Neoadjuvant Therapy in Microsatellite Stable Colorectal Carcinoma Induces Concomitant Loss of MSH6 and Ki67 Expression

Publication date: Available online 21 February 2017
Source:Human Pathology
Author(s): Shih-Fan Kuan, Bing Ren, Randall Brand, Beth Dudley, Reetesh K. Pai
Universal screening using immunohistochemistry for DNA mismatch-repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) is advocated by major professional medical organizations to identify Lynch syndrome-associated colorectal carcinoma. Loss of MSH6 expression independent of MSH2 expression has been reported in microsatellite stable (MSS) colorectal carcinoma following neoadjuvant therapy. The mechanism remains unclear. We studied the immunohistochemical expression of MSH2, MSH6, and Ki67 in MSS colorectal carcinoma with (n=50) or without (n=64) preoperative neoadjuvant therapy and Lynch syndrome-associated colorectal carcinoma with confirmed MSH6 germline mutation (n=3). Twelve of 50 MSS colorectal carcinoma post-neoadjuvant resections demonstrated reduced MSH6 expression with loss of expression ranging from 20 to 100% of tumor cells. Eight of 64 MSS colorectal carcinoma without neoadjuvant therapy also exhibited reduced MSH6 expression but to a lesser degree (10 to 50% of tumor cells with loss of expression). In both subgroups, concomitant loss of MSH6 and Ki67 expressions was demonstrated in the same tumor areas in consecutive tissue sections. However, 3 cases of Lynch syndrome-associated colorectal carcinoma due to germline MSH6 mutation revealed complete loss of MSH6 expression with discordant positive Ki67 staining in the tumor cells. The MSH2-independent, Ki67-related expression of MSH6 in colorectal carcinoma helps to explain the heterogeneous MSH6 staining in MSS colorectal carcinoma with or without neoadjuvant therapy.



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