The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease

Abstract

Abstract Introduction: Celiac Disease (CD) is associated with an increased risk of small bowel (SB) adenocarcinoma. The aims of this study were to investigate the molecular basis and assess outcomes of SB adenocarcinoma in CD. Methods: We performed a retrospective case control study of 18 biopsy-proven CD patients with SB adenocarcinoma, 51 age- and gender-matched control patients, and 40 age-, gender-, and stage-matched control patients with SB adenocarcinoma treated at our institution from 7/1960 to 11/2002. Mismatch Repair (MMR) status was assessed by microsatellite instability (MSI) and hMLH1 and hMSH2 protein expression by immunohistochemistry. Results: One CD patient was excluded due to postmortem diagnosis of cancer. High frequency MSI (MSI-H) was identified in 8/11 (73%) tumors in the CD group and 2/22 (9%) in the control groups. Expression of hMLH1 was lost in 6/8 and 2/2 MSI-H tumors in the CD and control groups, respectively. One MSI-H tumor lost hMSH2 expression in the CD group. CD patients presented with lower stage cancer compared to controls (P = 0.018). Survival was improved in the CD group when compared to stage-matched controls (5-year survival 64% versus 24%, P=0.025), and was not associated with stage in the CD group. Conclusions: CD patients with SB adenocarcinoma had remarkably high incidence of defective MMR and better survival compared to stage-matched controls. CD patients presented with earlier stage cancers and stage was not a strong prognostic indicator. Improved survival and earlier presentation of SB adenocarcinoma in CD may be biologically linked to defective MMR.