EBV Infection and Mismatch Repair Deficiency Mediated by Loss of hMLH1 Expression Independently Contribute to the Development of Multiple Synchronous Gastric Carcinomas.
Ha Y Park, Gu H Kang, Go E Bae, Seung E Lee, Nara Yoon, Kyeongmee Park, Cheol K Park, Kyoung Kim. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Sanggye Paik Hospital, Inje University, Seoul, Korea
Background: Multiple synchronous gastric carcinomas (MSGCs) are variously described in 1∼10% of patients. MSGCs occur typically in elderly men, intestinal in histologic type, and early in tumor stage. The incidence of MSGCs appears to be higher in Epstein-Barr virus (EBV)-associated GC than in EBV-negative carcinomas. To explore pathogenesis and the relationship between carcinomas in MSGC, we evaluated EBV infection with expression of hMLH1 and epidermal growth factor receptors.
Design: From 2004 to 2009, 141 cases of MSGCs were retrieved from 7,598 gastrectomies for carcinoma. For comparison, consecutive 161 single GCs during recent 3 months were used. In situ hybridization for EBV and immunohistochemical analyses for hMLH1, HER2, and EGFR were performed. For statistical analysis, Pearson's chi-square test and Fisher's exact test were used.
Results: MSGCs were closely associated with male preponderance (81.6% were male; P=0.039), older ages (P=0.007), and lower TNM stages (P=0.003) compared to single GCs. EBV-positivity was found in 31 MSGCs (21.9%) and 12 single GCs (7.5%) and this difference was statistically significant (P=0.000). In 31 EBV-positive MSGCs, EBV was concurrently positive in 18 cases (58.1%) and 13 cases (41.9%) were positive in a single carcinoma. Loss of hMLH1 expression was significantly frequent in MSGCs than single GCs (24.1% versus 6.7%, P= 0.004). Expression of HER2 and EGFR showed no significant differences between MSGCs and single GCs.
In MSGCs, all 31 EBV-positive MSGCs were exclusively found in male patients and the mean age was 59.4 years, which are younger than EBV-negative MSGCs (mean 65.0 years; P=0.017). Loss of hMLH1 expression was more frequently observed in EBV-negative MSGCs (29.1%) than EBV-positive MSGCs (6.5%) (P=0.009). In EBV-positive MSGCs, concordant immunoreactivity between separate carcinomas for hMLH1, HER2, and EGFR was 96.9%, 87.1%, and 96.9%. In EBV-negative MSGCs, concordance for hMLH1, HER2, and EGFR was 91.7%, 69.1% and 86.4%, respectively. Although concordance rate between carcinomas within MSGCs was slightly higher in EBV-positive MSGCs, there was no significant difference.
Conclusions: EBV infection and mismatch repair deficiency mediated by loss of hMLH1 expression may independently contribute to the development of MSGCs. The concordant immunoreactivity found in separate carcinomas of MSGC suggests that multiple carcinomas occur in the tumor-prone genetic background.
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 157, Tuesday Morning