NF2/Merlin Immunohistochemistry Helps Distinguish Collecting Duct Carcinoma From Upper Tract Urothelial Carcinoma

Collecting duct carcinoma (CDC) and upper tract urothelial carcinoma (UTUC) can exhibit overlapping morphologic features, particularly in limited biopsies, creating diagnostic challenges with significant therapeutic implications. Recent molecular studies have identified recurrent NF2 alterations in CDC, whereas pathogenic NF2 alterations are uncommon in UTUC. We evaluated the utility of NF2/Merlin immunohistochemistry (IHC) as a diagnostic tool in this differential diagnosis. NF2/Merlin IHC was performed on 16 cases of CDC and 35 UTUCs. Next-generation sequencing was performed on 13/16 CDC cases. NF2/Merlin loss by IHC was observed in 10/16 CDC cases (63%) compared with 0/35 UTUC cases (0%, P <0.000001). Among 13 CDC cases with available molecular data, 6 harbored NF2 mutations. Of these, 6/6 showed NF2/Merlin protein loss by IHC, while among 7 CDC cases lacking NF2 genetic alterations, 5 retained NF2/Merlin expression and 2 showed protein loss by IHC. Thus, overall NF2/Merlin loss by IHC demonstrates imperfect correlation with molecular studies but high specificity for CDC in the differential diagnosis with UTUC. While not present in all CDC cases, NF2/Merlin loss provides valuable diagnostic support for CDC, particularly in morphologically challenging cases where traditional urothelial markers are negative. While NF2/Merlin loss can be seen in a variety of renal cell carcinoma subtypes, consistent retention of NF2/Merlin expression in our UTUC cohort indicates that NF2/Merlin loss can be a useful adjunct that favors CDC in the challenging differential diagnosis with UTUC. This marker represents a useful addition to the immunohistochemical panel for evaluating infiltrative renal carcinomas with tubular architecture, offering objective support for the diagnosis of CDC in the appropriate morphologic and immunohistochemical context.