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ANATOMICAL PATHOLOGY| Volume 55, ISSUE 4, P508-513, June 2023

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IgG4 expression and IgG4/IgG ratio in the tumour invasion front predict long-term outcomes for patients with intrahepatic cholangiocarcinoma

Published:February 24, 2023DOI:https://doi.org/10.1016/j.pathol.2022.11.007

      Summary

      IgG4-positive plasma cells are reportedly increased in the tumour microenvironment, and a high number of these cells in tumours is a poor prognostic factor in several cancers. However, there are no reported analyses of IgG4 expression in intrahepatic cholangiocarcinoma (ICC). This study aimed to analyse the correlations between prognosis-related clinicopathological features of patients with ICC and IgG4 expression. We identified 37 ICC patients who underwent surgical resection between January 2010 and December 2020. The number of IgG-positive and IgG4-positive plasma cells in the tumour, invasion front, and stroma near the tumour was analysed by immunostaining. Furthermore, we examined the association of prognosis-related clinicopathological data with the number of IgG4-positive plasma cells and IgG4/IgG ratio in ICC patients. The IgG4-positive plasma cell percentages for the intra-tumour area, invasion front, and non-cancerous area (NCA) near the tumour were 91.9%, 56.8%, and 81.1%, respectively. IgG-positive plasma cells were observed in each region for all cases, except for NCA tissue in one case. A high IgG4 expression level and IgG4/IgG ratio in the invasion front were significantly associated with poor overall survival (OS) (log-rank test p=0.0438 and p=0.0338, respectively). Multivariate analysis for OS revealed that high IgG4 expression (p=0.0140), lymph node metastasis (p=0.0205), and positive surgical margin (p=0.0009) or a high IgG4/IgG ratio (p=0.0051), lymph node metastasis (p=0.0280), and positive surgical margin (p=0.0009) were independent poor prognostic factors. In conclusion, a high IgG4 expression level and IgG4/IgG ratio in the invasion front are independent poor prognostic factors for ICC. Targeted therapy for IgG4 may improve the prognosis for patients with ICC.

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      References

        • Tyson G.L.
        • El-Serag H.B.
        Risk factors for cholangiocarcinoma.
        Hepatology. 2011; 54: 173-184
        • Bergquist A.
        • von Seth E.
        Epidemiology of cholangiocarcinoma.
        Best Pract Res Clin Gastroenterol. 2015; 29: 221-232
        • Bertuccio P.
        • Malvezzi M.
        • Carioli G.
        • et al.
        Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.
        J Hepatol. 2019; 71: 104-114
        • Florio A.A.
        • Ferlay J.
        • Znaor A.
        • et al.
        Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
        Cancer. 2020; 126: 2666-2678
        • Marin J.J.G.
        • Prete M.G.
        • Lamarca A.
        • et al.
        Current and novel therapeutic opportunities for systemic therapy in biliary cancer.
        Br J Cancer. 2020; 123: 1047-1059
        • Mavros M.N.
        • Economopoulos K.P.
        • Alexiou V.G.
        • Pawlik T.M.
        Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis.
        JAMA Surg. 2014; 149: 565-574
        • Brahmer J.
        • Reckamp K.L.
        • Baas P.
        • et al.
        Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
        N Engl J Med. 2015; 373: 123-135
        • Postow M.A.
        • Chesney J.
        • Pavlick A.C.
        • et al.
        Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
        N Engl J Med. 2015; 372: 2006-2017
        • Kang Y.K.
        • Boku N.
        • Satoh T.
        • et al.
        Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2017; 390: 2461-2471
        • Galon J.
        • Bruni D.
        Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.
        Nat Rev Drug Discov. 2019; 18: 197-218
        • Carapeto F.
        • Bozorgui B.
        • Shroff R.T.
        • et al.
        The immunogenomic landscape of resected intrahepatic cholangiocarcinoma.
        Hepatology. 2022; 75: 297-308
        • Huang Y.H.
        • Zhang C.Z.
        • Huang Q.S.
        • et al.
        Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma.
        J Hepatol. 2021; 74: 838-849
        • Helmink B.A.
        • Reddy S.M.
        • Gao J.
        • et al.
        B cells and tertiary lymphoid structures promote immunotherapy response.
        Nature. 2020; 577: 549-555
        • Petitprez F.
        • de Reyniès A.
        • Keung E.Z.
        • et al.
        B cells are associated with survival and immunotherapy response in sarcoma.
        Nature. 2020; 577: 556-560
        • Wang H.
        • Xu Q.
        • Zhao C.
        • et al.
        An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy.
        J Immunother Cancer. 2020; 8e000661
        • Miyatani K.
        • Saito H.
        • Murakami Y.
        • et al.
        A high number of IgG4-positive cells in gastric cancer tissue is associated with tumor progression and poor prognosis.
        Virchows Arch. 2016; 468: 549-557
        • Liu Q.
        • Niu Z.
        • Li Y.
        • et al.
        Immunoglobulin G4 (IgG4)-positive plasma cell infiltration is associated with the clinicopathologic traits and prognosis of pancreatic cancer after curative resection.
        Cancer Immunol Immunother. 2016; 65: 931-940
        • Harada K.
        • Shimoda S.
        • Kimura Y.
        • et al.
        Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of IgG4 reaction in cancer tissue.
        Hepatology. 2012; 56: 157-164
        • Deshpande V.
        • Zen Y.
        • Chan J.K.
        • et al.
        Consensus statement on the pathology of IgG4-related disease.
        Mod Pathol. 2012; 25: 1181-1192
        • Lugli A.
        • Kirsch R.
        • Ajioka Y.
        • et al.
        Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016.
        Mod Pathol. 2017; 30: 1299-1311
        • Regmi P.
        • Paudyal A.
        • Paudyal P.
        • et al.
        Prognostic significance of tumor budding in biliary tract cancer.
        Eur J Surg Oncol. 2022; 48: 160-168
        • Petrova E.
        • Zielinski V.
        • Bolm L.
        • et al.
        Tumor budding as a prognostic factor in pancreatic ductal adenocarcinoma.
        Virchows Arch. 2020; 476: 561-568
        • Atanasov G.
        • Dietel C.
        • Feldbrügge L.
        • et al.
        Tumor necrosis and infiltrating macrophages predict survival after curative resection for cholangiocarcinoma.
        Oncoimmunology. 2017; 6e1331806
        • Wei C.
        • Yang C.
        • Wang S.
        • et al.
        Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis.
        Mol Cancer. 2019; 18: 64
        • Sugihara Y.
        • Taniguchi H.
        • Kushima R.
        • et al.
        Laser microdissection and two-dimensional difference gel electrophoresis reveal proteomic intra-tumor heterogeneity in colorectal cancer.
        J Proteomics. 2013; 78: 134-147
        • Wei Y.
        • Lao X.M.
        • Xiao X.
        • et al.
        Plasma cell polarization to the immunoglobulin G phenotype in hepatocellular carcinomas involves epigenetic alterations and promotes hepatoma progression in mice.
        Gastroenterology. 2019; 156: 1890-1904.e16
        • Aalberse R.C.
        • Stapel S.O.
        • Schuurman J.
        • Rispens T.
        Immunoglobulin G4: an odd antibody.
        Clin Exp Allergy. 2009; 39: 469-477
        • Hamano H.
        • Kawa S.
        • Horiuchi A.
        • et al.
        High serum IgG4 concentrations in patients with sclerosing pancreatitis.
        N Engl J Med. 2001; 344: 732-738
        • Karagiannis P.
        • Gilbert A.E.
        • Nestle F.O.
        • Karagiannis S.N.
        IgG4 antibodies and cancer-associated inflammation: insights into a novel mechanism of immune escape.
        Oncoimmunology. 2013; 2e24889
        • Gao G.
        • Wang Z.
        • Qu X.
        • Zhang Z.
        Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis.
        BMC Cancer. 2020; 20: 179
        • Zhang N.
        • Cao M.
        • Duan Y.
        • Bai H.
        • Li X.
        • Wang Y.
        Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis and experimental validation.
        Arch Med Sci. 2020; 16: 1092-1103
        • Kimura Y.
        • Harada K.
        • Nakanuma Y.
        Pathologic significance of immunoglobulin G4-positive plasma cells in extrahepatic cholangiocarcinoma.
        Hum Pathol. 2012; 43: 2149-2156
        • Ghazale A.
        • Chari S.T.
        • Zhang L.
        • et al.
        Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
        Gastroenterology. 2008; 134: 706-715