Abstract
Background:
Head and neck NUT carcinoma (HN-NUT) is a rare form of carcinoma diagnosed by NUT immunohistochemistry positivity and/or NUTM1 translocation. Although the prototype of HN-NUT is a primitive undifferentiated round cell tumor (URC) with immunopositivity for squamous markers, it is our observation that it may assume variant histology or immunoprofile.
Methods:
We conducted a detailed clinicopathologic review of a large retrospective cohort of 30 HN-NUT, aiming to expand its histologic and immunohistochemical spectrum.
Results:
The median age of patients with HN-NUT was 39 years (range 17–86). It affected the sinonasal tract (43%), major salivary glands (20%), thyroid (13%), oral cavity (7%), larynx (7%), neck (7%), and nasopharynx (3%). Although most cases of HN-NUT (63%) contained a URC component of primitive undifferentiated round cell (URC) tumor, 53% showed other histologic features, and 37% lacked a URC component altogether. Variant histologic features included basaloid (33%), differentiated squamous/squamoid (37%), clear cell changes (13%), glandular differentiation (7%), and papillary architecture (10%), which could coexist. While most HN-NUT were positive for keratins, p63, and p40, occasional cases (5% to 9%) were entirely negative. Immunopositivity for neuroendocrine markers and TTF-1 was observed in 33% and 36% of cases, respectively. The outcome of HN-NUT was dismal with a 3-year disease specific survival of 38%.
Conclusions:
HN-NUT can affect individuals across a wide age range and arise from various head and neck sites. It exhibits a diverse spectrum of histologic features and may be positive for neuroendocrine markers, potentially leading to underdiagnosis. A low threshold to perform NUT-specific tests is necessary to accurately diagnose HN-NUT.
Keywords: NUT carcinoma, NUTM1, head and neck
Graphical Abstract
In this study, we described detailed clinicopathologic features of 30 head and neck NUT carcinoma and expanded the histologic spectrum to include basaloid, differentiated squamous/squamoid, glandular, and papillary features and neuroendocrine marker immunopositivity.
Introduction
Nuclear protein of testis (NUT) is encoded by the NUTM1 gene located on chromosome 15q13. In 2003, French et al. reported the first case of NUT carcinoma1. Since then, NUT carcinoma has been described in a wide range of anatomic locations: the most common one is the thoracic cavity followed by the head and neck region2, 3.
Typically, NUT carcinoma is composed of sheets of monotonous primitive undifferentiated round cells, sometimes with abrupt keratinization2. By immunohistochemistry (IHC), these tumors frequently show a squamous immunophenotype by demonstrating immunopositivity for keratins (high molecular weight or low molecular weight), p63, and p40, although p40 immunostain may be less consistent2. As a group, NUT carcinoma is highly aggressive with a median survival of 7 months4. However, non-thoracic NUT carcinomas, most of which originate from the head and neck region, have significantly longer overall survival (Hazard ratio = 0.29) and event-free survival (hazard ratio = 0.31)4.
Recently, Wartenberg et al. and Singh et al. described two sinonasal NUT carcinomas showing extensive exophytic papillary architecture and a well-differentiated squamous morphology with bland tumor cells5. In our practice, we also noticed that head and neck NUT carcinoma (HN-NUT) may exhibit variant histologic features and aberrant immunoexpression other than the prototypic undifferentiated round cell morphology showing a squamous immunophenotype.
We therefore gathered 30 cases of HN-NUT from three tertiary centers and conducted a detailed clinicopathologic review, focusing particularly on the histologic spectrum, IHC profile, clinical features, and outcome of this rare tumor entity.
Material and Methods
Study cohort and diagnostic confirmation of NUT carcinoma
The pathology database of each participating site was searched to retrieve all NUT carcinomas originating in the head and neck region. A total of 30 cases were included in the current series, including 19 from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY, USA), eight from Emory University Hospital (Atlanta, GA, USA), and three from University Health Network/Sinai Health System (Toronto, ON, Canada). Four cases (one from sinonasal tract6 and three from thyroid7) were previously reported.
The diagnosis of NUT carcinoma was confirmed by detection of NUTM1 fusion using fluorescence in situ hybridization (FISH) or next generation (NGS) platforms (n= 23) or NUT immunopositivity alone (n=7). The detection methods included NUT IHC (n=26), FISH (n=6), and/or various RNA or DNA NGS platforms (n=18). The NGS platforms were either available commercially or described previously, including MSK-Fusion assay (Archer FusionPlex™ RNA sequencing, n=11)8, MSK-IMPACT (n=9)9, 10, FoundationOne™ (n=1, Cambridge, MA, USA), CARIS™ (n=2, Caris Life Sciences, Irving, TX, USA), and Illumina TruSight RNA fusion panel (n=3, Illumina, San Diego, CA, US)11. FISH for NUTM1 break-apart and/or its fusion partners BRD4 or BRD3 were performed using custom bacterial artificial chromosome (BAC) clone probes designed to flank the target genes based on the UCSC genome browser (http://genome.ucsc.edu/)11.
IHC for NUT protein was performed using a rabbit monoclonal antibody (clone C52B1, dilution: 1:50, Cell Signaling Technology Inc., Danvers, MA, USA). NUT IHC was classified as positive (defined as moderate to strong speckled nuclear stain in >50% of tumor cells) or focal/weak (weak nuclear staining or nuclear staining in 10% to 20% of tumor cells). None of the examined NUT carcinomas were negative for NUT IHC.
Clinicopathologic review
Clinical characteristics and outcome were collected from the patients’ chart at each participating site, including age, sex, site of origin, tumor size determined pathologically or radiologically, clinical or pathologic T stage (AJCC 8th edition), nodal metastasis at presentation, disease-specific survival (DSS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and chemoradiation therapy.
The pathologic slides were reviewed at each individual site and centrally by one of the authors (BX). The prototypic NUT carcinoma was a primitive undifferentiated medium-sized round cell tumor. Variant histology, including differentiated, basaloid, rhabdoid, or glandular differentiation, papillary architecture, clear cell changes, as well as any evidence of keratinization (including intracellular keratin and keratin pearls), were documented. Lymphovascular invasion, perineural invasion, and margin status were additionally recorded in resected cases.
Detailed immunoprofile was recorded. The primary antibodies utilized included CK8 (Clone CAM5.2, dilution 1:75, Becton & Dickinson), pan-cytokeratin (clone MNF116, dilution 1:100, Dako), CK5/6 (clone D5/16B4, ready to use [RTU], Ventana), high molecular weight cytokeratin (clone 34BE12, RTU, Ventana), p63 (clone 4A4, RTU, Ventana), p40 (clone BC28, dilution 1:400, Biocare), synaptophysin (clone 27G12, dilution 1:200, Leica Biosystems), chromogranin (Clone LK2H10, RTU, Ventana), INSM1 (clone A-8, dilution 1:250, Santa Cruz), p16 (clone E6H4, Ready to use, Ventana), and TTF-1 (clone 8G7G3/1, RTU, Ventana).
Results
Clinical features
The clinicopathologic features of the study cohort are summarized in Table 1 and Supplementary Table 1. The median age of diagnosis was 39 years, although HN-NUT might affect a wide age range from 17 years to 86 years. There was a male predominance with a male-to-female ratio of 2.3:1.
Table 1. Clinicopathologic features of head and neck NUT carcinoma.
Values are n (%) unless otherwise specified.
| Clinicopathologic features | n (%) |
|---|---|
| Age, years, median (range) | 39 (17–86) |
| Male: female ratio | 21:9 (2.3:1) |
| Anatomic site | |
| Sinonasal tract | 13 (43%) |
| Major salivary glands | 6 (20%) |
| Parotid gland | 5 |
| Submandibular gland | 1 |
| Thyroid | 4 (13%) |
| Oral cavity | 2 (7%) |
| Larynx | 2 (7%) |
| Neck | 2 (7%) |
| Nasopharynx | 1 (3%) |
| AJCC 8th T stage (n=24) | |
| T1 | 1 (4%) |
| T2 | 7 (29%) |
| T3 | 3 (13%) |
| T4 | 13 (54%) |
| Nodal metastasis | 13/17 (76%) |
| Adjuvant treatments (n=21) | |
| None | 2 (10%) |
| Chemotherapy | 1 (5%) |
| Radiation therapy | 2 (10%) |
| Chemoradiation | 16 (76%) |
| Initial diagnosis | |
| NUT carcinoma | 13 (43%) |
| Squamous cell carcinoma, non-keratinizing | 4 (13%) |
| Carcinoma with squamous features | 4 (13%) |
| Carcinoma with neuroendocrine features | 2 (7%) |
| Carcinoma with neuroendocrine and squamous features | 1 (3%) |
| Carcinoma, high grade | 2 (7%) |
| Poorly differentiated thyroid carcinoma | 2 (7%) |
| Mucoepidermoid carcinoma | 1 (3%) |
| Favor acinic cell carcinoma | 1 (3%) |
| Histologic features | |
| Undifferentiated round cell tumor | 19/30 (63%) |
| Squamous pearls/abrupt keratinization | 16/30 (53%) |
| Differentiated squamous/squamoid feature | 11/30 (37%) |
| Basaloid feature | 10/30 (33%) |
| Clear cell change | 4/30 (13%) |
| Papillary architecture | 3/30 (10%) |
| Glandular features/mucocytes | 2/30 (7%) |
| Rhabdoid feature | 1/30 (3%) |
| NUTM1 fusion (n=18) | |
| BRD4::NUTM1 | 13 (72%) |
| BRD3::NUTM1 | 3 (17%) |
| NSD3::NUTM1 | 2 (11%) |
| NUT Immunohistochemistry (n=26) | |
| Positive | 21 (81%) |
| Focal/weak | 5 (19%) |
| Other immunohistochemistry | |
| Pan-keratins (AE1/AE3 and CAM5.2) | 20/21 (95%) |
| High molecular weight keratins (s) | 13/14 (93%) |
| p63 | 13/13 (100%) |
| p40 | 21/23 (91%) |
| Neuroendocrine markers (synaptophysin, chromogranin, and INSM1) | 5/15 (33%) |
| TTF-1 | 4/11 (36%) |
| Lymphovascular invasion | 10/20 (50%) |
| Perineural invasion | 5/18 (28%) |
| Positive resection margin | 5/11 (45%) |
Within the head and neck region, the anatomic sites of origin of NUT carcinoma in descending order were sinonasal tract (43%), major salivary glands (parotid or submandibular gland, 20%), thyroid (13%), oral cavity (buccal mucosa and floor of mouth, 7%), larynx (7%), neck soft tissue (7%), and nasopharynx (3%). The majority of patients presented with T4 disease (54%) and nodal metastasis (76%). Most patients (76%) received chemoradiation therapy using a cisplatin-based regimen.
Histologic features
A significant proportion (17/30, 57%) of HN-NUT cases were initially misdiagnosed as other types of carcinoma, in descending order of frequency including squamous cell carcinoma, non-keratinizing subtype (n=4, 13%), carcinoma with squamous features (n=4, 13%), carcinoma with neuroendocrine features (n=2, 7%), poorly differentiated carcinoma (n=2, 7%), poorly differentiated thyroid carcinoma (n=2, 7%), carcinoma with neuroendocrine and squamous features (n=1, 3%), mucoepidermoid carcinoma (n=1, 3%), and carcinoma favor acinic cell carcinoma (n=1, 3%).
The prototypic histology (malignant primitive undifferentiated round cell tumor) was seen in 63% of HN-NUT. The tumor cells typically were of medium size with round centrally located nuclei, vesicular chromatin, prominent nucleoli, and a moderate amount of eosinophilic or basophilic cytoplasm (Figures 1A and 1B). Abrupt keratinization and keratin pearls were common findings in HN-NUT (53%), including 42% of HN-NUT with a primitive undifferentiated round cell component, but were not present in all cases (Figure 1B).
Figure 1. Histologic features of head and neck NUT carcinoma.
(A-B) The most common histologic appearance is a primitive undifferentiated round cell tumor. The tumor cells are of medium size with round nuclei, vesicular chromatin, prominent centrally located nucleoli, and abundant eosinophilic to basophilic cytoplasm. Abrupt keratinization/keratin pearls may be seen (B). Other variant histologic features of head and neck NUT carcinoma include basaloid (C), differentiated squamous/squamoid (D-G), clear cell change (D), glandular/mucocytes differentiation (E-F), prominent exophytic papillary architecture (G), and rhabdoid features (H). The basaloid morphology (C) shows prominent peripheral palisading (insert). The tumor cells have hyperchromatic nuclei, high nuclear/cytoplasmic ratio, and scanty cytoplasm. The differentiated squamous/squamoid areas (D/E) are composed of relatively bland tumor cells showing prominent squamous differentiation, sometimes with clear cell changes (D) or exophytic papillary architecture (G and G insert). (E/F) A parotid NUT carcinoma shows exclusive differentiated squamous/squamoid morphology admixed with scattered mucocytes (arrowheads and insert) and extracellular mucin on H&E and mucicarmine stain (M). (H) A thyroid NUT carcinoma shows prominent rhabdoid/plasmacytoid morphology with abundant cytoplasm and eccentrically located nuclei.
However, 37% of NUT carcinomas did not contain an undifferentiated round cell tumor component. Furthermore, 53% (16/30) showed other histologic appearances, either alone or admixed with an undifferentiated round cell tumor. A third (33%) of tumors showed basaloid features with prominent peripheral palisading, high nuclear/cytoplasmic ratio, hyperchromatic dark nuclei, and scanty cytoplasm (Figure 1C). Eleven NUT carcinomas (37%) contained a differentiated squamous/squamoid component (Figures 1D to 1H), which occurred with (n=2) or without (n=9) an undifferentiated round cell component. The differentiated squamous/squamoid areas exhibited diffuse maturation with extensive intracellular keratin and bland differentiated cytology. Some NUT carcinomas showed clear cell changes with abundant intracellular glycogen (n=4, 13%, Figure 1D) or glandular/mucocytes differentiation with mucin production (n=2, 7%, Figures 1G and 1H). The latter two changes may be mistaken as conventional non-keratinizing squamous cell carcinoma or mucoepidermoid carcinoma. Within the sinonasal tract, NUT carcinomas might exhibit an exophytic papillary architecture (n=3, 10%, Figure 1E and Supplementary Figure 1), although endophytic invasive growth was also present. In a thyroid carcinoma with NSD3::NUTM1 fusion, a proportion of the tumor cells showed prominent rhabdoid morphology with abundant eosinophilic cytoplasm and eccentrically located nuclei (Figure 1H).
Lymphovascular invasion, perineural invasion, and positive resection margin were seen in 50%, 28%, and 45% of HN-NUT carcinomas, respectively.
Immunohistochemical profile
Most (92% to 100%) HN-NUT carcinomas were positive for pan-keratins, high molecular weight keratins, as well as squamous markers p63 and p40. A very small percentage of NUT carcinoma was entirely negative for keratins (CAM 5.2 and cytokeratin AE1/AE3, n=1, 5%), high molecular weight keratins (34βE12 and CK5/6, n=1, 7%), and p40 (n=2, 8%, Table 1, Supplementary Tables 1 and 2).
A third (5/15, 33%) of HN-NUT carcinoma were positive for neuroendocrine markers, such as synaptophysin, chromogranin, and/or INSM1 focally and/or diffusely (Figures 2B–D), which led to their misdiagnosis as carcinomas with neuroendocrine features in three cases, including one from sinonasal tract and two from neck soft tissue. Additionally, four cases (3/11, 36%) of NUT carcinomas (two from thyroid, one from sinonasal tract, and one from neck region) were positive for TTF-1 (Figure 2E), which might explain their misdiagnosis as poorly differentiated thyroid carcinoma in the two cases located in the thyroid.
Figure 2. Immunohistochemistry profile of head and neck NUT carcinoma.
(A-F) A NUT carcinoma in the neck region with BRD4::NUTM1 fusion is initially diagnosed as carcinoma with neuroendocrine features. The tumor is positive for synaptophysin (B), chromogranin focally (C), INSM1 (D), and TTF-1 (E). The tumor cells show moderate to strong speckled nuclear immunopositivity for NUT (F). (G-I) A sinonasal NUT carcinoma with BRD4::NUTM1 fusion shows differentiated squamous and papillary features. The tumor is diffusely positive for p40 (H). NUT immunohistochemistry demonstrates weak speckled nuclear positivity.
P16 IHC and RNA in situ hybridization for high-risk HPV were negative in all tested cases (n=13 and 9, respectively).
NUT IHC and NUTM1 translocation
NUT IHC was performed in 26 cases. All tumors showed certain degree of NUT nuclear positivity. Among them, 21 (91%) showed moderate to strong speckled nuclear staining in >50% of tumor cells and were considered positive (Figure 2F), whereas the remaining five (19%) showed either weak nuclear staining (Figure 2I) or focal nuclear positivity in 10% to 20% of tumor cells. For these five cases, the presence of NUTM1 translocation was additionally confirmed using FISH (n=1) or NGS (n=4, BRD4::NUTM1 fusion in 3, and BRD3::NUTM1 fusion in 1).
The fusion partners were known in 18 cases, including BRD4::NUTM1 in 13 (72%), BRD3::NUTM1 in three (17%), and NSD3::NUTM1 in two (11%). Both tumors with NSD3::NUTM1 fusion occurred in the thyroid gland. No other translocations were detected using NGS platforms.
Clinical outcome
Twenty-three patients had follow-up data available with a median follow-up of 18 months (range: 0.5 to 285.6 months). Adverse events observed included 11 disease-related mortalities, 14 cases of persistent, recurrent, or metastatic disease, and nine distant metastases. The 1-year, 2-year, 3-year, and 5-year DSS, DFS, and DMFS are provided in Table 2. Overall, HN-NUT carcinoma was associated with a dismal outcome. The 3-year DSS, DFS, and DMFS were 38%, 35%, and 48%, respectively.
Table 2.
Disease specific survival (DSS), disease free survival (DFS), and distant metastasis free survival (DMFS) of head and neck NUT carcinoma.
| DSS | DFS | DMFS | |
|---|---|---|---|
| 1-year | 85% | 43% | 60% |
| 2-year | 60% | 35% | 60% |
| 3-year | 38% | 35% | 48% |
| 5-year | 28% | 18% | 48% |
Discussion
HN-NUT carcinoma is commonly underdiagnosed5, 6, 12–17. In a systematic review of 63 cases of HN-NUT carcinoma, 73% were initially diagnosed as other types of carcinoma, most frequently high-grade carcinoma (25%) and squamous cell carcinoma (17%), followed by neuroendocrine carcinoma (8%), mucoepidermoid carcinoma (4%), lymphoma (4%), and porocarcinoma (4%)12. Similarly, in the current series, 57% of HN-NUT carcinomas were underdiagnosed as other types of carcinomas, most frequently squamous cell carcinoma (13%) and carcinoma with squamous features (13%), followed by carcinoma with neuroendocrine features (7%), high-grade carcinoma (7%), and poorly differentiated thyroid carcinoma (7%). As a definite diagnosis of NUT carcinoma is based solely on demonstrating NUT immunopositivity and/or the presence of NUTM1 translocation, techniques that are not universally available in all pathology laboratories, it is not surprising that the diagnosis has been missed in the majority of cases.
The anatomic origin of HN-NUT carcinoma is broad. Although sinonasal tract is the most commonly affected site, as documented in a previous systematic review12 and in the current study, other reported sites of involvement included the thyroid gland7, 18, 19, major salivary glands (parotid14, 15, submandibular17, 20, 21, and sublingual22), lacrimal gland14, larynx16, hypopharynx23, mandibular bone12, ear canal12, oral cavity, nasopharynx, and neck soft tissue (current study). Although the median age of presentation of HN-NUT carcinoma is in the 30s (37 in a systematic review12 and 39 in the current study), the tumor may affect a wide age range from 5 years12 to 86 years (in the current study).
We herein presented the largest retrospective cohort of HN-NUT carcinoma with detailed pathology review and expanded the pathologic spectrum of HN-NUT carcinoma to a wide range of morphologic features. Although the prototype of HN-NUT carcinoma remains the malignant primitive undifferentiated round cell tumor with or without abrupt keratinization as previously described24, 25, other histologic features, including basaloid, differentiated squamous/squamoid, exophytic/papillary, clear cell, glandular, and rhabdoid features, were seen in 53% of cases, and 37% did not have an admixed undifferentiated round cell tumor component. In 2023, Wartenberg et al. reported the first case of NUT carcinoma showing extensive exophytic papillomatous architecture and well-differentiated squamous morphology in a NSD3::NUTM1-translocated carcinoma originating from the sinonasal tract5. We herein confirmed that differentiated squamous/squamoid morphology can be seen in 37% (11 cases) of HN-NUT carcinomas, including 9 cases without an undifferentiated round cell component. Besides the sinonasal tract, these NUT carcinomas with a differentiated squamous/squamoid component might occur in the thyroid gland, major salivary glands, and the oral cavity. Additionally, we confirmed what was reported by Wartenberg et al.5 that NUT carcinoma might assume an exophytic papillary architecture in the sinonasal tract. The fusion detected in NUT carcinomas with papillary architecture was BRD4::NUTM1 in two cases and BRD3::NUTM1 in one case. Taken together, it appears that papillary architecture may be specific to the sinonasal tract but is not unique to specific types of NUTM1 translocation.
Other variant histologies observed in our series included basaloid, clear cell, glandular and rhabdoid features. Realizing that HN-NUT carcinoma may assume other histologic features is important for the differential diagnosis and for initiating appropriate work up for NUT carcinoma. In major salivary glands, NUT carcinoma with basaloid, differentiated squamoid/squamous, clear cell, and glandular features may be mistaken for other salivary gland carcinomas, particularly mucoepidermoid carcinoma. Indeed, several previously reported NUT carcinomas of salivary glands12, 14, 17 and a parotid NUT carcinoma from the current series were initially diagnosed as mucoepidermoid carcinoma.
By IHC, over 90% of HN-NUT carcinomas exhibited a squamous phenotype and were positive for pancytokeratins, high molecular weight keratins, p63, and p40. However, it is worth mentioning that occasional cases (5–9%) of NUT carcinoma might be entirely negative for keratins and p40. Similarly, a recent study by Farooq et al.26 on 57 NUT carcinomas from all body sites, including 13 head and neck tumors, showed that 15% were negative for keratins, 35% were negative for p40, and 13% were negative for p63. Together, the evidence suggests that keratins and squamous marker positivity are not necessary for a diagnosis of NUT carcinoma.
Several published case reports and case series have documented immunopositivity of neuroendocrine markers, including synaptophysin and/or chromogranin, in NUT carcinoma of sinonasal tract, thyroid gland, and major salivary glands14, 19, 22, 26, 27. As a result, one of the HN-NUT carcinomas was misdiagnosed as small cell carcinoma14. We herein reported that neuroendocrine marker positivity, focal or diffuse, might be seen in up to a third of HN-NUT carcinomas, leading to misinterpretation of these tumors as high-grade neuroendocrine carcinoma or carcinoma with neuroendocrine features.
In the current study, we showed that NUT carcinoma might additionally be positive for TTF-1. The TTF-1 immunopositivity is particularly relevant when dealing with thyroid NUT carcinoma, as it may be confused with a thyroid follicular cell-derived carcinoma or medullary carcinoma. Several previous case reports and case series also documented TTF-1 immunopositivity in NUT carcinomas, either thyroid-based7, 18, 19, 28 or non-thyroid-based26, 29. Of note, although PAX8 was entirely negative in four cases (two thyroid, one parotid, and one sinonasal tract) tested from our series, PAX8 immunopositivity was also reported in NUT carcinoma7, 30.
The current study together with previous published series and case reports, demonstrates that age, anatomic site, histologic features, and immunoprofile vary widely in HN-NUT carcinoma. Therefore, an accurate diagnosis of these tumors relies heavily on high clinical suspicion, as well as a low threshold to perform specific diagnostic tests, including IHC and molecular tests, for NUT carcinoma. Fortunately, NUT IHC appears to be an entirely specific and highly sensitive screening tool for NUT carcinoma, with reported specificity and sensitivity of 100% and 87%, respectively31. Moderately to strong speckled nuclear staining in >50% tumor cells is diagnostic for NUT carcinoma2. However, weak or focal NUT nuclear immunopositivity has been described in the current study and previously18, 30. In cases showing equivocal weak or focal NUT immunopositivity, it is recommended to perform molecular testing for NUTM1 translocation. It should be noted that occasional false negativity has been reported for NUT IHC18, 19, 30, NUTM1 FISH32, 33, and NUTM1 NGS34. In the current series, case #9 had a false-negative NUTM1 FISH result performed in a commercial laboratory but demonstrated diffuse NUT immunopositivity and BRD3::NUTM1 fusion using ARCHER RNA sequencing. Therefore, multiple testing platforms may be considered to confirm the presence of NUTM1 translocation when facing conflicting or equivocal results.
Recently, NUTM1 fusion has also been described in sarcoma11, 30, 35. The fusion partners observed in sarcoma are MXD1, MDX4, and MGA11, 30, 35. In the current series, the fusions detected were limited to BRD4::NUTM1, BRD3::NUTM1, and NDS3::NUTM1. In vitro studies have shown that knock-down of endogenous expression of BRD4::NUT, BRD3::NUT, and NSD3::NUT induces epithelial differentiation, suggesting that tumors with these fusions differentiate towards carcinoma36, 37. Therefore, all tumors in this series were classified as carcinoma rather than sarcoma, even when occasional cases were negative for keratin expression.
Accurate diagnosis of HN-NUT carcinoma has prognostic and therapeutic implications. Prognostically, HN-NUT carcinoma is associated with a dismal and often lethal outcome. In our series, the 3-year DSS, DFS, and DMFS were 38%, 35%, and 48%, respectively. Similarly, Ramesh et al. reported a median overall and disease-specific survival of 15 months in 12 cases of sinonasal NUT38, while Bauer et al. reported 2-year overall survival and progression-free survival to be 27% and 16% in 19 patients with HN-NUT carcinoma3. NUT carcinoma may be eligible for targeted therapy with Bromodomain (BRD) and extra-terminal (BET) inhibitors. Phase 1/2 studies using novel BET inhibitors showed reasonable safety profile and promising response rate39, 40.
In conclusion, we have expanded the histologic spectrum and immunoprofile of HN-NUT carcinoma. These tumors may affect patients of a wide age range and various anatomic sites. Beyond the most common primitive undifferentiated round cell tumor morphology, HN-NUT carcinoma may show basaloid, clear cell, differentiated squamous/squamoid, glandular, and rhabdoid morphology. Although they are commonly positive for keratins and squamous markers, expression of neuroendocrine markers (synaptophysin, chromogranin, and INSM1) and TTF-1 may be seen in nearly one-third of cases. Therefore, a low threshold for NUT testing, either by IHC or by various molecular platforms, including but not limited to carcinomas with squamous/squamoid or neuroendocrine differentiation, is required to identify NUT carcinoma in the head and neck region, an entity associated with a dismal outcome which may benefit from BET inhibitor therapy.
Supplementary Material
Funding statement:
Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
Footnotes
Conflict of interest: No competing financial interests exist for all contributory authors.
Ethics approval statement: The research is approved by the Institutional Review Board (IRB) of each participating site.
Data Availability statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.