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A Poorly Differentiated Lung Malignancy in a Young Adult

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A young man in his early 20s presented with a 1-day history of pleuritic chest pain and shortness of breath, with no fever or cough. He smoked approximately 10 cigarettes per day for 4 years. Results of the physical examination were unremarkable. Radiography of the chest revealed an ill-defined consolidation in the right lower lung field. Laboratory investigations were significant for elevated levels of lactate dehydrogenase (273 U/L; reference range, 135-225 U/L [to convert to microkatals per liter, multiply by 0.0167]), C-reactive protein (125.3 mg/L; reference range, 0.0-4.9 mg/L [to convert to nanomoles per liter, multiply by 9.524]), and alkaline phosphatase (217 U/L; reference range, 40-129 U/L [to convert to microkatals per liter, multiply by 0.0167]). Computed tomography of the chest confirmed the presence of a dense consolidation involving most of the right middle lobe with right hilar and subcarinal lymphadenopathy (Figure, A). He underwent endobronchial ultrasonography-guided transbronchial needle aspiration of a fleshy, whitish endobronchial lesion obstructing both uptakes to the medial and lateral segments. Histologic analysis revealed a poorly differentiated malignant neoplasm (Figure, B). Most of the cells were relatively monotonous, with enlarged vesicular nuclei, prominent nucleoli, and a high ratio of nucleus to cytoplasm. Foci of abrupt squamous differentiation, including keratinization and intercellular bridges, were identified. Immunohistochemical staining showed tumor cells to be strongly and diffusely positive for keratin AE1/AE3, cytokeratin 5/6, and p63. However, findings were negative for S-100, melan A, placental alkaline phosphatase, CD56, thyroid transcription factor-1, terminal deoxynucleotidyl transferase, CD45, and cytokeratin 7. A positron emission tomography–computed tomography scan showed a fludeoxyglucose-enhanced avid right middle lobe mass, a large right-sided pleural effusion, and fludeoxyglucose-enhanced avid mediastinal and right hilar lymph nodes, with extensive skeletal metastases to both proximal humeri and scapulae, the sacrum, spine, iliac bones, and both hips.

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D. Nuclear protein in testis midline carcinoma

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive human cancer that presents as a poorly differentiated carcinoma originating from midline locations and does not arise from any specific tissue type or organ.1 NUT midline carcinoma is driven by a rearrangement of the NUT gene (OMIM 608963) located on chromosome 15. This rearrangement commonly occurs between the NUT gene and a member of the BET genes family, most commonly BRD4 (OMIM 608749), resulting in the formation of the fusion oncogene BRD4-NUT.2,3 NUT midline carcinoma is extremely aggressive, with most cases presenting at an advanced stage as widely metastatic and unresectable disease when diagnosed,3,4 and has a highly lethal course.5

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Article Information

Corresponding Author: Radowan Elnair, MD, Department of Internal Medicine, University of South Dakota Sanford School of Medicine, 1400 W 22nd St, Sioux Falls, SD 57105 (radowan.elnair@usd.edu).

Published Online: August 9, 2018. doi:10.1001/jamaoncol.2018.2648

Conflict of Interest Disclosures: None reported.

Additional Contributions: Jennifer Boland Froemming, MD (Mayo Clinic, Rochester, Minnesota), and Christopher French, MD (Brigham and Women’s Hospital, Boston, Massachusetts), assisted with and contributed to establishing the diagnosis. They received no compensation for this work.

References
1.
French  CA.  NUT midline carcinoma.  Cancer Genet Cytogenet. 2010;203(1):16-20. doi:10.1016/j.cancergencyto.2010.06.007PubMedGoogle ScholarCrossref
2.
Harada  Y, Koyama  T, Takeuchi  K, Shoji  K, Hoshi  K, Oyama  Y.  NUT midline carcinoma mimicking a germ cell tumor: a case report.  BMC Cancer. 2016;16(1):895. doi:10.1186/s12885-016-2944-3PubMedGoogle ScholarCrossref
3.
Ball  A, Bromley  A, Glaze  S, French  CA, Ghatage  P, Köbel  M.  A rare case of NUT midline carcinoma.  Gynecol Oncol Case Rep. 2012;3:1-3.PubMedGoogle Scholar
4.
Sholl  LM, Nishino  M, Pokharel  S,  et al.  Primary pulmonary NUT midline carcinoma: clinical, radiographic, and pathologic characterizations.  J Thorac Oncol. 2015;10(6):951-959. doi:10.1097/JTO.0000000000000545Google ScholarCrossref
5.
French  CA, Kutok  JL, Faquin  WC,  et al.  Midline carcinoma of children and young adults with NUT rearrangement.  J Clin Oncol. 2004;22(20):4135-4139. doi:10.1200/JCO.2004.02.107PubMedGoogle ScholarCrossref
6.
French  CA.  Pathogenesis of NUT midline carcinoma.  Annu Rev Pathol. 2012;7:247-265. doi:10.1146/annurev-pathol-011811-132438PubMedGoogle ScholarCrossref
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