Should immunohistochemical expression of mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis be routinely performed for poorly differentiated colorectal neuroendocrine carcinomas?

Abstract

Summary Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are typically associated with poor outcomes. The mechanisms of their aggressiveness are still being investigated. Microsatellite instability (MSI) has recently been found in colorectal NECs showing aberrant methylation of the MLH1 gene and is associated with improved prognosis. We present a 76-year-old lady with an ascending colon tumour showing features of a pT3 N0 R0, large cell NEC (LCNEC) following right hemicolectomy. The adjacent mucosa showed a sessile serrated lesion (SSL) with low-grade dysplasia. Immunohistochemistry showed loss of expression for MLH1 and PMS2 in both the LCNEC and dysplastic SSL. Molecular analysis indicated the sporadic nature of the MLH1 mismatch repair (MMR) protein-deficient status. Our patient did not receive adjuvant therapy and she is alive and disease-free after 34 months follow-up. This finding, similar to early-stage MMR-deficient colorectal adenocarcinoma, is likely practice-changing and will be critical in guiding the appropriate treatment pathway for these patients. We propose that testing of MMR status become routine for early-stage colorectal NECs. Learning points: Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are known to be aggressive and typically associated with poor outcomes. A subset of colorectal NECs can display microsatellite instability (MSI) with mismatch repair (MMR) protein-deficient status. MMR-deficient colorectal NECs have been found to have a better prognosis compared with MMR-proficient NECs. MMR status can be detected using immunohistochemistry. Immunohistochemistry for MMR status is routinely performed for colorectal adenocarcinomas. Immunohistochemical expression of MMR protein and MSI analysis should be performed routinely for early-stage colorectal NECs in order to identify a subgroup of MMR-deficient NECs which are associated with a significantly more favourable prognosis.

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

“…Currently, MSI and MMR protein deficiency have been explored in different malignancies, particularly to address an indication of ICPI [82][83][84][85][86][87][88]. Exploring the MMR/MSI status should become the new standard in poorly differentiated NEN, regardless of germline mutations consistent with LS [85][86][87][88].…”

Gastroenteropancreatic neuroendocrine tumours – an overview

“…Colorectal NECs are morphologically similar to neuroendocrine carcinoma of the lung, and they can be large or small cell carcinomas. Small cell NECs arise from the squamous mucosa from the anal canal, and large cell NECs from the glandular mucosa of the large intestine [118]. Small cell NECs possess cells with minimal amounts of cytoplasm as well as granular nuclear chromatin, and these cells form ribbon-like structures.…”

“…It was shown that early-stage MMR-deficient NECs have a better prognosis compared with MMR-proficient NECs. According to the Royal College of Pathologists in the United Kingdom, MMR protein expression status is a core data item of the histopathology report [118]. MicroRNAs are very promising markers in diag-nosing colorectal NENs.…”