Journal of Gastrointestinal Surgery

, Volume 22, Issue 7, pp 1171–1178 | Cite as

Immunohistochemical Predictors for Intestinal and Pancreatobiliary Types of Adenocarcinoma of The Ampulla of Vater

  • João Paulo Lemos da Silveira Santos
  • Carla Jorge Machado
  • Eduardo Paulino Junior
  • João Bernardo Sancio Rocha Rodrigues
  • Paula Teixeira Vidigal
  • Vivian ResendeEmail author
Original Article



To investigate immunohistochemical predictors for intestinal and pancreatobiliary types of adenocarcinoma of ampulla of Vater and identify clinicopathological characteristics associated with the histological types and patient survival.


Immunohistochemical markers included MUC1, MUC2, MUC5AC, CDX2, CK7, and CK20. The data were analyzed by univariate and multivariate methods. The two-step cluster method was used to determine the best immunohistochemical markers to discriminate the intestinal from the pancreatobiliary type.


This study identified 9 (33.3%) intestinal and 21 (66.7%) pancreatobiliary tumors. CK7 and CDX2 achieved the highest value (= 1) as predictor markers, while CK20, MUC1, and MUC2 showed degrees of importance equal to 0.77, 0.71, and 0.68, respectively. MUC5AC did not reach 0.50 of importance. In the univariate analysis, lymph node involvement, staging (TNM), and angiolymphatic and perineural invasions were associated with histological types. The independent clinicopathological variable in the multivariate model to predict the histological type was angiolymphatic invasion (p = 0.005), OR = 17 (95% CI 2.33 to 123.83). The final model showed positive nodes (N1) associated with shorter survival (HR = 9.5; p = 0.006). Overall survival at 12, 36, and 60 months was 88.5, 67.0, and 47.6%, respectively.


CDX2 and CK7 were the immunohistochemical markers that best discriminated the intestinal from the pancreatobiliary type. Lymph node involvement had a high impact on survival and proved to be more frequent in the pancreatobiliary type.


Ampulla of Vater Adenocarcinoma Immunohistochemistry Survival 


Author Contributions

João Paulo Lemos da Silveira Santos and João Bernardo Sancio Rocha Rodrigues: collecting data, drafting, and final approval of the work.

Carla Jorge Machado: statistical analysis, drafting, and final approval of the work.

Eduardo Paulino Junior and Paula Teixeira Vidigal: interpretation and immunohistochemical analysis, drafting and final approval of the work.

Vivian Resende: conception and design, drafting and final approval of the work.

Funding Information

This study is financially supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) .

Compliance with Ethical Standards

This research was approved by the Research Ethics Committee of the Federal University of Minas Gerais (UFMG), logged under protocol number CAAE 23377113.1.0000.5149.

Conflict of Interest

The authors declare that there is no conflict of interest.


  1. 1.
    Albores-Saavedra J, Schwartz AM, Batich K, Henson DE. Cancers of the ampulla of vater: demographics, morphology, and survival based on 5,625 cases from the SEER program. J Surg Oncol 2009; 100(7):598–605.CrossRefPubMedGoogle Scholar
  2. 2.
    Kimura W, Futakawa N, Yamagata S, Wada Y, Kuroda A, Muto T, Esaki Y. Different clinicopathologic findings in two histologic types of carcinoma of papilla of Vater. Jpn J Cancer Res 1994; 85(2):161–6.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Albores-Saavedra J. Tumors of the gallbladder, extrahepatic bile ducts, and ampulla of vater. in: Albores-Saavedra J, editor. Atlas of Tumor Pathology. Washington, D.C.: Armed Forces Institute of Pathology; 2000. p. 259:316.Google Scholar
  4. 4.
    Kimura W, Futakawa N, Zhao B. Neoplastic diseases of the papilla of Vater. J Hepatobiliary Pancreat Surg 2004; 11(4):223–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Perysinakis I, Margaris I, Kouraklis G. Ampullary cancer—a separate clinical entity? Histopathology 2014; 64(6):759–68..CrossRefPubMedGoogle Scholar
  6. 6.
    de Paiva Haddad LB, Patzina RA, Penteado S, Montagnini AL, da Cunha JE, Machado MC, Jukemura J. Lymph node involvement and not the histophatologic subtype is correlated with outcome after resection of adenocarcinoma of the ampulla of vater. J Gastrointest Surg 2010; 14(4):719–28.CrossRefPubMedGoogle Scholar
  7. 7.
    Resende V, Santos JP, Gomes RV, Vidigal PV, Pedrosa MS. Papillary neoplasias of the biliary tract. Rev Col Bras Cir 2014; 41(6):445–50CrossRefPubMedGoogle Scholar
  8. 8.
    Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, Clausen OP, Gladhaug IP. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer 2008; 8:170.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bronsert P, Kohler I, Werner M, Makowiec F, Kuesters S, Hoeppner J, Hopt UT, Keck T, Bausch D, Wellner UF. Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin. BMC Cancer 2013; 13: 428.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ohike N, Kim GE, Tajiri T, Krasinskas A, Basturk O, Coban I, Bandyopadhyay S, Morohoshi T, Goodman M, Kooby DA, Sarmiento JM, Adsay NV. Intra-ampullary papillary-tubular neoplasm (IAPN): characterization of tumoral intraepithelial neoplasia occurring within the ampulla: a clinicopathologic analysis of 82 cases. Am J Surg Pathol 2010; 34(12):1731–48.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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. 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 2012; 36(11):1592–608.CrossRefPubMedGoogle Scholar
  12. 12.
    Kawabata Y, Tanaka T, Nishisaka T, Inao T, Nishi T, Yano S. Cytokeratin 20 (CK20) and apomucin 1 (MUC1) expression in ampullary carcinoma: correlation with tumor progression and prognosis. Diagn Pathol 2010; 5:75.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Moriya T, Kimura W, Hirai I, Takasu N, Mizutani M. Expression of MUC1 and MUC2 in ampullary cancer. Int J Surg Pathol 2011; 19(4):441–7.CrossRefPubMedGoogle Scholar
  14. 14.
    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. Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma. Br J Cancer 2015; 113(1):64–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang T, Liang YM, Hu P, Cheng YF. Mucins differently expressed in various ampullary adenocarcinomas. Diagn Pathol 2011; 6: 102.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhou H, Schaefer N, Wolff M, Fischer HP. Carcinoma of the ampulla of Vater: comparative histologic/immunohistochemical classification and follow-up. Am J Surg Pathol 2004; 28( 7): 875–82.CrossRefPubMedGoogle Scholar
  17. 17.
    Carter JT, Grenert JP, Rubenstein L, Stewart L, Way LW. Tumors of the ampulla of vater: histopathologic classification and predictors of survival. J Am Coll Surg 2008; 207(2):210–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Klimstra DS, Albores-Saavedra J, Holuban RH, Zamboni G. Tumours of the ampullary region. In Boseman FT, Carneiro F, Hruban RH, Theise ND (eds) World Health Organization Classification of Tumours of the Digestive System. ed 4. Lyon: IARC; 2010;80-91.Google Scholar
  19. 19.
    Hatzaras I, George N, Muscarella P, Melvin WS, Ellison EC, Bloomston M. Predictors of survival in periampullary cancers following pancreaticoduodenectomy. Ann Surg Oncol 2010; 17(4):991–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Schiergens TS, Reu S, Neumann J, Renz BW, Niess H, Boeck S, Heinemann V, Bruns CJ, Jauch KW, Kleespies A. Histomorphologic and molecular phenotypes predict gemcitabine response and overall survival in adenocarcinoma of the ampulla of Vater. Surgery 2015; 158(1):151–61.CrossRefPubMedGoogle Scholar
  21. 21.
    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. Histomolecular phenotypes and outcome in adenocarcinoma of the ampulla of Vater. J Clin Oncol 2013; 31(10):1348–56.CrossRefPubMedGoogle Scholar
  22. 22.
    Kim WS, Choi DW, Choi SH, Heo JS, You DD, Lee HG. Clinical significance of pathologic subtype in curatively resected ampulla of vater cancer. J Surg Oncol 2012; 105(3):266–72.CrossRefPubMedGoogle Scholar
  23. 23.
    Kumari N, Prabha K, Singh RK, Baitha DK, Krishnani N. Intestinal and pancreatobiliary differentiation in periampullary carcinoma: the role of immunohistochemistry. Hum Pathol 2013; 44(10): 2213–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Morini S, Perrone G, Borzomati D, Vincenzi B, Rabitti C, Righi D, Castri F, Manazza AD, Santini D, Tonini G, Coppola R, Onetti Muda A. Carcinoma of the ampulla of Vater: morphological and immunophenotypical classification predicts overall survival. Pancreas 2013; 42(1): 60–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor location, immunohistochemistry and microsatellite instability. Virchows Arch 2007; 451(3): 649–57.CrossRefPubMedGoogle Scholar
  26. 26.
    Roh YH, Kim YH, Lee HW, Kim SJ, Roh MS, Jeong JS, Jung GJ. The clinicopathologic and immunohistochemical characteristics of ampulla of Vater carcinoma: the intestinal type is associated with a better prognosis. Hepatogastroenterology 2007; 54(78): 1641–4.PubMedGoogle Scholar
  27. 27.
    Ang DC, Shia J, Tang LH, Katabi N, Klimstra DS. The utility of immunohistochemistry in subtyping adenocarcinoma of the ampulla of vater. Am J Surg Pathol 2014; 38(10): 1371–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Chu PG, Schwarz RE, Lau SK, Yen Y, Weiss LM. Immunohistochemical staining in the diagnosis of pancreatobiliary and ampulla of Vater adenocarcinoma: application of CDX2, CK17, MUC1, and MUC2. Am J Surg Pathol 2005; 29(3): 359–67.CrossRefPubMedGoogle Scholar
  29. 29.
    Reid MD, Balci1 S, Ohike N, Xue Y, Kim GE, Tajiri T, Memis B, Coban I, Dolgun A, Krasinskas AM, Basturk O, Kooby DA, Sarmiento JM, Maithel SK, El-Rayes BF, Adsay V. Ampullary carcinoma is often of mixed or hybrid histologic type: an analysis of reproducibility and clinical relevance of classification as pancreatobiliary versus intestinal in 232 cases. Mod Pathol 2016; 29: 1575–85.CrossRefPubMedGoogle Scholar
  30. 30.
    Roggin KK, Yeh JJ, Ferrone CR, Riedel E, Gerdes H, Klimstra DS, Jaques DP, Brennan MF. Limitations of ampullectomy in the treatment of nonfamilial ampullary neoplasms. Ann Surg Oncol 2005; 12(12): 971–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Showalter TN, Zhan T, Anne PR, Chervoneva I, Mitchell EP, Yeo CJ, Rosato EL, Kennedy EP, Berger AC. The influence of prognostic factors and adjuvant chemoradiation on survival after pancreaticoduodenectomy for ampullary carcinoma. J Gastrointest Surg 2011; 15(8): 1411–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Colussi O, Voron T, Pozet A, Hammel P, Sauvanet A, Bachet JB, Vaillant JC, Rougier P, Nordlinger B, Berger A, Coriat R, Dousset B, Malka D, André T, Paye F, Aparicio T, Locher C, Cojean Zeleck D, Tchinou L, Bonnetain F, Taieb J. Prognostic score for recurrence after Whipple’s pancreaticoduodenectomy for ampullary carcinomas; results of an AGEO retrospective multicenter cohort. Eur J Surg Oncol 2015; 41(4): 520–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Ghaneh P, Halloran CM, Lerch MM, Oláh A, Rawcliffe CL, Verbeke CS, Campbell F, Büchler MW. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 2012; 308(2):147–56.CrossRefPubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2018

Authors and Affiliations

  • João Paulo Lemos da Silveira Santos
    • 1
  • Carla Jorge Machado
    • 2
  • Eduardo Paulino Junior
    • 3
  • João Bernardo Sancio Rocha Rodrigues
    • 1
  • Paula Teixeira Vidigal
    • 3
  • Vivian Resende
    • 1
    Email author
  1. 1.Department of Surgery, Medical SchoolUFMGBelo HorizonteBrazil
  2. 2.Department of Epidemiology, Medical SchoolUFMGBelo HorizonteBrazil
  3. 3.Department of Histopathology, Medical SchoolUFMGBelo HorizonteBrazil

Personalised recommendations