Clinicopathological Analysis and Literature Review of Four Cases of Lynch-like Syndrome

Abstract Background: Among CRC patients with mismatch repair protein deficiency or microsatellite instability (MSI), up to 50% of cases lack germline mutations in MMR genes, BRAFmutations, or MLH1 promoter methylation. Such cases are defined as Lynch-like syndrome (LLS). LLS is a heterogeneous group of diseases that may include both sporadic and hereditary cases. Although various methods have been proposed to distinguish between hereditary and sporadic cases, there is still a lack of consensus on the precise classification of these patients. Methods: Four cases of Lynch-like syndrome encountered in daily clinical pathological diagnostic work were reported. The histopathological characteristics and molecular pathological changes of related tumors were analyzed, and the diagnosis and treatment progress of this disease were reviewed via literature. Results: Lynch-like syndrome-related tumors can occur in the colorectum and extraintestinal organs. Colorectal tumors show no specific locational or histological features, while extraintestinal tumors often exhibit poor differentiation and abundant interstitial lymphocyte infiltration. Patients with Lynch-like syndrome all exhibit tumoral lesions with loss of MMR protein (MLH1, PMS2, MSH2, MSH6) expression, microsatellite instability (MSI-L/MSI-H), wild-type BRAF, and negative MLH1 promoter methylation. However, heterogeneity exists in MMR protein expression, MSI status, and MLH1 promoter methylation among tumors at different sites in the same patient. No germline pathogenic mutations in MMR genes were detected in any patient, but two cases showed suspected pathogenic mutations in MLH1, and one case had a variant of uncertain significance in PMS2. Conclusion: Extraintestinal tumors associated with Lynch-like syndrome mostly exhibit histopathological characteristics and MMR/MSI changes similar to classic Lynch syndrome, but without pathogenic germline MMR mutations or MLH1 promoter methylation. Some Lynch-like syndromes with suspected germline pathogenic MMR mutations may represent Lynch syndrome with rare mutation types. Most cases lack germline MMR mutations in normal tissues but harbor somatic MMR mutations in tumor tissues. Germline or somatic mutations in other genes related to MMR function may be observed in some cases.