Universal Mismatch Repair Protein Screening in Upper Tract Urothelial Carcinoma

Abstract

Objectives Universal screening of upper tract urothelial carcinoma (UTUC) for Lynch syndrome by mismatch repair (MMR) protein immunohistochemistry (IHC) has been recommended by some investigators. Herein, we assess this recommendation retrospectively by simulating its performance on a retrospective, unselected cohort of UTUCs, with comparison to the established setting of colorectal and endometrial adenocarcinoma. Methods We assessed for complete loss of MMR protein (MLH1, MSH2, MSH6, and PMS2) IHC in 74 consecutive cases of UTUC and then tabulated clinical and pathologic factors. MMR findings from same-institution colorectal and endometrial adenocarcinomas were tabulated for comparison. Results We observed loss of at least one MMR protein in 12% in our UTUC cohort (three MSH2/MSH6, three MSH6 only, one MLH1/PMS2, and two PMS2 only). Of these nine cases (seven males, two females, median age 67 years, five associated with colorectal adenocarcinoma), at least three (4% of the overall cohort) proved to be Lynch syndrome. Overall, MMR loss in UTUC was comparable to colorectal (11%; 50 of 471 cases) and endometrial (12%; 12 of 101 cases) adenocarcinomas. Conclusions The rate of MMR loss observed in UTUC was comparable to that in the established setting of colorectal and endometrial adenocarcinomas, supporting universal UTUC screening at our institution and others.

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…The inverted growth pattern, at least focally, and increased intra-tumoral lymphocytes have been shown to be predictive of MSI in some studies [66,72], but they did not reach statistical significance in others [25]. Otherwise, there is no significant difference in terms of tumor grade, stage [25], or age at onset, which is comparable to the general population (about 65-70 years old) [65][66][67]. Finally, there are too-few studies with a significant number of genetically characterized patients to identify the characteristics specific to LS.…”

“…About 3-12% of upper tract urothelial carcinomas (UTUC) exhibit dMMR, which most commonly manifests as a dual loss of MSH2 and MSH6 or isolated MSH6 loss (up to 86%) [25,[65][66][67]. Among tumors with a loss of MMR proteins, LS represents about 20-30% of the cases [65,67,68]. UTUC is the most common urologic malignancy, occurring in 5% of patients with LS [69,70].…”

Immunohistochemical Screening of Upper Tract Urothelial Carcinomas for Lynch Syndrome Diagnostics: A Systematic Review

“…In total, 82 studies were identified (Supplementary figure 1) and screened by reading the title and abstract. Of these, 15 full text articles were screened and 12 were included (16)(17)(18)(19)(20)(21)(22)(24)(25)(26)(27)(28). Country, time periods, study design, and quality of the studies are described in detail in Supplementary table 1.…”

“…Although Catto et al 2003 found loss of MLH1 in 27% of the cases and loss of MSH2 in 20%, the level of overlap between these cases were not given even though it was observed in the study (18). Focusing on studies reported to be unselected and/or consecutively collected, 77 of 1331 (5.8%) of the patients had UTUC with MMR loss (Supplementary table 1 and Table 1) (16,17,20,21,(24)(25)(26)(27)(28). Loss of MSH2, MSH6, or both were the most common and was found in 80.7% of the patients.…”

“…Lynch syndrome diagnosis was confirmed for 20 out of 970 (2.1%) individuals with a range between 0.8-5.2% in the individual cohorts (Table 3) (16,17,(19)(20)(21)26,27). In some studies, the genetic test result was not reported, and Lynch syndrome diagnoses were given to 31 individuals based on concordance between MMR loss/MSI and previous cancer history (16,17,19,20,25,27).…”