Journal of Gastroenterology

, Volume 47, Issue 2, pp 203–213 | Cite as

Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression

  • Dai Mohri
  • Yoshinari Asaoka
  • Hideaki Ijichi
  • Koji Miyabayashi
  • Yotaro Kudo
  • Motoko Seto
  • Miki Ohta
  • Motohisa Tada
  • Yasuo Tanaka
  • Tsuneo Ikenoue
  • Keisuke Tateishi
  • Hiroyuki Isayama
  • Fumihiko Kanai
  • Noriyoshi Fukushima
  • Minoru Tada
  • Takao Kawabe
  • Masao Omata
  • Kazuhiko Koike
Original Article—Liver, Pancreas, and Biliary Tract



Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.


Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.


There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).


There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.


Intraductal papillary mucinous neoplasm (IPMN) Gastric type Intestinal type KRAS Bone morphogenetic protein (BMP)-SMAD 



Bone morphogenetic protein


Epidermal growth factor receptor


Extracellular signal-regulated kinase


Intraductal papillary mucinous neoplasm


Intraductal papillary mucinous carcinoma


Pancreatic intraepithelial neoplasia


Pancreatic ductal adenocarcinoma


Polymerase chain reaction


Main pancreatic duct



We thank Drs. Norihiro Kokudo and Taku Aoki (Hepato-Biliary-Pancreatic Surgery Division, University of Tokyo) for the surgical sample acquisition. We also thank Mitsuko Tsubouchi and Sanae Ogawa for technical assistance. This study was supported by KAKENHI, grants of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT) to M.O., K.K., and H.I.

Conflict of interest

The authors have no competing interests to disclose.


  1. 1.
    Carpelan-Holmström M, Nordling S, Pukkala E, Sankila R, Lüttges J, Klöppel G, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005;54:385–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Warshaw A, Fernández-del Castillo C. Pancreatic carcinoma. N Engl J Med. 1992;326:455–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997;349:485–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Bardeesy N, DePinho R. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.PubMedCrossRefGoogle Scholar
  5. 5.
    Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004;28:977–87.PubMedCrossRefGoogle Scholar
  6. 6.
    Adsay N, Merati K, Andea A, Sarkar F, Hruban R, Wilentz R, et al. The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol. 2002;15:1087–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Tada M, Kawabe T, Arizumi M, Togawa O, Matsubara S, Yamamoto N, et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol. 2006;4:1265–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohashi K, Murakami F, Maruyama M. Four cases of the mucin-producing cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc. 1982;20:348–51.Google Scholar
  9. 9.
    Lüttges J, Zamboni G, Longnecker D, Klöppel G. The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol. 2001;25:942–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Yonezawa S, Taira M, Osako M, Kubo M, Tanaka S, Sakoda K, et al. MUC-1 mucin expression in invasive areas of intraductal papillary mucinous tumors of the pancreas. Pathol Int. 1998;48:319–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakamura A, Horinouchi M, Goto M, Nagata K, Sakoda K, Takao S, et al. New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy. J Pathol. 2002;197:201–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, et al. Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virchows Arch. 2005;447:794–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Adsay N, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng J, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an “intestinal” pathway of carcinogenesis in the pancreas. Am J Surg Pathol. 2004;28:839–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, et al. Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types. Am J Surg Pathol. 2006;30:1561–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Z’graggen K, Rivera J, Compton C, Pins M, Werner J, Fernández-del Castillo C, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg. 1997;226:491–8. (discussion 498-500).PubMedCrossRefGoogle Scholar
  16. 16.
    Satoh K, Shimosegawa T, Moriizumi S, Koizumi M, Toyota T. K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas. Pancreas. 1996;12:362–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Satoh K, Sawai T, Shimosegawa T, Koizumi M, Yamazaki T, Mochizuki F, et al. The point mutation of c-Ki-ras at codon 12 in carcinoma of the pancreatic head region and in intraductal mucin-hypersecreting neoplasm of the pancreas. Int J Pancreatol. 1993;14:135–43.PubMedGoogle Scholar
  18. 18.
    Sessa F, Solcia E, Capella C, Bonato M, Scarpa A, Zamboni G, et al. Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch. 1994;425:357–67.PubMedCrossRefGoogle Scholar
  19. 19.
    Tada M, Omata M, Ohto M. Ras gene mutations in intraductal papillary neoplasms of the pancreas. Analysis in five cases. Cancer. 1991;67:634–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Schönleben F, Qiu W, Bruckman K, Ciau N, Li X, Lauerman M, et al. BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Lett. 2007;249:242–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Biankin A, Biankin S, Kench J, Morey A, Lee C, Head D, et al. Aberrant p16(INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut. 2002;50:861–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K, et al. Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas. 2007;34:85–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Takahashi H, Oda T, Hasebe T, Aoyagi Y, Kinoshita T, Konishi M, et al. Biologically different subgroups of invasive ductal carcinoma of the pancreas: Dpc4 status according to the ratio of intraductal carcinoma components. Clin Cancer Res. 2004;10:3772–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Schönleben F, Qiu W, Ciau N, Ho D, Li X, Allendorf J, et al. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res. 2006;12:3851–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Jaffee E, Hruban R, Canto M, Kern S. Focus on pancreas cancer. Cancer Cell. 2002;2:25–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ishimura N, Yamasawa K, Karim Rumi M, Kadowaki Y, Ishihara S, Amano Y, et al. BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett. 2003;199:169–73.PubMedCrossRefGoogle Scholar
  27. 27.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMedCrossRefGoogle Scholar
  28. 28.
    Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Tanaka Y, Kanai F, Tada M, Asaoka Y, Guleng B, Jazag A, et al. Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Oncogene. 2006;25:2950–2.PubMedCrossRefGoogle Scholar
  30. 30.
    Shao R, Kato N, Lin L, Muroyama R, Moriyama M, Ikenoue T, et al. Absence of tyrosine kinase mutations in Japanese colorectal cancer patients. Oncogene. 2007;26:2133–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Ohta M, Sugimoto T, Seto M, Mohri D, Asaoka Y, Tada M, et al. Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II. Hum Pathol. 2008;39:1301–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Andrejevic-Blant S, Kosmahl M, Sipos B, Klöppel G. Pancreatic intraductal papillary-mucinous neoplasms: a new and evolving entity. Virchows Arch. 2007;451:863–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Naoki K, Chen T, Richards W, Sugarbaker D, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 2002;62:7001–3.PubMedGoogle Scholar
  34. 34.
    Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Karnoub A, Weinberg R. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Chadwick B, Willmore-Payne C, Tripp S, Layfield L, Hirschowitz S, Holden J. Histologic, immunohistochemical, and molecular classification of 52 IPMNs of the pancreas. Appl Immunohistochem Mol Morphol. 2009;17:31–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Nakata K, Nagai E, Ohuchida K, Aishima S, Hayashi A, Miyasaka Y, et al. REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms. Mod Pathol. 2009;22:460–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol. 2008;215:411–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Adsay N, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon K, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol. 2001;25:26–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut. 2008;57:1561–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Fernández-del Castillo C, Adsay N. Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2010;139:708–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Dai Mohri
    • 1
  • Yoshinari Asaoka
    • 1
  • Hideaki Ijichi
    • 1
  • Koji Miyabayashi
    • 1
  • Yotaro Kudo
    • 1
  • Motoko Seto
    • 2
  • Miki Ohta
    • 3
  • Motohisa Tada
    • 4
  • Yasuo Tanaka
    • 1
  • Tsuneo Ikenoue
    • 5
  • Keisuke Tateishi
    • 1
  • Hiroyuki Isayama
    • 1
  • Fumihiko Kanai
    • 4
  • Noriyoshi Fukushima
    • 6
  • Minoru Tada
    • 1
  • Takao Kawabe
    • 7
  • Masao Omata
    • 1
    • 8
  • Kazuhiko Koike
    • 1
  1. 1.Department of Gastroenterology, Graduate School of MedicineUniversity of TokyoTokyoJapan
  2. 2.Department of GastroenterologyKanto Central HospitalTokyoJapan
  3. 3.Department of GastroenterologySanno HospitalTokyoJapan
  4. 4.Department of Medicine and Clinical Oncology, Graduate School of MedicineChiba UniversityChibaJapan
  5. 5.Division of Clinical Genome Research, Institute of Medical SciencesUniversity of TokyoTokyoJapan
  6. 6.Department of Diagnostic PathologyJichi Medical UniversityShimotsukeJapan
  7. 7.Kawabe ClinicKoganeiJapan
  8. 8.Yamanashi Prefectural Hospital OrganizationKofuJapan

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