Genotype-Phenotype Characterization of Lynch Syndrome-associated Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is the most prevalent urologic malignancy among patients with Lynch syndrome (LS), which is caused by germline mutations in genes MSH2, MSH6, MLH1, and PMS2 involved in DNA mismatch repair (MMR). We describe clinical phenotypes of UTUC by MMR genotype and in comparison to sporadic UTUC.

Data for patients with confirmed LS and UTUC treated at a single cancer center were retrospectively reviewed. Patients were stratified by their underlying gene mutations and compared to patients with sporadic UTUC. Data on tumor immunohistochemistry (IHC) and microsatellite instability status on polymerase chain reaction were collected.

Of 37 patients with LS-UTUC, 25 had germline MSH2 mutations, eight had MSH6 mutations, three had MLH1 mutations, and one had a PMS2 mutation. Patients with MSH6 mutations were older (68.5 yr) at presentation than patients with MSH2 mutations (58.0 yr), were less likely to have had prior LS-associated cancers, and were more likely to present with low-grade tumors. Bilateral disease was more common in LS-UTUC (23%) than in sporadic UTUC (8%). IHC analysis revealed strong concordance with germline alterations: 90% of patients with germline MMR mutations had deficient MMR protein expression.

Patients with germline MSH6 mutations tended to be older at LS-UTUC onset and were less likely to have a personal and family history of cancer in comparison to patients with germline MSH2 or MLH1 mutations, bringing into question age as a discriminatory criterion for testing. Any new diagnosis of UTUC, especially in cases with bilateral disease, should prompt screening or germline testing given the heterogeneous phenotypes associated with LS.