Skip to main content
SpringerLink
Log in

Hepatocellular Carcinoma Pathology

  • Reference work entry
  • First Online:
Hepato-Pancreato-Biliary Malignancies

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Background cirrhosis is present in the majority of cases. Important clinical information needed at the time of surgery includes: (1) etiology of the underlying chronic liver disease, (2) location of tumor nodules on imaging, (3) history of neoadjuvant therapy and type of therapy, and (4) the presence or absence of a transjugular intrahepatic porto-systemic shunt (TIPS). Pathologists diagnose hepatocellular carcinoma using surgical resection specimens, core biopsies, or fine needle aspiration biopsy (FNAB). Microscopically, HCC resembles the normal liver but with important exceptions, such as the lack of portal tracts, expansion of hepatic trabeculae to three or more cells thick, loss of reticulin fibers, and cytologic atypia. HCC is the only malignancy that makes bile, a useful diagnostic clue if other malignancies are considered. There are histologic subtypes of HCC with distinct molecular alterations, and some subtypes have a better prognosis than others. Immunohistochemistry can confirm the diagnosis of HCC in difficult cases or differentiate HCC from other tumors that mimic HCC histologically. HCC has characteristic genomic mutations, and a molecular classification of HCC has been proposed with high proliferation and nonproliferation subtypes. Various histologic grading and staging systems are used to evaluate the extent of cancer, disease severity, predict survival, and ultimately drive therapy. Pathologists play a critical role in the diagnosis and staging of hepatocellular carcinoma, and with the ongoing discovery of novel prognostic biomarkers, pathologists are expanding their role into tumor prognosis and treatment optimization.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 329.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    CAS  Google Scholar 

  2. Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma in cirrhotic and non-cirrhotic liver: a clinic-histopathologic study of 804 North American patients. Am J Clin Pathol. 1996;105:65–75.

    CAS  Google Scholar 

  3. Thorgeirsson S, Grisham J. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–46.

    CAS  Google Scholar 

  4. Torrecilla S, Sia D, Harrington AN, et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol. 2017;67:1222–31.

    Google Scholar 

  5. Satyanarayana A, Manns MP, Rudolph KL. Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology. 2004;40:276–83.

    CAS  Google Scholar 

  6. Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.

    CAS  Google Scholar 

  7. Schulze K, Nault J-C, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol. 2016;65:1031–42.

    CAS  Google Scholar 

  8. 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;44:694–8.

    CAS  Google Scholar 

  9. Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44:1117–21.

    CAS  Google Scholar 

  10. Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–33.

    CAS  Google Scholar 

  11. Kim YC, Kim YH, Uhm SH, Seo YS, Park EK, Oh SY, Jeong E, Lee S, Choe JG. Radiation safety issues in Y-90 microsphere selective hepatic radioembolization therapy: possible radiation exposure from the patients. Nucl Med Mol Imaging. 2010;44(4):252–60.

    CAS  Google Scholar 

  12. Torbenson M, Zen Y, Yeh MM. Hepatocellular carcinoma. In: Tumors of the liver. AFIP Atlas of tumor pathology series 4, vol. 27. Washington, DC: ARP Press; 2018.

    Google Scholar 

  13. Madaleno J, Alves R, Silva N, Calretas S, Tome L, Ferrao J, Barros A, Diogo D, Cipriano A, Furtado E, Carvalho A. Incidentally discovered hepatocellular carcinoma in explanted liver: clinical, histopathologic features and outcome. Transplant Proc. 2015;47(4):1051–4.

    CAS  Google Scholar 

  14. Pinero F, Mendizabal M, Casciato P, Galdame O, Quiros R, Bandi J, Mullen E, Andriani O, de Santibanes E, Podesta LG, Gadano A, Silva M. Is recurrence rate of incidental hepatocellular carcinoma after liver transplantation similar to previously known HCC? Towards a predictive recurrence score. Ann Hepatol. 2014;13(2):211–8.

    Google Scholar 

  15. Perez P, Rodriguez-Peralvarez M, Guerrero L, Gonzalez V, Sanchez R, Centeno M, Poyato A, Briceno J, Sanchez-Frias M, Montero JL, de la Mata M. Incidental hepatocellular carcinoma after liver transplantation: Prevalence, histopathological features and prognostic impact. PLoS One. 2017;12(4):e0175010.

    Google Scholar 

  16. Patel N, Sharma B, Samant H (2020) Cryptogenic cirrhosis. [Updated 2020 Jun 25]. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534228/. Accessed 16 Aug 2020.

  17. Shafizadeh N, Ferrell LD, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol. 2008;21:1011–8.

    CAS  Google Scholar 

  18. Di Tommaso L, Franchi G, Park YN, et al. Diagnostic value of HSP70, glypican-3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology. 2007;45:725–34.

    Google Scholar 

  19. Niu ZS, Niu XJ, Wang WH, Zhao J. Latest developments in precancerous lesions of hepatocellular carcinoma. World J Gastroenterol. 2016;22(12):3305–14.

    CAS  Google Scholar 

  20. Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013;58:1693–702.

    CAS  Google Scholar 

  21. Park YN, Roncalli M. Large liver cell dysplasia: a controversial entity. J Hepatol. 2006;45:734–43.

    Google Scholar 

  22. Védie AL, Sutter O, Zioi M, Nault JC. Molecular classification of hepatocellular adenomas: impact on clinical practice. Hepat Oncol. 2018;5(1):HEP04.

    Google Scholar 

  23. Kakar S (2018) Evidence-based immunohistochemical panels for the diagnosis of well-differentiated hepatocellular neoplasms (Lecture). Park City AP Update, Park City UT, February 3–7, 2018.

    Google Scholar 

  24. Torbenson MS, Ng IOL, Park YN, Roncalli M, Sakamato M 2019 Hepatocellular carcinoma. Section: tumours of the liver and intrahepatic bile ducts. In: Digestive system tumours. W.H.O. classification of tumours, 5th ed. WHO Classification of Tumours Editorial Board. International agency for Research on Cancer, Lyon (France), 2019.

    Google Scholar 

  25. Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and tumour-like lesions of the liver. In: Burt AD, Ferrell LD, Hübscher SG, editors. MacSween’s pathology of the liver. 7th ed. Philadelphia: Elsevier; 2017.

    Google Scholar 

  26. Krings G, Ramachandran R, Jain D, Wu TT, Yeh MM, Torbenson M, Kakar S. Immunohistochemical pitfalls and the importance of glypican-3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol. 2013;26:782–91.

    CAS  Google Scholar 

  27. Kakizoe S, Kojiro M, Nakashima T. Hepatocellular carcinoma with sarcomatous change. Clinicopathologic and immunohistochemical studies in 14 autopsy cases. Cancer. 1987;59(2):310–6.

    CAS  Google Scholar 

  28. Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR, D’Angelica M, Abou-Alfa G, Blumgart LH, DeMatteo RP. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer. 2006;106(6):1331–8.

    Google Scholar 

  29. 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(11):1417–23.

    Google Scholar 

  30. Ross HM, Danial HDJ, Vivekanandan P, Kannangai R, Yeh MM, Wu TT, Makhlouf HR, Torbenson M. Fibrolamellar carcinomas are positive for CD68. Mod Pathol. 2011;24(3):390–5.

    CAS  Google Scholar 

  31. Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim IIP, Gleason CE, Murphy JM, Rosenberg BR, Teegan L, Takacs CN, Botero S, Belote R, Germer S, Emde AK, Vacic V, Bhanot U, LaQuaglia MP, Simon SM. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010–4.

    CAS  Google Scholar 

  32. Klein WM, Molmenti EP, Colombani PM, Grover DS, Schwarz KB, Boitnott J, Torbenson MS. Primary liver carcinoma arising in people younger than 30 years. Am J Clin Pathol. 2005;124(4):512–8.

    Google Scholar 

  33. Stevens WR, Johnson CD, Stephens DH, Nagorney DM. Fibrolamellar hepatocellular carcinoma: stage at presentation and results of aggressive surgical management. AJR Am J Roentgenol. 1995;164(5):1153–8.

    CAS  Google Scholar 

  34. Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara A, Rosenthal H, Bridge JA. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol. 2001;25(5):684–7.

    CAS  Google Scholar 

  35. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.

    CAS  Google Scholar 

  36. Burgart LJ, Shi C, Fitzgibbons PL, Frankel WL, Kakar S, Krasinskas AM, Mino-Kenudson M, Pawlik T, Vauthey JN, Washington MK. Protocol for the examination of specimens from patients with hepatocellular carcinoma. Version: Hepatocellular 4.1.0.0, protocol posting date: February 2020. http://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates. Accessed 11 Aug 2020.

  37. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. NEJM. 1996;334(11):693–9.

    CAS  Google Scholar 

  38. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394–403.

    CAS  Google Scholar 

  39. Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant. 2008;8(10):1982–9.

    CAS  Google Scholar 

  40. Abou-Alfa GK, Pawlik TM, Shindoh J, Vauthey JN. Liver. In: Amin MB, Ege SB, Greene FL, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017. p. 287–93.

    Google Scholar 

  41. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, Durnez A, Demetris AJ, Thorgeirsson SS. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40(3):667–76. https://doi.org/10.1002/hep.20375. PMID: 15349906

    Article  CAS  Google Scholar 

  42. Lau SH, Sham JST, Xie D, Tzang C-H, Tang D, Ma N, Hu L, Wang Y, Wen J-M, Xiao G, Zhang W-M, Lau GKK, Yang M, Guan X-Y. Clusterin plays an important role in hepatocellular carcinoma metastasis. Oncogene. 2006;25:1242–50.

    CAS  Google Scholar 

  43. Cao L, Cheng H, Jiang Q, Li H, Wu Z. APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma. Aging (Albany NY). 2020;12(5):4573–91.

    CAS  Google Scholar 

  44. Shen H, Wang Z, Ren S, Wang W, Duan L, Zhu D, Zhang C, Duan Y. Prognostic biomarker MITD1 and its correlation with immune infiltrates in hepatocellular carcinoma (HCC). Int Immunopharmacol. 2020;81(4):106222. https://doi.org/10.1016/j.intimp.2020.106222. ISSN 1567-5769

    Article  CAS  Google Scholar 

  45. Tan C, Cao J, Chen J, Xi X, Wang S, Zhu Y, Yang L, Ma L, Wang D, Yin J, Zhang T, Lu ZJ. Noncoding RNAs serve as diagnosis and prognosis biomarkers for hepatocellular carcinoma. Clin Chem. 2019;65(7):905–15.

    CAS  Google Scholar 

  46. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149:e1224.

    Google Scholar 

  47. Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 2014;4:730–43.

    CAS  Google Scholar 

  48. Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell. 2011;19:347–58.

    CAS  Google Scholar 

  49. Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019;25(7):2116–26.

    CAS  Google Scholar 

  50. Dominguez DA, Wang XW. Impact of next-generation sequencing on outcomes in hepatocellular carcinoma: how precise are we really? J Hepatocell Carcinoma. 2020;7:33–7.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Einstein Medical Center – Philadelphia, Philadelphia, PA, USA

    Ronald Miick, Corrado Minimo & Alessandro Bombonati

Authors
  1. Ronald Miick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corrado Minimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandro Bombonati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald Miick .

Editor information

Editors and Affiliations

  1. Medical Director, Capital Health Cancer Center, Director, CH Pancreas Center of Excellence, Director, CH Liver Center of Excellence, Pennington, NJ, USA

    Cataldo Doria

  2. Director of Interventional Gastroenterology, Capital Health Medical Center, Pennington, NJ, USA

    Jason N. Rogart

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Miick, R., Minimo, C., Bombonati, A. (2022). Hepatocellular Carcinoma Pathology. In: Doria, C., Rogart, J.N. (eds) Hepato-Pancreato-Biliary Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-41683-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-41683-6_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-41682-9

  • Online ISBN: 978-3-030-41683-6

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation