Abstract

The incidence of hepatocellular carcinoma (HCC) has been rising worldwide over the last 20 years and is expected to increase until 2030 in some countries including the United States, while in other countries, such as Japan, the incidence has started to decline [1.Petrick J.L. Kelly S.P. Altekruse S.F. et al.Future of hepatocellular carcinoma incidence in the United States forecast through 2030.J Clin Oncol. 2016; 34: 1787-1794Crossref PubMed Scopus (172) Google Scholar, 2.White D.L. Thrift A.P. Kanwal F. et al.Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012.Gastroenterology. 2017; 152: 812-820.e5Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 3.Globoscan. http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.aspGoogle Scholar]. In 2012, liver cancer represented the fifth most common cancer in men (554 000 new cases) and the ninth in women (228 000 new cases) and the second most common cause of cancer-related death (746 000 estimated deaths), worldwide [3.Globoscan. http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.aspGoogle Scholar]. The incidence varies from 3/100 000 in Western countries, to 78.1/100 000 in Mongolia, with the highest incidence in Africa and Asia, mapping the geographical distribution of viral hepatitis B (HBV) and hepatitis C (HCV), the most important causes of chronic liver disease and HCC [4.Ferlay J. Soerjomataram I. Dikshit R. et al.Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: e359-e386Crossref PubMed Scopus (18040) Google Scholar]. In Europe, in 2012 the estimated incidence rate was 10.0 in men and 3.3 in women per 100 000, respectively, while the estimated mortality rate was 9.1 and 3.3 per 100 000 in men and women, respectively [3.Globoscan. http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.aspGoogle Scholar]. The incidence of HCC shows a strong male preponderance and increases progressively with advancing age in all populations. The association of chronic liver disease and HCC represents the basis for preventive strategies, including universal vaccination at birth against HBV [I, A] [5.Chang M.H. Chen C.J. Lai M.S. et al.Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group.N Engl J Med. 1997; 336: 1855-1859Crossref PubMed Scopus (1489) Google Scholar] and early antiviral treatment of viral HBC and HCV [III, A] [6.Papatheodoridis G.V. Dalekos G.N. Yurdaydin C. et al.Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir.J Hepatol. 2015; 62: 363-370Abstract Full Text Full Text PDF PubMed Google Scholar, 7.Cardoso A.C. Moucari R. Figueiredo-Mendes C. et al.Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis.J Hepatol. 2010; 52: 652-657Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 8.Waziry R. Hajarizadeh B. Grebely J. et al.Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.J Hepatol. 2017; 67: 1204-1212Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar]. The prevalence of obesity and type 2 diabetes has greatly increased in the past decades, leading to a rising incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis and, eventually, HCC [9.Yatsuji S. Hashimoto E. Tobari M. et al.Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C.J Gastroenterol Hepatol. 2009; 24: 248-254Crossref PubMed Scopus (238) Google Scholar]. HCC related to NAFLD/NASH is probably underestimated [10.Bugianesi E. Leone N. Vanni E. et al.Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar] and is expected to rise in the future, possibly overtaking the other aetiologies in some areas of the world [11.Noureddin M. Rinella M.E. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.Clin Liver Dis. 2015; 19: 361-379Abstract Full Text Full Text PDF PubMed Google Scholar]. A significant proportion of patients with NAFLD/NASH-associated HCC do not have histological evidence of cirrhosis [12.Paradis V. Zalinski S. Chelbi E. et al.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.Hepatology. 2009; 49: 851-859Crossref PubMed Scopus (387) Google Scholar]. The control of other risk factors for chronic liver disease and cancer is more difficult to implement, such as cutting down on the consumption of alcohol and programmes aiming at a healthier lifestyle in the light of the obesity pandemic [13.El-Serag H.B. Richardson P.A. Everhart J.E. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans.Am J Gastroenterol. 2001; 96: 2462-2467Crossref PubMed Google Scholar, 14.Marrero J.A. Fontana R.J. Fu S. et al.Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol. 2005; 42: 218-224Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar]. In Africa, reduction of exposure to aflatoxin B1, especially in HBV-infected individuals, may lower the risk of HCC. HCC may evolve from subclasses of adenomas; in 1 cm diameter using one of these two modalities [III, A]. Compared with multiple detector CT (MDCT), multiphasic MRI offers a moderate increase in sensitivity for diagnosing HCC based on the typical vascular hallmarks [III, B] [24.Lee Y.J. Lee J.M. Lee J.S. et al.Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging-a systematic review and meta-analysis.Radiology. 2015; 275: 97-109Crossref PubMed Scopus (248) Google Scholar, 25.Ye F. Liu J. Ouyang H. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and multidetector-row computed tomography for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis.Medicine (Baltimore). 2015; 94: e1157.Crossref PubMed Scopus (0) Google Scholar, 26.Hanna R.F. Miloushev V.Z. Tang A. et al.Comparative 13-year meta-analysis of the sensitivity and positive predictive value of ultrasound, CT, and MRI for detecting hepatocellular carcinoma.Abdom Radiol (NY). 2016; 41: 71-90Crossref PubMed Scopus (92) Google Scholar, 27.Tang A. Bashir M.R. Corwin M.T. et al.Evidence supporting LI-RADS major features for CT- and MR imaging-based diagnosis of hepatocellular carcinoma: a systematic review.Radiology. 2018; 286: 29-48Crossref PubMed Scopus (124) Google Scholar]. Serum AFP has no role in the diagnostic algorithm [III, A]. Based on techniques such as diffusion-weighted imaging and the use of hepatobiliary contrast agents, MRI may identify and stratify nodules as high-risk nodules (either HCC not displaying the typical imaging hallmarks features or high-grade dysplastic nodules) [IV, B] [28.Kumada T. Toyoda H. Tada T. et al.Evolution of hypointense hepatocellular nodules observed only in the hepatobiliary phase of gadoxetate disodium-enhanced MRI.AJR Am J Roentgenol. 2011; 197: 58-63Crossref PubMed Scopus (120) Google Scholar, 29.Golfieri R. Grazioli L. Orlando E. et al.Which is the best MRI marker of malignancy for atypical cirrhotic nodules: hypointensity in hepatobiliary phase alone or combined with other features? Classification after Gd-EOB-DTPA administration.J Magn Reson Imaging. 2012; 36: 648-657Crossref PubMed Scopus (66) Google Scholar, 30.Bartolozzi C. Battaglia V. Bargellini I. et al.Contrast-enhanced magnetic resonance imaging of 102 nodules in cirrhosis: correlation with histological findings on explanted livers.Abdom Imaging. 2013; 38: 290-296Crossref PubMed Scopus (72) Google Scholar, 31.Yoon J.H. Lee J.M. Yang H.K. et al.Non-hypervascular hypointense nodules >/=1 cm on the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging in cirrhotic livers.Dig Dis. 2014; 32: 678-689Crossref PubMed Scopus (0) Google Scholar]. However, the impact of identification of additional nodules by diffusion-weighted imaging and hepatobiliary contrast agents on the therapeutic algorithm remains unclear and switching to palliative treatments after identification of potential premalignant nodules by these new techniques should be avoided. New imaging criteria for HCC diagnosis called CT/MRI LI-RADS® v2018 (Liver Imaging Reporting and Data System) include arterial phase enhancement, tumour size, washout, enhancing capsule and threshold growth and have been proposed to improve the diagnosis of HCC, especially for small nodules (Table 2) [32.Mitchell D.G. Bruix J. Sherman M. Sirlin C.B. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions.Hepatology. 2015; 61: 1056-1065Crossref PubMed Scopus (284) Google Scholar, 33.CT/MRI LI-RADS ® v2018. https://www.acr.org/-/media/ACR/Files/RADS/LI-RADS/LI-RADS-2018-Core.pdf?la=enGoogle Scholar].Table 2CT/MRI LI-RADS diagnostic tableUntreated observation without pathological proof in patient at high risk for HCCDefinitely benign: LR-1Probably benign: LR-2Not categorisable, due to image degradation or omission: LR-NCDefinite tumour in vein (TIV): LR-TIVProbably or definitely malignant but not HCC specific (e.g. if targetoid): LR-MOtherwise, use CT/MRI diagnostic table belowIntermediate probability of malignancy: LR-3Probably HCC: LR-4Definitely HCC: LR-5Arterial phase hyperenhancement (APHE)No APHEAPHE (not rim)Observation size (mm) 60 s) washout of a mild degree. Angiography and fluorodeoxyglucose-positron emission tomography (FDG-PET) scan are not recommended for HCC diagnosis. When tumour biopsy fails to demonstrate a correlate for a focal lesion, a second tumour biopsy, a different contrast-enhanced imaging modality or (if amenable) direct resection of the lesion may be considered according to tumour size [IV, B]. If the patient is a candidate for resection that can be carried out with an acceptable morbidity and mortality risk, then either biopsy or direct resection may be an option. Pathological diagnosis of HCC is based on a biopsy or a surgical specimen of the tumour. Concomitant analysis of the non-tumour liver may be useful in order to define its status and potential causative diseases. Assessment of resection and explant specimen follows the valid TNM (tumour, node, metastasis) classification including resection margin evaluation. Usually tumour grade is provided, but currently no uniform grading scheme is used worldwide and data on the independent prognostic value are inconclusive. Histopathological diagnosis of tumour biopsies relies on standard [e.g. haemotoxylin and eosin (H&E)] and special stains (e.g. reticulin), and—if required—immunohistochemistry (IHC). It should address different challenges: morphologically, highly differentiated HCC must be distinguished from benign/premalignant lesions (dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia). In particular, poorly differentiated HCC should be distinguished from intrahepatic CC, combined HCC/CC and some types of metastases (e.g. lung cancer, head and neck squamous cell carcinoma, breast cancer, neuroendocrine tumours). For this reason, histological analyses may be supplemented by IHC for lineage-specific markers. It is important to distinguish combined HCC/CC from HCC due to the different therapeutic modalities; however, the mixed differentiation features might not be visible in the biopsy. In addition, significant expression of cytokeratin 19 (CK19) has been evaluated and considered as a sign of poor prognosis in HCC [IV, B]. In highly differentiated HCC, definitive signs of malignancy (interstitial or vascular invasion) are frequently absent from biopsy. Further consented histological (trabecular alterations—more than two cell broad trabeculae, pseudoglands, reticulin loss, capsule formation) and cytological criteria (increased nuclear/cytoplasmic ratio, i.e. 'nuclear crowding', increased cytoplasmic basophilia) support HCC diagnosis [III, B] [37.International Consensus Group for Hepatocellular Neoplasia Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (548) Google Scholar]. IHC should be carried out in unclear cases: capillarisation of sinusoids could be assessed using CD34 IHC [IV, B] [37.International Consensus Group for Hepatocellular Neoplasia Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (548) Google Scholar]. Further immunohistochemical markers have been shown to improve the diagnosis of highly differentiated HCC, including glutamine synthetase, glypican 3, general stress protein (CTC), enhancer of zeste homologue 2 (EZH2) and heat shock protein 70 (HSP70) [IV, B]. A combination of the three markers glutamine synthetase, glypican 3 and HSP70 has been consented as a diagnostic panel (2/3 marker positivity has 70% sensitivity and 100% specificity for HCC) and the use of further markers seems to increase the sensitivity [IV, B] [38.Sciarra A. Di Tommaso L. Nakano M. et al.Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications.J Hepatol. 2016; 64: 87-93Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. Moreover, histological subtypes of HCC have been defined (e.g. fibrolamellar, chromophobe, macrotrabecular massive) which specifically correlate with clinical and molecular features [39.Calderaro J. Couchy G. Imbeaud S. et al.Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.J Hepatol. 2017; 67: 727-738Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 40.Yeh M.M. Liu Y. Torbenson M. Steatohepatitic variant of hepatocellular carcinoma in the absence of metabolic syndrome or background steatosis: a clinical, pathological, and genetic study.Hum Pathol. 2015; 46: 1769-1775Crossref PubMed Google Scholar], which may have future clinical impact. It is now well accepted that the potential risks of tumour biopsy, bleeding and needle track seeding, are infrequent, manageable and do not affect the course of the disease or overall survival (OS) and, therefore, should not be seen as a reason to abstain from diagnostic liver biopsy. In a comprehensive meta-analysis, the risk of tumour seeding after liver biopsy was reported to be 2.7%, with a median time interval between biopsy and seeding of 17 months [41.Silva M.A. Hegab B. Hyde C. et al.Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis.Gut. 2008; 57: 1592-1596Crossref PubMed Scopus (304) Google Scholar], but even lower rates are expected in experienced centres. It was reported that needle track seeding can be treated well (e.g. by excision or radiation) and did not affect outcome of oncological treatment [42.Fuks D. Cauchy F. Fusco G. et al.Preoperative tumour biopsy does not affect the oncologic course of patients with transplantable HCC.J Hepatol. 2014; 61: 589-593Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] and OS [41.Silva M.A. Hegab B. Hyde C. et al.Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis.Gut. 2008; 57: 1592-1596Crossref PubMed Scopus (304) Google Scholar]. In a meta-analysis of the bleeding risk, mild bleeding complications ranged around 3%–4%, while severe bleeding complications, requiring transfusions, were reported in 0.5% of the cases [43.Rockey D.C. Caldwell S.H. Goodman Z.D. et al.Liver biopsy.Hepatology. 2009; 49: 1017-1044Crossref PubMed Scopus (1241) Google Scholar]. Staging of HCC is important to determine outcome and planning of optimal therapy and includes assessment of tumour extent, AFP level, liver function, portal pressure and clinical performance status (PS) (Table 1) [III, A]. Relevant techniques to evaluate tumour extent (number and size of nodules, vascular invasion, extrahepatic spread) include CEMRI or helical CT. CT of the chest, abdomen and pelvis is recommended to rule out extrahepatic spread. There is no justification for routine preoperative bone scintigraphy to detect asymptomatic skeletal metastases in patients with resectable HCC [44.Witjes C.D. Verhoef C. Kwekkeboom D.J. et al.Is bone scintigraphy indicated in surgical work-up for hepatocellular carcinoma patients?.J Surg Res. 2013; 181: 256-261Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and there are no data in the context of advanced HCC. There is no demonstrated clinical benefit of carrying out FDG-PET scan as a staging modality, despite some evidence that there is a correlation of higher FDG uptake with poor differentiation, tumour size, serum AFP levels and microvascular invasion [IV, D] [45.Boussouar S. Itti E. Lin S.J. et al.Functional imaging of hepatocellular carcinoma using diffusion-weighted MRI and (18)F-FDG PET/CT in patients on waiting-list for liver transplantation.Cancer Imaging. 2016; 16: 4Crossref PubMed Scopus (17) Google Scholar, 46.Hyun S.H. Eo J.S. Song B.I. et al.Preoperative prediction of microvascular invasion of hepatocellular carcinoma using 18F-FDG PET/CT: a multicenter retrospective cohort study.Eur J Nucl Med Mol Imaging. 2018; 45: 720-726Crossref PubMed Scopus (23) Google Scholar]. Liver function is classically assessed by the Child-Pugh scoring system (serum bilirubin, serum albumin, ascites, prothrombin time and hepatic encephalopathy) [III, A]. Within the Child-Pugh A group, measurement of the albumin-bilirubin (ALBI) score (a model incorporating serum albumin and bilirubin levels alone) is able to split that group into good prognosis (ALBI 1) and poor prognosis (ALBI 2), with median survivals of 26 versus 14 months, respectively [IV, B] [47.Johnson P.J. Berhane S. Kagebayashi C. et al.Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.J Clin Oncol. 2015; 33: 550-558Crossref PubMed Scopus (802) Google Scholar]. A platelet count > 150 × 109 cells/L and a non-invasive liver stiffness measurement < 20 kPa excludes clinically significant portal hypertension (Baveno VI criteria) [48.Augustin S. Pons M. Maurice J.B. et al.Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease.Hepatology. 2017; 66: 1980-1988Crossref PubMed Scopus (115) Google Scholar]. Otherwise, the finding of oesophageal varices and/or splenomegaly with blood platelet counts of 100 × 109 cells/L suggests clinically important portal hypertension, which can also be measured invasively by the transjugular route (hepatic-venous pressure gradi