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MMR-associated upper tract urothelial carcinoma

Tuesday 28 August 2018

Lynch syndrome-associated upper tract urothelial carcinoma


- 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