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Journal of Gastrointestinal Surgery

, Volume 23, Issue 11, pp 2216–2224 | Cite as

Tumor-Infiltrating Lymphocytes and Macrophages in Intrahepatic Cholangiocellular Carcinoma. Impact on Prognosis after Complete Surgery

  • Luca Vigano
  • Cristiana Soldani
  • Barbara Franceschini
  • Matteo Cimino
  • Ana Lleo
  • Matteo Donadon
  • Massimo Roncalli
  • Alessio Aghemo
  • Luca Di Tommaso
  • Guido TorzilliEmail author
Original Article
  • 137 Downloads

Abstract

Background

Immune infiltrate impacts prognosis of several tumors. To assess the prognostic impact of tumor-infiltrating lymphocytes and macrophages in patients undergoing resection for intrahepatic cholangiocellular carcinoma (ICC).

Methods

All consecutive patients undergoing surgery for ICC between 2008 and 2016 were considered. Inclusion criteria were complete resection and follow-up > 12 months. Tissue sections were immunostained for CD3+, CD4+, CD8+, Foxp3+, and CD68+. The number of positive cells was quantified using a computer-aided image analysis system. Different cut-off values were tested as predictors of overall survival (OS).

Results

Fifty-three patients were analyzed. ICC were T1 in 28 patients, multifocal in 11, and N+ in 13. After a median follow-up of 42 months, 5-year OS was 52.1%. The following immune infiltrate values were associated with better OS: CD3+ > 0.10% (5-year OS 63.3% vs. 13.6% if ≤ 0.10%, p = 0.001); CD8+ > 0.10% (56.2% vs. 28.6% if ≤ 0.10%, p = 0.051); Foxp3+ absent (59.4% vs. 16.0% if present, p = 0.049). CD4+ and CD68+ infiltrates were not associated with OS. Three-year OS rates in patients with 0, 1, and ≥ 2 negative prognostic factors were 73.6%, 47.3%, and 14.3%, respectively (p < 0.001). CD3+ infiltrate stratified prognosis in T1 tumors (3-year OS 71.7% if CD3+ > 0.10% vs. 14.3% if ≤ 0.10%, p < 0.001).

Conclusions

Tumor-infiltrating lymphocytes are associated with prognosis of ICC patients after complete surgery. CD3+ and CD8+ infiltrate is associated with higher survival and lower recurrence risk, while Foxp3+ infiltrate is associated with worse prognosis. CD3+ infiltrate allows refining prediction of prognosis in early tumors.

Keywords

Intrahepatic cholangiocellular carcinoma Tumor-infiltrating lymphocytes and macrophages Liver surgery Prognosis and survival Staging Immunology 

Notes

Authors’ Contribution

Substantial contributions to the conception or design of the work: Viganò, Roncalli, Aghemo, Torzilli

Acquisition, analysis, or interpretation of data for the work: Viganò, Soldani, Franceschini, Cimino, Lleo, Donadon, Di Tommaso

Drafting the work: Viganò, Soldani, Franceschini, Cimino, Lleo, Donadon, Di Tommaso

Revising it critically for important intellectual content: Viganò, Roncalli, Aghemo, Torzilli

Final approval of the version to be published: all the authors

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all the authors

Compliance with Ethical Standards

The Institutional Review Board of our hospital approved this retrospective study and the requirement of informed consent was waived.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

11605_2019_4111_MOESM1_ESM.docx (154 kb)
ESM 1 P values of different cut-offs values of CD3+ and CD8+ infiltrates (every 0.05% increase) when tested as predictors of overall survival. The lowest p value (white arrow) was used for the analyses. Dotted green line: p = 0.05 (DOCX 153 kb)

References

  1. 1.
    Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472–477.PubMedGoogle Scholar
  2. 2.
    Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB 2008;10:77–82.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Ebata T, Ercolani G, Alvaro D, Ribero D, Di Tommaso L, Valle JW. Current Status on Cholangiocarcinoma and Gallbladder Cancer. Liver Cancer. 2016;6:59–65.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RI, Raggi C, Perugorria MJ, Gaudio E, Boberg KM, Marin JJ, Alvaro D. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016;13:261–280.PubMedGoogle Scholar
  5. 5.
    De Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Gamblin TC, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Schulick RD, Choti MA, Gigot JF, Mentha G, Pawlik TM. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140–3145.PubMedGoogle Scholar
  6. 6.
    Kim Y, Moris DP, Zhang XF, Bagante F, Spolverato G, Schmidt C, Dilhoff M, Pawlik TM. Evaluation of the 8th edition American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: A surveillance, epidemiology, and end results (SEER) analysis. J Surg Oncol 2017;116:643–650.PubMedGoogle Scholar
  7. 7.
    Si A, Li J, Xiang H, Zhang S, Bai S, Yang P, Zhang X, Xia Y, Wang K, Yan Z, Lau WY, Shi L, Shen F. Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma. Oncotarget 2017;8:44521–44532.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Farges O, Fuks D, Boleslawski E, Le Treut YP, Castaing D, Laurent A, Ducerf C, Rivoire M, Bachellier P, Chiche L, Nuzzo G, Regimbeau JM. Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann Surg 2011;254:824–829.PubMedGoogle Scholar
  9. 9.
    Ribero D, Pinna AD, Guglielmi A, Ponti A, Nuzzo G, Giulini SM, Aldrighetti L, Calise F, Gerunda GE, Tomatis M, Amisano M, Berloco P, Torzilli G, Capussotti L. Surgical Approach for Long-term Survival of Patients With Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 434 Patients. Arch Surg 2012;147:1107–1113.PubMedGoogle Scholar
  10. 10.
    Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol 2008;15:2787–2794.PubMedGoogle Scholar
  11. 11.
    Tang H, Lu W, Li B, Meng X, Dong J. Influence of surgical margins on overall survival after resection of intrahepatic cholangiocarcinoma: A meta-analysis. Medicine 2016;95:e4621.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Nicoli P, Cappellani A, Malfermoni G, Iacono C. Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg 2009;33:1247–1254.PubMedGoogle Scholar
  13. 13.
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017;14:399–416.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991–998.PubMedGoogle Scholar
  15. 15.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007;450:903–907.PubMedGoogle Scholar
  16. 16.
    Holcombe RF, Jacobson J, Dakhil SR, Stewart RM, Betzing KS, Kannan K, Macdonald JS. Association of immune parameters with clinical outcome in stage III colon cancer: results of Southwest Oncology Group Protocol 9009. Cancer Immunol Immunother 1999;48:533–539.PubMedGoogle Scholar
  17. 17.
    Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998;58:3491–3494.PubMedGoogle Scholar
  18. 18.
    Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005;353:2654–2666.PubMedGoogle Scholar
  19. 19.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960–1964.PubMedGoogle Scholar
  20. 20.
    Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009;27:5944–5951.PubMedGoogle Scholar
  21. 21.
    Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, Zlobec I, Berger A, Bifulco C, Botti G, Tatangelo F, Britten CM, Kreiter S, Chouchane L, Delrio P, Arndt H, Asslaber M, Maio M, Masucci GV, Mihm M, Vidal-Vanaclocha F, Allison JP, Gnjatic S, Hakansson L, Huber C, Singh-Jasuja H, Ottensmeier C, Zwierzina H, Laghi L, Grizzi F, Ohashi PS, Shaw PA, Clarke BA, Wouters BG, Kawakami Y, Hazama S, Okuno K, Wang E, O’Donnell-Tormey J, Lagorce C, Pawelec G, Nishimura MI, Hawkins R, Lapointe R, Lundqvist A, Khleif SN, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Palmqvist R, Nagtegaal ID, Wang Y, D’Arrigo C, Kopetz S, Sinicrope FA, Trinchieri G, Gajewski TF, Ascierto PA, Fox BA. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 2012;10:205.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Yao Q, Bao X, Xue R, Liu H, Liu H, Li J, Dong J, Duan Z, Ren M, Zhao J, Song Q, Yu H, Zhu Y, Lu J, Meng Q. Prognostic value of immunoscore to identify mortality outcomes in adults with HBV-related primary hepatocellular carcinoma. Medicine 2017;96:e6735.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, Reddy S, Kleiner D, Fishbein T, Johnson L, Island E, Satoskar R, Banovac F, Jha R, Kachhela J, Feng P, Zhang T, Tesfaye A, Prins P, Loffredo C, Marshall J, Weiner L, Atkins M, He AR. Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC. Cancer Immunol Res 2016;4:419–430.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Sun C, Xu J, Song J, Liu C, Wang J, Weng C, Sun H, Wei H, Xiao W, Sun R, Tian Z. The predictive value of centre tumour CD8+ T cells in patients with hepatocellular carcinoma: comparison with Immunoscore. Oncotarget 2015;6:35602–35615.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Asukai K, Kawamoto K, Eguchi H, Konno M, Nishida N, Koseki J, Noguchi K, Hasegawa S, Ogawa H, Yamada D, Tomimaru Y, Tomokuni A, Asaoka T, Noda T, Wada H, Gotoh K, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H. Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2015;22:S1524–1531.PubMedGoogle Scholar
  26. 26.
    Gu FM, Gao Q, Shi GM, Zhang X, Wang J, Jiang JH, Wang XY, Shi YH, Ding ZB, Fan J, Zhou J. Intratumoral IL-17+ cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol 2012;19:2506–2514.PubMedGoogle Scholar
  27. 27.
    Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M, Klauschen F, Joehrens K, Warth A, Renner M, Mehrabi A, Hafezi M, Thelen A, Schirmacher P, Weichert W. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 2013; 109:2665–2674.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Torzilli G, Montorsi M, Donadon M, Palmisano A, Del Fabbro D, Gambetti A, Olivari N, Makuuchi M. “Radical but conservative” is the main goal for ultrasonography-guided liver resection: prospective validation of this approach. J Am Coll Surg 2005;201:517–528.PubMedGoogle Scholar
  29. 29.
    Torzilli G. Ultrasond-guided liver surgery. An atlas. 1st ed. Springer, 2014.Google Scholar
  30. 30.
    Viganò L, Procopio F, Cimino M, Donadon M, Gatti A, Costa G, Del Fabbro D, Torzilli G. Is Tumor Detachment from Vascular Structures Equivalent to R0 Resection in Surgery for Colorectal Liver Metastases? An Observational Cohort. Ann Surg Oncol 2016;23:1352–1360.PubMedGoogle Scholar
  31. 31.
    Torzilli G, Procopio F, Viganò L, Cimino M, Costa G, Del Fabbro D, Donadon M. Hepatic vein management in a parenchyma-sparing policy for resecting colorectal liver metastases at the caval confluence. Surgery 2018;163:277–284.PubMedGoogle Scholar
  32. 32.
    Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santibañes E, Pekolj J, Slankamenac K, Bassi C, Graf R, Vonlanthen R, Padbury R, Cameron JL, Makuuchi M. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187–189.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Okano K, Maeba T, Moroguchi A, Ishimura K, Karasawa Y, Izuishi K, Goda F, Usuki H, Wakabayashi H, Maeta H. Lymphocytic infiltration surrounding liver metastases from colorectal cancer. J Surg Oncol 2003;82:28–33.PubMedGoogle Scholar
  34. 34.
    Halama N, Spille A, Lerchl T, Brand K, Herpel E, Welte S, Keim S, Lahrmann B, Klupp F, Kahlert C, Weitz J, Grabe N, Jaeger D, Zoernig I. Hepatic metastases of colorectal cancer are rather homogeneous but differ from primary lesions in terms of immune cell infiltration. Oncoimmunology 2013;2:e24116.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, Feyen N, Martens UM, Beckhove P, Gnjatic S, Schirmacher P, Herpel E, Weitz J, Grabe N, Jaeger D. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 2011;71:5670–5677.PubMedGoogle Scholar
  36. 36.
    Wagner P, Koch M, Nummer D, Palm S, Galindo L, Autenrieth D, Rahbari N, Schmitz-Winnenthal FH, Schirrmacher V, Büchler MW, Beckhove P, Weitz J. Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer. Ann Surg Oncol 2008;15:2310–2317.PubMedGoogle Scholar
  37. 37.
    Katz SC, Pillarisetty V, Bamboat ZM, Shia J, Hedvat C, Gonen M, Jarnagin W, Fong Y, Blumgart L, D’Angelica M, DeMatteo RP. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol 2009;16:2524–2530PubMedGoogle Scholar
  38. 38.
    Donadon M, Hudspeth K, Cimino M, Di Tommaso L, Preti M, Tentorio P, Roncalli M, Mavilio D, Torzilli G. Increased Infiltration of Natural Killer and T Cells in Colorectal Liver Metastases Improves Patient Overall Survival. J Gastrointest Surg 2017;21:1226–1236.PubMedGoogle Scholar
  39. 39.
    Ghidini M, Cascione L, Carotenuto P, Lampis A, Trevisani F, Previdi MC, Hahne JC, Said-Huntingford I, Raj M, Zerbi A, Mescoli C, Cillo U, Rugge M, Roncalli M, Torzilli G, Rimassa L, Santoro A, Valeri N, Fassan M, Braconi C. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur J Cancer 2017;86:158–165.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kasper HU, Drebber U, Stippel DL, Dienes HP, Gillessen A. Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. World J Gastroenterol 2009;15:5053–5057.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol 2009;10:877–884.PubMedGoogle Scholar
  42. 42.
    Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011;105:93–103.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Kito A, Tanaka K, Fujimaki H, Nakazawa M, Togo S, Minami M, Shimada H. Tumor doubling time and local immune response to hepatic metastases from colorectal cancer. J Surg Oncol 2007;96:525–533.PubMedGoogle Scholar
  44. 44.
    Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, Sozaki M, Tanaka M, Onishi H, Morisaki T, Katano M. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653–661.PubMedGoogle Scholar
  45. 45.
    Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186–192.PubMedGoogle Scholar
  46. 46.
    Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010;222:350–366.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Liu Z, Huang Q, Liu G, Dang L, Chu D, Tao K, Wang W. Presence of FOXP3(+)Treg cells is correlated with colorectal cancer progression. Int J Clin Exp Med 2014;7:1781–1785PubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM, Zhang X, Pang ZZ, Wan DS, Zeng YX, Zhang XS. The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med 2010;8:13.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Omichi K, Cloyd JM, Yamashita S, Tzeng CD, Conrad C, Chun YS, Aloia TA, Vauthey JN. Neutrophil-to-lymphocyte ratio predicts prognosis after neoadjuvant chemotherapy and resection of intrahepatic cholangiocarcinoma. Surgery 2017;162:752–765.PubMedGoogle Scholar
  50. 50.
    Lin G, Liu Y, Li S, Mao Y, Wang J, Shuang Z, Chen J, Li S. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget 2016;7:50963–50971.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Chen Q, Dai Z, Yin D, Yang LX, Wang Z, Xiao YS, Fan J, Zhou J. Negative impact of preoperative platelet-lymphocyte ratio on outcome after hepatic resection for intrahepatic cholangiocarcinoma. Medicine 2015;94:e574.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Xue TC, Zhang L, Xie XY, Ge NL, Li LX, Zhang BH, Ye SL, Ren ZG. Prognostic significance of the neutrophil-to-lymphocyte ratio in primary liver cancer: a meta-analysis. PLoS One 2014;9:e96072.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Pellino A, Loupakis F, Cadamuro M, Dadduzio V, Fassan M, Guido M, Cillo U, Indraccolo S, Fabris L. Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol. 2018;3:40.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Robbins PF. Tumor-Infiltrating Lymphocyte Therapy and Neoantigens. Cancer J 2017;23:138–143.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Fontugne J, Augustin J, Pujals A, Compagnon P, Rousseau B, Luciani A, Tournigand C, Cherqui D, Azoulay D, Pawlotsky JM, Calderaro J. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget 2017;8:24644–24651.PubMedPubMedCentralGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  • Luca Vigano
    • 1
    • 2
  • Cristiana Soldani
    • 1
  • Barbara Franceschini
    • 1
  • Matteo Cimino
    • 1
  • Ana Lleo
    • 2
    • 3
  • Matteo Donadon
    • 1
    • 2
  • Massimo Roncalli
    • 2
    • 4
  • Alessio Aghemo
    • 2
    • 3
  • Luca Di Tommaso
    • 2
    • 4
  • Guido Torzilli
    • 1
    • 2
    Email author
  1. 1.Department of Surgery, Division of Hepatobiliary & General SurgeryHumanitas Clinical and Research Center, IRCCSRozzano - MilanItaly
  2. 2.Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly
  3. 3.Division of Internal Medicine and Hepatology, Department of Internal MedicineHumanitas Clinical and Research Center, IRCCSRozzanoItaly
  4. 4.Pathology UnitHumanitas Clinical and Research Center, IRCCSRozzanoItaly

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