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| Year : 2020 | Volume
: 63
| Issue : 1 | Page : 103-105 |
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| Sinonasal NUT midline carcinoma: A new histological entity |
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Pragya N Vakani1, Jainil Maheshwari2, Mukesh Maheshwari1, Bhoomi Shah3
1 Consultant Pathologist, Nirmaan Pathology Laboratory, Ahmedabad, Gujarat, India
2 Research Fellow at Nirmaan Pathology Laboratory, Ahmedabad, Gujarat, India
3 Tutor SMS Medical College, Ahmedabad, Gujarat, India
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| Date of Web Publication | 31-Jan-2020 |
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 Abstract | | |
Nuclear protein in testis (NUT) midline carcinoma is poorly differentiated carcinoma defined by rearrangement of NUT gene on 15 to other genes, usually BRD4 on 19. It is first described in 1991. These tumors are most commonly seen in the mediastinum and 35% occur in head and neck. It is a highly aggressive tumor with a median survival of 7 months because of ineffective chemotherapy and undefined treatment. Hence, we must differentiate these tumors from other poorly differentiated tumors. Here, we present a case of NUT midline carcinoma of 44-year male, who presented with headache and dizziness, confirmed by immunohistochemistry of NUT antibody. The aim of this case report is to increase the awareness about this entity in adults with brief review of relevant literature.
Keywords: Head and neck, immunohistochemistry, mediastinum, NUT midline carcinoma, poorly differentiated neoplasm
How to cite this article:
Vakani PN, Maheshwari J, Maheshwari M, Shah B. Sinonasal NUT midline carcinoma: A new histological entity. Indian J Pathol Microbiol 2020;63:103-5 |
| Introduction | |  |
Nuclear protein in testis (NUT), i.e., NUT midline carcinomas (NMCs) are malignant epithelial tumors that have chromosomal rearrangements of the gene encoding NUT at 15 to other genes, usually BRD4 on 19 and other protein-like BRD3 and NSD3, creating chimeric genes that encode BRD-NUT fusion proteins, which leads to proliferation of immature neoplastic cells and blocking of squamous differentiation.[1],[2],[3],[4] NMCs mostly arises in younger patients but has been reported in a wide range of ages from newborns to the elderly (0–78 years).[5] Most cases were reported in midline structures such as mediastinum, thymus, and head and neck, but other sites are also reported.[6],[7] Histologically, it is undifferentiated epitheloid cells with variable focal squamous differentiation. It is necessary to differentiate it from other carcinoma, as it is metastatically aggressive carcinoma, treatment of which is not defined. There is no effective guideline or current approach to treatments. Immunohistochemistry (IHC) for NUT and fluorescent in situ hybridization or reverse transcriptase-polymerase chain reaction is needed for confirmation of diagnosis.
| Case History | | |
A 44-year-old male presented with a history of headache and dizziness since 15 days. The patient also noted mild proptosis on the right side. Magnetic resonance imaging was suggestive of a neoplastic lesion involving right sphenoid sinus. Computer tomography (CT) scan was suggestive of highly infective etiology or neoplastic etiology involving right sphenoidsinus, wing, and sella region. F18 FDG PET-CECT was showing mild heterogeneously enhancing soft tissue density mass in right side sphenoid sinus involving the sphenoid body, sella, and cavernous region causing erosion of the wall of right sphenoid sinus, clivus, and petrous bone, suggestive of a mass lesion. We received a piecemeal biopsy.
Histologically, it was showing tumor composed of sheets of undifferentiated cells in between the areas of coagulative necrosis and inflammation. The cells have clear to eosinophilic cytoplasm, irregular nuclei, fine to vesicular chromatin, and prominent nucleoli. Mitotic figures, apoptotic bodies, and an intra tumoral inflammatory infiltrate of neutrophils are also seen [Figure 1]a and [Figure 1]b. | Figure 1: (a) NUT carcinoma shows undifferentiated cells with monotonous round nuclei with open chromatin, prominent nucleoli with clear to eosinophilic cytoplasm (H and E STAIN 100×) and (b) Poorly differentiated epithelial cells with intratumoral infiltrate of neutrophils (H and E STAIN 400×)
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On IHC tumor cell express, cytokeratin, p63, synaptophysin (focal), and NUT antibody are immunonegative for SALL4 (To rule out possibility of germ cell tumor) and chromogranin [Figure 2]a [Figure 2]b [Figure 2]c [Figure 2]d. | Figure 2: (a) The tumor cells show diffuse and strong speckled nuclear positivity for NUT antibody, (b) The tumor cells show nuclear positivity for P63, (c) The tumor cells show cytoplasmic membrane positivity for pan-CK (cytokeratin), and (d) The tumor cells show focal positivity for synaptophysin and immunohistochemical (IHC) stain 100×
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| Discussion | | |
NUT carcinoma can be seen in patients of any age (0 to 78 years), but it occurs most often in children or young adults with a median age of 22 years.[5] Most common presenting symptoms of NUT carcinoma are related to a rapidly growing mass such as epistaxis, nasal obstruction, nasal discharge, pain in sinonasal origin, and eye-related symptoms such as proptosis. Radiologically, there is frequent involvement of the orbit, cribriform plate, or cranial cavity with regional and/or distant metastases.
Histologically, these tumors are poorly differentiated, grows as nests and sheets of cells in the submucosa with necrosis and a high mitotic rate. These tumors are highly infiltrative, with a frequent invasion of nerves, vessels, and bone. It is also characterized by a strikingly monotonous cellular population of medium-sized cells with round to oval nuclei showing minimal pleomorphism. The nuclei have open chromatin and a prominent nucleolus. An intra tumoral inflammatory infiltrate of neutrophils may be seen. In general, NUT carcinoma can also demonstrate a predominantly primitive, undifferentiated appearance, but most cases exhibit foci of squamous differentiation in the form of a peculiar pattern of “abrupt” keratinization, which is previously believed to be an aggressive subtype of squamous cell carcinoma [Figure 1]. NMCs are characterized by chromosomal rearrangements of the gene encoding a NUT at 15 to other genes, usually BRD4 on 19 and other protein like BRD3 creating chimeric genes that encode BRD-NUT fusion proteins.[1] On IHC, these cells are positive for NUT protein in >50% of cells, usually positive for pan-keratin, p63, p40, and CD34, and occasionally, positive for synaptophysin, p16, TTF-1, and CD99.[8]
Pathologic differential diagnosis is sinonasal undifferentiated carcinoma (SNUC), poorly differentiated squamous cell carcinoma (SCC), neuroendocrine carcinoma, Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), germ cell tumor, and olfactory neuroblastoma (ONB). NUT carcinoma is most commonly misdiagnosed as SNUC, but SNUC is negative for NUT protein and does not demonstrate histologic or immunophenotypic evidence of squamous differentiation. SCC is another consideration, but sinonasal SCC typically lacks the nuclear monotony and abrupt keratinization of NUT carcinoma and is NUT-negative. The primitive cellular appearance of NUT carcinoma and occasional CD99 positivity may cause confusion with ES/PNET. However, ES/PNET typically lacks cytokeratin and p40 immunostaining and harbors a different gene fusion (most often EWSR1-FLI1). Finally, ONB and other sinonasal small round cell tumors can enter the differential diagnosis but are easily excluded by IHC.
The diagnosis of NUT carcinoma is confirmed by demonstrating a rearrangement of NUTM1, which can be done by molecular techniques, by detecting gene fusion of NUT-BRD4, or more simply by IHC for NUT protein, which is highly sensitive (87%) and specific (100%).[1],[9]
NUT immunolabeling must be present in more than 50% cells and usually demonstrates a speckled staining pattern [Figure 2a]. NUT carcinoma is also positive for cytokeratins and usually positive for the squamous markers p63, p40, and CK5/6. NUT carcinoma can uncommonly demonstrate neuroendocrine differentiation (synaptophysin and chromogranin) or positivity for CD99. NUT carcinoma is occasionally p16-positive but is not positive for high-risk human papilloma virus (HPV).
NUT carcinoma has the worst prognosis with a median survival of 7 months.[10] Few clinical trials are underway investigating the use of bromodomain inhibitors that target the NUTM1-BRD4 gene fusions.
| Conclusion | | |
NUT carcinoma is rapidly fatal and aggressive disease. Recent advances of understanding the molecular biology of NMC of BRD4-NUT fusion protein causing aberrant histone acetylation and inhibits cellular differentiation led to the use of histone deacetylase inhibitors as an additional treatment option. In addition, targeted therapy using direct-acting inhibitors of the BRD3 and BRD4 bromodomains (BET inhibitors) are also under development. Hence, it is important for pathologist to become aware of pathologic features of NMC, and subsequently, educate other clinicians about this entity, to identify effective treatment and analyze treatment outcomes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | French C. Demystified molecular pathology of NUT midline carcinomas. J Clin Pathol 2010;63:492-6.  |
| 2. | French C. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013;7:11-6. |
| 3. | French CA, Rahman S, Walsh EM, Kühnle S, Grayson AR, Lemieux ME, et al. NSD3-NUT fusion oncoprotein in NUT midline carcinoma: Implications for a novel oncogenic mechanism. Cancer Discov 2014;4:928-41. |
| 4. | Napolitano M, Venturelli M, Molinaro E, Toss A. NUT midline carcinoma of the head and neck: Current perspectives. OncoTargets Ther; 12:3235-44. |
| 5. | Stelow EB. Areview of NUT midline carcinoma. Head NeckPathol 2011;5:31-5. |
| 6. | French CA, KutokJL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 2004;22:4135-9. |
| 7. | Polsani A, Braithwaite KA, Alazraki AL, Abramowsky C, Shehata BM. NUT midline carcinoma: An imaging case series and review of literature. Pediatr Radiol 2012;42:205-10. |
| 8. | Fang W, French CA, Cameron MJ, Han Y, Liu H. Clinicopathological significance of NUT rearrangements in poorly differentiated malignant tumors of the upper respiratory tract. Int J Surg Pathol 2013;21:102-10. |
| 9. | Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, et al. Diagnosis of NUT midline carcinoma using a NUT-specificmonoclonal antibody. Am J Surg Pathol2009;33:984-91. |
| 10. | Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC, et al. Clinicopathologic features andlong-term outcomes of NUT midline carcinoma. Clin Cancer Res2012;18:5773-9. |
Correspondence Address:
Pragya N Vakani
101, Ashoka Complex, Sardar Patel Stadium Road, Navrangpura, Ahmedabad - 380 014, Gujarat
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/IJPM.IJPM_373_19
[Figure 1], [Figure 2] |
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