Stephanie Roessler1,2, Benjamin Goeppert3,4,5, Alphonse Charbel6,7, Luca Tavernar6,7, Thomas Albrecht6,7, Fritz Brinkmann6,7, Joanne Verheij8, Eva Roos8, Monika Nadja Vogel9, Bruno Köhler7,10, Christoph Springfeld7,10, Alexander Brobeil6,11, Peter Schirmacher6,7, Stephan Singer12, Arianeb Mehrabi7,13. 1. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Stephanie.Roessler@med.uni-heidelberg.de. 2. Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany. Stephanie.Roessler@med.uni-heidelberg.de. 3. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Benjamin.Goeppert@rkh-gesundheit.de. 4. Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany. Benjamin.Goeppert@rkh-gesundheit.de. 5. Institute of Pathology and Neuropathology, Hospital RKH Kliniken Ludwigsburg, Ludwigsburg, Germany. Benjamin.Goeppert@rkh-gesundheit.de. 6. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 7. Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany. 8. Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 9. Diagnostic and Interventional Radiology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany. 10. Department of Medical Oncology, National Centre for Tumour Diseases, University Hospital Heidelberg, Heidelberg, Germany. 11. Tumor Bank Unit, Tissue Bank of the National Center for Tumor Diseases, Heidelberg, Germany. 12. Institute of Pathology, University of Tübingen, Tübingen, Germany. 13. Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Abstract
BACKGROUND: Intraductal papillary neoplasms (IPN) and biliary epithelial neoplasia (BilIN) are well-defined precursor lesions of biliary tract carcinoma (BTC). The aim of this study was to provide a comprehensive characterisation of the inflammatory microenvironment in BTC precursor lesions. METHODS: Immunohistochemistry was employed to assess tumour-infiltrating immune cells in tissue samples from patients, for whom precursor lesions were identified alongside invasive BTC. The spatiotemporal evolution of the immune microenvironment during IPN-associated carcinogenesis was comprehensively analysed using triplet sample sets of non-neoplastic epithelium, precursor lesion and invasive BTC. Immune-cell dynamics during IPN- and BilIN-associated carcinogenesis were subsequently compared. RESULTS: Stromal CD3+ (P = 0.002), CD4+ (P = 0.007) and CD8+ (P < 0.001) T cells, CD20+ B cells (P = 0.008), MUM1+ plasma cells (P = 0.012) and CD163+ M2-like macrophages (P = 0.008) significantly decreased in IPN compared to non-tumorous biliary epithelium. Upon transition from IPN to invasive BTC, stromal CD68+ (P = 0.001) and CD163+ (P < 0.001) macrophages significantly increased. In contrast, BilIN-driven carcinogenesis was characterised by significant reduction of intraepithelial CD8+ T-lymphocytic infiltration from non-tumorous epithelium via BilIN (P = 0.008) to BTC (P = 0.004). CONCLUSION: IPN and BilIN are immunologically distinct entities that undergo different immune-cell variations during biliary carcinogenesis. Intraepithelial CD8+ T-lymphocytic infiltration of biliary tissue decreased already at the IPN-precursor stage, whereas BilIN-associated carcinogenesis showed a slowly progressing reduction towards invasive carcinoma.
BACKGROUND: Intraductal papillary neoplasms (IPN) and biliary epithelial neoplasia (BilIN) are well-defined precursor lesions of biliary tract carcinoma (BTC). The aim of this study was to provide a comprehensive characterisation of the inflammatory microenvironment in BTC precursor lesions. METHODS: Immunohistochemistry was employed to assess tumour-infiltrating immune cells in tissue samples from patients, for whom precursor lesions were identified alongside invasive BTC. The spatiotemporal evolution of the immune microenvironment during IPN-associated carcinogenesis was comprehensively analysed using triplet sample sets of non-neoplastic epithelium, precursor lesion and invasive BTC. Immune-cell dynamics during IPN- and BilIN-associated carcinogenesis were subsequently compared. RESULTS: Stromal CD3+ (P = 0.002), CD4+ (P = 0.007) and CD8+ (P < 0.001) T cells, CD20+ B cells (P = 0.008), MUM1+ plasma cells (P = 0.012) and CD163+ M2-like macrophages (P = 0.008) significantly decreased in IPN compared to non-tumorous biliary epithelium. Upon transition from IPN to invasive BTC, stromal CD68+ (P = 0.001) and CD163+ (P < 0.001) macrophages significantly increased. In contrast, BilIN-driven carcinogenesis was characterised by significant reduction of intraepithelial CD8+ T-lymphocytic infiltration from non-tumorous epithelium via BilIN (P = 0.008) to BTC (P = 0.004). CONCLUSION: IPN and BilIN are immunologically distinct entities that undergo different immune-cell variations during biliary carcinogenesis. Intraepithelial CD8+ T-lymphocytic infiltration of biliary tissue decreased already at the IPN-precursor stage, whereas BilIN-associated carcinogenesis showed a slowly progressing reduction towards invasive carcinoma.
Authors: Jesus M Banales; Jose J G Marin; Angela Lamarca; Pedro M Rodrigues; Shahid A Khan; Lewis R Roberts; Vincenzo Cardinale; Guido Carpino; Jesper B Andersen; Chiara Braconi; Diego F Calvisi; Maria J Perugorria; Luca Fabris; Luke Boulter; Rocio I R Macias; Eugenio Gaudio; Domenico Alvaro; Sergio A Gradilone; Mario Strazzabosco; Marco Marzioni; Cédric Coulouarn; Laura Fouassier; Chiara Raggi; Pietro Invernizzi; Joachim C Mertens; Anja Moncsek; Sumera Rizvi; Julie Heimbach; Bas Groot Koerkamp; Jordi Bruix; Alejandro Forner; John Bridgewater; Juan W Valle; Gregory J Gores Journal: Nat Rev Gastroenterol Hepatol Date: 2020-06-30 Impact factor: 46.802
Authors: Sumera Rizvi; Shahid A Khan; Christopher L Hallemeier; Robin K Kelley; Gregory J Gores Journal: Nat Rev Clin Oncol Date: 2017-10-10 Impact factor: 66.675
Authors: Ghassan K Abou-Alfa; Vaibhav Sahai; Antoine Hollebecque; Gina Vaccaro; Davide Melisi; Raed Al-Rajabi; Andrew S Paulson; Mitesh J Borad; David Gallinson; Adrian G Murphy; Do-Youn Oh; Efrat Dotan; Daniel V Catenacci; Eric Van Cutsem; Tao Ji; Christine F Lihou; Huiling Zhen; Luis Féliz; Arndt Vogel Journal: Lancet Oncol Date: 2020-03-20 Impact factor: 41.316