Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor‐1 and neuroendocrine markers

Abstract

Aims Nuclear protein in testis (NUT) carcinoma, an aggressive tumour 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, showing extensive pleural involvement and diffuse thyroid transcription factor‐1 (TTF‐1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum. Methods and results We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA‐based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31–80 years; four never‐smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3–12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF‐1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT‐positive cases were found by immunohistochemical 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 tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive‐appearing tumours, regardless of their immunophenotypic features.

Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma

“…The best OS of patients stage IVA who underwent surgery or chemoradiotherapy in the first-line and Atezolizumab in the second-line was only 2.2 months ( 13 , 39 ), which is similar to the mOS of primary pulmonary NUT carcinoma. Atezolizumab does not seem to improve the prognosis of advanced patients.…”

“…Except for a small amount of pleural effusions on CT, there is no evidence of disease involvement in the contralateral lung ( Figure 2 ). The extrathoracic metastatic sites were predominantly bones, with osteolytic changes on CT. Liver, adrenal gland, soft tissue involvement has also been reported.To our knowledge, case of brain metastasis in primary pulmonary NUT carcinoma has not been reported so far ( 13 , 15 , 38 , 39 ).…”

“…Up to now, most of the cases who had lost the opportunity for surgery have received chemoradiotherapy or chemotherapy. In patients receiving chemoradiotherapy, the shorter OS was 2 months to 4 months ( 39 , 55 ), and the longer OS reached 148weeks ( 47 , 54 , 57 , 61 ). The OS was significantly higher than the mOS of primary pulmonary NUT carcinoma.…”

“…Two patients received the combination treatment including Pembrolizumab as the first-line treatment, the OS had exceeded 12 months ( 36 ), suggesting that first-line use of Pembrolizumab may improve the prognosis. The OS of two non-surgical patients staging III who had previously received chemoradiotherapy and then received Nivolumab or Pembrolizumab was significantly prolonged [11.6 months ( 39 ), 26.7 months ( 13 ) respectively]. The OS of one non-surgical patient staging IVA who received chemotherapy in the first-line and Nivolumab in the second-line (The PFS was 6 weeks) was 4 months ( 49 ), and that of one non-surgical patient staging IVA who received radiotherapy in the first-line and Pembrolizumab in the second-line (The PFS was 21 weeks) was 19.5 months ( 13 ).…”

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…NUT carcinomas express cytokeratins (Figure 2) and P63 but are often negative for neuroendocrine markers and TTF1 [300]. However, some rare tumors can nonetheless be positive for TTF1, chromogranin (Figure 2), synaptophysin, or P40 or be negative for P63 [300][301][302][303]. Finally, NUT carcinoma can be identified with cytological samples using anti-NUT antibodies and confirmed by NGS [298,304] (Figure 2).…”