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Diagnosis and Discussion: Case 1160

Final Diagnosis

NUT Carcinoma

Discussion

NUT carcinoma is a highly aggressive, poorly differentiated neoplasm defined by genetic rearrangements in NUT family member 1 (NUTM1) (1,2). To date, specific etiologies remain unknown as do associated risks or contributing environmental factors (1). Sites of origin based on data from a large NUT carcinoma tumor registry reveals that the majority of cases arise in the thorax (51%), followed by the head and neck (41%), bone and soft tissue (6%), and kidney (1%) (3). Exceedingly rare, but additionally reported sites include the liver/pancreas (4) and bladder (5). NUT carcinoma has an almost even gender split with large cohort data showing an incidence of 52% in females and 48% in males (3). NUT carcinoma while skewed towards younger populations with a median age of 23.6 years; is found to occur across the age continuum with an incidence range encompassing 18 days to 80 years (3).

Common findings on initial imaging studies report extensive invasion and encasement of surrounding structures and often prominent metastatic disease (6, 7, 8). CT demonstrates a low density, heterogeneously enhancing mass with T1 hypointensity and T2 hyperintensity by MRI (6,7). NUT carcinoma demonstrates high FDG-avidity by PET, consistent with its highly aggressive nature (6, 7, 9). Gross findings are notable for a tan-white cut surface often with associated necrosis and hemorrhage (1,7,10,11).

Histologic findings are notable for a uniform, primitive cell population that is small to intermediate in size and arranged in sheets or nests (1). Nuclear features include membrane irregularities, vesicular chromatin and prominent nucleoli surrounded by eosinophilic to basophilic cytoplasm with or without granularity (1). Mirroring the macroscopic findings, areas of necrosis and brisk mitotic activity are often present (1). Large study cohorts found squamous differentiation in 33% of cases, 54% resembled carcinoma without a squamous component, and the remaining 12% did not have features of epithelial differentiation (3). The absence of nuclear molding and glandular differentiation can aid in formulating a differential (1). Rarely reported cases of mesenchymal differentiation exist in anatomic sites outside of the thorax (1, 11, 12). Cytology specimens are highly cellular and predominantly dyscohesive with occasional smears demonstrating tight cellular fragments or syncytial formations (13,14,15). Nuclei are round to oval with fine to coarse granular chromatin that can occasionally be vesicular (13,15). One study reported a neuroendocrine appearance (14) which was identified less frequently in other sources (13,15).  Macronucleoli are a prevalent feature, while the degree of anisonucleosis varies (13,14,15). Cytoplasm is usually minimal and delicate while areas with squamous differentiation when present are notably dense and opaque (13,14,15). The background frequently contains karyorrhectic debris, necrosis, mixed inflammation, and occasionally stripped nuclei (13,14,15).

NUT carcinomas are generally positive for pancytokeratin with many studies showing varying reactivities based on molecular weights (5,10,16) while rare cases have reported non-reactivity (17). Squamous differentiation can be highlighted by p40 and p63 when present (1,10,16). Diagnostic pitfalls can arise in cases with varying or subtle degrees of reactivity for CD34, TTF-1, synaptophysin, chromogranin A, CD5, CD138, CD117 and PLAP (1,5,10,16,17). Speckled nuclear staining for NUT remains highly reliable when expression is present in greater than 50% of nuclei with a sensitivity of 87% and a specificity approaching 100% (18). Molecular studies can aid in diagnosis in equivocal or borderline cases through proof of NUTM1 rearrangement (1). Common fusion partners detected in order of decreasing frequency are NUTM1-BRD4 (75%), NUTM1-NSD3 (8.3%), and NUTM1-BRD3 (4.2%) (19).  

No longer characterized as a strictly a midline entity or neoplasm arising solely in younger populations; NUT carcinoma is essential to remain in a differential diagnosis when encountering a morphologically primitive neoplasm. Overlap in squamous and neuroendocrine markers in addition to occasional TTF-1 reactivity can lead to misdiagnosis as poorly differentiated squamous cell carcinoma or small cell carcinoma (1). Histologically small round cell tumors can also enter the differential and based on age one can entertain entities such as Ewing, germ cell tumors and SMARC deficient tumors (15).     

Overall prognosis is poor given the highly aggressive behavior with a median overall survival (OS) time of 6.5 months (3). However, one study identified differences in prognosis based on anatomic site and molecular alteration (3). Patients with non-thoracic, NUT-BRD3, or NUT-NSD3 were found to have better OS (36.5 months), followed by non-thoracic, NUT-BRD4 (10 months), with the worst outcomes identified in thoracic origin independent of NUT rearrangement (4.4 months) (3).

References

  1. French CA, Deepali J, Badve S, den Bakker MA. NUT carcinoma of the thorax. In: WHO Classification of Tumours Editorial Board. Thoracic tumours. Lyon (France): International Agency for Research on Cancer; 2021. . (WHO classification of tumours series, 5th ed.; vol. 5). https://publications.iarc.fr/595.
  2. Ju, Y., Velazquez, M., Sherrod, A., & Wang, T. (2024). Diagnostic significance and cytological features of NUT carcinoma by EBUS‐FNA, a case report and literature review. Cytopathology (Oxford), 35(4), 497–502. https://doi.org/10.1111/cyt.13379
  3. Chau, N. G., Ma, C., Danga, K., Al-Sayegh, H., Nardi, V., Barrette, R., Lathan, C. S., DuBois, S. G., Haddad, R. I., Shapiro, G. I., Sallan, S. E., Dhar, A., Nelson, J. J., & French, C. A. (2020). An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients. JNCI Cancer Spectrum, 4(2), pkz094. https://doi.org/10.1093/jncics/pkz094
  4. Shehata, B. M., Steelman, C. K., Abramowsky, C. R., Olson, T. A., French, C. A., Saxe, D. F., Ricketts, R. R., & Katzenstein, H. M. (2010). NUT Midline Carcinoma in a Newborn with Multiorgan Disseminated Tumor and a 2-Year-Old with a Pancreatic/Hepatic Primary. Pediatric and Developmental Pathology, 13(6), 481–485. https://doi.org/10.2350/09-10-0727-CR.1
  5. French, C. A., Kutok, J. L., Faquin, W. C., Toretsky, J. A., Antonescu, C. R., Griffin, C. A., Nose, V., Vargas, S. O., Moschovi, M., Tzortzatou-Stathopoulou, F., Miyoshi, I., Perez-Atayde, A. R., Aster, J. C., & Fletcher, J. A. (2004). Midline Carcinoma of Children and Young Adults With NUT Rearrangement. Journal of Clinical Oncology, 22(20), 4135–4139. https://doi.org/10.1200/JCO.2004.02.107
  6. Polsani, A., Braithwaite, K. A., Alazraki, A. L., Abramowsky, C., & Shehata, B. M. (2012). NUT midline carcinoma: an imaging case series and review of literature. Pediatric Radiology, 42(2), 205–210. https://doi.org/10.1007/s00247-011-2272-3
  7. Rosenbaum, D. G., Teruya-Feldstein, J., Price, A. P., Meyers, P., & Abramson, S. (2012). Radiologic features of NUT midline carcinoma in an adolescent. Pediatric radiology, 42(2), 249–252. https://doi.org/10.1007/s00247-011-2288-8
  8. Nelson, B. A., Lee, E. Y., French, C. A., Bauer, D. E., & Vargas, S. O. (2010). BRD4-NUT Carcinoma of the Mediastinum in a Pediatric Patient: Multidetector Computed Tomography Imaging Findings. Journal of Thoracic Imaging, 25(3), W93–W96. https://doi.org/10.1097/RTI.0b013e3181b5d84d
  9. Niederkohr, R. D., Cameron, M. J., & French, C. A. (2011). FDG PET/CT Imaging of NUT Midline Carcinoma. Clinical Nuclear Medicine, 36(9), e124–e126. https://doi.org/10.1097/RLU.0b013e31821c9a23
  10. Tanaka, M., Kato, K., Gomi, K., Yoshida, M., Niwa, T., Aida, N., Kigasawa, H., Ohama, Y., & Tanaka, Y. (2012). NUT Midline Carcinoma: Report of 2 Cases Suggestive of Pulmonary Origin. The American Journal of Surgical Pathology, 36(3), 381–388. https://doi.org/10.1097/PAS.0b013e31824230a8
  11. Dickson, B. C., Sung, Y.-S., Rosenblum, M. K., Reuter, V. E., Harb, M., Wunder, J. S., Swanson, D., & Antonescu, C. R. (2018). NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. The American Journal of Surgical Pathology, 42(5), 636–645. https://doi.org/10.1097/PAS.0000000000001021
  12.  den Bakker, M. A. , Beverloo, B. H. , van den Heuvel-Eibrink, M. M. , Meeuwis, C. A. , Tan, L. M. , Johnson, L. A. , French, C. A. & van Leenders, G. J. (2009). NUT Midline Carcinoma of the Parotid Gland With Mesenchymal Differentiation. The American Journal of Surgical Pathology, 33 (8), 1253-1258. doi: 10.1097/PAS.0b013e3181abe120.
  13. Bellizzi, A. M., Bruzzi, C., French, C. A., & Stelow, E. B. (2009). The cytologic features of NUT midline carcinoma. Cancer, 117(6), 508–515. https://doi.org/10.1002/cncy.20044 
  14. Bishop, J. A., French, C. A., & Ali, S. Z. (2016). Cytopathologic features of NUT midline carcinoma: A series of 26 specimens from 13 patients. Cancer Cytopathology, 124(12), 901–908. https://doi.org/10.1002/cncy.21761 
  15. Dutta, R., Nambirajan, A., Mittal, S., Roy‐Chowdhuri, S., & Jain, D. (2021). Cytomorphology of primary pulmonary NUT carcinoma in different cytology preparations. Cancer Cytopathology, 129(1), 53–61. https://doi.org/10.1002/cncy.22342
  16. Zhu, B., Laskin, W., Chen, Y., French, C. A., Cameron, M. J., Nayar, R., & Lin, X. (2011). NUT midline carcinoma: a neoplasm with diagnostic challenges in cytology. Cytopathology (Oxford), 22(6), 414–417. https://doi.org/10.1111/j.1365-2303.2010.00838.x
  17. Evans, A. G., French, C. A., Cameron, M. J., Fletcher, C. D. M., Jackman, D. M., Lathan, C. S., & Sholl, L. M. (2012). Pathologic Characteristics of NUT Midline Carcinoma Arising in the Mediastinum. The American Journal of Surgical Pathology, 36(8), 1222–1227. https://doi.org/10.1097/PAS.0b013e318258f03b
  18. Haack, H., Johnson, L. A., Fry, C. J., Crosby, K., Polakiewicz, R. D., Stelow, E. B., Hong, S.-M., Schwartz, B. E., Cameron, M. J., Rubin, M. A., Chang, M. C., Aster, J. C., & French, C. A. (2009). Diagnosis of NUT Midline Carcinoma Using a NUT-specific Monoclonal Antibody. The American Journal of Surgical Pathology, 33(7), 984–991. https://doi.org/10.1097/PAS.0b013e318198d666 
  19. Stevens, T. M., Morlote, D., Xiu, J., Swensen, J., Brandwein-Weber, M., Miettinen, M. M., Gatalica, Z., & Bridge, J. A. (2019). NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum. Modern Pathology, 32(6), 764–773. https://doi.org/10.1038/s41379-019-0206-z.