Unveiling the Enigmatic Primary Pulmonary NUT Carcinoma with WHSC1L1::NUTM1-Rearrangement : A Case-Based Insight and Contemporary Literature Review

Unveiling the Enigmatic Primary Pulmonary NUT Carcinoma with WHSC1L1::NUTM1-Rearrangement : A Case-Based Insight and Contemporary Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Unveiling the Enigmatic Primary Pulmonary NUT Carcinoma with WHSC1L1::NUTM1-Rearrangement : A Case-Based Insight and Contemporary Literature Review Majumdar Pallavi, Paul Paramita, Arvind Suresh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7584149/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract NUT carcinoma (NC) is a rare, aggressive, and genetically defined epithelial malignancy characterized by rearrangements involving the NUTM1 gene, most commonly BRD4::NUTM1 fusions. Although classically and initially described as involving midline location, especially the sinonasal region affecting children and young adults, NC has been found to have myriad localizations and age affliction, with primary pulmonary involvement being exceedingly uncommon. A 60-year-old female presented with a non-productive cough, weight loss, and anorexia. Imaging revealed a right upper lobe lung mass with mediastinal involvement and subcarinal lymphadenopathy. Biopsy demonstrated an undifferentiated carcinoma with focal abrupt keratinization and immunohistochemical strong positivity for p40 and NUT protein, confirming the diagnosis of NC. PD-L1 testing revealed a tumor proportion score (TPS) of 70%. Next-generation sequencing identified a rare WHSC1L1::NUTM1 fusion. The patient was treated with paclitaxel and carboplatin with partial thoracic response; however, new skeletal metastases developed, and she was transitioned to palliative care. Figures Figure 1 Figure 2 Figure 3 Introduction NUT carcinoma (NC) is a highly aggressive and infrequently encountered epithelial malignancy with extensive local invasion and a predilection for skeletal metastases classically described as arising in midline anatomical sites like upper aerodigestive tract and mediastinum of adolescents and young adults (median age ~ 22 years), with no significant sex predilection. [ 1 – 4 ] The pathognomonic genetic hallmark is a fusion of NUTM1 (NUT midline carcinoma family member 1) (chromosome 15q14) with BRD4 (Bromodomain-containing protein 4) (chromosome 19p13.1), observed in over 70% of cases. Other partner genes, including Bromodomain-containing protein 3 (BRD3), (chromosome 19p13.1) Nuclear Receptor Binding SET Domain Protein 3 (NSD3), Zinc Finger Protein 532 (ZNF532), Zinc Finger Protein 592 (ZNF592), Capicua transcriptional repressor (CIC), and other genes like MGA, MXD1, MXI1, CIC, and MXD4 genes may also be involved in pathogenesis. [ 5 – 6 ] These fusion oncoproteins result in aberrant chromatin remodeling and transcriptional dysregulation, through enhanced histone acetylation and constitutive activation of oncogenic drivers such as MYC which profoundly impairs cellular differentiation and promotes relentless tumor proliferation. [ 7 ] The tumor spectrum also includes sarcomas, MXD1, MXD4, MAG being the fusion partners in tumors reported in the stomach, colon, ovary, and lung with round to spindled and rhabdoid morphology. [ 8 ] Primary pulmonary NC is an exceptionally rare and aggressive malignancy, with less than 50 cases reported in the literature to date. [ 9 ] In this article, we present a case of pulmonary NC characterized by an uncommon WHSC1L1::NUTM1gene fusion. CASE A 60-year-old woman with no known comorbidities or smoking history presented with a two-month history of non-productive cough, weight loss, and decreased appetite. Contrast-enhanced computed tomography (CECT) of the thorax revealed a mass in the lung (right upper lobe) measuring 5.3 × 4.9 cm, abutting the mediastinal pleura and involving the right hilum. Mild right-sided pleural effusion was noted, along with multiple enlarged hilar lymph nodes, the largest being a subcarinal node measuring 3.7 cm. F-18-FDG PET/CT revealed a FDG-avid necrotic soft tissue mass involving the upper lobe of the right lung, infiltrating the hilar region, conglomerated with a subcarinal nodal mass and causing complete cut off of the right main bronchus, measuring 3.4x3.7x5.3cm with a SUVmax of 15.99. (Fig. 1 ) FDG avid nodes included right paratracheal, right hilar, subcarinal, the largest necrotic subcarinal nodal mass measured 3.2x2.4cm (SUVmax 7.04). FDG avid bilateral adrenal lesions (SUVmax 11.03 left), (Fig. 1 ) and a lytic lesion with soft tissue component involving left scapula SUVmax 8.05) were noted. (Fig. 1 ) No FDG avid lesions were noted in the liver, left lung. A CT-guided lung biopsy revealed an infiltrating neoplasm arranged in nests and sheets.(Fig. 2 A) The cells were small to intermediate in size, undifferentiated, with coarse granular chromatin and scant cytoplasm. (Fig. 2 B and 2 C) Foci of abrupt keratinization. (Fig. 2 B and 2 D) were identified, and extensive areas of necrosis with comedo necrosis were identified. (Fig. 2 B) Immunohistochemically, the tumor cells exhibited strong nuclear positivity for p40. (Fig. 3 C) and speckled nuclear positivity for NUT-1. (Fig. 3 A) supporting the diagnosis of NC. The tumor cells were negative for CD99, NKX2.2,(Fig. 3 B) and CD20. Programmed death-ligand 1 (PD-L1) immunohistochemistry was performed using the Dako 22C3 pharmDx assay on the Ventana Benchmark Ultra platform, which exhibited a tumor proportion score (TPS) of 70%. (Fig. 3 D) Next-generation sequencing (NGS) was performed on formalin-fixed, paraffin-embedded (FFPE) tissue using a limited gene panel designed to detect clinically relevant genomic alterations in solid tumors. The assay employed the Ion Torrent™ Oncomine™ Comprehensive Assay v3 and was conducted on the Ion GeneStudio™ S5 platform. Molecular analysis ratified the presence of a pathogenic fusion transcript involving WHSC1L1::NUTM1, detected at the RNA level. No clinically actionable DNA mutations or copy number variations were identified in this assay. Additional missense variants of uncertain significance (VUS) were detected in the FGFR4 (p.G388R), NOTCH1 (p.R1114H), and FANCI (p.S1271F) genes, which currently lack established therapeutic implications in this tumor type but may warrant future re-evaluation as knowledge of their roles evolves. The patient has received six cycles of paclitaxel and carboplatin and one dose of nivolumab. A repeat CT scan of the thorax on follow up revealed near-complete resolution of the initial necrotic soft tissue mass in the right upper lobe. There was a marked reduction in the size of the associated subcarinal nodal mass, decreasing from 3.4 × 3.7 cm to 1.2 × 0.9 cm. The patient developed new-onset osseous and left paraortic lymph nodes metastasis and an increase in size of the left adrenal lesion indicating systemic disease progression. The follow-up duration since diagnosis is eight months. DISCUSSION NC registry, encompassing data from 141 patients across 17 countries between 1993 and 2017. provided critical insights into the clinicopathological and molecular spectrum. The median age at diagnosis was 23.6 years (range: 18 days to 80 years), with a slight female predominance (52%). [2] The most common sites included the thorax (51%), followed by the head and neck region (41%), bone and soft tissues (6%) and kidney (1%). Molecular analysis revealed BRD4::NUTM1 gene fusion in 78% of cases, while BRD3::NUTM1 and NSD3::NUTM1 fusions were identified in 15% and 6% of cases, respectively. Histologically, 54% of tumors lacked evidence of squamous differentiation, whereas 33% exhibited overt squamous features. [2] Microscopically, the tumor typically consists of nests of monomorphic small- to medium-sized undifferentiated cells, frequently associated with extensive necrosis, prominent neutrophilic infiltration, and a high mitotic rate. NC, being an undifferentiated tumor where the abrupt keratinization might be absent or missed in biopsy specimens, has a broad list of differential diagnoses discussed in Table 1. Table 1 Differential diagnosis with immunohistochemical and molecular findings. Immunohistochemistry Positive (+) markers Negative (-) markers Molecular alteration Basaloid SCC P63 P40 NUTM1 TP53 Thymic CA (basaloid variant) P63/P40/CD117/PAX8/CD5 NUTM1 - SCNEC TTF1, INSM1, chromogranin and synaptophysin P63/P40/NUTM1 TP53 RB LCNEC CD56, chromogranin and synaptophysin, TTF1+/- P63/P40/NUTM1 TP53 RB SMARCA4-deficient undifferentiated tumor SALL4 CD34 CK SOX2 NUTM1, TTF1, P40 Loss of SMARCA4/BRG1 SWI/SNFchromatin remodeling complex Germ cell tumor SALL4 OCT3/4(Seminoma, EC) Cd117,D2 40, CD30, AFP,Glypican: Depending on the type NUTM1, p63, p40 12p amplification or isochromosome 12p Desmoplastic Small Round Cell Tumor Desmin (dot like) WT1(C terminus) CK (dot like) NUTM1, p63, p40 EWSR1–WT1 fusion Alveolar Rhabdomyosarcoma Desmin Myogenin/ MyoD1 CD99(+/-) NUTM1, p63, p40 PAX3/7–FOXO1 fusions Leukemia / Non-Hodgkin Lymphoma CD45 CD20/CD3 according to type NUTM1, p63, p40 Depends on the type of lymphoma Ewing Sarcoma / Adamantinoma like Ewing Sarcoma CD99 NKX2.2 CK+/- P40/p63(ALES) NUTM1 EWSR1-FLI1 (~ 85–90%) EWSR1-ERG fusion (~ 5–10%) Rare fusion partners of EWSR1: ETV1 , ETV4, E1AF and FEV Synovial Sarcoma(poorly differentiated) TLE SSX18 CK(+/-) CD99 BCL2 NUTM1, p63, p40 SS18–SSX1/2 (SYT–SSX) fusion Rhabdoid Tumors / Vimentin, Desmin,EMA, CD99, CK NUTM1 Loss of INI-1 SMARCB1 (INI1) loss Amelanotic Melanoma S100, HMB45, SOX10 NUTM1 BRAF NUTM1-Rearranged Sarcoma NUTM1 CK+/- CD34+/- P63 P40 MXD4::NUTM1 MXI1::NUTM1 MGA::NUTM1 Abbreviation : SCC- Squamous cell carcinoma; SCNEC: Neuroendocrine carcinoma - Small cell LCNEC : Large cell neuroendocrine carcinoma; EMA – Epithelial Membrane Antigen; WT1 – Wilms Tumor 1; INI1 – Integrase Interactor 1 (SMARCB1); CD45 – Leukocyte Common Antigen. SYT-SSX1 / SYT-SSX2 : Synovial Sarcoma Translocation t(X;18) fusions; PAX3-FOXO1 / PAX7-FOXO1 : Paired Box 3/7 – Forkhead Box O1 fusion genes; WT1 (C-terminus) : Wilms Tumor 1 protein, C-terminal antibody; EWS-WT1 : Ewing Sarcoma – Wilms Tumor 1 fusion gene. SMA : Smooth muscle actin; CK : Cytokeratin; INSM1 : Insulinoma-associated protein 1; RB : retinoblastoma 1 gene; ; BRAF :v-raf murine sarcoma viral oncogene homolog B; CD : Cluster of Differentiation; NKX2.2 : NK2 Homeobox 2: CK – Cytokeratin; LCA: leukocyte Common antigen; TLE : Transducin-Like Enhancer of split; SOX10 : SRY-related HMG-box 10; EWSR1-FLI1 : Ewing Sarcoma Breakpoint Region 1 - Friend Leukemia Integration 1; ERG: ETS-Related Gene; EWSR1-ATF / EWSR1-CREB : Ewing Sarcoma Breakpoint Region 1 – Activating Transcription Factor / cAMP Response Element-Binding Protein; ALES : Adamantinoma like Ewing Sarcoma ; BRG : Brahma-related gene-1; SWI/SNF : Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex ; +/– = Variable expression A definitive diagnosis of NC requires demonstration of the presence of the NUTM1 gene rearrangement, by IHC with a NUT-specific monoclonal antibody (clone C52). Based on 30 cases with NUT carcinoma, the sensitivity of the C52 IHC and fluorescence in situ hybridization or polymerase chain reaction–based tests was 87% and 93%, respectively, and the specificity was 100%, while the combination of the FISH and C52 IHC tests achieved 100% diagnostic sensitivity. [10] Cytopathological insights are lacking for NC. The largest series of 15 cases reported by Dutta et al comprised primary pulmonary and metastatic sites, sputum, and effusions. Aspirate smears were cellular and demonstrated fragments and cohesive clusters of primitive tumor cells with scant cytoplasm, ovoid nuclei with coarse granular chromatin, and consistently conspicuous single nucleoli in a frequently neutrophil-rich necrotic background with dispersed bare tumor nuclei. In fluid cytology, tight, 3-dimensional tumor clusters and singly lying tumor cells were observed. Squamous differentiation in the form of sheets and singly lying polygonal tumor cells with abundant dense cytoplasm was noted focally in rare cases. The cytological diagnoses signed out were poorly differentiated carcinoma, poorly differentiated squamous cell carcinoma, and malignant small round cell tumor. [11] In a recent large-scale analysis, thoracic NC representing over half of all reported cases was associated with the poorest outcomes. At initial presentation, up to 70% of patients have already developed distant metastases, frequently involving the lymph nodes, bones, bone marrow, and pleural surfaces. Patients with thoracic tumors demonstrated a median survival of 4.4 months , with only 5% surviving beyond two years . By contrast, non-thoracic tumors harboring BRD3–NUTM1 or NSD3–NUTM1 gene fusions showed significantly improved prognoses, with a median survival of 36 months and a 2-year survival rate of 64% . Non-thoracic cases involving the BRD4–NUTM1 fusion exhibited an intermediate outcome, with a median survival of 10 months and 2-year survival of 28% . [2] Table 2 depicts a brief review of literature. Table 2 : Review of literature Parameter Current Case Chau et al., 2019 2 Bauer et al., 2012 3 Kakkar et al., 2018 4 Number of Patients 1 124 63 5 Age Range (years) 60 Median 23.6 (range: 0.05–80) Median 16 (range: 0.1–78) 9–54 Sex Female Slight female predominance (52%) 56% male 3 Male, 2 Female Primary Site Lung (Right upper lobe) Thorax (51%), Head and Neck (41%) Thorax (56%), Head and Neck (19%) Head and neck (n=2), lung (n=2), mediastinum (n=1) Fusion Partner WHSC1L1::NUTM1 BRD4 (67%), BRD3 (16%), NSD3 (6%), Unknown/Others (11%) BRD4 (75%), BRD3 (22%), Unknown (3%) BRD4::NUTM1 in 4, unknown in 1 Histology Undifferentiated carcinoma with abrupt keratinization 33% with squamous features, 54% undifferentiated Abrupt squamous differentiation (56%), undifferentiated in remainder Abrupt keratinization in 3 cases Diagnostic Tools IHC (p40, NUT), NGS (RNA fusion) IHC (NUT), FISH, RT-PCR IHC (NUT), FISH, RT-PCR IHC (NUT), FISH PD-L1 Expression High (TPS 70%) Not reported Not reported Not reported Treatment Given Paclitaxel + Carboplatin Heterogeneous treatments; radiation + surgery showed improved survival Various (chemo, radiation, surgery), no standard approach 2 received chemo, 1 surgery, others supportive Response to Therapy Partial thoracic response, new skeletal mets, palliative care Radiation + surgery: best outcomes; thoracic tumors had worst prognosis Overall poor response; no durable remission One patient had long survival (33 months), others progressed rapidly Survival / Follow-up 7 months (ongoing) Median OS: 6.5 months overall; thoracic NC: 4.4 months; non-thoracic BRD3-fused: ~36 months Median OS: 6.7 months Range: 2 to 33 months Notable Points Rare WHSC1L1 fusion; high PD-L1; older non-smoking woman Developed site/genotype-based prognostic model; thoracic site & BRD4 fusion had worst prognosis One of first and largest detailed series; highlighted diagnostic IHC and survival variation by fusion Indian series; one case with unusually prolonged survival despite initial aggressiveness Management of NUT carcinoma remains challenging. Combining radiotherapy with complete surgical resection may contribute to improved progression-free and overall survival(OS) . A variety of chemotherapeutic protocols have been explored, including those incorporating alkylating agents , platinum compounds , and anthracyclines . BRD proteins are potential therapeutic targets because of their involvement in modulating the nuclear factor kappa B (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathways. [12] Bromo- and extra-terminal domain (BET) inhibitors impede the activity of the BRD4-NUT fusion protein by interfering with the action of BET proteins, including BRD4. In a variety of cancer types, BET inhibitors increase cell proliferation, decrease apoptosis, and slow the repair of DNA damage caused by poly (ADP-ribose) polymerase (PARP). This implies that a variety of carcinogenic pathways may be regulated by BET inhibitors. The lack of selectivity among the various BRD proteins, the development of resistance or harmful side effects, and the short half-life of BET inhibitors have all contributed to the inconsistent results of the early clinical trials. However, preclinical research showed that employing small-molecule BET inhibitors to target BRD decreased cell invasion, proliferation, and triggered apoptosis. The effectiveness of BET inhibitors either alone or in conjunction with immunotherapy or chemotherapy needs exploration. [12] Variable expression of PD-L1 (0-80%) has been reported in NUT-midline carcinoma, which suggests the potential for immunotherapy. [13] A combination treatment with pembrolizumab improved the OS by more than 12 months. [14] Conclusion NC, a rare and aggressive epithelial malignancy, though it typically affects young individuals, a high index of suspicion should prevail across all age groups, especially in a tumor with undifferentiated morphology. The detection of high PD-L1 expression and a novel WHSC1L1::NUTM1 fusion further exemplifies the molecular heterogeneity of this tumor and may have future therapeutic relevance. Abbreviations NC: NUT carcinoma NUTM1: NUT midline carcinoma family member 1 NUT: Nuclear protein in testis BRD4: Bromodomain-containing protein 4 F-18-FDG PET/CT: 18F-flourodeoxyglucose positron emission tomography/computed tomography SUVmax: Standardized uptake value BET: Bromodomain and extraterminal domain NF-Κb: Nuclear factor kappa B JAK/STAT: Janus kinase/signal transducer and activator of transcription PD-L1:Programmed death-ligand 1 TPS: Tumor proportion score NGS: Next-generation sequencing FFPE : Formalin-fixed, paraffin-embedded Declarations Institutional Review Board (IRB) approval: The institutional review board has a waiver for case reports, all appropriate consents were obtained. Consent to participate The authors certify that they have obtained all appropriate patient consent forms. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Availability of data and materials No datasets were generated or analysed during the current study Declaration of interest Conflicts of interest: none' Declaration of generative AI in scientific writing No AI tool was used . Submission declaration and verification The work described has not been published previously that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder Author contributions PM: conceptualization, methodology, formal analysis, resources, data curation, writing- original draft. PP: conceptualization, methodology, formal analysis, resources, data curation, writing- original draft, reviewing and editing, visualization, supervision. AS: Drafting final report. Both PM and PP the authors have equally contributed in writing original draft. Acknowledgements Nil References Chirieac LR, French CA, Sholl L, Yatabi Y. Lung: other and unclassified carcinomas. In: Travis WD, Brambila E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer; 2015:97-98. Chau NG, Ma C, Danga K, et al. An anatomical site and genetic-based prognostic model for patients with nuclear protein in testis (NUT) midline carcinoma: analysis of 124 patients. JNCI Cancer Spectr. 2019;4:pkz094. Bauer DE, Mitchell CM, Strait KM, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res. 2012;18:5773-5779. Kakkar A, Antony VM, Irugu DVK, Adhikari N, Jain D. NUT midline carcinoma: a series of five cases, including one with unusual clinical course. Head Neck Pathol. 2018;12:230-236 French CA, Ramirez CL, Kolmakova J, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008;27:2237-2242. Alekseyenko AA, Walsh EM, Zee BM, et al. Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma. Proc Natl Acad Sci U S A. 2017;114:E4184-E4192 Grayson AR, Walsh EM, Cameron MJ, et al. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene. 2014;33:1736-1742. McEvoy CR, Fox SB, Prall OWJ. Emerging entities in NUTM1-rearranged neoplasms. Genes Chromosomes Cancer. 2020 Jun;59(6):375-385. Sholl LM, Nishino M, Pokharel S, et al. Primary pulmonary NUT midline carcinoma: clinical, radiographic, and pathologic characterizations. J Thorac Oncol. 2015;10:951-959. Haack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT midline car cinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol. 2009;33:984-991. Dutta R, Nambirajan A, Mittal S, Roy-Chowdhuri S, Jain D. Cytomorphology of primary pulmonary NUT carcinoma in different cytology preparations. Cancer Cytopathol. 2021;129(1):53-61. Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, et al. Bromodomain and extraterminal (BET) proteins: Biological functions, diseases, and targeted therapy. Signal Transduct Target Ther 2023;8:420 Rooper LM, London NR, Taube JM, Westra WH, Bishop JA, Kang H. Abstract 1191: PD-L1 expression and the tumor immune microenvironment in NUT carcinoma. Cancer Res. 2019;79 (13_ Supplement):1191 Xie XH, Wang LQ, Qin YY, Lin XQ, Xie ZH, Liu M, et al. Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma. Orphanet J Rare Dis 2020;15:183 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 30 Sep, 2025 Reviews received at journal 25 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers invited by journal 15 Sep, 2025 Editor assigned by journal 12 Sep, 2025 Submission checks completed at journal 12 Sep, 2025 First submitted to journal 10 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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15:49:32","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":314427,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/715e35f6ddc80a37ee76a89e.png"},{"id":92010974,"identity":"1974a5cf-1d8d-425b-bb94-b95df0210264","added_by":"auto","created_at":"2025-09-23 15:41:32","extension":"xml","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":83318,"visible":true,"origin":"","legend":"","description":"","filename":"acd4a339ba09416b928ef9f230e52da41structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/d955a285cd30e54f49b07b68.xml"},{"id":92012911,"identity":"9a6f05ef-0408-4b5e-823a-9e87bfd58945","added_by":"auto","created_at":"2025-09-23 15:57:32","extension":"html","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91432,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/7a7cea453a1bc2a4d2f0d2b9.html"},{"id":92010950,"identity":"68677f25-2536-4608-bf52-7986fedba469","added_by":"auto","created_at":"2025-09-23 15:41:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152989,"visible":true,"origin":"","legend":"\u003cp\u003e18FDG PET :Blue arrow: primary in the right lung Green arrow: metastatic soft tissue deposit eroding the left scapula Violet arrow: metastatic bilateral adrenal lesions\u003c/p\u003e","description":"","filename":"FIG1.png","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/0bda297e2880dabf5ea41db0.png"},{"id":92011800,"identity":"d79b285f-ba4c-4d02-8475-408c80ad0016","added_by":"auto","created_at":"2025-09-23 15:49:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":901875,"visible":true,"origin":"","legend":"\u003cp\u003eMicroscopic images of the biopsy shows linear cores of lung parenchyma with sheets of round blue cells (A, H\u0026amp;E), undifferentiated tumor cells enclosing comedo necrosis. (B, H\u0026amp;E), some of the areas show round to elongated tumor cells with hyperchromatic nucleus and scant cytoplasm. Vague nuclear moulding noted. (C, H\u0026amp;E), Undifferentiated tumor cells with abrupt keratinization were noted. (D,H\u0026amp;E, ×100 ).\u003c/p\u003e","description":"","filename":"FIG2.png","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/51b9435874034300058af3dd.png"},{"id":92010953,"identity":"2db79759-9836-4927-b573-b5225b0db11c","added_by":"auto","created_at":"2025-09-23 15:41:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":747942,"visible":true,"origin":"","legend":"\u003cp\u003eThe tumor cells show punctate nuclear positivity for NUTM1 (A, immuoperoxidase), negative for NKX2.2 (B, immuoperoxidase) are diffusely positive for P40 (C, immuoperoxidase,), PDL1 shows moderate to strong membranous positivity for PDL1 (D, immuoperoxidase)\u003c/p\u003e","description":"","filename":"FIG3.png","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/df466d387f6ba78cc65f8133.png"},{"id":92014435,"identity":"93bb7e43-74f1-4283-9036-ad184bd4d432","added_by":"auto","created_at":"2025-09-23 16:13:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3126750,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7584149/v1/a79706d0-b651-4b07-9c37-857f405146c7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eUnveiling the Enigmatic Primary Pulmonary NUT Carcinoma with WHSC1L1::NUTM1-Rearrangement : A Case-Based Insight and Contemporary Literature Review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNUT carcinoma (NC) is a highly aggressive and infrequently encountered epithelial malignancy with extensive local invasion and a predilection for skeletal metastases classically described as arising in midline anatomical sites like upper aerodigestive tract and mediastinum of adolescents and young adults (median age\u0026thinsp;~\u0026thinsp;22 years), with no significant sex predilection. \u003csup\u003e[\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e The pathognomonic genetic hallmark is a fusion of NUTM1 (NUT midline carcinoma family member 1) (chromosome 15q14) with BRD4 (Bromodomain-containing protein 4) (chromosome 19p13.1), observed in over 70% of cases. Other partner genes, including Bromodomain-containing protein 3 (BRD3), (chromosome 19p13.1) Nuclear Receptor Binding SET Domain Protein 3 (NSD3), Zinc Finger Protein 532 (ZNF532), Zinc Finger Protein 592 (ZNF592), Capicua transcriptional repressor (CIC), and other genes like MGA, MXD1, MXI1, CIC, and MXD4 genes may also be involved in pathogenesis. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e These fusion oncoproteins result in aberrant chromatin remodeling and transcriptional dysregulation, through enhanced histone acetylation and constitutive activation of oncogenic drivers such as MYC which profoundly impairs cellular differentiation and promotes relentless tumor proliferation. \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e The tumor spectrum also includes sarcomas, MXD1, MXD4, MAG being the fusion partners in tumors reported in the stomach, colon, ovary, and lung with round to spindled and rhabdoid morphology. \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003ePrimary pulmonary NC is an exceptionally rare and aggressive malignancy, with less than 50 cases reported in the literature to date. \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e In this article, we present a case of pulmonary NC characterized by an uncommon WHSC1L1::NUTM1gene fusion.\u003c/p\u003e"},{"header":"CASE","content":"\u003cp\u003eA 60-year-old woman with no known comorbidities or smoking history presented with a two-month history of non-productive cough, weight loss, and decreased appetite. Contrast-enhanced computed tomography (CECT) of the thorax revealed a mass in the lung (right upper lobe) measuring 5.3 \u0026times; 4.9 cm, abutting the mediastinal pleura and involving the right hilum. Mild right-sided pleural effusion was noted, along with multiple enlarged hilar lymph nodes, the largest being a subcarinal node measuring 3.7 cm. F-18-FDG PET/CT revealed a FDG-avid necrotic soft tissue mass involving the upper lobe of the right lung, infiltrating the hilar region, conglomerated with a subcarinal nodal mass and causing complete cut off of the right main bronchus, measuring 3.4x3.7x5.3cm with a SUVmax of 15.99. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) FDG avid nodes included right paratracheal, right hilar, subcarinal, the largest necrotic subcarinal nodal mass measured 3.2x2.4cm (SUVmax 7.04). FDG avid bilateral adrenal lesions (SUVmax 11.03 left), (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and a lytic lesion with soft tissue component involving left scapula SUVmax 8.05) were noted. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) No FDG avid lesions were noted in the liver, left lung.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA CT-guided lung biopsy revealed an infiltrating neoplasm arranged in nests and sheets.(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) The cells were small to intermediate in size, undifferentiated, with coarse granular chromatin and scant cytoplasm. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) Foci of abrupt keratinization. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD) were identified, and extensive areas of necrosis with comedo necrosis were identified. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eImmunohistochemically, the tumor cells exhibited strong nuclear positivity for p40. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC) and speckled nuclear positivity for NUT-1. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) supporting the diagnosis of NC. The tumor cells were negative for CD99, NKX2.2,(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) and CD20. Programmed death-ligand 1 (PD-L1) immunohistochemistry was performed using the Dako 22C3 pharmDx assay on the Ventana Benchmark Ultra platform, which exhibited a tumor proportion score (TPS) of 70%. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext-generation sequencing (NGS) was performed on formalin-fixed, paraffin-embedded (FFPE) tissue using a limited gene panel designed to detect clinically relevant genomic alterations in solid tumors. The assay employed the Ion Torrent\u0026trade; Oncomine\u0026trade; Comprehensive Assay v3 and was conducted on the Ion GeneStudio\u0026trade; S5 platform. Molecular analysis ratified the presence of a pathogenic fusion transcript involving WHSC1L1::NUTM1, detected at the RNA level. No clinically actionable DNA mutations or copy number variations were identified in this assay. Additional missense variants of uncertain significance (VUS) were detected in the FGFR4 (p.G388R), NOTCH1 (p.R1114H), and FANCI (p.S1271F) genes, which currently lack established therapeutic implications in this tumor type but may warrant future re-evaluation as knowledge of their roles evolves.\u003c/p\u003e\u003cp\u003eThe patient has received six cycles of paclitaxel and carboplatin and one dose of nivolumab. A repeat CT scan of the thorax on follow up revealed near-complete resolution of the initial necrotic soft tissue mass in the right upper lobe. There was a marked reduction in the size of the associated subcarinal nodal mass, decreasing from 3.4 \u0026times; 3.7 cm to 1.2 \u0026times; 0.9 cm. The patient developed new-onset osseous and left paraortic lymph nodes metastasis and an increase in size of the left adrenal lesion indicating systemic disease progression. The follow-up duration since diagnosis is eight months.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNC registry, encompassing data from 141 patients across 17 countries between 1993 and 2017. provided critical insights into the clinicopathological and molecular spectrum. The median age at diagnosis was 23.6 years (range: 18 days to 80 years), with a slight female predominance (52%). \u003csup\u003e[2]\u003c/sup\u003e The most common sites included the thorax (51%), followed by the head and neck region (41%), bone and soft tissues (6%) and kidney (1%). Molecular analysis revealed BRD4::NUTM1 gene fusion in 78% of cases, while BRD3::NUTM1 and NSD3::NUTM1 fusions were identified in 15% and 6% of cases, respectively. Histologically, 54% of tumors lacked evidence of squamous differentiation, whereas 33% exhibited overt squamous features. \u003csup\u003e[2]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMicroscopically, the tumor typically consists of nests of monomorphic small- to medium-sized undifferentiated cells, frequently associated with extensive necrosis, prominent neutrophilic infiltration, and a high mitotic rate. NC, being an undifferentiated tumor where the abrupt keratinization might be absent or missed in biopsy specimens, has a broad list of differential diagnoses discussed in Table 1.\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eDifferential diagnosis with immunohistochemical and molecular findings.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eImmunohistochemistry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePositive (+) markers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNegative (-) markers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMolecular alteration\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBasaloid SCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP63\u003c/p\u003e\n \u003cp\u003eP40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTP53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eThymic CA (basaloid variant)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP63/P40/CD117/PAX8/CD5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSCNEC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTTF1, INSM1, chromogranin and synaptophysin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP63/P40/NUTM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTP53\u003c/p\u003e\n \u003cp\u003eRB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLCNEC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD56, chromogranin and synaptophysin, TTF1+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP63/P40/NUTM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTP53\u003c/p\u003e\n \u003cp\u003eRB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMARCA4-deficient undifferentiated tumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSALL4\u003c/p\u003e\n \u003cp\u003eCD34\u003c/p\u003e\n \u003cp\u003eCK\u003c/p\u003e\n \u003cp\u003eSOX2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, TTF1, P40\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLoss of SMARCA4/BRG1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSWI/SNFchromatin remodeling complex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGerm cell tumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSALL4\u003c/p\u003e\n \u003cp\u003eOCT3/4(Seminoma, EC)\u003c/p\u003e\n \u003cp\u003eCd117,D2 40, CD30, AFP,Glypican: Depending on the type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, p63, p40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12p amplification or isochromosome 12p\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDesmoplastic Small Round Cell Tumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDesmin (dot like)\u003c/p\u003e\n \u003cp\u003eWT1(C terminus)\u003c/p\u003e\n \u003cp\u003eCK (dot like)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, p63, p40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEWSR1–WT1 fusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlveolar Rhabdomyosarcoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDesmin\u003c/p\u003e\n \u003cp\u003eMyogenin/ MyoD1\u003c/p\u003e\n \u003cp\u003eCD99(+/-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, p63, p40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAX3/7–FOXO1 fusions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeukemia / Non-Hodgkin Lymphoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD45\u003c/p\u003e\n \u003cp\u003eCD20/CD3 according to type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, p63, p40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepends on the type of lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEwing Sarcoma / Adamantinoma like Ewing Sarcoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD99\u003c/p\u003e\n \u003cp\u003eNKX2.2\u003c/p\u003e\n \u003cp\u003eCK+/-\u003c/p\u003e\n \u003cp\u003eP40/p63(ALES)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEWSR1-FLI1 (~ 85–90%)\u003c/p\u003e\n \u003cp\u003eEWSR1-ERG\u0026nbsp;fusion (~ 5–10%)\u003c/p\u003e\n \u003cp\u003eRare fusion partners of EWSR1: ETV1\u0026nbsp;,\u0026nbsp;ETV4, E1AF and\u0026nbsp;FEV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSynovial Sarcoma(poorly differentiated)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTLE\u003c/p\u003e\n \u003cp\u003eSSX18\u003c/p\u003e\n \u003cp\u003eCK(+/-)\u003c/p\u003e\n \u003cp\u003eCD99\u003c/p\u003e\n \u003cp\u003eBCL2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1, p63, p40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSS18–SSX1/2 (SYT–SSX) fusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRhabdoid Tumors /\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVimentin, Desmin,EMA, CD99, CK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLoss of INI-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMARCB1 (INI1) loss\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmelanotic Melanoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS100, HMB45, SOX10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRAF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNUTM1-Rearranged Sarcoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNUTM1\u003c/p\u003e\n \u003cp\u003eCK+/-\u003c/p\u003e\n \u003cp\u003eCD34+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP63\u003c/p\u003e\n \u003cp\u003eP40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMXD4::NUTM1\u003c/p\u003e\n \u003cp\u003eMXI1::NUTM1\u003c/p\u003e\n \u003cp\u003eMGA::NUTM1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u003cstrong\u003eAbbreviation\u003c/strong\u003e: SCC- Squamous cell carcinoma; \u003cstrong\u003eSCNEC: Neuroendocrine carcinoma\u003c/strong\u003e - Small cell \u003cstrong\u003eLCNEC\u003c/strong\u003e: Large cell neuroendocrine carcinoma; EMA – Epithelial Membrane Antigen; WT1 – Wilms Tumor 1; INI1 – Integrase Interactor 1 (SMARCB1); CD45 – Leukocyte Common Antigen. \u003cstrong\u003eSYT-SSX1 / SYT-SSX2\u003c/strong\u003e: Synovial Sarcoma Translocation t(X;18) fusions; \u003cstrong\u003ePAX3-FOXO1 / PAX7-FOXO1\u003c/strong\u003e: Paired Box 3/7 – Forkhead Box O1 fusion genes; \u003cstrong\u003eWT1 (C-terminus)\u003c/strong\u003e: Wilms Tumor 1 protein, C-terminal antibody; \u003cstrong\u003eEWS-WT1\u003c/strong\u003e: Ewing Sarcoma – Wilms Tumor 1 fusion gene. \u003cstrong\u003eSMA\u003c/strong\u003e: Smooth muscle actin; \u003cstrong\u003eCK\u003c/strong\u003e: Cytokeratin; \u003cstrong\u003eINSM1\u003c/strong\u003e: Insulinoma-associated protein 1; \u003cstrong\u003eRB\u003c/strong\u003e: retinoblastoma 1 gene; ; \u003cstrong\u003eBRAF\u003c/strong\u003e:v-raf murine sarcoma viral oncogene homolog B; \u003cstrong\u003eCD\u003c/strong\u003e: Cluster of Differentiation; \u003cstrong\u003eNKX2.2\u003c/strong\u003e: NK2 Homeobox 2: \u003cstrong\u003eCK\u003c/strong\u003e – Cytokeratin; LCA: leukocyte Common antigen; \u003cstrong\u003eTLE\u003c/strong\u003e: Transducin-Like Enhancer of split; \u003cstrong\u003eSOX10\u003c/strong\u003e: SRY-related HMG-box 10; \u003cstrong\u003eEWSR1-FLI1\u003c/strong\u003e: Ewing Sarcoma Breakpoint Region 1 - Friend Leukemia Integration 1; ERG: ETS-Related Gene; \u003cstrong\u003eEWSR1-ATF / EWSR1-CREB\u003c/strong\u003e: Ewing Sarcoma Breakpoint Region 1 – Activating Transcription Factor / cAMP Response Element-Binding Protein;\u003cstrong\u003eALES\u003c/strong\u003e: Adamantinoma like Ewing Sarcoma ; \u003cstrong\u003eBRG\u003c/strong\u003e: Brahma-related gene-1; \u003cstrong\u003eSWI/SNF\u003c/strong\u003e : Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex ;\u003cstrong\u003e+/–\u003c/strong\u003e = Variable expression\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;A definitive diagnosis of NC requires demonstration of the presence of the NUTM1 gene rearrangement, by IHC with a NUT-specific monoclonal antibody (clone C52). Based on 30 cases with NUT carcinoma, the sensitivity of the C52 IHC and fluorescence in situ hybridization or polymerase chain reaction–based tests was 87% and 93%, respectively, and the specificity was 100%, while the combination of the FISH and C52 IHC tests achieved 100% diagnostic sensitivity. \u003csup\u003e[10]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCytopathological insights are lacking for NC. The largest series of 15 cases reported by Dutta et al comprised primary pulmonary and metastatic sites, sputum, and effusions. Aspirate smears were cellular and demonstrated fragments and cohesive clusters of primitive tumor cells with scant cytoplasm, ovoid nuclei with coarse granular chromatin, and consistently conspicuous single nucleoli in a frequently neutrophil-rich necrotic background with dispersed bare tumor nuclei. In fluid cytology, tight, 3-dimensional tumor clusters and singly lying tumor cells were observed. Squamous differentiation in the form of sheets and singly lying polygonal tumor cells with abundant dense cytoplasm was noted focally in rare cases. The cytological diagnoses signed out were poorly differentiated carcinoma, poorly differentiated squamous cell carcinoma, and malignant small round cell tumor. \u003csup\u003e[11]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn a recent large-scale analysis, thoracic NC representing over half of all reported cases was associated with the poorest outcomes. At initial presentation, up to 70% of patients have already developed distant metastases, frequently involving the lymph nodes, bones, bone marrow, and pleural surfaces. Patients with thoracic tumors demonstrated a \u003cstrong\u003emedian survival of 4.4 months\u003c/strong\u003e, with only \u003cstrong\u003e5% surviving beyond two years\u003c/strong\u003e. By contrast, \u003cstrong\u003enon-thoracic tumors\u003c/strong\u003e harboring \u003cstrong\u003eBRD3–NUTM1\u003c/strong\u003e or \u003cstrong\u003eNSD3–NUTM1\u003c/strong\u003e gene fusions showed significantly improved prognoses, with a \u003cstrong\u003emedian survival of 36 months\u003c/strong\u003e and a \u003cstrong\u003e2-year survival rate of 64%\u003c/strong\u003e. Non-thoracic cases involving the \u003cstrong\u003eBRD4–NUTM1\u003c/strong\u003e fusion exhibited an intermediate outcome, with a \u003cstrong\u003emedian survival of 10 months\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003e2-year survival of 28%\u003c/strong\u003e\u003c/strong\u003e. \u003csup\u003e[2] \u0026nbsp;\u003c/sup\u003eTable 2 depicts a brief review of literature.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2 : Review of literature\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent Case\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eChau et al., 2019 \u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBauer et al., 2012 \u003csup\u003e3\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eKakkar et al., 2018 \u003csup\u003e4\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAge Range (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian 23.6 (range: 0.05–80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian 16 (range: 0.1–78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9–54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSlight female predominance (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56% male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 Male, 2 Female\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Site\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLung (Right upper lobe)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eThorax (51%), Head and Neck (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eThorax (56%), Head and Neck (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHead and neck (n=2), lung (n=2), mediastinum (n=1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFusion Partner\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWHSC1L1::NUTM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBRD4 (67%), BRD3 (16%), NSD3 (6%), Unknown/Others (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBRD4 (75%), BRD3 (22%), Unknown (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBRD4::NUTM1 in 4, unknown in 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUndifferentiated carcinoma with abrupt keratinization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33% with squamous features, 54% undifferentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbrupt squamous differentiation (56%), undifferentiated in remainder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbrupt keratinization in 3 cases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic Tools\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIHC (p40, NUT), NGS (RNA fusion)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIHC (NUT), FISH, RT-PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIHC (NUT), FISH, RT-PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIHC (NUT), FISH\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePD-L1 Expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh (TPS 70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Given\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaclitaxel + Carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHeterogeneous treatments; radiation + surgery showed improved survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eVarious (chemo, radiation, surgery), no standard approach\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 received chemo, 1 surgery, others supportive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to Therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePartial thoracic response, new skeletal mets, palliative care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRadiation + surgery: best outcomes; thoracic tumors had worst prognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOverall poor response; no durable remission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOne patient had long survival (33 months), others progressed rapidly\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSurvival / Follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 months (ongoing)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian OS: 6.5 months overall; thoracic NC: 4.4 months; non-thoracic BRD3-fused: ~36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian OS: 6.7 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRange: 2 to 33 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNotable Points\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRare WHSC1L1 fusion; high PD-L1; older non-smoking woman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDeveloped site/genotype-based prognostic model; thoracic site \u0026amp; BRD4 fusion had worst prognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOne of first and largest detailed series; highlighted diagnostic IHC and survival variation by fusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIndian series; one case with unusually prolonged survival despite initial aggressiveness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Management of NUT carcinoma remains challenging. Combining \u003cstrong\u003eradiotherapy with complete surgical resection\u003c/strong\u003e may contribute to improved \u003cstrong\u003eprogression-free and overall survival(OS)\u003c/strong\u003e. A variety of chemotherapeutic protocols have been explored, including those incorporating \u003cstrong\u003ealkylating agents\u003c/strong\u003e\u003cstrong\u003e, \u003cstrong\u003eplatinum compounds\u003c/strong\u003e\u003c/strong\u003e, and \u003cstrong\u003eanthracyclines\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e BRD proteins are potential therapeutic targets because of their involvement in modulating the nuclear factor kappa B (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathways.\u003csup\u003e[12]\u003c/sup\u003e Bromo- and extra-terminal domain (BET) inhibitors impede the activity of the BRD4-NUT fusion protein by interfering with the action of BET proteins, including BRD4. In a variety of cancer types, BET inhibitors increase cell proliferation, decrease apoptosis, and slow the repair of DNA damage caused by poly (ADP-ribose) polymerase (PARP). This implies that a variety of carcinogenic pathways may be regulated by BET inhibitors. The lack of selectivity among the various BRD proteins, the development of resistance or harmful side effects, and the short half-life of BET inhibitors have all contributed to the inconsistent results of the early clinical trials. However, preclinical research showed that employing small-molecule BET inhibitors to target BRD decreased cell invasion, proliferation, and triggered apoptosis. The effectiveness of BET inhibitors either alone or in conjunction with immunotherapy or chemotherapy needs exploration. \u003csup\u003e[12]\u003c/sup\u003e Variable expression of PD-L1 (0-80%) has been reported in NUT-midline carcinoma, which suggests the potential for immunotherapy. \u003csup\u003e[13]\u003c/sup\u003e A combination treatment with pembrolizumab improved the OS by more than 12 months. \u003csup\u003e[14]\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNC, a rare and aggressive epithelial malignancy, though it typically affects young individuals, a high index of suspicion should prevail across all age groups, especially in a tumor with undifferentiated morphology. The detection of high PD-L1 expression and a novel WHSC1L1::NUTM1 fusion further exemplifies the molecular heterogeneity of this tumor and may have future therapeutic relevance.\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eNC: NUT carcinoma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNUTM1: NUT midline carcinoma family member 1\u003c/p\u003e\n\u003cp\u003eNUT: Nuclear protein in testis\u003c/p\u003e\n\u003cp\u003eBRD4: Bromodomain-containing protein 4\u003c/p\u003e\n\u003cp\u003eF-18-FDG PET/CT: 18F-flourodeoxyglucose positron emission tomography/computed tomography\u003c/p\u003e\n\u003cp\u003eSUVmax: Standardized uptake value\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBET: Bromodomain and extraterminal domain\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNF-\u0026Kappa;b: Nuclear factor kappa B\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJAK/STAT: Janus kinase/signal transducer and activator of transcription\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD-L1:Programmed death-ligand 1\u003c/p\u003e\n\u003cp\u003eTPS: Tumor proportion score\u003c/p\u003e\n\u003cp\u003eNGS: Next-generation sequencing \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFFPE : Formalin-fixed, paraffin-embedded\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eInstitutional Review Board (IRB) approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe institutional review board has a waiver for case reports, all appropriate consents were obtained.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors certify that they have obtained all appropriate patient consent forms.\u0026nbsp;Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study\u003c/p\u003e\n\u003ch4\u003eDeclaration of interest\u003c/h4\u003e\n\u003cp\u003eConflicts of interest: none\u0026apos;\u003c/p\u003e\n\u003ch4\u003eDeclaration of generative AI in scientific writing\u003c/h4\u003e\n\u003cp\u003e\u0026nbsp;No AI tool was used .\u003c/p\u003e\n\u003ch4\u003eSubmission declaration and verification\u003c/h4\u003e\n\u003cp\u003eThe work described has not been published previously that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eAuthor contributions\u003c/h4\u003e\n\u003col\u003e\n \u003cli\u003ePM: conceptualization, methodology, formal analysis, resources, data curation, writing- original draft.\u003c/li\u003e\n \u003cli\u003ePP: conceptualization, methodology, formal analysis, resources, data curation, writing- original draft, reviewing and editing, visualization, supervision.\u003c/li\u003e\n \u003cli\u003eAS: Drafting final report.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eBoth PM and PP the authors have equally contributed in writing original draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNil\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChirieac LR, French CA, Sholl L, Yatabi Y. Lung: other and unclassified carcinomas. In: Travis WD, Brambila E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. International Agency for Research on Cancer; 2015:97-98. \u003c/li\u003e\n\u003cli\u003eChau NG, Ma C, Danga K, et al. An anatomical site and genetic-based prognostic model for patients with nuclear protein in testis (NUT) midline carcinoma: analysis of 124 patients. JNCI Cancer Spectr. 2019;4:pkz094. \u003c/li\u003e\n\u003cli\u003eBauer DE, Mitchell CM, Strait KM, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res. 2012;18:5773-5779. \u003c/li\u003e\n\u003cli\u003eKakkar A, Antony VM, Irugu DVK, Adhikari N, Jain D. NUT midline carcinoma: a series of five cases, including one with unusual clinical course. Head Neck Pathol. 2018;12:230-236\u003c/li\u003e\n\u003cli\u003eFrench CA, Ramirez CL, Kolmakova J, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008;27:2237-2242. \u003c/li\u003e\n\u003cli\u003eAlekseyenko AA, Walsh EM, Zee BM, et al. Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma. Proc Natl Acad Sci U S A. 2017;114:E4184-E4192\u003c/li\u003e\n\u003cli\u003eGrayson AR, Walsh EM, Cameron MJ, et al. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene. 2014;33:1736-1742. \u003c/li\u003e\n\u003cli\u003eMcEvoy CR, Fox SB, Prall OWJ. Emerging entities in NUTM1-rearranged neoplasms. Genes Chromosomes Cancer. 2020 Jun;59(6):375-385. \u003c/li\u003e\n\u003cli\u003eSholl LM, Nishino M, Pokharel S, et al. Primary pulmonary NUT midline carcinoma: clinical, radiographic, and pathologic characterizations. J Thorac Oncol. 2015;10:951-959.\u003c/li\u003e\n\u003cli\u003eHaack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT midline car cinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol. 2009;33:984-991.\u003c/li\u003e\n\u003cli\u003eDutta R, Nambirajan A, Mittal S, Roy-Chowdhuri S, Jain D. Cytomorphology of primary pulmonary NUT carcinoma in different cytology preparations. Cancer Cytopathol. 2021;129(1):53-61. \u003c/li\u003e\n\u003cli\u003eWang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, et al. Bromodomain and extraterminal (BET) proteins: Biological functions, diseases, and targeted therapy. Signal Transduct Target Ther 2023;8:420 \u003c/li\u003e\n\u003cli\u003eRooper LM, London NR, Taube JM, Westra WH, Bishop JA, Kang H. Abstract 1191: PD-L1 expression and the tumor immune microenvironment in NUT carcinoma. Cancer Res. 2019;79 (13_ Supplement):1191\u003c/li\u003e\n\u003cli\u003eXie XH, Wang LQ, Qin YY, Lin XQ, Xie ZH, Liu M, et al. Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma. Orphanet J Rare Dis 2020;15:183\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":false,"email":"[email protected]","identity":"surgical-and-experimental-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"saep","sideBox":"Learn more about [Surgical and Experimental Pathology](http://surgexppathol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/SAEP/default.aspx","title":"Surgical and Experimental Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7584149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7584149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNUT carcinoma (NC) is a rare, aggressive, and genetically defined epithelial malignancy characterized by rearrangements involving the NUTM1 gene, most commonly BRD4::NUTM1 fusions. Although classically and initially described as involving midline location, especially the sinonasal region affecting children and young adults, NC has been found to have myriad localizations and age affliction, with primary pulmonary involvement being exceedingly uncommon. A 60-year-old female presented with a non-productive cough, weight loss, and anorexia. Imaging revealed a right upper lobe lung mass with mediastinal involvement and subcarinal lymphadenopathy. Biopsy demonstrated an undifferentiated carcinoma with focal abrupt keratinization and immunohistochemical strong positivity for p40 and NUT protein, confirming the diagnosis of NC. PD-L1 testing revealed a tumor proportion score (TPS) of 70%. Next-generation sequencing identified a rare WHSC1L1::NUTM1 fusion. The patient was treated with paclitaxel and carboplatin with partial thoracic response; however, new skeletal metastases developed, and she was transitioned to palliative care.\u003c/p\u003e","manuscriptTitle":"Unveiling the Enigmatic Primary Pulmonary NUT Carcinoma with WHSC1L1::NUTM1-Rearrangement : A Case-Based Insight and Contemporary Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 15:41:27","doi":"10.21203/rs.3.rs-7584149/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-30T12:39:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-25T13:39:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74797369715037865485814977185530699754","date":"2025-09-16T21:44:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-15T19:56:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-12T09:47:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-12T09:43:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Surgical and Experimental Pathology","date":"2025-09-10T14:46:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"surgical-and-experimental-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"saep","sideBox":"Learn more about [Surgical and Experimental Pathology](http://surgexppathol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/SAEP/default.aspx","title":"Surgical and Experimental Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3e8f96a3-322a-4840-8fc6-32b9a77315ed","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-12T14:24:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 15:41:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7584149","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7584149","identity":"rs-7584149","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}