title: Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype.
abstract: OBJECTIVE
  To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes.
  
  
  BACKGROUND
  Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types.
  
  
  METHODS
  Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs.
  
  
  RESULTS
  Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC.
  
  
  CONCLUSIONS
  Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Ideno
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Oda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aishima
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Kousei
authors.initials: K
authors.lastname: Ishigami
authors.forename: Shoji
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Kenoki
authors.initials: K
authors.lastname: Ohuchida
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takahata
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D002864:Chromogranins; D003062:Codon; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D010641:Phenotype; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018709:Statistics, Nonparametric; D013274:Stomach Neoplasms / Q000473:pathology*; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: D002864:Chromogranins; D003062:Codon; C117307:KRAS protein, human; D009077:Mucins; D011518:Proto-Oncogene Proteins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins