Clinical Impact of Mismatch Repair Protein Testing on Outcome of Early Staged Colorectal Carcinomas

Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening.

From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study. Details of each patient related to their demographic profile and tumour profile were recorded. All the cases were grossed and staged according to College of American Pathologist (CAP) guidelines. The expression of MMR proteins (which was earlier validated on normal as well as tumour tissue) in FFPE tumour tissue using IHC for mut L homologue 1 (MLH1), mut S homologue 2 (MSH2), mut S homologue 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was studied. Information regarding stage, treatment, clinical outcome and overall survival was retrieved when available.

Out of a total of 371 cases, 62 (16.7%) cases were of stage II CRC, out of which 43 (12%) were treatment naive. Among the selected 62 cases, 26 (41.9%) demonstrated loss of MMR proteins and 36 (58.0%) cases had intact nuclear expression. Out of the cases with MMR loss, 38.4% showed loss of MLH1 and PMS2, 30.7% showed loss of MSH2 and MSH6, 26.9% showed isolated loss of PMS2 and 3.8% showed isolated loss of MSH6. Right-sided location (57.6%) was more common than left-sided (19.2%) and transverse colon (23.0%). Majority of the cases were moderately differentiated (65.3%) in morphology. There was no intratumoural infiltrate in most of the cases (53.8%), and only 3.8% cases showed marked intratumoural infiltrate. Also, peritumoural lymphocytic infiltrate was mild to moderate in most of the cases (26.9%) and marked Crohn’s-like infiltrate was seen in only 7.6% cases.

Our study shows that the routine evaluation of MMR proteins is achievable and essential for the purpose of prognostication, planning of treatment strategies and ascertaining a hereditary basis of CRC. The incidence of MMR protein loss was quite high in our study compared to other studies probably due to a difference in ethnicity. Though a right-sided predominance was supported, none of the typical morphological features of microsatellite instability (MSI) tumours were substantiated by our study, highlighting the lack of importance of histology for predicting MSI, and emphasising the point that MSI testing should be done as a routine procedure in all stage II CRC. A short follow-up was done for all our cases and comparison between the survival of the chemotherapy treated MSI cases versus those which were treatment naïve was performed and revealed that chemotherapy (CT) did not provide additional benefit to survival; MSI tumours in general are a better prognostic category and do not require additional chemotherapy.