8 recurrent). CONCLUSION These data confirm that the HYPER-HYPO pattern at CEUS is definitely diagnostic for HCC in cirrhosis and that the HYPER-ISO pattern has a similar PPV, indicating that this pattern is highly suspicious for HCC. The ISO-ISO pattern was found in > 50% of recurrent nodules and indicates a high risk of HCC.

Treatment of hepatocellular carcinoma in Child-Pugh B patients.

BACKGROUND The frequency with which patients in Child-Pugh B having hepatocellular carcinoma are treated following the international guidelines according to the Barcelona Clinic Liver Cancer stages is unknown. AIMS To investigate treatment allocation for Child-Pugh B patients in different tumour stages, with particular interest in the intermediate stage. METHODS Patients were retrospectively identified from a consecutively collected series. Treatment was carried out primarily according to the guidelines. RESULTS Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were 46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7% respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In the intermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child-Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediate patients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P=0.048). Survival of the intermediate stage patients undergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8. CONCLUSIONS Approximately half of the intermediate stage patients can undergo locoregional treatment with good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting that this tumour stage be refined.

Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure

BACKGROUND No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. METHODS Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. RESULTS Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). CONCLUSIONS Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study.

The ART score is not effective to select patients for transarterial chemoembolization retreatment in an Italian series.

Background: The ART score (a point score for the assessment of retreatment with transarterial chemoembolization, TACE) has been recently developed in Austria to differentiate patients who may benefit from multiple sessions of TACE for hepatocellular carcinoma (HCC) treatment. The primary aim of the study was to test the validity of the ART score in an Italian study cohort. The secondary aims were to evaluate overall survival (OS) and clinical determinants of improved survival in patients treated with multiple TACE sessions. Methods: The ART score and the clinical outcome of 51 consecutive patients with HCC submitted to multiple TACE sessions from April 2002 to December 2009 were retrospectively analyzed. Results: Median OS was 26.0 months (95% confidence interval 18.4-33.6) with 1-, 3- and 5-year survival rates of 75, 33 and 11%, respectively). Thirty-three patients had an ART score of 0-1.5 and in 18 it was ≥2.5, but in our patient series, the ART score was not found to be a predictor of survival (p = 0.173). At univariate analysis, tumor extent (uni- vs. bilobar: 34.0 vs. 9.0 months; p < 0.001), Child-Pugh score before the second TACE (A vs. B7 vs. B8-9: 26.0 vs. 16.0 vs. 5.0 months; p = 0.005) and Child-Pugh score increase between the first and second TACE (absent vs. + 1 point vs. + ≥2 points: 27.0 vs. 4.0 vs. 5.0 months; p < 0.001) were statistically related with survival. At multivariate analysis, only Child-Pugh score increase remained a significant predictor of worse survival (p = 0.001, hazard rate = 11.6). Conclusions: The ART score was not found to work as an objective tool to guide TACE retreatment in our Italian patient series, only the Child-Pugh score increase was an independent predictor of a shorter survival.

Efficacy of radioembolization according to tumor morphology and portal vein thrombosis in intermediate–advanced hepatocellular carcinoma

PURPOSE We analyzed overall survival (OS) following radioembolization according to macroscopic growth pattern (nodular vs infiltrative) and vascular invasion in intermediate-advanced hepatocellular carcinoma (HCC). METHODS Between September 2005 and November 2013, 104 patients (50.0% portal vein thrombosis [PVT], 29.8% infiltrative morphology) were treated. RESULTS Median OS differed significantly between patients with segmental and lobar or main PVT (p = 0.031), but was 17 months in both those with patent vessels and segmental PVT. Median OS did not differ for infiltrative and nodular HCC. Median OS was prolonged in patients with a treatment response at 3 months (p = 0.023). Prior TACE was also a significant predictor of improved OS. CONCLUSION A further indication for radioembolization might be infiltrative HCC, since OS was similar to nodular types.

Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules

Background & Aims. The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned for the risk of false positive diagnosis in case of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS LI-RADS) classifying lesions at risk for HCC investigated by CEUS. Aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. Methods. A total of 1006 nodules in 848 patients with chronic liver disease at risk for HCC collected in 5 Italian centers were retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥ 1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 seconds after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (=506) or histology (n=500). Results. Median size was 2 cm. Of 1006 nodules, HCC were 820 (81%), cholangiocarcinoma 40 (4%), regenerative nodules (±dysplastic) 116 (11%). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96=47%) and the LR-4 202 (HCC 173=87%). Conclusions. The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non invasive diagnosis.BACKGROUND & AIMS The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS®]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. METHODS A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). RESULTS The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). CONCLUSIONS The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. LAY SUMMARY This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis.

Ongoing challenges in the diagnosis of hepatocellular carcinoma

ABSTRACT In 2001, the European Association for the Study of the Liver (EASL) endorsed the possibility of achieving a non-invasive diagnosis of Hepatocellular Carcinoma (HCC) for the first time. Since then, various refinements of the criteria and techniques capable of achieving this diagnosis and the role of plasma and tissue oncomarkers have been reported in the literature and have been accepted to different extents in various geographical areas. Such tools can also potentially imply prognostic significance. The present article critically discusses some of the most relevant and debated challenges which have emerged in this field, including the role of contrast-enhanced ultrasound, and of hepatocyte-specific magnetic resonance contrast agents, the pitfall of transient hepatic attenuation differences, the reliability of biopsy and the status of biomarkers.

Contents Vol. 32, 2014

Europe F. Bazzoli, Bologna M.W. Büchler, Heidelberg P. Dítě, Brno J.E. Domínguez-Muñoz, Santiago de Compostela P. Ferenci, Vienna J.-P. Galmiche, Nantes G. Gasbarrini, Bologna S.D. Ladas, Athens L. Lundell, Stockholm K.E.L. McColl, Strathblane P. Michetti, Lausanne C. O’Morain, Dublin G. Rogler, Zürich Z. Tulassay, Budapest G.N.J. Tytgat, Amsterdam Asia Pacifi c M. Asaka, Sapporo J.-Y. Fang, Shanghai K.M. Fock, Singapore K.L. Goh, Kuala Lumpur J.D. Sollano, Manila K. Sugano, Shimotsuke J.Y. Sung, Hong Kong N.J. Talley, Callaghan, N.S.W.