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REVIEW

Understanding the Immunoenvironment of Primary Liver Cancer: A Histopathology Perspective

, & ORCID Icon
Pages 1149-1169 | Received 14 Jul 2022, Accepted 01 Sep 2022, Published online: 02 Nov 2022

References

  • Lokuhetty D, White VA, Watanabe R, Cree IA; World Health Organisation, International Agency for Research on Cancer. The 2019 WHO Classification of Tumours of the Digestive System. 5th ed. Lyon: International Agency for Research on Cancer; 2019.
  • Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
  • Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525–543. doi:10.1038/s41575-021-00438-0
  • Jeng K, Chang C, Jeng W, Sheen I, Jeng C. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol. 2015;94(3):337–347. doi:10.1016/j.critrevonc.2015.01.009
  • Nguyen PHD, Ma S, Phua CZJ, et al. Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat Commun. 2021;12(1):1–13.
  • Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72(2):250–261. doi:10.1016/j.jhep.2019.08.025
  • Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–491.e1. doi:10.1053/j.gastro.2018.08.065
  • Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857
  • Kudo M, Finn RS, Qin S, 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(10126):1163–1173. doi:10.1016/S0140-6736(18)30207-1
  • Rizzo A, Ricci AD, Gadaleta-Caldarola G, Brandi G. First-line immune checkpoint inhibitor-based combinations in unresectable hepatocellular carcinoma: current management and future challenges. Expert Rev Gastroenterol Hepatol. 2021;15(11):1245–1251. doi:10.1080/17474124.2021.1973431
  • Yau T, Park J, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. doi:10.1016/S1470-2045(21)00604-5
  • Finn RS, Ryoo B, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. JCO. 2020;38(3):193–202. doi:10.1200/JCO.19.01307
  • Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745
  • Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070
  • Rizzo A, Ricci AD, Brandi G. Systemic adjuvant treatment in hepatocellular carcinoma: tempted to do something rather than nothing. Future Oncol. 2020;16(32):2587–2589. doi:10.2217/fon-2020-0669
  • De Lorenzo S, Tovoli F, Barbera MA, et al. Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept. Sci Rep. 2018;8(1):1–7. doi:10.1038/s41598-018-28337-6
  • Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14(10):996–1006. doi:10.1038/ni.2691
  • Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13(3):267–276. doi:10.1038/cmi.2016.3
  • Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681–700. doi:10.1038/nrgastro.2015.173
  • Capece D, Fischietti M, Verzella D, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2012;2013:e187204.
  • Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–232. doi:10.1038/s41590-018-0044-z
  • Chew V, Tow C, Teo M, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2010;52(3):370–379. doi:10.1016/j.jhep.2009.07.013
  • Sun C, Sun H, Xiao W, Zhang C, Tian Z. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin. 2015;36(10):1191–1199. doi:10.1038/aps.2015.41
  • Chew V, Chen J, Lee D, et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut. 2012;61(3):427–438. doi:10.1136/gutjnl-2011-300509
  • Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol. 2008;129(3):428–437. doi:10.1016/j.clim.2008.08.012
  • Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29(1):235–271. doi:10.1146/annurev-immunol-031210-101324
  • Wu Y, Kuang D, Pan W, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013;57(3):1107–1116. doi:10.1002/hep.26192
  • Pang Y, Zhang H, Peng J, et al. The immunosuppressive tumor microenvironment in hepatocellular carcinoma. Cancer Immunol Immunother. 2009;58(6):877–886. doi:10.1007/s00262-008-0603-5
  • Kamimura H, Yamagiwa S, Tsuchiya A, et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J Hepatol. 2012;56(2):381–388. doi:10.1016/j.jhep.2011.06.017
  • Hou J, Zhang H, Sun B, Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: basic concepts and therapeutic implications. J Hepatol. 2020;72(1):167–182. doi:10.1016/j.jhep.2019.08.014
  • Heymann F, Peusquens J, Ludwig-Portugall I, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62(1):279–291. doi:10.1002/hep.27793
  • Tian Z, Hou X, Liu W, Han Z, Wei L. Macrophages and hepatocellular carcinoma. Cell Biosci. 2019;9. doi:10.1186/s13578-019-0342-7
  • Yeung OWH, Lo C, Ling C, et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015;62(3):607–616. doi:10.1016/j.jhep.2014.10.029
  • Yu L, Ling Y, Wang H. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2(1):6. doi:10.1038/s41698-018-0048-z
  • Zhu X, Zhang J, Zhuang P, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. JCO. 2008;26(16):2707–2716. doi:10.1200/JCO.2007.15.6521
  • Dong N, Shi X, Wang S, et al. M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer. 2019;121(1):22–33. doi:10.1038/s41416-019-0482-x
  • Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell. 2019;179(4):829–845.e20. doi:10.1016/j.cell.2019.10.003
  • Pagès F, Galon J, Dieu-Nosjean M, Tartour E, Sautès-Fridman C, Fridman W. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2010;29(8):1093–1102. doi:10.1038/onc.2009.416
  • Zheng C, Zheng L, Yoo J, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017;169(7):1342–1356.e16. doi:10.1016/j.cell.2017.05.035
  • Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology. 2017;153(4):1107–1119.e10. doi:10.1053/j.gastro.2017.06.017
  • Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58–67. doi:10.1182/blood-2017-06-741033
  • Chen D, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10. doi:10.1016/j.immuni.2013.07.012
  • Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 2017;66(2):342–351. doi:10.1136/gutjnl-2015-310814
  • Shao Y, Lo CM, Ling CC, et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett. 2014;355(2):264–272. doi:10.1016/j.canlet.2014.09.026
  • Kessel A, Haj T, Peri R, et al. Human CD19+CD25high B regulatory cells suppress proliferation of CD4+ T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun Rev. 2012;11(9):670–677. doi:10.1016/j.autrev.2011.11.018
  • Zhang Z, Ma L, Goswami S, et al. Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma. OncoImmunology. 2019;8(4):e1571388. doi:10.1080/2162402X.2019.1571388
  • Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer. Science. 2022;375. doi:10.1126/science.abf9419
  • Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307–325. doi:10.1038/s41568-019-0144-6
  • Fridman WH, Zitvogel L, Sautès–Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–734. doi:10.1038/nrclinonc.2017.101
  • Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561–565. doi:10.1038/s41586-019-1914-8
  • Di Caro G, Bergomas F, Grizzi F, et al. Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin Cancer Res. 2014;20(8):2147–2158. doi:10.1158/1078-0432.CCR-13-2590
  • Liu X, Tsang JYS, Hlaing T, et al. Distinct tertiary lymphoid structure associations and their prognostic relevance in HER2 positive and negative breast cancers. Oncologist. 2017;22(11):1316–1324. doi:10.1634/theoncologist.2017-0029
  • Dieu-Nosjean M, Goc J, Giraldo NA, Sautès-Fridman C, Fridman WH. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 2014;35(11):571–580. doi:10.1016/j.it.2014.09.006
  • Colbeck EJ, Ager A, Gallimore A, Jones GW. Tertiary lymphoid structures in cancer: drivers of antitumor immunity, immunosuppression, or bystander sentinels in disease? Front Immunol. 2017;8. doi:10.3389/fimmu.2017.01830
  • Calderaro J, Petitprez F, Becht E, et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 2019;70(1):58–65. doi:10.1016/j.jhep.2018.09.003
  • Li H, Wang J, Liu H, et al. Existence of intratumoral tertiary lymphoid structures is associated with immune cells infiltration and predicts better prognosis in early-stage hepatocellular carcinoma. Aging. 2020;12(4):3451–3472. doi:10.18632/aging.102821
  • Li H, Liu H, Fu H, et al. Peritumoral tertiary lymphoid structures correlate with protective immunity and improved prognosis in patients with hepatocellular carcinoma. Front Immunol. 2021;12:648812.
  • Finkin S, Yuan D, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 2015;16(12):1235–1244. doi:10.1038/ni.3290
  • Hoshida Y, Nijman SMB, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–7392. doi:10.1158/0008-5472.CAN-09-1089
  • Boyault S, Rickman DS, de Reyniès A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42–52. doi:10.1002/hep.21467
  • Kudo M. Limited impact of anti-PD-1/PD-L1 monotherapy for hepatocellular carcinoma. LIC. 2020;9(6):629–639.
  • Kurebayashi Y, Ojima H, Tsujikawa H, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology. 2018;68(3):1025–1041. doi:10.1002/hep.29904
  • Calderaro J, Rousseau B, Amaddeo G, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016;64(6):2038–2046. doi:10.1002/hep.28710
  • Foerster F, Hess M, Gerhold-Ay A, et al. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci Rep. 2018;8(1):1–11. doi:10.1038/s41598-018-21937-2
  • Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153(3):812–826. doi:10.1053/j.gastro.2017.06.007
  • Shimada S, Mogushi K, Akiyama Y, et al. Comprehensive molecular and immunological characterization of hepatocellular carcinoma. EBioMedicine. 2019;40:457–470. doi:10.1016/j.ebiom.2018.12.058
  • Kurebayashi Y, Kubota N, Sakamoto M. Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: relationship with histopathological and molecular classifications. Hepatol Res. 2021;51(1):5–18. doi:10.1111/hepr.13539
  • Zhang Q, Lou Y, Yang J, et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut. 2019;68(11):2019–2031. doi:10.1136/gutjnl-2019-318912
  • Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label Phase 2 trial. Lancet Oncol. 2018;19(7):940–952. doi:10.1016/S1470-2045(18)30351-6
  • Xue R, Li R, Guo H, et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):998–1008. doi:10.1053/j.gastro.2015.12.033
  • Vij M, Calderaro J. Pathologic and molecular features of hepatocellular carcinoma: an update. World J Hepatol. 2021;13(4):393–410. doi:10.4254/wjh.v13.i4.393
  • Calderaro J, Ziol M, Paradis V, Zucman-Rossi J. Molecular and histological correlations in liver cancer. J Hepatol. 2019;71(3):616–630. doi:10.1016/j.jhep.2019.06.001
  • Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 1998;27(2):407–414. doi:10.1002/hep.510270214
  • Chan AWH, Tong JHM, Pan Y, et al. Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome. Am J Surg Pathol. 2015;39(3):304–312. doi:10.1097/PAS.0000000000000376
  • 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(5):737–746. doi:10.1016/j.humpath.2011.07.005
  • Salomao M, Yu WM, Brown RS, 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(11):1630–1636. doi:10.1097/PAS.0b013e3181f31caa
  • Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51(5):1820–1832. doi:10.1002/hep.23594
  • Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017;67(4):727–738. doi:10.1016/j.jhep.2017.05.014
  • Ziol M, Poté N, Amaddeo G, et al. Macrotrabecular-massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance. Hepatology. 2018;68(1):103–112. doi:10.1002/hep.29762
  • Calderaro J, Meunier L, Nguyen CT, et al. ESM1 as a marker of macrotrabecular-massive hepatocellular carcinoma. Clin Cancer Res. 2019;25(19):5859–5865. doi:10.1158/1078-0432.CCR-19-0859
  • Nagata H, Komatsu S, Takaki W, et al. Granulocyte colony-stimulating factor-producing hepatocellular carcinoma with abrupt changes. World J Clin Oncol. 2016;7(5):380–386. doi:10.5306/wjco.v7.i5.380
  • Araki K, Kishihara F, Takahashi K, et al. Hepatocellular carcinoma producing a granulocyte colony-stimulating factor: report of a resected case with a literature review. Liver Int. 2007;27(5):716–721. doi:10.1111/j.1478-3231.2007.01468.x
  • Torbenson MS. Morphologic subtypes of hepatocellular carcinoma. Gastroenterol Clin North Am. 2017;46(2):365–391. doi:10.1016/j.gtc.2017.01.009
  • Ross HM, Daniel HD, Vivekanandan P, et al. Fibrolamellar carcinomas are positive for CD68. Mod Pathol. 2011;24(3):390–395. doi:10.1038/modpathol.2010.207
  • Ward SC, Huang J, Tickoo SK, Thung SN, Ladanyi M, Klimstra DS. Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation. Mod Pathol. 2010;23(9):1180–1190. doi:10.1038/modpathol.2010.105
  • Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343:1010–1014. doi:10.1126/science.1249484
  • Vyas M, Hechtman JF, Zhang Y, et al. DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. Mod Pathol. 2020;33(4):648–656. doi:10.1038/s41379-019-0398-2
  • Kim AK, Gani F, Layman AJ, et al. Multiple immune-suppressive mechanisms in fibrolamellar carcinoma. Cancer Immunol Res. 2019;7(5):805–812. doi:10.1158/2326-6066.CIR-18-0499
  • Murtha-Lemekhova A, Fuchs J, Schulz E, et al. Scirrhous hepatocellular carcinoma: systematic review and pooled data analysis of clinical, radiological, and histopathological features. J Hepatocell Carcinoma. 2021;8:1269–1279. doi:10.2147/JHC.S328198
  • Kim Y, Rhee H, Yoo JE, et al. Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma. Histopathology. 2017;71(2):217–226. doi:10.1111/his.13219
  • Kurogi M, Nakashima O, Miyaaki H, Fujimoto M, Kojiro M. Clinicopathological study of scirrhous hepatocellular carcinoma. J Gastroenterol Hepatol. 2006;21(9):1470–1477. doi:10.1111/j.1440-1746.2006.04372.x
  • Wood LD, Heaphy CM, Daniel HD, 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(12):1586–1593. doi:10.1038/modpathol.2013.68
  • Kang HJ, Oh J, Kim YW, et al. Clinicopathological and molecular characterization of chromophobe hepatocellular carcinoma. Liver Int. 2021;41(10):2499–2510. doi:10.1111/liv.14975
  • Dilley RL, Greenberg RA. ALTernative telomere maintenance and cancer. Trends Cancer. 2015;1(2):145–156. doi:10.1016/j.trecan.2015.07.007
  • Zhang J, Zou L. Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks. Cell Biosci. 2020;10. doi:10.1186/s13578-020-00391-6
  • Li T, Fan J, Qin L, 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(7):1955–1963. doi:10.1245/s10434-010-1540-z
  • Lee JH, Shin DH, Park WY, et al. IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing. World J Surg Oncol. 2017;15. doi:10.1186/s12957-017-1144-1
  • Yang H, Lu S, Liaw Y, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347(3):168–174. doi:10.1056/NEJMoa013215
  • Saito I, Miyamura T, Ohbayashi A, et al. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990;87(17):6547–6549. doi:10.1073/pnas.87.17.6547
  • El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264–1273.e1. doi:10.1053/j.gastro.2011.12.061
  • Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut. 2019;68(5):916–927. doi:10.1136/gutjnl-2018-316510
  • Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–257. doi:10.1038/nature16969
  • Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26(4):549–564. doi:10.1016/j.ccell.2014.09.003
  • van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018;68(4):1347–1360. doi:10.1002/hep.29914
  • Oquiñena S, Guillen-Grima F, Iñarrairaegui M, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: a systematic review. Eur J Gastroenterol Hepatol. 2009;21(3):254–257. doi:10.1097/MEG.0b013e328324b6a2
  • Cole WH, Everson TC. Spontaneous regression of cancer: preliminary report. Ann Surg. 1956;144(3):366–383. doi:10.1097/00000658-195609000-00007
  • Sakamaki A, Kamimura K, Abe S, et al. Spontaneous regression of hepatocellular carcinoma: a mini-review. World J Gastroenterol. 2017;23(21):3797–3804. doi:10.3748/wjg.v23.i21.3797
  • Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB. 2012;14(8):500–505. doi:10.1111/j.1477-2574.2012.00478.x
  • McCaughan GW, Bilous MJ, Gallagher ND. Long-term survival with tumor regression in androgen-induced liver tumors. Cancer. 1985;56(11):2622–2626. doi:10.1002/1097-0142(19851201)56:11<2622::AID-CNCR2820561115>3.0.CO;2-0
  • Abiru S, Kato Y, Hamasaki K, Nakao K, Nakata K, Eguchi K. Spontaneous regression of hepatocellular carcinoma associated with elevated levels of interleukin 18. Am J Gastroenterol. 2002;97(3):774–775. doi:10.1111/j.1572-0241.2002.05580.x
  • Ohba K, Omagari K, Nakamura T, et al. Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metastasis. Gut. 1998;43(4):575–577. doi:10.1136/gut.43.4.575
  • Jozuka H, Jozuka E, Suzuki M, Takeuchi S, Takatsu Y. Psycho-neuro-immunological treatment of hepatocellular carcinoma with major depression--A single case report. Curr Med Res Opin. 2003;19(1):59–63. doi:10.1185/030079902125001362
  • Arjunan V, Hansen A, Deutzmann A, Sze DY, Dhanasekaran R. Spontaneous regression of hepatocellular carcinoma: when the immune system stands up to cancer. Hepatology. 2021;73(4):1611–1614. doi:10.1002/hep.31489
  • Pectasides E, Miksad R, Pyatibrat S, Srivastava A, Bullock A. Spontaneous regression of hepatocellular carcinoma with multiple lung metastases: a case report and review of the literature. Dig Dis Sci. 2016;61(9):2749–2754. doi:10.1007/s10620-016-4141-2
  • Heianna J, Miyauchi T, Suzuki T, Ishida H, Hashimoto M, Watarai J. Spontaneous regression of multiple lung metastases following regression of hepatocellular carcinoma after transcatheter arterial embolization. A case report. Hepatogastroenterology. 2007;54(77):1560–1562.
  • Lendvai G, Szekerczés T, Illyés I, et al. Cholangiocarcinoma: classification, histopathology and molecular carcinogenesis. Pathol Oncol Res. 2020;26(1):3–15. doi:10.1007/s12253-018-0491-8
  • Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019;39(S1):19–31. doi:10.1111/liv.14095
  • Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med. 2007;4(7):e201. doi:10.1371/journal.pmed.0040201
  • Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145(6):1215–1229. doi:10.1053/j.gastro.2013.10.013
  • Bragazzi MC, Ridola L, Safarikia S, et al. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol. 2018;31(1):42–55. doi:10.20524/aog.2017.0209
  • Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54(1):173–184. doi:10.1002/hep.24351
  • Guedj N, Blaise L, Cauchy F, Albuquerque M, Soubrane O, Paradis V. Prognostic value of desmoplastic stroma in intrahepatic cholangiocarcinoma. Mod Pathol. 2021;34(2):408–416. doi:10.1038/s41379-020-00656-y
  • Comito G, Giannoni E, Segura CP, et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33(19):2423–2431. doi:10.1038/onc.2013.191
  • Gentilini A, Pastore M, Marra F, Raggi C. The role of stroma in cholangiocarcinoma: the intriguing interplay between fibroblastic component, immune cell subsets and tumor epithelium. Int J Mol Sci. 2018;19(10):2885. doi:10.3390/ijms19102885
  • Hasita H, Komohara Y, Okabe H, et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010;101(8):1913–1919. doi:10.1111/j.1349-7006.2010.01614.x
  • Whiteside TL. What are regulatory T cells (treg) regulating in cancer and why? Semin Cancer Biol. 2012;22(4):327–334. doi:10.1016/j.semcancer.2012.03.004
  • Zhang M, Yang H, Wan L, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol. 2020;73(5):1118–1130. doi:10.1016/j.jhep.2020.05.039
  • Goeppert B, Frauenschuh L, Zucknick M, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013;109(10):2665–2674. doi:10.1038/bjc.2013.610
  • Liu D, Heij LR, Czigany Z, et al. The role of tumor-infiltrating lymphocytes in cholangiocarcinoma. J Exp Clin Cancer Res. 2022;41(1):127. doi:10.1186/s13046-022-02340-2
  • Yugawa K, Itoh S, Yoshizumi T, et al. Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes. Mod Pathol. 2021;34(4):798–807. doi:10.1038/s41379-020-00702-9
  • Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557–588. doi:10.1038/s41575-020-0310-z
  • Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45(8):1630–1638. doi:10.1016/j.humpath.2014.03.014
  • Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–79. doi:10.1634/theoncologist.2011-0386
  • Yoon JG, Kim MH, Jang M, et al. Molecular characterization of biliary tract cancer predicts chemotherapy and programmed death 1/programmed death-ligand 1 blockade responses. Hepatology. 2021;74(4):1914–1931. doi:10.1002/hep.31862
  • Wang J, Dong M, Xu Z, et al. Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene. 2018;37(24):3229–3242. doi:10.1038/s41388-018-0188-1
  • Guest RV, Boulter L, Kendall TJ, et al. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res. 2014;74(4):1005–1010. doi:10.1158/0008-5472.CAN-13-1911
  • Komuta M, Spee B, Vander Borght S, et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology. 2008;47(5):1544–1556. doi:10.1002/hep.22238
  • Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142(4):1021–1031.e15. doi:10.1053/j.gastro.2011.12.005
  • Cardinale V, Renzi A, Carpino G, et al. Profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am J Pathol. 2015;185(6):1724–1739. doi:10.1016/j.ajpath.2015.02.010
  • Carapeto F, Bozorgui B, Shroff RT, et al. The immunogenomic landscape of resected intrahepatic cholangiocarcinoma. Hepatology. 2022;75(2):297–308. doi:10.1002/hep.32150
  • Piha-Paul SA, Oh D, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147(8):2190–2198. doi:10.1002/ijc.33013
  • Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144(4):829–840. doi:10.1053/j.gastro.2013.01.001
  • Job S, Rapoud D, Santos AD, et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology. 2020;72(3):965–981. doi:10.1002/hep.31092
  • Fontugne J, Augustin J, Pujals A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget. 2017;8(15):24644–24651. doi:10.18632/oncotarget.15602
  • Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18(3):197–218. doi:10.1038/s41573-018-0007-y
  • Oishi N, Kumar MR, Roessler S, et al. Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatology. 2012;56(5):1792–1803. doi:10.1002/hep.25890
  • Ding G, Ma J, Yun J, et al. Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma. J Hepatol. 2022;76(3):608–618. doi:10.1016/j.jhep.2021.10.030
  • Martin-Serrano MA, Kepecs B, Torres-Martin M, et al. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut. 2022;gutjnl-2021–326514. doi:10.1136/gutjnl-2021-326514
  • Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European network for the study of cholangiocarcinoma (ENS-CCA). Nat Rev. 2016;13(5):261–280. doi:10.1038/nrgastro.2016.51
  • Kitano Y, Okabe H, Yamashita Y, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer. 2018;118(2):171–180. doi:10.1038/bjc.2017.401
  • Lim YJ, Koh J, Kim K, et al. High ratio of programmed cell death protein 1 (PD-1)+/CD8+ tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy. Radiother Oncol. 2015;117(1):165–170. doi:10.1016/j.radonc.2015.07.003
  • Walter D, Herrmann E, Schnitzbauer AA, et al. PD-L1 expression in extrahepatic cholangiocarcinoma. Histopathology. 2017;71(3):383–392. doi:10.1111/his.13238
  • Montal R, Sia D, Montironi C, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol. 2020;73(2):315–327. doi:10.1016/j.jhep.2020.03.008
  • Goodman ZD, Ishak KG, Langloss JM, Sesterhenn IA, Rabin L. Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study. Cancer. 1985;55(1):124–135. doi:10.1002/1097-0142(19850101)55:1<124::AID-CNCR2820550120>3.0.CO;2-Z
  • Kassahun WT, Hauss J. Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract. 2008;62(8):1271–1278. doi:10.1111/j.1742-1241.2007.01694.x
  • Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. J Gastroenterol Hepatol. 2010;25(9):1485–1492. doi:10.1111/j.1440-1746.2010.06430.x
  • Sapisochin G, Fidelman N, Roberts JP, Yao FY. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transplant. 2011;17(8):934–942. doi:10.1002/lt.22307
  • Lunsford KE, Court C, Lee YS, et al. Propensity-matched analysis of patients with mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing liver transplantation. Liver Transplant. 2018;24(10):1384–1397. doi:10.1002/lt.25058
  • Garancini M, Goffredo P, Pagni F, et al. Combined hepatocellular-cholangiocarcinoma: a population-level analysis of an uncommon primary liver tumor. Liver Transplant. 2014;20(8):952–959. doi:10.1002/lt.23897
  • Nguyen CT, Caruso S, Maille P, et al. Immune profiling of combined hepatocellular- cholangiocarcinoma reveals distinct subtypes and activation of gene signatures predictive of response to immunotherapy. Clin Cancer Res. 2022;28(3):540–551. doi:10.1158/1078-0432.CCR-21-1219
  • Lu S, Stein JE, Rimm DL, et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis. JAMA Oncol. 2019;5(8):1195–1204. doi:10.1001/jamaoncol.2019.1549
  • Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70(1):46–58. doi:10.1016/j.ymeth.2014.08.016
  • Gerner M, Kastenmuller W, Ifrim I, Kabat J, Germain R. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity. 2012;37(2):364–376. doi:10.1016/j.immuni.2012.07.011
  • Li W, Germain RN, Gerner MY. Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (Ce3D). Proc Natl Acad Sci U S A. 2017;114(35):E7321–E7330. doi:10.1073/pnas.1708981114
  • Widodo SS, Hutchinson RA, Fang Y, et al. Toward precision immunotherapy using multiplex immunohistochemistry and in silico methods to define the tumor immune microenvironment. Cancer Immunol Immunother. 2021;70(7):1811–1820. doi:10.1007/s00262-020-02801-7
  • Sabdyusheva Litschauer I, Becker K, Saghafi S, et al. 3D histopathology of human tumours by fast clearing and ultramicroscopy. Sci Rep. 2020;10(1):1–16. doi:10.1038/s41598-020-71737-w
  • Weinstein RS. Prospects for telepathology. Hum Pathol. 1986;17(5):433–434. doi:10.1016/S0046-8177(86)80028-4
  • Pallua JD, Brunner A, Zelger B, Schirmer M, Haybaeck J. The future of pathology is digital. Pathology. 2020;216(9):153040. doi:10.1016/j.prp.2020.153040
  • Araújo ALD, Arboleda LPA, Palmier NR, et al. The performance of digital microscopy for primary diagnosis in human pathology: a systematic review. Virchows Arch. 2019;474(3):269–287. doi:10.1007/s00428-018-02519-z
  • Fuchs TJ, Buhmann JM. Computational pathology: challenges and promises for tissue analysis. Comput Med Imaging Graph. 2011;35(7):515–530. doi:10.1016/j.compmedimag.2011.02.006
  • van der Laak J, Litjens G, Ciompi F. Deep learning in histopathology: the path to the clinic. Nat Med. 2021;27(5):775–784. doi:10.1038/s41591-021-01343-4
  • Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A. Artificial intelligence in digital pathology — new tools for diagnosis and precision oncology. Nat Rev Clin Oncol. 2019;16(11):703–715. doi:10.1038/s41571-019-0252-y
  • Niazi MKK, Parwani AV, Gurcan MN. Digital pathology and artificial intelligence. Lancet Oncol. 2019;20(5):e253–e261. doi:10.1016/S1470-2045(19)30154-8
  • Ehteshami Bejnordi B, Veta M, Johannes van Diest P, et al. Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer. JAMA. 2017;318(22):2199–2210. doi:10.1001/jama.2017.14585
  • Kelly CJ, Karthikesalingam A, Suleyman M, Corrado G, King D. Key challenges for delivering clinical impact with artificial intelligence. BMC Med. 2019;17(1):195. doi:10.1186/s12916-019-1426-2
  • Abels E, Pantanowitz L, Aeffner F, et al. Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the digital pathology association. J Pathol. 2019;249(3):286–294. doi:10.1002/path.5331