title: Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions.
abstract: The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.
authors.affiliation: Institute of Pathology, University of Regensburg, Regensburg, Germany. petra.ruemmele@klinik.uni-regensburg.de
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Frauke
authors.initials: F
authors.lastname: Bataille
authors.forename: Annette
authors.initials: A
authors.lastname: Kaiser
authors.forename: Peter-Heinz
authors.initials: PH
authors.lastname: Wuensch
authors.forename: Ernst
authors.initials: E
authors.lastname: Heinmoeller
authors.forename: Kia
authors.initials: K
authors.lastname: Homayounfar
authors.forename: Jutta
authors.initials: J
authors.lastname: Luettges
authors.forename: Guenter
authors.initials: G
authors.lastname: Kloeppel
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.forename: Tina Bocker
authors.initials: TB
authors.lastname: Edmonston
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Monika
authors.initials: M
authors.lastname: Klinkhammer-Schalke
authors.forename: Armin
authors.initials: A
authors.lastname: Pauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Schick
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000737:chemistry / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014670:Ampulla of Vater / Q000737:chemistry / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D003138:Common Bile Duct Neoplasms / Q000737:chemistry / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005060:Europe; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000737:chemistry / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein