title: Fundic gland differentiation of oncocytic/pancreatobiliary subtypes of pancreatic intraductal papillary mucinous neoplasm.
abstract: OBJECTIVE
  Intraductal papillary mucinous neoplasms (IPMNs) differentiate in several histological directions, which are related to their clinical behaviour. Differentiation of IPMNs to the gastric foveolar epithelium/pyloric gland (PG) is well known. However, no study has been conducted regarding fundic gland (FG) differentiation. The aim of this study was to determine the frequency of FG differentiation and its relationship with the clinicopathological features of IPMNs, by studying 48 surgically resected IPMN cases consisting of 17 gastric IPMNs, 15 intestinal IPMNs, 10 pancreatobiliary IPMNs, and six oncocytic IPMNs.
  
  
  RESULTS
  Clinicopathological data, including histological tumour grade, immunohistochemical data for mucins (MUCs), pepsinogen I, pepsinogen II, and H,K-ATPase, and GNAS/KRAS status, were analysed. Pepsinogen I and H,K-ATPase were used to assess FG differentiation, and pepsinogen II and MUC6 were used to identify the equivalent cell type of the normal FG. Reverse transcription polymerase chain reaction (RT-PCR) for PGA5/PGC (pepsinogen I and pepsinogen II mRNA, respectively) and quantitative real-time RT-PCR (qRT-PCR) for PGA5 were performed to confirm the immunohistochemistry results. Pepsinogen I expression was detected in 12.5% (6/48) of total IPMNs, of which 66.7% (4/6) of oncocytic IPMNs and 20.0% (2/10) of pancreatobiliary IPMNs were pepsinogen I-positive. No H,K-ATPase-positive cases were detected. Three oncocytic IPMNs with pepsinogen I expression showed similar histology to normal FG. RT-PCR and qRT-PCR confirmed the immunohistochemical results. All IPMNs with FG differentiation were of the oncocytic or pancreatobiliary subtype, were of histologically high grade, and were without GNAS mutation.
  
  
  CONCLUSIONS
  The differentiation of IPMNs to gastric FG is related to oncocytic and pancreatobiliary subtypes, and to high grade. This is the first report to describe differentiation of IPMNs to the FG, and to reveal its relationship with the clinicopathological features of IPMNs.
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Osman
authors.initials: O
authors.lastname: Mamat
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan. yfuku@juntendo.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fukumura
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan.|Department of Pathology, Japan Labour Health and Welfare Organization, Kanto Rosai Hospital, Kawasaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.affiliation: Department of Gastroenterology, Juntendo University, Tokyo, Japan.
authors.forename: Jin Kan
authors.initials: JK
authors.lastname: Sai
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawasaki
authors.affiliation: Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000473:pathology*; D000231:Adenocarcinoma, Papillary / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002454:Cell Differentiation; D005260:Female; D005748:Gastric Fundus / Q000473:pathology; D005753:Gastric Mucosa / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor
keywords: GNAS; fundic gland differentiation; high-grade IPMN; intraductal papillary mucinous neoplasm; oncocytic type; pancreatobiliary type