Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome

Summary

Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P < .002). All patients with colorectal carcinomas demonstrating isolated loss of MSH6 expression had Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome–associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome–associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor.

Introduction

Identification of individuals at risk for Lynch syndrome is important, as these individuals and their relatives benefit from genetic counseling and increased surveillance that can result in early cancer detection and decreased disease-specific mortality. Universal screening for Lynch syndrome among all newly diagnosed colorectal carcinomas has been advocated by the Evaluation of Genomic Applications in Practice Prevention (EGAPP) working group, a project sponsored the Centers for Disease Control and Prevention [1], and is also advocated by the recent National Cancer Center Network guidelines for colorectal carcinoma [2]. Increasing evidence for Lynch syndrome screening in newly diagnosed endometrial carcinoma is also emerging [3], [4]. Lynch syndrome is genetically heterogeneous with most patients harboring mutations in 1 of 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, or PMS2, or germline deletions of the 3′ end of EPCAM that lead to epigenetic silencing of the MSH2 gene [1], [5]. Increasing universal screening efforts in colorectal and endometrial carcinomas have led to the identification of patients with abnormal DNA MMR protein expression within their tumor concerning for Lynch syndrome. However, some patients have no evidence of a germline mutation in DNA MMR genes or EPCAM and have been described as having Lynch-like syndrome [6]. Patients with Lynch-like syndrome represent a major challenge in Lynch syndrome screening, as it is uncertain whether such patients should undergo the same intensive lifelong screening protocol used for patients with confirmed Lynch syndrome.

The clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome are unknown. In this study, we identified patients with tumors harboring DNA MMR deficiency concerning for Lynch syndrome during universal screening efforts in colorectal and endometrial carcinomas and correlated clinicopathological features with germline mutation status. The objective of this study was to compare the clinical and histologic features of carcinomas in patients with Lynch-like syndrome and confirmed Lynch syndrome identified at our institution. In so doing, we demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome–associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor.