Thoracic NUT carcinoma: expanded pathologic spectrum with expression of TTF-1 and neuroendocrine markers.

AIMS NUT carcinoma, a rare aggressive tumor driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, demonstrating extensive pleural involvement and diffuse TTF-1 expressions initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathologic spectrum. METHODS AND RESULTS We queried for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumors interrogated by RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified 6 patients (5 men; 1 woman; age 31-80 years; 4 never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including 5 with positive NUT immunohistochemistry). They died at 2.3-12.9 (median 2.8) months after presentation. Two patients were diagnosed by histopathologic assessment, whereas the remainder 4 (including the index patient) were recognized by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers along with TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted in this and 3 additional cases. We found no additional NUT-positive cases by immunohistochemistry screening. CONCLUSIONS Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine and other tumors. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumors, regardless of their immunophenotypic features.