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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

Abstract

Background

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.

Methods

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.

Results

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%).

Conclusions

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.

Keywords

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

Abbreviations

BMP

Bone morphogenetic protein

EGFR

Epidermal growth factor receptor

ERK

Extracellular signal-regulated kinase

IPMN

Intraductal papillary mucinous neoplasm

IPMC

Intraductal papillary mucinous carcinoma

PanIN

Pancreatic intraepithelial neoplasia

PDAC

Pancreatic ductal adenocarcinoma

PCR

Polymerase chain reaction

MPD

Main pancreatic duct

Notes

Acknowledgments

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.

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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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