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IL‐33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
Author(s) -
Tomioka Yuichiro,
Sung YouNa,
Sawada Ryuichiro,
Hong SeungMo,
Akita Masayuki,
Itoh Tomoo,
Ajiki Tetsuo,
Fukumoto Takumi,
Zen Yoh
Publication year - 2019
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.13863
Subject(s) - gallbladder , kras , medicine , gallbladder cancer , bile duct , gastroenterology , carcinogenesis , pathology , carcinoma , cancer , colorectal cancer
Aims To investigate whether genetic or inflammatory pro‐oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). Methods and results Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM‐associated ( n = 31) and non‐associated gallbladder cancers ( n = 49). The tissue expression of IL‐6 and IL‐33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real‐time PCR and in‐situ hybridisation. The incidence of KRAS mutations was similarly low in PBM‐associated (five of 32 cases; 16%) and non‐associated cancers (four of 49 cases; 8%) ( P = 0.272). The tissue expression of IL‐33 mRNA, but not IL‐6 mRNA, was significantly higher in PBM‐associated gallbladder cancers than in gallbladder cancers without PBM ( P = 0.004). A similar degree of IL‐33 overexpression was also observed in the background non‐cancerous mucosa in cases of PBM‐associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone ( P < 0.001). The results of in‐situ hybridisation indicated that the source of IL‐33 production in PBM‐associated carcinomas was the endothelium, cancer cells and non‐neoplastic biliary epithelium. In a combined PBM‐associated and non‐associated cohort, IL‐33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large‐duct cholangiocarcinomas. Conclusions KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL‐33 overexpression may provide a pro‐oncogenic microenvironment in the gallbladder mucosa of patients with PBM.