J Liver Cancer.  2020 Mar;20(1):17-24. 10.17998/jlc.20.1.17.

Histopathological Variants of Hepatocellular Carcinomas: an Update According to the 5th Edition of the WHO Classification of Digestive System Tumors

• Kim H
• Jang M
• Park YN

• KMID: 2505838
• DOI: http://doi.org/10.17998/jlc.20.1.17

Abstract

Hepatocellular carcinoma (HCC) is heterogeneous in pathogenesis, phenotype and biological behavior. Various histopathological features of HCC had been sporadically described, and with the identification of common molecular alterations of HCC and its genomic landscape over the last decade, morpho-molecular correlation of HCC has become possible. As a result, up to 35% of HCCs can now be classified into histopathological variants, many of which have unique molecular characteristics. This review will provide an introduction to the variously described histopathological variants of HCC in the updated WHO Classification of Digestive System Tumors.

Keyword

Classification; Hepatocellular carcinoma; Pathology

Figure

• 

  Figure 1. Hepatocellular carcinoma, conventional. (A) An expanding nodular tumor with a slightly bulging cut surface is seen. The tumor is slightly bile-tinged with small foci of hemorrhage. (B) Microscopic examination of a typical hepatocellular carcinoma shows tumor cells with eosinophilic cytoplasm arranged in a trabecular pattern (hematoxylin-eosin stain, ×200).

• 

  Figure 2. Hepatocellular carcinoma, steatohepatitic variant. (A) The tumor shows a yellowish hue on gross examination due to the lipid content. (B) At low power magnification, there is extensive intratumoral steatosis (right, hematoxylin-eosin stain, ×12.5). (C) Higher power magnification demonstrates the histological features of steatohepatitis, including steatosis, hepatocyte ballooning and Mallory-Denk bodies (hematoxylineosin stain, ×100). (D) The perisinusoidal “chicken-wire pattern” fibrosis is highlighted by Masson’s trichrome stain (×100).

• 

  Figure 3. Hepatocellular carcinoma, clear cell variant. (A) Gross feature of the tumor. (B) The tumor (upper left) appears lighter compared to the adjacent hepatic parenchyma at low power (hematoxylin-eosin stain, ×12.5). (C) Most of the tumor cells show clear cytoplasm, due to intracytoplasmic glycogen accumulation (hematoxylin-eosin stain, ×200).

• 

  Figure 4. Hepatocellular carcinoma, macrotrabecular massive variant. (A) Gross feature of the tumor. (B) At low power magnification, thick tumor cell trabeculae are seen in more than 50% of the tumor (hematoxylin-eosin stain, ×12.5). (C) The tumor cell trabeculae are more than 10 cells thick (hematoxylin-eosin stain, ×100).

• 

  Figure 5. Hepatocellular carcinoma, scirrhous variant. (A) Gross feature of the tumor. (B) Dense intratumoral fibrosis is seen at low power magnification (hematoxylin-eosin stain, ×12.5). (C) The tumor cell nests are separated by the thick fibrous stroma (hematoxylin-eosin stain, ×100).

• 

  Figure 6. Hepatocellular carcinoma, lymphocyte-rich variant. (A) Gross appearance of the tumor. (B) At low power magnification, the tumor is massively infiltrated by lymphocytes (hematoxylin-eosin stain, ×40). (C) The tumor cell trabeculae or nests are separated by dense lymphoid cell infiltrates (hematoxylin-eosin stain, ×100).

Reference

1. Torbenson MS, Ng IOL, Park YN, Roncalli M, Sakamoto M. Hepatocellular carcinoma. In: WHO Classification of Tumours Editorial Board, editor. Digestive system tumours. WHO classification of tumours series. 5th ed. Lyon: International Agency for Research on Cancer;2019. 229–39.

2. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist. 2010; 15 Suppl 4:14–22.

3. Degasperi E, Colombo M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol. 2016; 1:156–164.

4. 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.

5. Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and tumourlike lesions of the liver. In : Burt AD, Ferrell LD, Hubscher SG, editors. MacSween’s Pathology of the Liver. 7th ed. Philadelphia: Philadelphia: Elsevier;2018. p. 780–879.

6. Theise ND, Curado MP, Franceschi S, Hytiroglou P, Kudo M, Park YN, et al. Hepatocellular Carcinoma. In : Bosman FT, Carneiro F, Hruban RH, Theise RH, editors. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC;2010. p. 205–16.

7. 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.

8. 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.

9. 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.

10. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004; 40:667–676.

11. 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.

12. Lee JS, Yoo JE, Kim H, Rhee H, Koh MJ, Nahm JH, et al. Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma. PLoS One. 2017; 12:e0171922.

13. Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum Pathol. 2012; 43:737–746.

14. 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.

15. Li T, Fan J, Qin LX, Zhou J, Sun HC, Qiu SJ, et al. Risk factors, prognosis, and management of early and late intrahepatic recurrence after resection of primary clear cell carcinoma of the liver. Ann Surg Oncol. 2011; 18:1955–1963.

16. Reuter VE, Argani P, Zhou M, Delahunt B; Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the kidney tumors: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014; 38:e35–e49.

17. 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.

18. Kurogi M, Nakashima O, Miyaaki H, Fujimoto M, Kojiro M. Clinicopathological study of scirrhous hepatocellular carcinoma. J Gastroenterol Hepatol. 2006; 21:1470–1477.

19. Matsuura S, Aishima S, Taguchi K, Asayama Y, Terashi T, Honda H, et al. ‘Scirrhous’ type hepatocellular carcinomas: a special reference to expression of cytokeratin 7 and hepatocyte paraffin 1. Histopathology. 2005; 47:382–390.

20. 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 epithelialmesenchymal transition. Hepatology. 2012; 55:1776–1786.

21. Kim SH, Lim HK, Lee WJ, Choi D, Park CK. Scirrhous hepatocellular carcinoma: comparison with usual hepatocellular carcinoma based on CT-pathologic features and long-term results after curative resection. Eur J Radiol. 2009; 69:123–130.

22. Wood LD, Heaphy CM, Daniel HD, Naini BV, Lassman CR, Arroyo MR, et al. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod Pathol. 2013; 26:1586–1593.

23. Chagas AL, Kikuchi L, Herman P, Alencar RS, Tani CM, Diniz MA, et al. Clinical and pathological evaluation of fibrolamellar hepatocellular carcinoma: a single center study of 21 cases. Clinics (Sao Paulo). 2015; 70:207–213.

24. Kim YJ, Rhee H, Yoo JE, Alves VAF, Kim GJ, Kim HM, et al. Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma. Histopathology. 2017; 71:217–226.

25. Graham RP, Jin L, Knutson DL, Kloft-Nelson SM, Greipp PT, Waldburger N, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015; 28:822–829.

26. Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim II, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014; 343:1010–1014.

27. Kakar S, Burgart LJ, Batts KP, Garcia J, Jain D, Ferrell LD. Clinicopathologic features and survival in fibrolamellar carcinoma: comparison with conventional hepatocellular carcinoma with and without cirrhosis. Mod Pathol. 2005; 18:1417–1423.

28. Malouf GG, Brugières L, Le Deley MC, Faivre S, Fabre M, Paradis V, et al. Pure and mixed fibrolamellar hepatocellular carcinomas differ in natural history and prognosis after complete surgical resection. Cancer. 2012; 118:4981–4990.

29. Torbenson MS. Morphologic subtypes of hepatocellular carcinoma. Gastroenterol Clin North Am. 2017; 46:365–391.

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

31. 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.

32. 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.

33. 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.

34. Calderaro J, Petitprez F, Becht E, Laurent A, Hirsch TZ, Rousseau B, et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 2019; 70:58–65.