Immunohistochemistry (IHC) for mismatch repair (MMR) proteins has been incorporated into routine screening for MMR deficient colorectal cancer and Lynch syndrome (the most common hereditary form of colorectal carcinoma). The four major MMR proteins form two pairs of functional heterodimers (MLH1/ PMS2 and MSH2/MSH6), and the usual pattern of MMR compromise is when there is a loss of staining in one of the subsystems. From a cancer evolution perfective, the high mutation burdens resulting from deficient MMR may promote intra-tumour heterogeneity, clonal selection and subclonal evolution. We present here two cases with unusual MMR IHC patterns. The first case is an 88-year-old female with a right colon adenocarcinoma that showed a mixture of conventional, mucinous and poorly differentiated solid growth patterns. MLH1/PMS2 showed loss of staining throughout the entire tumour while MSH6 showed loss of staining only in the high-grade component. MSH2 and BRAF V600E staining were positive throughout. The second case is a 76-year-old female with two synchronous adenocarcinomas in the right colon. Despite both having low-grade morphology, one tumour had a mucinous component and increased tumour infiltrating lymphocytes. This tumour also showed loss of MLH1/PMS2 staining with retained MSH2/MSH6 staining. BRAF V600E was positive. In contrast, its synchronous counterpart showed retention of all four MMR proteins. Positive BRAF in both cases suggested that the MMR deficiency was likely to be sporadic. The unusual loss of MSH6 in the first case is likely to be a secondary somatic event in the setting of genetic instability caused by MLH1/PMS2 defects. The different MMR stain patterns of the two synchronous tumours suggest divergent evolutionary process of two independent clones. Our cases provide insights into intra-tumoural and inter-tumoural heterogeneity of colorectal carcinoma and subclonal evolution as evidenced by heterogenous morphology and MMR IHC staining patterns.
Shen et al. (Sun,) studied this question.