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CASE REPORT Jonathan Irish, MD, FRCSC, Section Editor Nuclear protein in testis midline carcinoma of larynx: An underdiagnosed entity Ajay Kundra, MD,1 Mirela Andrei, MD,1 William Westra, MD,2 Rashid Chaudhry, MD,3 Harry Moussouris, MD,4 Arash Gohari, MD,5 Jen C. Wang, MD1* 1 Division of Hematology and Oncology, Brookdale University Hospital and Medical Center, Brooklyn, New York, 2Division of Pathology, Oncology, and Otolaryngology/Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, 3Division of Otolaryngology/Head and Neck Surgery, Brookdale University Hospital and Medical Center, Brooklyn, New York, 4Division of Pathology, Brookdale University Hospital and Medical Center, Brooklyn, New York, 5Division of Radiology, Brookdale University Hospital and Medical Center, Brooklyn, New York. Accepted 30 December 2015 Published online 29 March 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24418 ABSTRACT: Background. Nuclear protein in testis (NUT) carcinomas are very rare and have a very poor survival rate. The most common sites of involvement include the nasal cavity, sinus, and mediastinum. Laryngeal NUT midline carcinoma is extremely rare, with only 2 cases reported thus far. Here, we are describing another case of NUT laryngeal carcinoma. Methods and Results. The patient was a light smoker and nondrinker who presented with upper respiratory tract obstruction. Imaging and laryngoscopic evaluation revealed a large intraluminal laryngeal mass. Biopsy demonstrated poorly differentiated carcinoma with intact mucosa and only focal coexpression of CK5/6 and p40. NUT protein immune- stain positivity conclusively established the diagnosis of NUT midline carcinoma. Conclusion. Absence of well-known risk factors, pathologic finding of lack of mucosal involvement and lack of squamous differentiation with poorly differentiated carcinoma, should prompt clinicians to consider this C 2016 Wiley Periodicals, Inc. Head rare entity as a possible diagnosis. V Neck 38: E2471–E2474, 2016 INTRODUCTION of the soft tissue in the neck showed a large supraglottic laryngeal mass of 3.7 3 2.8 3 2.6 cm with near complete occlusion of the supraglottic laryngeal airway and distended hypopharyngeal airway. The mass extended into the paralaryngeal fat, the inner margin of the thyroid, and hyoid cartilages. There was no gross extra laryngeal spread or radiologic evidence of lymph node enlargement (Figures 1A and 1B). A CT scan of the chest, abdomen, and pelvis did not reveal any distant pathology. Because of severely compromised upper airway, the patient underwent emergent insertion of a tracheostomy tube along with tumor debulking and biopsy. A large, ill-defined, fungating mass was observed on laryngoscopic evaluation, mostly arising from right supraglottis and extending to piriformis. There was no evidence of true vocal cord involvement, but it was difficult to check for mobility. Fiber-optic bronchoscopy did not show mucosal lesions distal to the mass. A cervical esophagoscopy was negative for upper esophageal pathology as well. The tissue biopsy on hematoxylin-eosin stain showed a high-grade malignant neoplasm with a diffuse infiltrative pattern and prominent associated tumor necrosis. On light microscopy, the mucosa was intact, the neoplastic cells appeared small to medium sized, and very rare large cells with moderate-high nuclear cytoplasmic ratio. The chromatin was open with prominent single nucleoli and soft nuclear outlines with delicate nuclear membranes in the more viable portions of the sampling (Figures 2A and 2B). As the tumor did not show microscopic evidence of any specific Nuclear protein in testis (NUT) carcinomas arising from midline structures are very rare but particularly aggressive neoplasms with a very poor survival. The most common sites of involvement include the nasal cavity, sinus, and mediastinum. Laryngeal NUT midline carcinoma is extremely rare with only 2 cases reported thus far. Hence, we are describing another case of a 39-year-old man with NUT laryngeal carcinoma to supplement existing literature. Although this rare disease has been published since 2000, it seems to be an unrecognized and, hence, underdiagnosed entity. Given the significantly adverse clinical course, it is important to recognize NUT midline carcinoma and to identify it as a distinct entity from undifferentiated squamous cell carcinoma of the larynx. CASE REPORT A 39-year-old man presented with 2-week history of hemoptysis and hoarseness. His medical history was unremarkable. He was a former light smoker with no history of alcohol intake. Symptoms started a few months before presentation when he noticed progressive unintentional weight loss of about 50 pounds, followed by right-sided ear pain, shortness of breath, and dysphagia. A CT scan *Corresponding author: J. C. Wang, Division of Hematology and Oncology, Brookdale University Hospital and Medical Center, Brooklyn, NY 11212. E-mail: [email protected] KEY WORDS: nuclear protein in testis (NUT) midline carcinoma, laryngeal carcinoma HEAD & NECK—DOI 10.1002/HED AUGUST 2016 E2471 KUNDRA ET AL. FIGURE 1. CT scan of the soft tissue of the neck of a 39-year-old man with large supraglottic laryngeal mass. (A) Sagittal CT image showed a large laryngeal mass. (B) Axial CT image showed near complete occlusion of the supraglottic laryngeal airway. differentiation, the differential diagnosis was very broad and included carcinoma, lymphoma, mucosal melanoma, primitive sarcoma, and primitive neuroectodermal tumor. An extensive immunohistochemical (IHC) panel confirmed epithelial differentiation (focal staining for CK5/6, p40, CAM 5.2, and AE-1/AE-3) and failed to demonstrate any evidence of lymphoid (negative staining for CD10, CD20, CD43, CD3, CD23, BCL-2, BCL-6, and MUM-1), melanocytic (negative staining for S100, MELAN-1, MART-1, and HMB-45), mesenchymal (negative staining for actin, desmin, and myogenin), neuroectodermal (negative staining for FLI-1), or neuroendocrine (negative staining for chromogranin and synaptophysin) differentiation. Oncovirus analysis was negative (p16-negative by IHC; and Epstein–Barr virus negative, and high-risk human papillomavirus negative by in situ hybridization). The cell proliferation marker study (K1-67) showed 100% positive nuclear staining. Then, the tissue was evaluated for nuclear reactivity for NUT protein using a monoclonal antibody at Johns Hopkins laboratory. Final result showed positive staining with a diffuse and strong nuclear reactivity, consistent with diagnosis of NUT laryngeal carcinoma (Figures 3A and 3B). The sensitivity and specificity of NUT antibody are excellent; hence, there was no need for further confirmatory tests, such as cytogenetics, fluorescent in situ hybridization, or reverse transcriptase polymerase chain reaction. DISCUSSION NUT midline carcinoma belongs to a subset of squamous cell carcinoma with a predisposition for upper aerodigestive tract and, less commonly, infradiaphragmatic or nonmidline structures involvement.1 Common locations include the nasal cavity, sinuses, and mediastinum/thymus.2 NUT midline carcinomas that arise in the larynx are extremely rare, only 2 cases reported thus far; in a 78-year-old woman and 13-year-old girl.3,4 The most comprehensive review was reported by Bauer et al5 establishing a clinical database using retrospective data of 63 published and unpublished cases. Clinicopathologic features and demographics were available for all patients, with survival analysis done for 54 cases. Primaries involved the thorax (n 5 31), head and neck (n 5 19), and other sites (n 5 4). Of the 63 tumors, a little over half of the cases have been reported in patients <18 years of age. In meta-analysis of 32 cases reported by FIGURE 2. (A) Hematoxylin-eosin stain section magnification 320 of a high-grade laryngeal nuclear protein in testis (NUT) carcinoma; mucosa appeared intact. (B) Magnification 340 of small to medium-sized cells with round nuclear contour and clear cytoplasm. E2472 HEAD & NECK—DOI 10.1002/HED AUGUST 2016 NUCLEAR PROTEIN IN TESTIS MIDLINE CARCINOMA OF LARYNX FIGURE 3. Immunohistochemistry of high-grade laryngeal nuclear protein in testis (NUT) carcinoma. On 320 magnification, the tumor demonstrates a solid growth pattern with no mucosal involvement (A). Diffuse, speckled, nuclear staining using NUT-specific monoclonal antibody at 340 magnification, consistent with a diagnosis of NUT midline carcinoma (B). Nakamura et al,6 approximately one-third involved the mediastinum/thymus (n 5 12), 5 involved the nasal cavity or paranasal sinuses, 1 case each involved the epiglottis, nasopharynx/hypopharynx, or other infrequent sites (orbit/supraorbit, parotid/submandibular glands, tonsil, lung, hepatic/pancreatic, or bladder). Almost half of the cases (n 5 15) occurred in patients <18 years of age and 5 patients were older than 35 years. The case with laryngeal involvement included a 13-year-old girl with a rapidly growing epiglottic mass leading to superior vena cava syndrome and rapidly fatal course within 9 months of diagnosis. The tumor displayed features of poorly differentiated carcinoma and showed cytogenetic evidence of chromosomal 15;19 translocation. The patient was treated with 3 cycles of docetaxel, cisplatin, 5fluorouracil, and leucovorin with partial response, followed by radiation and left modified radical neck dissection. Shortly after the neck dissection, the patient presented with a rapidly progressing deep left posterior neck metastasis unresponsive to subsequent palliative chemotherapy. The other reported case of right supraglottic laryngeal NUT carcinoma has been that of a 78-yearold woman in whom original cytologic diagnosis was suggestive of poorly differentiated neoplasms consistent with metastatic disease. The diagnosis of laryngeal NUT carcinoma was confirmed by fluorescent in situ hybridization. The patient was treated with chemoradiotherapy, laryngectomy, and neck dissection. Despite aggressive treatment, the patient died in 8 months.3 Clinical symptoms depend on the site of presentation but invariably included pain and swelling of the surrounding structures because of mass effect. Other reported signs and symptoms were site specific, such as hoarseness and wheezing with upper airway involvement, and shortness of breath with mediastinal involvement. In general, imaging tests are nonspecific and may mimic other diseases, such as lymphoma, sarcoma, and metastatic tumors. On contrastenhanced multidetector CT, NUT midline carcinoma appears as a low attenuation mass with heterogeneous enhancement associated with necrotic lymph nodes.7,8 Fluorodeoxyglucose-positron emission tomography imaging usually reveals hypermetabolic activity well correlated with multidetector CT findings.9 The rarity of this tumor type, a general lack of awareness among pathologist, its nonspecific morphologic features, and the way these features overlap with a large and diverse group of other poorly differentiated neoplasm, all contribute to the difficulty in establishing a diagnosis of NUT midline carcinoma. This difficulty may be intensified when a NUT midline carcinoma is encountered in an unexpected site in an older patient. There are few histologic clues that may aid in the recognition of this tumor and guide further diagnostic evaluation. First, for a high-grade carcinoma, NUT midline carcinomas are comprised of remarkably uniform small round cells with minimal variation in size and shape. Second, sheets of these uniformly small round cells are sometimes punctuated by abrupt foci of keratinization. There is poor response of NUT midline carcinomas to chemotherapeutic drugs designed to treat carcinomas.5 There is an exception of 1 patient with NUT midline carcinoma treated with Ewing sarcoma regimen resulting in cure.10 There has been an increasing trend toward using Ewing sarcoma protocol for NUT midline carcinomas. This has also led to an increased interest in proper diagnosis of NUT midline carcinomas.11 A genetic abnormality involving fusion of the NUT gene and 1 member of the BET family constitutes the genetic hallmark of NUT midline carcinomas. In 80% of cases, the gene fusion occurs between NUT and BRD4, and in the remaining tumors, BRD3 or NUT-variant fusion. The NUT-BRD4 fusion transcript encodes an oncoprotein that arrests normal cellular differentiation and maintains tumor growth.12 NUT IHC has greatly simplified the diagnosis by demonstration of nuclear reactivity for NUT protein by using a monoclonal antibody. Haack et al13 demonstrated that immunohistochemical staining with C52 antibody correlated with rearrangement of the NUT and provided a highly sensitive and specific assay for diagnosing NUT midline carcinoma. Because NUT HEAD & NECK—DOI 10.1002/HED AUGUST 2016 E2473 KUNDRA ET AL. midline carcinomas are uncommon yet highly aggressive, a high index of suspicion is required for timely diagnosis and prompt initiation of therapy. Based on the largest clinical database analysis reported by Bauer et al,5 different intensive chemotherapy regimens have been used, including those used to treat patients with germ cell tumors, squamous cell carcinoma of the head and neck, non-small cell lung carcinoma, and sarcoma. Most patients received combination chemotherapy consisting of platinum-based therapy, anthracyclines, or nonplatinum alkylating agents. Because of the rarity of this malignancy and nonspecific multiagent chemotherapy used, an analysis that identifies a specific chemotherapeutic regimen that results in improved outcome was not possible. However, it was noted that the extent of surgical resection and initial radiotherapy was associated with a slight extension of survival. Overall, prognosis is extremely poor with median overall survival of 6.7 months with no significant differences between younger or older patients. Thoracic involvement and metastatic spread were associated with lower progression-free survival and overall survival. Unlike most solid tumors that are classified according to the tissue of origin, NUT midline carcinomas are defined genetically. NUT midline carcinomas are characterized by specific reciprocal chromosomal translocation, t(15;19), which differentiates them from other poorly differentiated carcinomas. The most common and studied fusion genes are NUT and BRD4. The NUT gene is located on the long arm of chromosome 15q14 that encodes NUT protein, normally expressed only in testis tissue.14 The normal function of NUT protein is not well characterized. However, it is hypothesized that it is involved in chromatin compaction during spermatogenesis, interfering with the balance of histone acetylation/ deacetylation.15 As shown by French,16 NUT remains bound to chromatin upon fusion to BRD4 or BRD3 and activates a histone acetyl-transferase, p300, that is essential to the oncogenic function of BRD4-NUT. The presence of a consistent chromosomal rearrangement may provide a specific target for biological therapeutic agents. Indeed, preliminary studies using histone deacetylase inhibitors and BET inhibitors have shown promising results both in vitro and in vivo, and clinical trials using these agents are forthcoming.16,17 Clearly, the recognition of NUT midline carcinoma is very important from both a prognostic and therapeutic perspective. In conclusion, we present a rare case of laryngeal NUT midline carcinoma occurring in a 39-year-old man. In E2474 HEAD & NECK—DOI 10.1002/HED AUGUST 2016 essence, this entity should be considered in the differential diagnosis in patients with clinical presentation of rapidly growing midline tumors. Lack of typical histologic and IHC hallmarks of squamous differentiation should prompt clinicians to consider this rare entity as a possible diagnosis. In general, these tumors have variable responses to initial combination treatment modalities. Eventually, however, they have a rapidly progressive and fatal course. The ongoing developments will hopefully improve the outcome of patients with this challenging disease. REFERENCES 1. Mills AF, Lanfranchi M, Wein RO, et al. NUT midline carcinoma: a case report with a novel translocation and review of the literature. Head Neck Pathol 2014;8:182–186. 2. Stelow EB. A review of NUT midline carcinoma. Head Neck Pathol 2011; 5:31–35. 3. Bellizzi AM, Bruzzi C, French CA, Stelow EB. The cytologic features of NUT midline carcinoma. Cancer 2009;117:508–515. 4. Vargas SO, French CA, Faul PN, et al. Upper respiratory tract carcinoma with chromosomal translocation 15;19: evidence for a distinct disease entity of young patients with rapidly fatal course. Cancer 2001;92:1195– 1203. 5. 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. 6. Nakamura H, Tsuta K, Tsuda H, et al. NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: a case report and a literature review. Pathol Res Pract 2015;211:92–98. 7. Nelson BA, Lee EY, French CA, Bauer DE, Vargas SO. BRD4-NUT carcinoma of the mediastinum in a pediatric patient: multidetector computed tomography imaging findings. J Thorac Imaging 2010;25:W93–W96. 8. Polsani A, Braithwaite KA, Alazraki AL, Abramowsky C, Shehata BM. NUT midline carcinoma: an imaging case series and review of literature. Pediatr Radiol 2012;42:205–210. 9. 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Dey A, Ellenberg J, Farina A, et al. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol 2000;20:6537–6549. 16. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012;7:247–265. 17. Schwartz BE, Hofer MD, Lemieux ME, et al. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 2011;71:2686– 2696.