J Liver Cancer.  2022 Mar;22(1):14-22. 10.17998/jlc.2022.03.18.

A clinical and pathological update on hepatocellular carcinoma

• Renne SL
• Tommaso LD

• KMID: 2528292
• DOI: http://doi.org/10.17998/jlc.2022.03.18

Abstract

It is estimated that more than 1 million individuals will be affected annually by hepatocellular carcinoma (HCC) by 2025. HCC can be broadly grouped into two major molecular subgroups, each of which is characterized by specific morphological and phenotypic features that mirror the genetic background. The use of these tissue biomarkers in the daily practice of pathologists promises to better allocate patients with HCC with adequate treatments. In turn, this will likely boost the attitude of clinicians toward obtaining a pre-treatment biopsy.

Keyword

Carcinoma; hepatocellular; Tumor microenvironment; Angiogenesis modulators; Diagnosis; Prognosis

Figure

• 

  Figure 1 Microscopic pathology of hepatocellular carcinoma (HCC) (hematoxylin-eosin stain). (A, B) A well-differentiated HCC with a thick perilesional capsule, characterized at higher magnification by pseudoglandular structures filled with bile and showing strong and homogenous immunoreactivity to glutamine synthetase (inset). These findings are consistent with the diagnosis of CTNNB1-mutated-HCC. (C, D) HCC showing a homogenous and diffuse presence of macrotrabeculae, consistent with the diagnosis of macrotrabecular-massive HCC. (E, F) This HCC is characterized by diffuse steatosis at scanning magnification and hepatocytes with Mallory-Denk bodies and ballooning, intermingled with scattered inflammatory infiltrates at higher magnification. These features are consistent with the diagnosis of steatohepatitic HCC. (G, H) HCC showing homogenous presence of a rich immune infiltrate, which at higher magnification are confirmed to be lymphocytes surrounding neoplastic cells. These findings are consistent with the diagnosis of lymphocyte-rich HCC. (I, J) Scirrhous HCC characterized by the diffuse presence of fibrous stroma, surrounding neoplastic cells. (K, L) This HCC is characterized by the diffuse presence of clear cell changes, consistent with a clear cell variant.

• 

  Figure 2 Molecular pathology of hepatocellular carcinoma (HCC). A summary of the correlations among molecular, genetic, morphological and clinical features of HCC. TGFβ, transforming growth factor beta; IL6-JAK-STAT, interleukin 6-Janus kinase-signal transducers and activators of transcription protein; HCC, hepatocellular carcinoma; MTM, macrotrabecular-massive; HBV, hepatitis B virus; AFP, α-fetoprotein; CRP, C-reactive protein; GS, glutamine synthetase; HCV, hepatitis C virus; NASH, non-alcoholic steatohepatitis.

• 

  Figure 3 Vascularization of hepatocellular carcinoma (HCC) (CD34 immunohistochemistry, original magnification ×20). (A) Approximately 40% of HCC cases are characterized by a continuous layer of CD34+ vessels encapsulating clusters of neoplastic cells, featuring a peculiar vascular phenotype described as VETC. (B) In the remaining cases, CD34 staining reveals a capillary distribution of vessels.

Reference

References

1. Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of hepatocellular carcinoma incidence in the United States forecast through 2030. J Clin Oncol. 2016; 34:1787–1794.

2. International Agency for Research on Cancer. GLOBOCAN 2018 [Internet]. Geneva: World Health Organization;[cited 2022 Feb 1]. Available from: https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=0&statistic=5&prevalence=0&population_groupearth&color_palette=default&map_scale=uantile&map_nb_colors=5&continent=0&rotate=%255B10%252C0%255D .

3. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018; 68:723–750.

4. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018; 69:182–236.

5. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004; 127(5 Suppl 1):S35–S50.

6. Lok AS. Chronic hepatitis B. N Engl J Med. 2002; 346:1682–1683.

7. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017; 153:996–1005e1.

8. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006; 45:529–538.

9. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018; 15:11–20.

10. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018; 67:123–133.

11. van der Pol CB, Lim CS, Sirlin CB, McGrath TA, Salameh JP, Bashir MR, et al. Accuracy of the liver imaging reporting and data system in computed tomography and magnetic resonance image analysis of hepatocellular carcinoma or overall malignancy-A systematic review. Gastroenterology. 2019; 156:976–986.

12. Jang JY, Lee JS, Kim HJ, Shim JJ, Kim JH, Kim BH, et al. The general rules for the study of primary liver cancer. J Liver Cancer. 2017; 17:19–44.

13. Hui AM, Takayama T, Sano K, Kubota K, Akahane M, Ohtomo K, et al. Predictive value of gross classification of hepatocellular carcinoma on recurrence and survival after hepatectomy. J Hepatol. 2000; 33:975–979.

14. Shimada M, Rikimaru T, Hamatsu T, Yamashita Y, Terashi T, Taguchi K, et al. The role of macroscopic classification in nodular-type hepatocellular carcinoma. Am J Surg. 2001; 182:177–182.

15. Tsujita E, Yamashita Y, Takeishi K, Matsuyama A, Maeda T, Tsutsui S, et al. The clinicopathological impact of gross classification on solitary small hepatocellular carcinoma. Hepatogastroenterology. 2013; 60:1726–1730.

16. Lee Y, Park H, Lee H, Cho JY, Yoon YS, Choi YR, et al. The clinicopathological and prognostic significance of the gross classification of hepatocellular carcinoma. J Pathol Transl Med. 2018; 52:85–92.

17. WHO. Classification of Tumours Editorial Board. Digestive system tumours. 1:5th ed. Lyon: International Agency for Research on Cancer;2019.

18. Monga SP. β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015; 148:1294–1310.

19. Calderaro J, Ziol M, Paradis V, Zucman-Rossi J. Molecular and histological correlations in liver cancer. J Hepatol. 2019; 71:616–630.

20. Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017; 153:812–826.

21. Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouzé E, Blanc JF, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017; 67:727–738.

22. Audard V, Grimber G, Elie C, Radenen B, Audebourg A, Letourneur F, et al. Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations. J Pathol. 2007; 212:345–352.

23. Renne SL, Woo HY, Allegra S, Rudini N, Yano H, Donadon M, et al. Vessels encapsulating tumor clusters (VETC) is a powerful predictor of aggressive hepatocellular carcinoma. Hepatology. 2020; 71:183–195.

24. Ziol M, Poté N, Amaddeo G, Laurent A, Nault JC, Oberti F, et al. Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance. Hepatology. 2018; 68:103–112.

25. Calderaro J, Meunier L, Nguyen CT, Boubaya M, Caruso S, Luciani A, et al. ESM1 as a marker of macrotrabecular-massive hepatocellular carcinoma. Clin Cancer Res. 2019; 25:5859–5865.

26. Seok JY, Na DC, Woo HG, Roncalli M, Kwon SM, Yoo JE, et al. A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition. Hepatology. 2012; 55:1776–1786.

27. Salomao M, Yu WM, Brown RS Jr, Emond JC, 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 Pathol. 2010; 34:1630–1636.

28. Qin J, Higashi T, Nakagawa S, Fujiwara N, Yamashita YI, Beppu T, et al. Steatohepatitic variant of hepatocellular carcinoma is associated with both alcoholic steatohepatitis and nonalcoholic steatohepatitis: a study of 2 cohorts with molecular insights. Am J Surg Pathol. 2020; 44:1406–1412.

29. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021; 592:450–456.

30. Chan AW, Tong JH, Pan Y, Chan SL, Wong GL, Wong VW, et al. Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome. Am J Surg Pathol. 2015; 39:304–312.

31. Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016; 64:2038–2046.

32. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017; 18:1009–1021.

33. Pinyol R, Sia D, Llovet JM. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin Cancer Res. 2019; 25:2021–2023.

34. Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology. 2018; 68:1025–1041.

35. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013; 4:2218.

36. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015; 149:1226–1239e4.

37. Ahn SM, Jang SJ, Shim JH, Kim D, Hong SM, Sung CO, et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology. 2014; 60:1972–1982.

38. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015; 47:505–511.

39. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012; 44:694–698.

40. Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014; 46:1267–1273.

41. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009; 69:7385–7392.

42. Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007; 45:42–52.

43. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008; 68:6779–6788.

44. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017; 169:1327–1341e23.

45. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006; 12:410–416.

46. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334:693–699.

47. Roayaie S, Obeidat K, Sposito C, Mariani L, Bhoori S, Pellegrinelli A, et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013; 57:1426–1435.

48. Tabrizian P, Holzner M, Halazun K, Agopian VG, Busuttil RW, Yao F, et al. A US multicenter analysis of 2529 HCC patients undergoing liver transplantation: 10-year outcome assessing the role of down-staging to within Milan criteria [abstract]. Hepatology. 2019; 70(Suppl 1):10A.

49. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018; 67:358–380.

50. Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgrò G, Burroughs AK. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis. J Hepatol. 2010; 52:380–388.

51. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009; 49:453–459.

52. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003; 37:429–442.

53. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29(Suppl 4):iv238–iv255.

54. Llovet JM, De Baere T, Kulik L, Haber PK, Greten TF, Meyer T, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18:293–313.

55. Salem R, Gordon AC, Mouli S, Hickey R, Kallini J, Gabr A, et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2016; 151:1155–1163e2.

56. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378–390.

57. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391:1163–1173.

58. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389:56–66.

59. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379:54–63.

60. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20:282–296.

61. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382:1894–1905.

62. Fang JH, Zhou HC, Zhang C, Shang LR, Zhang L, Xu J, et al. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. Hepatology. 2015; 62:452–465.

63. Fang JH, Xu L, Shang LR, Pan CZ, Ding J, Tang YQ, et al. Vessels that encapsulate tumor clusters (VETC) pattern is a predictor of sorafenib benefit in patients with hepatocellular carcinoma. Hepatology. 2019; 70:824–839.

64. Kurebayashi Y, Matsuda K, Ueno A, Tsujikawa H, Yamazaki K, Masugi Y, et al. Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments. Hepatology. 2021; Oct. 17. DOI: 10.1002/hep.32201. [Epub ahead of print].

65. Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: looking outside the box. J Hepatol. 2020; 72:342–352.