Histopathology of hepatocellular carcinoma - when and what

Abstract

When do you need to take biopsies of the liver, and what information will you get is the topic of this review on hepatocellular carcinoma (HCC). If, clinically, the differential diagnosis of HCC after imaging is suggested, a biopsy has become obligatory as a diagnostic confirmation of HCC in the non-cirrhotic liver prior to definitive therapeutic interventions, as well as in a palliative therapy concept. In the case of hepatic lesions with an uncharacteristic contrast uptake, a biopsy should be performed immediately to confirm the diagnosis of HCC. After diagnosing HCC, a treatment strategy is evaluated. Further, the biopsy, or in case of surgical treatment, the resected tissue, shows us the different subtypes of HCC, with the steatohepatitic subtype being the most common and the lymphocyte-rich subtype being the least common. Further, the histological grade of HCC is determined according to the grading system of the WHO or the Edmonson and Steiner System. Through biopsies, HCC can be differentiated from intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma or metastases of other malignant tumors, especially metastases of the gastrointestinal tract. In summary, biopsies are fundamental in the diagnosis of HCC.

Keywords

Hepatocellular carcinoma / biopsies / histology

References

[1] GCO Global Cancer Observatory. The Global Cancer Observatory (GCO) is an interactive web-based platform presenting global cancer statistics to inform cancer control and research. Available from: https://gco.iarc.fr [Last accessed on 31 Dec 2021]

[2] European Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[3] ZfKD Zentrum für Krebsregisterdaten. Das Zentrum für Krebsregisterdaten (ZfKD) am Robert Koch-Institut in Berlin führt Daten der Landeskrebsregister auf Bundesebene zusammen. Available from: http://krebsdaten.de/ [Last accessed on 31 Dec 2021]

[4] De Toni EN,Fuchs M.Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study.Gut2020;69:168-76 PMCID:PMC6943246

[5] Erhardt A,Petry W.[Hepatocellular carcinoma: rising incidence of hepatitis C virus-associated cases at a university clinic in Germany].Dtsch Med Wochenschr2002;127:2665-8

[6] Zhou L,Luo F.Serum tumor markers for detection of hepatocellular carcinoma.World J Gastroenterol2006;12:1175-81 PMCID:PMC4124425

[7] Spangenberg HC,Blum HE.Serum markers of hepatocellular carcinoma.Semin Liver Dis2006;26:385-90

[8] Nassar A,Siddiqui MT.Utility of glypican-3 and survivin in differentiating hepatocellular carcinoma from benign and preneoplastic hepatic lesions and metastatic carcinomas in liver fine-needle aspiration biopsies.Diagn Cytopathol2009;37:629-35

[9] Edmondson HA.Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies.Cancer1954;7:462-503

[10] Nzeako UC,Ishak KG.Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients.Am J Clin Pathol1996;105:65-75

[11] Nzeako UC,Ishak KG.Comparison of tumor pathology with duration of survival of north american patients with hepatocellular carcinoma.Cancer1995;76:579-88

[12] Paradis VFM. PYSP, tumors of the liver and intrahepatic bile ducts. In: WHO Classification of Tumours Editorial Board WHO-Classification of Tumours. 5th ed. Digestive system tumours. International Agency for Research on Cancer; 2019. p. 215-64.

[13] Wittekind C.TNM Klassifikation maligner Tumoren: Korrigierter Nachdruck 2020 mit allen Ergänzungen der UICC aus den Jahren 2017 b is 2019. 8th ed. Weinheim: Wiley-VCH; 2020.

[14] Bray F,Laversanne M.Cancer incidence in five continents: inclusion criteria, highlights from volume X and the global status of cancer registration.Int J Cancer2015;137:2060-71

[15] Altekruse SF,Cucinelli JE.Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States.Am J Gastroenterol2014;109:542-53 PMCID:PMC4148914

[16] Horigome H,Saso K,Joh T.Limitations of imaging diagnosis for small hepatocellular carcinoma: comparison with histological findings.J Gastroenterol Hepatol1999;14:559-65

[17] Ikai I,Kojiro M.Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey.Cancer2004;101:796-802

[18] Kojiro M.Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view.Liver Transpl2004;10:S3-8

[19] Krücker J,Glossop N.Electromagnetic tracking for thermal ablation and biopsy guidance: clinical evaluation of spatial accuracy.J Vasc Interv Radiol2007;18:1141-50 PMCID:PMC2555977

[20] Hakime A,De Carvalho EG,Auperin A.Electromagnetic-tracked biopsy under ultrasound guidance: preliminary results.Cardiovasc Intervent Radiol2012;35:898-905

[21] Kang TW.Recent advances in tumor ablation for hepatocellular carcinoma.Liver Cancer2015;4:176-87 PMCID:PMC4608649

[22] S3-leitlin. Diagnostik und Ther. des Hepatozellulären Karzinoms und biliärer Karzinome. Available from: https://www.leitlinienprogramm-onkologie.de/leitlinien/hcc-und-biliaere-karzinome/ [Last accessed on 19 October 2021]

[23] Di Tommaso L,Seok JY.The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma.J Hepatol2009;50:746-54

[24] Di Tommaso L,Park YN.Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis.Hepatology2007;45:725-34

[25] Koehne de Gonzalez AK, Salomao MA, Lagana SM. Current concepts in the immunohistochemical evaluation of liver tumors.World J Hepatol2015;7:1403-11 PMCID:PMC4450203

[26] Neuberger J,Caldwell H.Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology.Gut2020;69:1382-403 PMCID:PMC7398479

[27] Ichim VA,Mircea PA,Crisan D.Accuracy of endoscopic ultrasound-guided biopsy of focal liver lesions.Med Ultrason2020;22:20-5

[28] Colloredo G,Sonzogni A.Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease.J Hepatol2003;39:239-44

[29] Bedossa P,Paradis V.Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology2003;38:1449-57

[30] Schiano T,Bodian C.Importance of specimen size in accurate needle liver biopsy evaluation of patients with chronic hepatitis C.Clin Gastroenterol Hepatol2005;3:930-5

[31] Wyatt J,Bellamy C.Tissue pathways for liver biopsies for the investigation of medical disease and for focal leasions.The Royal College of Pathologists2014;

[32] Chi H,Tang WY.Multiple biopsy passes and the risk of complications of percutaneous liver biopsy.Eur J Gastroenterol Hepatol2017;29:36-41

[33] Maharaj B.Complications associated with percutaneous needle biopsy of the liver when one, two or three specimens are taken.Postgrad Med J1992;68:964-7 PMCID:PMC2399495

[34] Perrault J,Ott BJ.Liver biopsy: complications in 1000 inpatients and outpatients.Gastroenterology1978;74:103-6

[35] Rockey DC,Goodman ZD,Smith AD.American Association for the Study of Liver DiseasesLiver biopsy.Hepatology2009;49:1017-44

[36] Silva MA,Hyde C,Buckels JA.Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis.Gut2008;57:1592-6

[37] Müllhaupt B,Roskams T,Heim M.Is tumor biopsy necessary?.Liver Transpl2011;17 Suppl 2:S14-25

[38] Fuks D,Fusco G,Durand F.Preoperative tumour biopsy does not affect the oncologic course of patients with transplantable HCC.J Hepatol2014;61:589-93

[39] Kokudo T,Yamamoto S.Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis.J Hepatol2014;61:583-8

[40] Lee YH,Huang YH.Vascular invasion in hepatocellular carcinoma: prevalence, determinants and prognostic impact.J Clin Gastroenterol2014;48:734-41

[41] Amitrano L,Brancaccio V.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol2004;40:736-41

[42] Psutka SP,Thompson RH.Clinical and radiographic predictors of the need for inferior vena cava resection during nephrectomy for patients with renal cell carcinoma and caval tumour thrombus.BJU Int2015;116:388-96

[43] Aslam Sohaib S, Teh J, Nargund VH, Lumley JS, Hendry WF, Reznek RH. Assessment of tumor invasion of the vena caval wall in renal cell carcinoma cases by magnetic resonance imaging.J Urol2002;167:1271-5

[44] Quencer KB,Sheth R.Tumor thrombus: incidence, imaging, prognosis and treatment.Cardiovasc Diagn Ther2017;7:S165-77 PMCID:PMC5778532

[45] Yang L,Lin XY.Ultrasound-guided fine needle aspiration biopsy in differential diagnosis of portal vein tumor thrombosis.Hepatobiliary Pancreat Dis Int2005;4:234-8

[46] Lukianchenko AB,Karseladze AI.Morphology classification of liver tumors (comparison of the last and previous WHO classifications 2010 and 2019).Medicinskaâ vizualizaciâ2020;24:138-43

[47] Kim H,Park YN.Histopathological variants of hepatocellular carcinomas: an update according to the 5th edition of the WHO classification of digestive system tumors.J Liver Cancer2020;20:17-24

[48] Nagtegaal ID,Klimstra D.WHO Classification of Tumours Editorial BoardThe 2019 WHO classification of tumours of the digestive system.Histopathology2020;76:182-8 PMCID:PMC7003895

[49] Kleiner DE.Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists.Gastroenterology2015;149:1305-8

[50] Shimada M,Hamatsu T.The role of macroscopic classification in nodular-type hepatocellular carcinoma.Am J Surg2001;182:177-82

[51] Eggel H.Über das primäre Carcinom der Leber.Beitr Pathol Anat Allg Pathol1901;30:506

[52] Zimmermann A.Hepatocellular carcinoma (Ordinary Hepatocellular Carcinoma). Tumors and tumor-like lesions of the hepatobiliary tract. Cham: Springer International Publishing; 2016. p. 1-38.

[53] Yuki K,Sakamoto M,Shimosato Y.Growth and spread of hepatocellular carcinoma: a review of 240 consecutive autopsy cases.Cancer1990;66:2174-9

[54] Schlageter M,D'Angelo S.Histopathology of hepatocellular carcinoma.World J Gastroenterol2014;20:15955-64 PMCID:PMC4239483

[55] Paradis V.Histopathology of Hepatocellular Carcinoma. In: Vauthey J, Brouquet A, editors. Multidisciplinary treatment of hepatocellular carcinoma. Berlin: Springer Berlin Heidelberg; 2013. p. 21-32.

[56] Feo F.Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis?.Ann Transl Med2015;3:4 PMCID:PMC4293477

[57] Chianchiano P,Kim A.Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations.Hum Pathol2018;72:127-34 PMCID:PMC6435273

[58] Furuta M,Fujimoto A.Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors.J Hepatol2017;66:363-73

[59] Shimada S,Akiyama Y.Comprehensive molecular and immunological characterization of hepatocellular carcinoma.EBioMedicine2019;40:457-70 PMCID:PMC6412165

[60] Kurogi M,Miyaaki H,Kojiro M.Clinicopathological study of scirrhous hepatocellular carcinoma.J Gastroenterol Hepatol2006;21:1470-7

[61] Nakashima T,Kojiro M.Pathology of hepatocellular carcinoma in Japan: 232 consecutive cases autopsied in ten years.Cancer1983;51:863-77

[62] Yeh CN,Jeng LB.Pedunculated hepatocellular carcinoma: clinicopathologic study of 18 surgically resected cases.World J Surg2002;26:1133-8

[63] Bosman FT,Hruban RH. WHO classification of tumors of digestive system. WHO press; 2010. p. 304.

[64] Torbenson MS.Morphologic subtypes of hepatocellular carcinoma.Gastroenterol Clin North Am2017;46:365-91

[65] Rastogi A,Ramakrishna G.Hepatocellular carcinoma: clinicopathologic associations amidst marked phenotypic heterogeneity.Pathol Res Pract2021;217:153290

[66] Leong AS,Tsui WM.Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma.Histopathology1998;33:318-24

[67] Lin F,Meschter S.Diagnostic utility of CD10 in differentiating hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration biopsy (FNAB) of the liver.Diagn Cytopathol2004;30:92-7

[68] Shafizadeh N,Kakar S.Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum.Mod Pathol2008;21:1011-8

[69] Wee A.Diagnostic utility of immunohistochemistry in hepatocellular carcinoma, its variants and their mimics.Appl Immunohistochem Mol Morphol2006;14:266-72

[70] Minervini MI,Lee RG.Utilization of hepatocyte-specific antibody in the immunocytochemical evaluation of liver tumors.Mod Pathol1997;10:686-92

[71] Liu H,Lu W.Prognostic significance of glypican-3 expression in hepatocellular carcinoma: a meta-analysis.Medicine (Baltimore)2018;97:e9702 PMCID:PMC5794382

[72] Salomao M,Lefkowitch JH.Steatohepatitic hepatocellular carcinoma: a novel histologic variant associated with steatohepatitis and metabolic syndrome.Lab Invest2011;91:

[73] Salomao M,Vaughan R,Lefkowitch JH.The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis.Hum Pathol2012;43:737-46

[74] Salomao M,Brown RS Jr,Lefkowitch JH.Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.Am J Surg Pathol2010;34:1630-6

[75] Yeh MM,Torbenson M.Steatohepatitic variant of hepatocellular carcinoma in the absence of metabolic syndrome or background steatosis: a clinical, pathological, and genetic study.Hum Pathol2015;46:1769-75

[76] Bannasch P,Su Q.Clear cell hepatocellular carcinoma: origin, metabolic traits and fate of glycogenotic clear and ground glass cells.Hepatobiliary Pancreat Dis Int2017;16:570-94

[77] Liu Z,Li H.Clinicopathological and prognostic features of primary clear cell carcinoma of the liver.Hepatol Res2008;38:291-9

[78] Ji SP,Dong H.Therapy and prognostic features of primary clear cell carcinoma of the liver.World J Gastroenterol2010;16:764-9 PMCID:PMC2817067

[79] Ziol M,Amaddeo G.Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance.Hepatology2018;68:103-12

[80] Calderaro J,Imbeaud S.Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.J Hepatol2017;67:727-38

[81] Renne SL,Allegra S.Vessels encapsulating tumor clusters (VETC) is a powerful predictor of aggressive hepatocellular carcinoma.Hepatology2020;71:183-95

[82] Lee JH,Gwak GY.Clinicopathologic characteristics and long-term prognosis of scirrhous hepatocellular carcinoma.Dig Dis Sci2012;57:1698-707

[83] Matsuura S,Taguchi K.'Scirrhous' type hepatocellular carcinomas: a special reference to expression of cytokeratin 7 and hepatocyte paraffin 1.Histopathology2005;47:382-90

[84] Kim YJ,Yoo JE.Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma.Histopathology2017;71:217-26

[85] Choi SY,Min JH.Added value of ancillary imaging features for differentiating scirrhous hepatocellular carcinoma from intrahepatic cholangiocarcinoma on gadoxetic acid-enhanced MR imaging.Eur Radiol2018;28:2549-60

[86] Craig JR,Edmondson HA.Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features.Cancer1980;46:372-9

[87] Eggert T,Duffy A,Greten TF.Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: a detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database.United European Gastroenterol J2013;1:351-7 PMCID:PMC4040774

[88] Stipa F,Liau KH.Outcome of patients with fibrolamellar hepatocellular carcinoma.Cancer2006;106:1331-8

[89] Kakar S,Batts KP,Jain D.Clinicopathologic features and survival in fibrolamellar carcinoma: comparison with conventional hepatocellular carcinoma with and without cirrhosis.Mod Pathol2005;18:1417-23

[90] Berman MA,Sheahan DG.Fibrolamellar carcinoma of the liver: an immunohistochemical study of nineteen cases and a review of the literature.Human Pathology1988;19:784-94

[91] Ringe B,Weimann A.Results of hepatic resection and transplantation for fibrolamellar carcinoma.Surg Gynecol Obstet1992;175:299-305

[92] Titelbaum DS,Meranze SG.Fibrolamellar hepatocellular carcinoma: pitfalls in nonoperative diagnosis.Radiology1988;167:25-30

[93] McLarney JK,Bender GN,Kashitani N.Fibrolamellar carcinoma of the liver: radiologic-pathologic correlation.Radiographics1999;19:453-71

[94] Edmondson HA.Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood.AMA J Dis Child1956;91:168-86

[95] Torbenson MS.Steatohepatitic hepatocellular carcinoma.Hepatoma Res2021;7:38

[96] Lin F.Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin.Arch Pathol Lab Med2014;138:1583-610

[97] Miettinen M,McCue PA.SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases.Am J Surg Pathol2014;38:410-20 PMCID:PMC4041084