Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair

Background-Despite intensive research into the molecular abnormalities asso ciated with colorectal cancer (CRC), no diagnostic tests have emerged which usefully complement standard histopathological assessments. Aims-To assess the feasibility of using immunohistochemistry to detect repl ication error (RER) positive CRCs and determine the incidence of RER positi vity within distinct patient subgroups. Methods-502 CRCs were analysed for RER positivity (at least two markers aff ected) and/or expression of hMSH2 and hMLH1. Results-There were 15/30 (50%) patients with metachronous CRCs, 16/51 (31%) with synchronous CRCs, 14/45 (31%) with a proximal colon carcinoma, and 4/ 23 University of Leeds, (17%) who developed a CRC under the age of 50 showe d RER positivity. However, 0/54 patients who developed a solitary carcinoma of the rectum/left colon over the age of 50 showed RER positivity. Immunoh istochemical analysis revealed that 66/66 (100%) RER positive carcinomas we re associated with complete lack of expression of either hMSH2 or hMLH1. Th is correlation was confirmed using a further 101 proximal colon carcinomas. Patients with a mismatch repair defective carcinoma showed improved surviv al but a 5.54 times relative risk of developing a metachronous CRC. A prosp ective immunohistochemical study revealed 13/117 (11%) patients had a misma tch repair defective carcinoma. A fivefold excess of hMLH1 defective cases was noted. Conclusions-Ah RER positive carcinomas were identified by the immunohistoch emical test. This is the first simple laboratory test which can be performe d routinely on all CRCs. It will provide a method for selecting patients wh o should be investigated for HNPCC, offered long term follow up, and who ma y not respond to standard chemotherapy regimens.