Cancer Immunology, Immunotherapy

, Volume 68, Issue 3, pp 443–454 | Cite as

Distinct immunological properties of the two histological subtypes of adenocarcinoma of the ampulla of Vater

  • Min Hwan Kim
  • Mi Jang
  • Hoguen Kim
  • Woo Jung Lee
  • Chang Moo KangEmail author
  • Hye Jin ChoiEmail author
Original Article


Adenocarcinoma of the ampulla of Vater (AOV) is classified into intestinal type (IT) and pancreatobiliary type (PB); however, the immunological properties of these subtypes remain to be characterized. Here, we evaluated the clinical implications of PD-L1 expression and CD8+ T lymphocyte density in adenocarcinomas of the AOV and their potential association with Yes-associated protein (YAP). We analyzed 123 adenocarcinoma-of-the-AOV patients who underwent surgical resection, and tumors were classified into IT or PB type. Tumor or inflammatory cell PD-L1 expression, CD8+ T lymphocyte density in the cancer cell nest (intratumoral) or in the adjacent stroma, and YAP localization and intensity were analyzed using immunohistochemical staining. PB-type tumors showed higher tumoral PD-L1 expression than IT-type tumors, and tumoral PD-L1 expression was associated with a shorter disease-free survival (DFS) [hazard ratio (HR), 1.77; p = 0.045] and overall survival (OS) (HR 1.99; p = 0.030). Intratumoral CD8+ T lymphocyte density was higher in IT type than in PB type and was associated with a favorable DFS (HR 0.47; p = 0.022). The nuclear staining pattern of YAP in tumor cells, compared to non-nuclear staining patterns, was more frequently associated with PB type and increased tumoral PD-L1 expression. Nuclear YAP staining was a significant prognostic factor for OS (HR 2.21; p = 0.022). These results show that the two subtypes of adenocarcinoma of the AOV exhibit significant differences in tumoral PD-L1 expression and intratumoral CD8+ T lymphocyte density, which might contribute to their distinct clinical features.


Adenocarcinoma of the ampulla of Vater PD-L1 CD8 T lymphocytes YAP Prognosis Immunohistochemistry 



American Joint Committee on Cancer


Ampulla of Vater


Disease-free survival






Myeloid-derived suppressor cells


Overall survival




Yes-associated protein


Author contributions

MHK, MJ, HK, CMK, and HJC conceived the study. MJ and HK performed and interpreted the pathologic review. Clinical data collection and interpretation were done by MHK, CMK, WJL, and HJC. MHK, MJ, CMK, and HJC wrote the manuscript.


This study was supported by a Grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA16C0018) and by a faculty research Grant for Yonsei University College of Medicine for 2015 (6-2015-0053).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

This study was reviewed and approved by the Institutional Review Board of Severance Hospital, Seoul, Korea (approval number: 4-2017-0542).

Informed consent

Informed consent was obtained from all patients at the time of surgery for the analysis of tumor specimens used for investigations. The requirement for informed consent for the retrospective study was waived by the Institutional Review Board, because this study was performed more than 5 years after the surgery and acquisition of the tumor tissues.

Supplementary material

262_2018_2293_MOESM1_ESM.pdf (693 kb)
Supplementary material 1 (PDF 692 KB)


  1. 1.
    Zhou H, Schaefer N, Wolff M, Fischer HP (2004) Carcinoma of the ampulla of Vater: comparative histologic/immunohistochemical classification and follow-up. Am J Surg Pathol 28(7):875–882CrossRefGoogle Scholar
  2. 2.
    Kimura W, Futakawa N, Yamagata S, Wada Y, Kuroda A, Muto T, Esaki Y (1994) Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater. Jpn J Cancer Res 85(2):161–166CrossRefGoogle Scholar
  3. 3.
    Schueneman A, Goggins M, Ensor J, Saka B, Neishaboori N, Lee S, Maitra A, Varadhachary G, Rezaee N, Wolfgang C, Adsay V, Wang H, Overman MJ (2015) Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma. Br J Cancer 113(1):64–68CrossRefGoogle Scholar
  4. 4.
    Chang DK, Jamieson NB, Johns AL, Scarlett CJ, Pajic M, Chou A, Pinese M, Humphris JL, Jones MD, Toon C, Nagrial AM, Chantrill LA, Chin VT, Pinho AV, Rooman I, Cowley MJ, Wu J, Mead RS, Colvin EK, Samra JS, Corbo V, Bassi C, Falconi M, Lawlor RT, Crippa S, Sperandio N, Bersani S, Dickson EJ, Mohamed MA, Oien KA, Foulis AK, Musgrove EA, Sutherland RL, Kench JG, Carter CR, Gill AJ, Scarpa A, McKay CJ, Biankin AV (2013) Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of vater. J Clin Oncol 31(10):1348–1356CrossRefGoogle Scholar
  5. 5.
    Kitamura H, Yonezawa S, Tanaka S, Kim YS, Sato E (1996) Expression of mucin carbohydrates and core proteins in carcinomas of the ampulla of Vater: their relationship to prognosis. Jpn J Cancer Res 87(6):631–640CrossRefGoogle Scholar
  6. 6.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854CrossRefGoogle Scholar
  7. 7.
    Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29(15):1949–1955CrossRefGoogle Scholar
  8. 8.
    Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105(1):93–103CrossRefGoogle Scholar
  9. 9.
    Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL (2015) Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 107(3):dju435. CrossRefGoogle Scholar
  10. 10.
    Spranger S (2016) Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 28(8):383–391CrossRefGoogle Scholar
  11. 11.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800CrossRefGoogle Scholar
  12. 12.
    Muller T, Braun M, Dietrich D, Aktekin S, Hoft S, Kristiansen G, Goke F, Schrock A, Bragelmann J, Held SAE, Bootz F, Brossart P (2017) PD-L1: a novel prognostic biomarker in head and neck squamous cell carcinoma. Oncotarget 8(32):52889–52900CrossRefGoogle Scholar
  13. 13.
    Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J (2009) Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 15(3):971–979CrossRefGoogle Scholar
  14. 14.
    Massi D, Brusa D, Merelli B, Ciano M, Audrito V, Serra S, Buonincontri R, Baroni G, Nassini R, Minocci D, Cattaneo L, Tamborini E, Carobbio A, Rulli E, Deaglio S, Mandala M (2014) PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics. Ann Oncol 25(12):2433–2442CrossRefGoogle Scholar
  15. 15.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571CrossRefGoogle Scholar
  16. 16.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, Investigators K- (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028CrossRefGoogle Scholar
  17. 17.
    Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X, Ji X, Ji F, Gong XG, Li L, Bai X, Feng XH, Liang T, Ji J, Chen L, Wang H, Zhao B (2017) Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev 31(3):247–259CrossRefGoogle Scholar
  18. 18.
    Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA (2016) Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov 6(1):80–95CrossRefGoogle Scholar
  19. 19.
    Yu FX, Zhao B, Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163(4):811–828CrossRefGoogle Scholar
  20. 20.
    Kim MH, Kim J (2017) Role of YAP/TAZ transcriptional regulators in resistance to anti-cancer therapies. Cell Mol Life Sci 74(8):1457–1474CrossRefGoogle Scholar
  21. 21.
    Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X (2010) Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 101(5):1279–1285CrossRefGoogle Scholar
  22. 22.
    Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D (2013) Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder. BMC Cancer 13:349CrossRefGoogle Scholar
  23. 23.
    Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z (2017) Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene. Google Scholar
  24. 24.
    Lee BS, Park DI, Lee DH, Lee JE, Yeo MK, Park YH, Lim DS, Choi W, Lee DH, Yoo G, Kim HB, Kang D, Moon JY, Jung SS, Kim JO, Cho SY, Park HS, Chung C (2017) Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma. Biochem Biophys Res Commun 491(2):493–499CrossRefGoogle Scholar
  25. 25.
    Kim MH, Kim CG, Kim SK, Shin SJ, Choe EA, Park SH, Shin EC, Kim J (2018) YAP-induced PD-L1 expression drives immune evasion in BRAFi-resistant melanoma. Cancer Immunol Res. Google Scholar
  26. 26.
    Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H, Sun B, Yin D, Sun J, Song R, Pan S, Sun Y, Jiang H, Zheng T, Liu L (2015) YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 6(19):17206–17220CrossRefGoogle Scholar
  27. 27.
    Gruber R, Panayiotou R, Nye E, Spencer-Dene B, Stamp G, Behrens A (2016) YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology 151(3):526–539CrossRefGoogle Scholar
  28. 28.
    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 (2013) Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 109(10):2665–2674CrossRefGoogle Scholar
  29. 29.
    Sideras K, Biermann K, Yap K, Mancham S, Boor PPC, Hansen BE, Stoop HJA, Peppelenbosch MP, van Eijck CH, Sleijfer S, Kwekkeboom J, Bruno MJ (2017) Tumor cell expression of immune inhibitory molecules and tumor-infiltrating lymphocyte count predict cancer-specific survival in pancreatic and ampullary cancer. Int J Cancer 141(3):572–582CrossRefGoogle Scholar
  30. 30.
    Adsay V, Ohike N, Tajiri T, Kim GE, Krasinskas A, Balci S, Bagci P, Basturk O, Bandyopadhyay S, Jang KT, Kooby DA, Maithel SK, Sarmiento J, Staley CA, Gonzalez RS, Kong SY, Goodman M (2012) Ampullary region carcinomas: definition and site specific classification with delineation of four clinicopathologically and prognostically distinct subsets in an analysis of 249 cases. Am J Surg Pathol 36(11):1592–1608CrossRefGoogle Scholar
  31. 31.
    Kakar S, Shi C, Adsay NV, Fitzgibbons P, Frankel WL, Krasinskas AM, Pawlik T, Vauthey J-N, Washington MK (2017) Protocol for the examination of specimens from patients with carcinoma of the ampulla of Vater. College of American Pathologists. Accessed 3 Sept 2018
  32. 32.
    Ang DC, Shia J, Tang LH, Katabi N, Klimstra DS (2014) The utility of immunohistochemistry in subtyping adenocarcinoma of the ampulla of vater. Am J Surg Pathol 38(10):1371–1379CrossRefGoogle Scholar
  33. 33.
    Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, Blute ML, Sebo TJ, Cheville JC, Kwon ED (2006) Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66(7):3381–3385CrossRefGoogle Scholar
  34. 34.
    Grosso J, Inzunza D, Wu Q, Simon J, Singh P, Zhang X, Phillips T, Simmons P, Cogswell J (2013) Programmed death-ligand 1 (PD-L1) expression in various tumor types. J Immunother Cancer 1(Suppl 1):P53CrossRefGoogle Scholar
  35. 35.
    Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145CrossRefGoogle Scholar
  36. 36.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465CrossRefGoogle Scholar
  37. 37.
    von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7(3 Suppl):925 s–932 sGoogle Scholar
  38. 38.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefGoogle Scholar
  39. 39.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330CrossRefGoogle Scholar
  40. 40.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128CrossRefGoogle Scholar
  41. 41.
    Bang Y, Doi T, De Braud F, Piha-Paul S, Hollebecque A, Razak AA, Lin C, Ott P, He A, Yuan S (2015) 525 safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer 51:S112CrossRefGoogle Scholar
  42. 42.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Medical Oncology, Department of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
  2. 2.Pancreaticobiliary Cancer ClinicYonsei Cancer Center, Severance HospitalSeoulRepublic of Korea
  3. 3.Department of PathologyYonsei University College of MedicineSeoulRepublic of Korea
  4. 4.Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryYonsei University College of MedicineSeoulRepublic of Korea

Personalised recommendations