January 2023 – Pulmonary

A 40-year-old man who was a lifetime nonsmoker presented with shortness of breath for one month. Imaging revealed a large left upper lobe mass, for which he underwent endobronchial biopsy and eventual resection. H&E photomicrographs of the mass are pictured below. Immunohistochemistry revealed the tumor cells stained focally positive for cytokeratin AE1/AE3, p40, and synaptophysin, with punctate nuclear positivity for NUT. The neoplastic cells stained negative for TTF1, CD45, CD99, and SALL4. BRG1 and INI-1 were retained. 

Figure 1: H&E 100x original magnification
Figure 2: H&E 400x original magnification

Which of the following genetic abnormalities is most likely to be identified in this tumor?

  • t(11;22) (EWSR1::FLI1)
  • 17p13 (TP53) mutation
  • t(15;19) (BRD4::NUTM1)
  • Isochromosome 12p

The correct answer is ...

t(15;19) (BRD4::NUTM1).

Nuclear protein in testis (NUT) carcinoma is a rare and aggressive poorly differentiated carcinoma. Though initially described in midline structures, NUT carcinomas have been reported in many locations, most commonly in the thoracic cavity. Morphologically, these tumors are characterized by sheets or nests of primitive-appearing cells, sometimes with abrupt foci of squamous differentiation. They are characterized by speckled nuclear positivity with NUT immunohistochemistry and/or NUT gene rearrangements (most commonly BRD4::NUTM1).1 By immunohistochemistry, NUT carcinomas can display variable positivity for keratin, squamous markers, and neuroendocrine markers.

The differential diagnosis for NUT carcinoma includes other small round blue cell tumors, such as Ewing sarcoma and desmoplastic small round cell tumor (DSRCT). Unlike NUT carcinoma, Ewing sarcoma and DSRCT lack foci of squamous differentiation, and commonly contain EWSR1::FLI1 fusion products by FISH.2 NUT carcinomas may also morphologically resemble lymphoma, but typically stain negative for CD45. 

Primitive germ cell tumors may also resemble NUT carcinoma by morphology. Germ cell tumor immunohistochemical markers such as SALL4, OCT4, and glypican 3 can be useful in ruling out these entities. In contrast to NUT carcinoma, metastatic testicular germ cell tumors most commonly display abnormalities involving chromosome 12.3

Given the variable positivity for neuroendocrine markers in NUT carcinomas, small cell carcinoma is often on the differential. However, the clinical presentation of small cell carcinoma differs from NUT carcinoma, mainly affecting older patients who smoke. Chromosome 17p, which encodes the TP53 gene, is implicated in the genetic basis of many carcinomas, including small cell lung carcinoma.4


  1. French, C. Demystified molecular pathology of NUT midline carcinomas. J Clin Pathol. 2010;63(6):492-6.
  2. Yamaguchi U, Hasegawa T, et al. J Clin Pathol. 2005;58(10):1051-1056. 
  3. Sheikine Y, Genega E, et al. Molecular genetics of testicular germ cell tumors. Am J Cancer Res. 2012;2(2):153-167.
  4. Semenova E, Nagel R, et al. Genes Dev. 2015;29(14)1447-1462.

Allison Kerper, MD

Resident, Anatomic and Clinical Pathology 
Mayo Clinic

Ying-Chun Lo, M.D., Ph.D.

Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.