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Update on Hepatocellular Carcinoma: a Brief Review from Pathologist Standpoint

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Abstract

Hepatocellular carcinoma is one of the most common cancers and an important health problem all over the world. Its prognosis is poor. For better patient care, early diagnosis is essential. Although new imaging techniques have a big impact on hepatocellular carcinoma diagnosis, histopathological examination is still the gold standard for precise diagnosis. Histopathological evaluation gives exact diagnosis in the meaning of tumor size, histological subtypes, grading, and differential diagnosis from metastasis and other tumors. Immunohistochemistry as a part of diagnostic histopathological technique plays an important role in routine practice. Immunohistochemistry is useful for confirming of hepatocytic origin, supporting hepatocellular malignancy, and differential diagnosis. It also gives prognostic information. There are growing attempts to classify tumors by their molecular genetic signatures. This is also actual for hepatocellular carcinoma. This mini review focuses on the histopathology of hepatocellular carcinoma including subtypes; differential diagnosis and immunohistochemistry as an ancillary diagnostic tool, updated or added entities, i.e., combined hepatocellular-cholangiocarcinoma; small hepatocellular carcinoma; correlation with molecular studies; and future perspectives.

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References

  1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.

    Article  Google Scholar 

  2. Rastogi A. Changing role of histopathology in the diagnosis and management of hepatocellular carcinoma. World J Gastroenterol. 2018;24(35):4000–13. https://doi.org/10.3748/wjg.v24.i35.4000.

    Article  Google Scholar 

  3. Mezale D, Strumfa I, Vanags A, Kalva A, Balodis D, Strumfs B, et al. Diagnostic algorithm of hepatocellular carcinoma: classics and innovations in radiology and pathology. 2018. https://doi.org/10.5772/intechopen.76136.

  4. Agni RM. Diagnostic histopathology of hepatocellular carcinoma: a case-based review. Semin Diagn Pathol. 2017;34(2):126–37. https://doi.org/10.1053/j.semdp.2016.12.008.

    Article  Google Scholar 

  5. Liu ZK, Zhang RY, Yong YL, Zhang ZY, Li C, Chen ZN, et al. Identification of crucial genes based on expression profiles of hepatocellular carcinomas by bioinformatics analysis. PeerJ. 2019;7:e7436. https://doi.org/10.7717/peerj.7436.

    Article  Google Scholar 

  6. Sun S, Li Y, Han S, Jia H, Li X, Li X. A comprehensive genome-wide profiling comparison between HBV and HCV infected hepatocellular carcinoma. BMC Med Genet. 2019;12:147. https://doi.org/10.1186/s12920-019-0580-x.

    Article  Google Scholar 

  7. Ueno A, Masugi Y, Yamazaki K, Kurebayashi Y, Tsujikawa H, Effendi K, et al. Precision pathology analysis of the development and progression of hepatocellular carcinoma: implication for precision diagnosis of hepatocellular carcinoma. Pathol Int. 2020;70:140–54. https://doi.org/10.1111/pin.12895.

    Article  Google Scholar 

  8. Vyas M, Jain D. A practical diagnostic approach to hepatic masses. Indian J Pathol Microbiol. 2018;61:2–17. https://doi.org/10.4103/IJPM.IJPM_578_17.

    Article  Google Scholar 

  9. Quaglia A. Hepatocellular carcinoma: a review of diagnostic challenges for the pathologist. J Hepatocell Carcinoma. 2018;5:99–108. https://doi.org/10.2147/JHC.S159808.

    Article  CAS  Google Scholar 

  10. Park BV, Gaba RC, Huang YH, Chen YF, Guzman G, Lokken R. Histology of hepatocellular carcinoma: association with clinical features, radiological findings, and locoregional therapy outcomes. J Clin Imaging Sci. 2019;9:52. https://doi.org/10.25259/JCIS_111_2019.

    Article  Google Scholar 

  11. Poté N, Cauchy F, Albuquerque M, Cros J, Soubrane O, Bedossa P, et al. Contribution of virtual biopsy to the screening of microvascular invasion in hepatocellular carcinoma: a pilot study. Liver Int. 2018;38:687–94. https://doi.org/10.1111/liv.13585.

    Article  CAS  Google Scholar 

  12. Cassinotto C, Aubé C, Dohan A. Diagnosis of hepatocellular carcinoma: an update on international guidelines. Diagn Intervent Imaging. 2017;98:379–91. https://doi.org/10.1016/j.diii.2017.01.014.

    Article  CAS  Google Scholar 

  13. Huh J, Kim KW, Kim J, Yu E. Pathology-MRI correlation of hepatocarcinogenesis: recent update. J Pathol Transl Med. 2015;49(3):218–29. https://doi.org/10.4132/jptm.2015.04.15.

    Article  Google Scholar 

  14. Calderaro J, Ziol M, Paradis V, Zucman-Rossi J. Molecular and histological correlations in liver cancer. J Hepatol. 2019;71(3):616–30. https://doi.org/10.1016/j.jhep.2019.06.001.

    Article  CAS  Google Scholar 

  15. 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. p. 229–39.

    Google Scholar 

  16. Martins-Filho SN, Alves VAF. The strengths and weaknesses of gross and histopathological evaluation in hepatocellular carcinoma: a brief review. Surg Exp Pathol. 2019;2:23. https://doi.org/10.1186/s42047-019-0047-6.

    Article  Google Scholar 

  17. 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. https://doi.org/10.4132/jptm.2017.11.13.

    Article  Google Scholar 

  18. 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. https://doi.org/10.17998/jlc.17.1.19.

    Article  Google Scholar 

  19. Zhang XP, Chen ZH, Zhou TF, Li LQ, Chen MS, Wen T, et al. A nomogram to predict early postoperative recurrence of hepatocellular carcinoma with portal vein tumour thrombus after R0 liver resection: a large-scale, multicenter study. Eur J Surg Oncol. 2019;45:1644–51. https://doi.org/10.1016/j.ejso.2019.03.043.

    Article  Google Scholar 

  20. Shimada S, Kamiyama T, Orimo T, Nagatsu A, Asahi Y, Sakamoto Y, et al. Long-term prognostic factors of patients with hepatocellular carcinoma who survive over 10 years after hepatectomy. J Surg Oncol. 2020;121:1209–17. https://doi.org/10.1002/jso.25910.

    Article  Google Scholar 

  21. Kim H, Jang M, Park YN. Histopathological variants of hepatocellular carcinomas: an update according to the 5th Edition of the WHO Classification of Digestive System. J Liver Cancer. 2020;20(1):17–24. https://doi.org/10.17998/jlc.20.1.17.

    Article  Google Scholar 

  22. Martins-Filho SN, Paiva C, Azevedo RS, Alves VAF. Histological grading of hepatocellular carcinoma—a systematic review of literature. Front Med. 2017;4:193. https://doi.org/10.3389/fmed.2017.00193.

    Article  Google Scholar 

  23. Di Tommaso L, Spadaccini M, Donadon M, Personeni N, Elamin A, Aghemo A, et al. Role of liver biopsy in hepatocellular carcinoma. World J Gastroenterol. 2019;25(40):6041–52. https://doi.org/10.3748/wjg.v25.i40.6041.

    Article  CAS  Google Scholar 

  24. Lo RCL. An update on the histological subtypes of hepatocellular carcinoma. Hepatoma Res. 2019;5:41. https://doi.org/10.20517/2394-5079.2019.021.

    Article  CAS  Google Scholar 

  25. El Jabbour T, Lagana SM, Lee H. Update on hepatocellular carcinoma: pathologists’ review. World J Gastroenterol. 2019;25(14):1653–65. https://doi.org/10.3748/wjg.v25.i14.1653.

    Article  CAS  Google Scholar 

  26. Jeon Y, Benedict M, Taddei T, Jain D, Zhang X. Macrotrabecular hepatocellular carcinoma. An aggressive subtype of hepatocellular carcinoma. Am J Surg Pathol. 2019 Jul;43(7):943–8. https://doi.org/10.1097/PAS.0000000000001289.

    Article  Google Scholar 

  27. 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(1):103–12. https://doi.org/10.1002/hep.29762.

    Article  Google Scholar 

  28. Torbenson M. Fibrolamellar carcinoma: 2012 update. Scientifica (Cairo). 2012;2012:743790. https://doi.org/10.6064/2012/743790.

  29. Brunt E, Aishima S, Clavien PA, Fowler K, Goodman Z, Gores G, et al. cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentiation. Hepatology. 2018;68(1):113–26. https://doi.org/10.1002/hep.29789.

  30. Pittman ME. Hepatocellular carcinoma: a practical review for the surgical pathologist. Diagn Histopathol. 2018;24(12):500–7. https://doi.org/10.1016/j.mpdhp.2018.09.005.

    Article  Google Scholar 

  31. Koehne de Gonzalez A, Lagana SM. Update on ancillary testing in the evaluation of high-grade liver tumors. surgical pathology. Surg Pathol. 2018;11:367–75. https://doi.org/10.1016/j.path.2018.02.004.

    Article  Google Scholar 

  32. Chen D, Li Z, Song Q, Qian L, Xie B, Zhu J. Clinicopathological features and differential diagnosis of hepatocellular carcinoma in extrahepatic metastases. Medicine (Baltimore). 2018;97(50):e13356. https://doi.org/10.1097/MD.0000000000013356.

    Article  Google Scholar 

  33. Uthamalingam P, Das A, Behra A, Kalra N, Chawla Y. Diagnostic value of glypican3, heat shock protein 70 and glutamine synthetase in hepatocellular carcinoma arising in cirrhotic and non-cirrhotic livers. J Clin Exp Hepatol. 2018;8:173–80. https://doi.org/10.1016/j.jceh.2017.09.005.

    Article  Google Scholar 

  34. Walther Z, Jain D. Molecular pathology of hepatic neoplasms: classification and clinical significance. Pathol Res Int. 2011:403929. https://doi.org/10.4061/2011/403929.

  35. Carr B, Ince V, Bag HG, Ersan V, Usta S, Yilmaz S. Microscopic vascular invasion by hepatocellular carcinoma in liver transplant patients. Clin Pract. 2020;17(3):1487–97.

    Google Scholar 

  36. 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. 2019;71(1):183–95. https://doi.org/10.1002/hep.30814.

    Article  CAS  Google Scholar 

  37. 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;70:824–39. https://doi.org/10.1002/hep.30366.

    Article  CAS  Google Scholar 

  38. Huang A, Wang YP, Wang J, Fu PY, Zhang X, Cao Y, et al. Limited bias effect of intratumoral heterogeneity on genetic profiling of hepatocellular carcinoma. J Gastrointest Oncol. 2020;11(1):112–20. https://doi.org/10.21037/jgo.2019.09.13.

    Article  Google Scholar 

  39. Yim SY, Lee JS. The genomic landscape and its clinical implications in hepatocellular carcinoma. J Liver Cancer. 2019;19(2):97–107. https://doi.org/10.17998/jlc.19.2.97.

    Article  Google Scholar 

  40. Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38:396. https://doi.org/10.1186/s13046-019-1396-4.

    Article  Google Scholar 

  41. Roderburg C, Wree A, Demir M, Schmelzle M, Tacke F. The role of the innate immune system in the development and treatment of hepatocellular carcinoma. Hepat Oncol. 2020;7(1):HEP17. https://doi.org/10.2217/hep-2019-0007.

    Article  Google Scholar 

  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. https://doi.org/10.1002/hep.21467.

    Article  CAS  Google Scholar 

  43. 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;69:7385–92. https://doi.org/10.1158/0008-5472.

    Article  Google Scholar 

  44. 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;67:727–38. https://doi.org/10.1016/j.jhep.2017.05.014.

    Article  CAS  Google Scholar 

  45. 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;53:812–26. https://doi.org/10.1053/j.gastro.2017.06.007.

    Article  CAS  Google Scholar 

  46. Ding X, He M, Chan AWH, Song QX, Sze SC, Chen H, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology. 2019;157:1630–45. https://doi.org/10.1053/j.gastro.2019.09.005.

    Article  CAS  Google Scholar 

  47. 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;68:1025–41. https://doi.org/10.1002/hep.29904.

    Article  CAS  Google Scholar 

  48. Kang HJ, Oh JH, Chun SM, Kim D, Ryu YM, Hwang HS, et al. Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes. J Hepatol. 2019 Jul;71(1):91–103. https://doi.org/10.1016/j.jhep.2019.03.018.

    Article  CAS  Google Scholar 

  49. Ye Q, Ling S, Zheng S, Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol Cancer. 2019;18:114. https://doi.org/10.1186/s12943-019-1043-x.

    Article  CAS  Google Scholar 

  50. Wu X, Li J, Gassa A, Buchner D, Alakus H, Dong Q, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci. 2020;16(9):1551–62. https://doi.org/10.7150/ijbs.44024.

    Article  CAS  Google Scholar 

  51. Liao H, Xiong T, Peng J, Xu L, Liao M, Zhang Z, et al. Classification and prognosis prediction from histopathological images of hepatocellular carcinoma by a fully automated pipeline based on machine learning. Ann Surg Oncol. 2020;27:2359–69. https://doi.org/10.1245/s10434-019-08190-1.

    Article  Google Scholar 

  52. Lu L, Daigle BJ. Prognostic analysis of histopathological images using pre-trained convolutional neural networks: application to hepatocellular carcinoma. Peer J. 2020;8:e8668. https://doi.org/10.7717/peerj.8668.

    Article  Google Scholar 

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  1. Department of Pathology, Faculty of Medicine, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey

    Nese Karadag Soylu

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Karadag Soylu, N. Update on Hepatocellular Carcinoma: a Brief Review from Pathologist Standpoint. J Gastrointest Canc 51, 1176–1186 (2020). https://doi.org/10.1007/s12029-020-00499-5

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