A Tough NUT to Crack: A 47-Year-Old With Diplopia From a Rare Malignancy

A 47-year-old previously healthy woman was transferred to our facility when she developed asymmetric bilateral sixth nerve palsies during treatment of intractable sinusitis. Her symptoms had started 2 weeks previously with headache and sinus congestion for which she received amoxicillin-clavulanic acid and prednisone. A few days later, she saw an otolaryngologist for worsening symptoms. She had bloody material on nasal endoscopy and was prescribed clindamycin and dexamethasone.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD A Tough NUT to Crack: A 47-Year-Old With Diplopia From a Rare Malignancy Lauren Maloley, MD, Jason Helvey, MD, Julia Bridge, MD, FACMG, Dominick DiMaio, MD, Deepta Ghate, MD, Sachin Kedar, MD Drs. Maloley and Ghate: A Dr. Helvey: 47-year-old previously healthy woman was transferred to our facility when she developed asymmetric bilateral sixth nerve palsies during treatment of intractable sinusitis. Her symptoms had started 2 weeks previously with headache and sinus congestion for which she received amoxicillin- clavulanic acid and prednisone. A few days later, she saw an otolaryngologist for worsening symptoms. She had bloody material on nasal endoscopy and was prescribed clindamycin and dexamethasone. One week later, she was admitted to an outside facility because of worsening headaches and blurred vision in the left eye. She was treated with intravenous levofloxacin and methylprednisolone. A maxillofacial and head computed tomographic (CT) scan was reported to show "complete opacification of bilateral sphenoid and right maxillary sinuses with mucosal thickening in the posterior ethmoid sinus and no intracranial abnormalities." Nasal endoscopy revealed edematous turbinates and mucosanguineous drainage from the right sphenoid ostium without nasopharyngeal masses. Baseline laboratory studies were unremarkable except for mild elevation of the white blood cell count (13.3 cells/mL) and C-reactive protein (20.6 mg/L). Neuro-ophthalmic examination revealed visual acuity of 20/25 in both eyes, a left Horner syndrome, and an esotropia with bilateral abduction deficits (worse on the left). Visual field testing showed no defects, and fundus examination was normal. Neurological testing, including corneal and facial sensation, revealed no deficits. MRI of the brain and orbits was obtained. MRI of the brain and orbits show a contrast-enhancing sellar mass with extension superiorly to the hypothalamus, laterally into both cavernous sinuses, anteriorly into the sphenoid sinus and inferiorly into the clivus (Fig. 1). The mass shows areas of necrosis and osseous destruction with extensive invasion into adjacent structures. It is hypointense on T1 images and hyperintense on T2 images. The differential diagnosis based on the images is primarily neoplastic, including pituitary adenoma or adenocarcinoma, squamous cell carcinoma, or other less common carcinomas arising from the sphenoid sinus or nasopharynx, such as chordoma, chondrosarcoma, and metastatic disease. Fungal infection and granulomatous inflammatory disease were considered to be less likely. Stanley M. Truhlsen Eye Institute (LM, DG, SK), University of Nebraska Medical Center, Omaha, Nebraska; Departments of Radiology (JH), Pathology and Microbiology (JB, DD), and Neurological Sciences (SK), University of Nebraska Medical Center, Omaha, Nebraska. Dr. DiMaio: J. Bridge: reports being on the scientific advisory board for Merck. D. Ghate: reports being a coinventor for the Advanced Pupil Simulator licensed by EON Reality Inc. The remaining authors report no conflicts of interest. Address correspondence to Sachin Kedar, MD, Department of Neurological Sciences, University of Nebraska Medical Center, 988435 Nebraska Medical Center, Omaha, NE 68198; E-mail: sachin. [e-mail] Maloley et al: J Neuro-Ophthalmol 2019; 39: 129-133 Drs. Maloley and Ghate: Treatment was started with broad-spectrum antibiotics including vancomycin, ceftriaxone, and metronidazole for potential infectious etiology while planning for a biopsy. Extensive studies for autoimmune and infectious conditions (including fungal) were unremarkable. The patient underwent bilateral sphenoidotomy and a right maxillary anstrostomy. Pathology showed nonspecific reactive changes and necrotic debris with negative cultures. Accordingly, the following week, the patient underwent an excisional biopsy using a transnasal transphenoidal approach. Intraoperatively, the mass was found to be an ill-defined, firm, rubbery, and erosive lesion in the sphenoid and sellar region protruding through the sellar face and eroding the clivus. The mass seemed to be extradural and separate from the pituitary gland. Despite maximum debulking, a small amount of the mass was left behind. Histopathology of the mass shows sheets of atypical epitheloidappearing cells with extensive areas of necrosis and absence of glandular or squamous differentiation (Fig. 2A). The tumor cells have a high nuclear-to-cytoplasm ratio and small nucleoli (Fig. 2B). An extensive battery of immunohistochemistry staining was inconclusive and contradictory. Multiple epithelial and lymphoma immunostains were negative. Stains were negative for epithelial membrane antigen, CK5/6, pancytokeratin, OCT3/4, neuron-specific enolase, PLAP, Melan A, S100, HMB45, 129 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Brain MRI. An expansile skull base mass is detected on precontrast axial (A) and sagittal (B) T1 images and on postcontrast axial (C) and coronal (D) scans. The mass is causing osseous destruction with invasion of the clivus, sphenoid sinus, posterior ethmoid cells, sella, cavernous sinuses and suprasellar cistern. CD56, CD30, MiTF, CD34, CD117, CD68, MPO, synaptophysin, HMB-45, desmin, p40, CAM5.2, FLI-1, chromogranin, EBV, CD45, CD20, Pax5, EGERG, ERG, Pax8, GATA3, or calretinin. Based on diffuse positive staining for SOX10, a preliminary diagnosis of melanoma was considered (Fig. 2C). However, lack of staining for additional melanocytic markers, including S100, HMB45, Melan A, and MiTF argued against that diagnosis. Because of conflicting immunohistochemistry findings, conventional cytogenetic analysis was performed. This revealed a reciprocal translocation involving chromosomes 15q and 19p (Fig. 3A). Confirmatory studies were performed using fluorescence in situ hybridization (FISH) methods, which showed rearrangement and fusion of the BRD4 with NUTM1 locus (Fig. 3B, C) and confirmed the diagnosis as nuclear protein of the testis (NUT) carcinoma. Dr. Helvey: A positron emission tomography-CT scan was obtained as part of a metastatic work-up. It showed increased uptake of 2 left-sided cervical lymph nodes suspicious for metastatic disease. An ultrasound of the neck showed normal-sized nodes with fatty hila, which were not felt to be malignant. Drs. Maloley, Ghate, and Kedar: The patient underwent radiation therapy to the sella and sphenoid sinus with concurrent chemotherapy of cisplatin 130 and docetaxol every 3 weeks for a total of 4 cycles. Unfortunately, she continued to deteriorate and developed multiple abdominal metastases leading to recurrent hospitalizations for various complications. She received palliative radiation therapy to the abdominal metastases and died 5 months after diagnosis from septic shock and multiorgan failure. Final Diagnosis Nuclear protein of the testis (NUT) carcinoma. Drs. Maloley, Ghate, and Kedar: NUT carcinoma is an exceedingly rare malignancy first described in the 1990s (1). The tumor nomenclature is derived from the transcription product of the NUTM1 gene, which is expressed only in the testes and ciliary ganglion (1). In the largest review of NUT carcinoma to date, fewer than 120 reported cases are described (2). This malignancy is believed to represent a poorly characterized squamous cell carcinoma, which typically arises in the midline structures of the head, neck, and thorax. A few cases involving the orbit presenting with proptosis and decreased vision also have been described (3). Initially thought to be a tumor predominantly affecting children or adolescents, more cases are being described in adults likely, in part, due to increased genetic testing in the adult population (1). The tumor is highly aggressive, with greater than 50% of patients Maloley et al: J Neuro-Ophthalmol 2019; 39: 129-133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study genetically by the presence of a NUT rearrangement, most often NUTM1 gene on chromosome 15 to BRD4 gene on chromosome 19 (6). The BRD4-NUT fusion oncogene inactivates histone acetylation, which inhibits expression of genes involved in epithelial differentiation. This ultimately leads to differentiation arrest and unregulated growth of undifferentiated neoplastic cells. The single translocation of NUT carcinoma is similar to that of leukemia or lymphoma and contrasts with most solid malignancies, including squamous cell carcinoma, that require several mutational hits over years leading to complex karyotypes and aneuploidy (1,4). It is hypothesized that the single translocation in NUT carcinoma gives this malignancy a genetic "shortcut" to the development of squamous cell carcinoma (7). Drs. DiMaio and Bridge: Tissue diagnosis of NUT carcinoma is difficult because it lacks consistent and characteristic cytologic and histopathologic features. The histology ranges from entirely undifferentiated carcinomas to carcinomas with focal or even diffuse squamous differentiation. Histologic clues to prompt consideration of NUT carcinoma include smallto-medium size cells with monotonous nuclei that are round or oval, clear cytoplasm, and areas of squamous differentiation (1). The cells often stain for p63 and p40, markers of squamous cells (3,8). However, this is not always the case as in our patient, where these stains were negative. Dr. Helvey: Similar to histopathologic uncertainty, the imaging appearance of NUT carcinoma is nonspecific. CT scanning shows an infiltrative hypoattenuating mass with heterogeneous enhancement, areas of necrosis, and intralesional calcifications (1,8). On MRI, the tumor is typically heterogeneous and hypointense on T1-weighted images and hyperintense on T2-weighted images, as in our patient. As might be expected, MRI is superior to CT imaging in delineating tumor margins and detecting metastases. Once a NUT carcinoma is diagnosed, fluorodeoxyglucose positron emission tomography-CT is recommended for assessment of bony metastases and disease staging (1). FIG. 2. Biopsy specimen of skull base mass. A. Sheets of large atypical cells are present without evidence of glandular or squamous differentiation (hematoxylin and eosin, ·200). B. The individual tumor cells have small nucleoli and high nuclear-to-cytoplasmic ratio. Scattered neutrophils are present among the tumor cells (hematoxylin and eosin, ·400). C. Immunoperoxidase staining is positive for SOX10 (·200). demonstrating distant metastasis at diagnosis (4), most often to the lymph nodes, bone, and bone marrow (4,5). Unlike most solid malignancies that are classified based on tissue site of origin, NUT carcinoma is defined Maloley et al: J Neuro-Ophthalmol 2019; 39: 129-133 Drs. Maloley and Kedar: In the past, a diagnosis of NUT carcinoma was made by demonstrating the pathognomonic translocation by cytogenetic analysis, split-apart fluorescent in situ hybridization (FISH) assay, or reverse transcriptase polymerase chain reaction. Diagnosis can now be made by immunohistochemistry using the commercially available rabbit monoclonal antibody, C52B1, and cell signaling technology (4-10). The monoclonal antibody against recombinant NUT protein has 87% sensitivity, 100% specificity, and 100% positive predictive value (9). 131 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. A. Cytogenetic analysis reveals the presence of an abnormal diploid clone characterized by a reciprocal translocation involving 15q and 9p. B. FISH analysis with a probe set flanking NUTM1 shows 1 fused orange/green (yellow) and separate orange and green signals in several cells indicating rearrangement of the NUTM1 locus (proximal, spectrum green; distal, spectrum orange; magnification ·600). C. FISH analysis with a probe set spanning NUTM1 and BRD4 shows 1 fused orange/green (yellow) and separate orange and green signals in several cells indicating fusion of the BRD4 and NUTM1 loci [spectrum orange (spanning BRD4); spectrum green (spanning NUTM1); (·600)]. Unfortunately, there is no established or effective treatment regimen for NUT carcinoma, which has a median survival of 6.7-9.5 months (2,4). Patients undergo a debulking surgery followed by a combination of chemotherapy and radiation. Recent advances in understanding the molecular biology of NUT carcinoma have led to promising novel targeted therapies termed histone deacetylase (HDAC) inhibitors and bromodomain (BRD) inhibitors. The HDAC inhibitors promote histone acetylation, whereas the BRD inhibitors interfere with NUT oncoprotein binding to chromatin (10,11) and thus arrest tumor growth by inducing squamous differentiation. Phase I/II clinical trials using HDAC and BRD inhibitors are currently underway and have shown promise in slowing tumor growth (4). 132 REFERENCES 1. Bair RJ, Chick JF, Chauhan NR, French C, Madan R. Demystifying NUT midline carcinoma: radiologic and pathologic correlations of an aggressive malignancy. AJR Am J Roentgenol. 2014;203:391-399. 2. Giridhar P, Mallick S, Kashyap L, Rath GK. Patterns of care and impact of prognostic factors in the outcome of NUT midline carcinomas: a systematic review and individual patient data analysis of 119 cases. Eur Arch Otorhinolaryngol. 2018;275:815-821. 3. 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. 4. 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