Primary Pulmonary NUT Midline Carcinoma: Clinical, Radiographic, and Pathologic Characterizations

Abstract

NUT midline carcinoma (NMC) is a poorly differentiated tumor typically driven by a t(15;19) rearrangement leading to a NUT fusion event. This rare and uniformly fatal tumor arises in multiple organ sites; however the clinical, radiographic, and pathologic characteristics of primary pulmonary NMC are poorly defined. We identified eight cases of primary pulmonary NMC in our consult practice over 4 years and, using a NUT immunohistochemistry screen, retrospectively identified one additional case from 166 (0.6%) consecutive in-house biopsies of lung carcinomas lacking glandular differentiation. Eight cases had available clinical and radiographic data and shared a remarkable degree of similarity. The median age at presentation was 30 (range 21-68). Six patients had little or no smoking history. All complained of 1 to 3 months of cough at presentation. Computed tomography scans showed a large, centrally located primary mass with confluent involvement of mediastinal lymph nodes, pleural disease, and sparing of the contralateral lung. Lytic bone metastases were common but brain metastases were absent in all cases. Pathologically, all cases showed primitive-appearing round to epitheloid cells growing in nests and sheets. All tumors expressed keratin, p63 or p40, and NUT protein. Eight cases had a fluorescence in situ hybridization-proven BRD4-NUT or BRD3-NUT rearrangement; one case was presumed to have a NUT-variant fusion event. Median overall survival was 2.2 months. Despite the rarity of primary pulmonary NMC, it is important to recognize this entity to counsel patients regarding outcome and to identify candidates for targeted BRD inhibitors currently in clinical trials.

Figure 1

Contrast enhanced CT scan of the chest demonstrated a large, poorly-defined mass in the right lower lobe (arrow, panel A), located centrally and confluent with right hilar and mediastinal adenopathy (arrows, panel B). Note right pleural effusion (black asterisk, panel A) and obstructive atelectasis on the right (white asterisk, panel A). There was no evidence of involvement of the left lung. Bone metastasis was present, demonstrating lytic lesions (black arrow, panel C). Whole body image of the FDG-PET scan demonstrated marked FDG avidity of the dominant lung lesion (white arrow, panel D), as well as metastatic sites including innumerable osseous lesions and a subcutaneous lesion in the right flank (black arrow, panel D). Most of the osseous lesions were more noticeable on PET than CT, and Tc-99m MDP bone scintigraphy was negative for osseous metastasis.

Figure 2

A) Hematoxylin and eosin stain (400X) of a Nut midline carcinoma showing B) weak, scattered nuclear positivity for thyroid transcription factor-1 (TTF-1). C) Hematoxylin and eosin stain (200X) of a Nut midline carcinoma with crush artifact and nuclear molding (lower right) and B) scattered tumor cells with membranous CD56 expression.

Figure 3

Retrospectively identified primary pulmonary Nut midline carcinoma. A) Hematoxylin and eosin-stained slide at 400X showing a primitive cell population surrounded by a proliferation of reactive respiratory epithelial cells and marked neutrophilic infiltrate. B) NUT immunohistochemistry is positive in the primitive-appearing cells. C) Dual color FISH using probes flanking the NUT locus shows split-apart of red and green signals (white arrows) consistent with NUT rearrangement. D) Dual color FISH using probes flanking the BRD4 locus shows split-apart of red and green signals (white arrows) consistent with BRD4 rearrangement. Together with Fig. 3C, the findings are consistent with a BRD4-NUT fusion.