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