NF2/Merlin loss favours collecting duct over urothelial carcinoma

Design

Diagnostic immunohistochemistry study with next-generation sequencing correlation

Population

16 collecting duct carcinomas and 35 upper tract urothelial carcinomas

Primary outcome

NF2/Merlin loss to distinguish collecting duct from urothelial carcinoma

Effect

Loss in 10/16 (63%) collecting duct vs 0/35 (0%) urothelial (P<0.000001)

Collecting duct carcinoma and upper tract urothelial carcinoma can look alike, especially in small biopsies, yet they are managed very differently. This study tested whether NF2/Merlin immunohistochemistry, reflecting the NF2 alterations recurrent in collecting duct carcinoma, can help.

Merlin loss by immunohistochemistry was seen in 10 of 16 collecting duct carcinomas (63%) and in none of 35 upper tract urothelial carcinomas (0%, P<0.000001). The stain did not perfectly track NF2 mutation status: of 13 collecting duct cases with sequencing, all 6 with NF2 mutations showed loss, but 2 of 7 without mutations also showed loss and 5 retained expression. So loss is highly specific for collecting duct carcinoma in this differential, but retained expression does not exclude it.

The practical use is as a panel adjunct. In an infiltrative renal carcinoma with tubular architecture where urothelial markers are negative, Merlin loss offers objective support for collecting duct carcinoma. It should be read with morphology and the rest of the panel, not alone.

• Merlin loss by immunohistochemistry occurred in 63% (10/16) of collecting duct carcinomas and 0% (0/35) of upper tract urothelial carcinomas.
• Loss is highly specific for collecting duct carcinoma in this differential but only moderately sensitive.
• Immunohistochemical loss did not perfectly match NF2 mutation status.
• Use it as a panel adjunct for infiltrative renal carcinoma with tubular architecture and negative urothelial markers.
• Retained Merlin expression does not exclude collecting duct carcinoma.

Why it matters

The two tumours overlap on morphology but diverge on treatment, so an objective marker that tips the diagnosis changes management.

Don't overread it

Sensitivity was only 63% and loss did not perfectly match NF2 mutation, so retained expression cannot exclude collecting duct carcinoma, and the series was small.

The statistics, in plain English

A specificity of 100% in this series means a positive (lost) result strongly supports collecting duct carcinoma, but 63% sensitivity means a normal result is uninformative; the imperfect match with mutation status reflects that protein loss has causes other than the mutation tested.

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