MMR-associated upper tract urothelial carcinoma

Predisposition

 Lynch syndrome

• Lynch syndrome (LS) is defined by germline mutations in DNA mismatch repair (MMR) genes, and affected patients are at high risk for multiple cancers.
• Reflexive testing for MMR protein loss by immunohistochemistry (IHC) is currently only recommended for colorectal and endometrial cancers, although upper tract urothelial carcinoma (UTUC) is the third-most common malignancy in patients with LS.
• A study found that 9% of UTUC showed MMR IHC loss (8 MSH6 alone; 1 MSH2 and MSH6; 1 MLH1 and PMS2; n=117) compared with 1% of BUC (1 MSH6 alone; n=160) (P=0.001).
• Of these, 4/10 (40%) of UTUC (3% overall; 3 MSH6 alone; 1 MLH1 and PMS2) and none (0%) of BUC had high microsatellite instability on molecular testing (P=0.03).
• The only predictive clinicopathologic feature for MMR loss was a personal history of colorectal cancer (P=0.0003).
• However, UTUC presents at a similar age to colon carcinoma in LS and thus UTUC may be the sentinel event in some patients.
• Combining our results with those of other studies suggests that 1% to 3% of all UTUC cases may represent LS-associated carcinoma.
• LS accounts for 2% to 6% of both colorectal and endometrial cancers.
• As LS likely accounts for a similar percentage of UTUC, we suggest that reflexive MMR IHC screening followed by microsatellite instability testing be included in diagnostic guidelines for all UTUC.

Paywall references

 Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas. Ju JY, Mills AM, Mahadevan MS, Fan J, Culp SH, Thomas MH, Cathro HP. Am J Surg Pathol. 2018 Aug 24. doi : 10.1097/PAS.0000000000001141 PMID: 30148743