C a r d i o p u l m o n a r y I m a g i n g • C l i n i c a l Pe r s p e c t i ve Bair et al. Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Cardiopulmonary Imaging Clinical Perspective
Demystifying NUT Midline Carcinoma: Radiologic and Pathologic Correlations of an Aggressive Malignancy Ryan J. Bair 1 Jeffrey F. Chick1 Nikunj R. Chauhan1 Christopher French2 Rachna Madan1 Bair RJ, Chick JF, Chauhan NR, French C, Madan R
OBJECTIVE. NUT midline carcinoma is a rare poorly differentiated aggressive subtype of squamous cell carcinoma. To date, fewer than 100 total cases have been reported. CONCLUSION. Given the rarity of this disease process and lack of pathognomonic imaging findings, a definitive diagnosis based solely on imaging findings alone is untenable. Select cases are used to emphasize the particularly infiltrative and aggressive nature of NUT midline carcinoma, which shows a complete disregard for normal tissue boundaries and rapid progression during brief intervals.
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Keywords: aggressive malignancy, genetic typing, NUT midline carcinoma DOI:10.2214/AJR.13.12401 Received December 14, 2013; accepted after revision February 15, 2014. 1 Department of Radiology, Division of Thoracic Imaging, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. Address correspondence to R. Madan ([email protected]). 2 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
WEB This is a web exclusive article. AJR 2014; 203:W391–W399 0361–803X/14/2034–W391 © American Roentgen Ray Society
UT midline carcinoma is a rare poorly differentiated aggressive subtype of squamous cell carcinoma. This malignancy is commonly found in the midline structures of children and young adults but is increasingly being diagnosed in all age groups. Although the genetic, epigenetic, molecular biologic, and pathologic features of this disease process have been extensively described in the recent literature, the imaging findings have not been adequately illustrated. This article provides a concise review of the current basic science literature and provides insight and detail into the chest radiography, CT, MRI, and PET findings characteristic of NUT midline carcinoma. What Is Unique and Why Is It Important? Background and Genetic Characteristics Originally called thymic carcinomas with t(15;19) translocation, NUT midline carcinoma was first described in Japan in the early 1990s [1, 2]. The term “NUT midline carcinoma” is used because this cancer is defined by rearrangement and translocation of the NUT (NUTM1) gene, and most of these tumors (≈ 90%) arise from midline anatomic sites [3]. This aggressive malignancy is unique because it is defined genetically, differing from other malignancies, which are classified according to their site of origin [4]. In most cases (70%), NUT on chromosome 15 is translocated to BRD4 on chromosome 19, forming a BRD4-NUT
fusion oncogene [5]. In the remaining cases, NUT is fused to the closely related gene BRD3 or to other, yet to be identified, partner genes [4, 6]. Most studies have focused on BRD4-NUT. NUT (nuclear protein in testis) is expressed only in the testes and ciliary ganglion, whereas BRD4 is ubiquitously expressed and plays an important role in chromatin reading and transcriptional elongation [7–11]. The BRD4-NUT fusion protein acts, in part, through aberrant histone acetylation and activation of MYC to promote growth and block cellular differentiation [6, 12, 13]. Although classified as a poorly differentiated squamous cell carcinoma, the NUT midline carcinoma cytogenetic feature of a single translocation and simple karyotype appear more similar to leukemia and lymphoma rather than to squamous cell carcinoma [3]. This contrasts with most solid malignancies because they typically show complex karyotypes and aneuploidy [3]. These dichotomous findings suggest a unique pathologic mechanism through which the NUT midline carcinoma malignant phenotype is obtained [14]. Epidemiology NUT midline carcinoma is an uncommon and highly aggressive malignancy. To date, there have been fewer than 100 total cases reported in the literature [15]. Because institutional resources limit cytogenetic and molecular evaluation, this disease entity is often undiagnosed or misdiagnosed. Given these limitations, the true incidence and preva-
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Bair et al. lence of this malignancy are currently unknown [3, 15, 16]. NUT midline carcinoma does not appear to have a predilection for either sex. The median age at diagnosis is 16 years (range, 0.1–78 years) [4]. Some reports have suggested a bias in diagnosis of these tumors in the younger age group because more tumors are sent for molecular and genetic analysis in children and young adults [15]. Recently, however, the number of reported cases has increased among all ages, suggesting that this is not primarily a pediatric disease, but likely shows a more uniform prevalence among all ages [3, 15]. The two most common sites of disease presentation are the thorax and the head and neck [15]. Other reported locations include the pancreas [17], abdomen [18], bladder [4], and axial skeleton [19]. Clinical Presentation and Outcomes The clinical presentation of NUT midline carcinoma of the thorax includes pleuritic chest pain [20, 21], nonproductive cough [21, 21], shortness of breath [21], and weight loss [22]. NUT midline carcinoma is known to be an aggressive malignancy, with high mortality rates and a median survival of 6.7 months [15]. The reported 1- and 2-year overall survival rates are 30% and 19%, respectively [15]. Patients with metastatic disease or tumor originating from the thorax have the worst overall survival [15]. To date, there is only one known case of curative treatment in NUT midline carcinoma; the patient presented with a large iliac mass and, after definitive chemoradiation therapy, is now free of disease with nearly 14 years of follow-up [19]. Diagnosis: What, How, and Why? Pathologic Features NUT midline carcinoma lacks pathognomonic cytologic and histopathologic features; however, there are certain unique characteristics that should place NUT midline carcinoma high on the differential diagnosis during pathologic evaluation. The cells in NUT midline carcinoma are typically small-to-medium in size with monotonous nuclei that are usually round-to-oval with clear cytoplasm and a uniform appearance [3]. Importantly, these cells may show areas of focal squamous differentiation, indicating that the tumor is predominately undifferentiated and lacking the intermediate differentiation seen in typical squamous cell carcinomas [3, 14, 23].
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Immunohistochemistry The reference standard for diagnosing NUT midline carcinoma is through immunohistochemistry. The diagnosis is obtained when a monoclonal antibody shows nuclear reactivity for NUT [24], with nuclei stained with a speckled distribution [14]. The specificity and sensitivity are 100% and 87%, respectively [24]. Given the high positive predictive value, confirmation with fluorescence in situ hybridization, polymerase chain reaction, or cytogenetic analysis is no longer necessary. Genetic Evaluation As further advancements are being made into the understanding of the genetic and epigenetic characteristics of this disease process, we recommend additional diagnostic evaluation to determine the underlying fusion gene product driving the oncologic process. The gene products include BRD4NUT, BRD3-NUT, and NUT variant. This information may be obtained using fluorescence in situ hybridization, reverse-transcriptase polymerase chain reaction, or conventional cytogenetics [3, 14]. Imaging Characteristics: Infiltrative and Rapidly Aggressive Chest Radiography In our institutional experience, patients generally present with advanced disease, with initial radiographs showing partial or complete opacification of the hemithorax (Figs. 1A, 2A, and 3A). This may be secondary to large effusions; however, an underlying mass should be suspected given the convex margins of the pleural and parenchymal opacities (Fig. 1A) and the presence of an abrupt cutoff of the bronchus (Fig. 3A). Patients may also present with a widened mediastinum, indicating the presence of an underlying mass (Figs. 2A and 4A). NUT midline carcinoma shows extremely rapid disease progression, often presenting as a large opacity and then progressing to complete opacification of the hemithorax within a 2- to 8-week period, highlighting the rapid temporal evolution of this disease. CT On CT, NUT midline carcinoma typically appears as a hypoattenuating heterogeneously enhancing infiltrative mass with poorly defined margins [18, 22]. The tumor usually shows necrosis [18, 25] and occasionally tumoral calcification [18] and has a propensity to invade adjacent structures, including the
heart, pericardium, esophagus, central airways, and vessels within the mediastinum [18, 20, 22]. Given the aggressive nature of the tumor and its proclivity to invade vascular structures and the central airways, contrastenhanced CT of the chest is useful to evaluate these critical structures and provide guidance for urgent debulking surgery if deemed necessary [26] (Fig. 2). Furthermore, radiographs are limited in their ability to differentiate tumor from pleural effusion. Patients with rapidly worsening opacification on chest radiographs may require repeat chest CT examinations to differentiate tumor from effusion and facilitate thoracentesis if necessary. CT features of heterogeneous enhancement of the primary tumor and low attenuation of involved lymph nodes correlate with pathologic evidence of hemorrhage and necrosis (secondary to rapid tumor growth unsupported by the blood supply) on patients’ pathologic specimens after surgical resection in NUT midline carcinoma [26, 27]. The radiographic findings in our institutional series are largely in agreement with the previously reported findings throughout the literature. In contrast, however, we did not find evidence of tumoral calcification in any of the primary or metastatic sites of disease and only rarely noted tumor hemorrhage [18, 26]. Our series powerfully shows the extremely aggressive clinical and radiographic imaging findings associated with NUT midline carcinoma. A number of cases emphasize the particularly infiltrative nature of NUT midline carcinoma, which shows a complete disregard for normal tissue boundaries and rapid progression during brief intervals (Figs. 1, 3, and 4). MRI Contrast-enhanced chest CT is currently considered the standard in the initial staging of NUT midline carcinoma at our institution. MRI plays an adjunctive role to CT and is used when there are findings concerning for chest wall or vascular invasion [28]. In cases with suspected myocardial invasion, cardiac MRI may be used. The use of dark-blood sequences, such as double inversion recovery and HASTE (Fig. 2), offer superior delineation of intracardiac and intravascular tumor extension [29]. Myocardial tagging sequences obtained in multiple planes may confirm myocardial invasion in select cases. Unfortunately, because this process requires patient cooperation to minimize respiratory motion, these types of images may be challenging to obtain in patients with dyspnea secondary to
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma tumor mass effect on bronchovascular structures. Additionally, in patients receiving chemotherapy or radiation, MRI may be used to assess treatment response and disease progression [26]. MRI is superior to CT in differentiating gross tumor extent from tumorrelated hemorrhage, and in detecting bone metastases [22, 30, 31]. Similarly, MRI provides superior soft-tissue delineation compared with CT for evaluation of masses involving the head and neck [32] and musculoskeletal system [33] and should be used in conjunction with CT during radiographic evaluation when NUT midline carcinoma arises in these locations. When NUT midline carcinoma involves the head and neck, MRI may provide information regarding the presence of bone marrow invasion, perineural involvement, and skull base invasion [31]; this information is critical in radiation therapy treatment planning and helps determine the feasibility of surgical resection [31]. This information allows the most appropriate treatment modality to be used for each patient (Fig. 4). The MRI features of these tumors have been described as heterogeneous with predominantly hypointense signal on T1weighted images and hyperintense signal on T2-weighted images. Contrast-enhanced images show in exquisite detail the marked central necrosis in these lesions and also reveal smaller lesions not appreciated on CT [22]. PET/CT After a confirmed diagnosis of NUT midline carcinoma, 18F-FDG PET/CT is considered the imaging modality of choice when assessing for metastatic disease (Figs. 4 and 5). Whole-body scintigraphy has inferior sensitivity and specificity compared with FDG PET/CT in detecting bony metastases [26]. This observation is similar to that seen in other tumors with predominantly lytic appearances on CT, where FDG PET/CT is superior to whole-body scintigraphy. Those authors thought that the differing specificities may be secondary to a lytic process intrinsic to NUT midline carcinoma [26]. FDG PET/CT evaluation may also underestimate the disease burden in both the primary tumor and lymph nodes because areas of necrosis may show FDG avidity inconsistent with the actually metabolic process of the tumor [26]. FDG PET/CT is also very useful in directing percutaneous tissue biopsy to obtain viable tissue, especially if previous biopsies have been inconclusive because of extensive necrosis.
FDG PET/CT shows objective responses to treatment and assesses disease activity over time [26, 34, 35]. This information can provide real-time evaluation of the effectiveness of the current treatment regimen. In a telling case report from the literature, FDG PET/CT after first-line chemotherapy showed a minimal response to therapy; after transitioning to second-line chemotherapy, the subsequent PET/CT showed a favorable response to second-line chemotherapy and a marked decrease in the size and activity of both the patient’s primary and metastatic lesions [34]. Misdiagnoses and Differential Diagnosis on Imaging Given the rarity of this disease process and the lack of pathognomonic imaging findings, a definitive diagnosis based solely on imaging findings alone is untenable. Regardless of the lack of definitive features, NUT midline carcinoma should be included in the differential diagnosis of masses with abnormal clinical presentations, aggressive imaging features, and an accelerated clinical and radiologic course unusual for most solid malignancies [18]. The differential diagnosis is based on the anatomic location of the abnormality, the patient’s age, the presumed tissue of origin, and the observed radiographic findings. For example, in a 40-year-old patient with a rapidly progressive neck mass, NUT midline carcinoma should be added to human papilloma virus–related oropharyngeal cancer, other head and neck malignancies, and lymphoma. Similarly, in patients with mediastinal and pleuroparenchymal disease consistent with primary lung malignancy, NUT midline carcinoma should be included in the differential diagnosis along with non–small cell lung cancer, small cell lung cancer, intrathoracic sarcoma, and lymphoma. A similar differential diagnosis paradigm should also be applied within the pediatric population. Current Treatment Options Because of the rarity of NUT midline carcinoma, a multitude of treatment paradigms have been used in the treatment of this disease, including head-and-neck and non– small cell lung cancer regimens [2, 36, 37], lymphoma regimens [2, 36, 38], and sarcoma regimens [19, 20]. The chemotherapy used in these regimens is nonuniform and contains a multiple of chemotherapeutic agents used alone or in concert, with no effective regi-
men identified to date. To identify effective treatment, a registry for NUT midline carcinoma has been developed to prospectively analyze treatment outcomes [39]. Recent advances in the understanding of the molecular biology of NUT midline carcinoma have found that the BRD4-NUT fusion protein causes aberrant histone acetylation and inhibits cellular differentiation. These discoveries have led to the use of histone deacetylase inhibitors as an additional treatment option [13]. In addition, targeted therapy using direct-acting inhibitors of the BRD3 and BRD4 bromodomains (BET inhibitors) are also under development [40] and there is currently an open phase 1 clinical trial using these inhibitors for NUT midline carcinoma [41]. Conclusion NUT midline carcinoma is a rapidly aggressive and nearly uniformly fatal disease entity initially described just over 20 years ago. Since its discovery, a number of strides in the identification of its genetic make-up, oncologic mechanism, and pathologic features have been elucidated. These advances have led to the development of targeted therapies with the goal of more effectively treating this disease. As treatment options and outcomes continue to improve, it becomes increasingly more important for radiologists to become aware of radiologic features of NUT midline carcinoma, learn to recognize the aggressive imaging characteristics suggestive of NUT midline carcinoma, and subsequently educate other clinicians about this disease. This review serves as a foundation for describing the chest radiography, CT, MRI, and PET findings characteristic of NUT midline carcinoma. References 1. Kees UR, Mulcahy MT, Willoughby ML. Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Am J Pediatr Hematol Oncol 1991; 13:459–464 2. Kubonishi I, Takehara N, Iwata J, et al. Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 1991; 51:3327– 3328 3. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012; 7:247–265 4. French CA, Kutok JL, Faquin WC, et al. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 2004; 22:4135–4139 5. French CA, Miyoshi I, Kubonishi I, Grier HE,
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Bair et al. Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 2003; 63:304–307 6. 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 7. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 2003; 100:8758– 8763 8. Dey A, Ellenberg J, Farina A, et al. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition. Mol Cell Biol 2000; 20:6537–6549 9. Mochizuki K, Nishiyama A, Jang MK, et al. The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 2008; 283:9040–9048 10. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of PTEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 2005; 19:523– 534 11. Yang Z, Yik JH, Chen R, et al. Recruitment of PTEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 2005; 19:535–545 12. 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 13. Schwartz BE, Hofer MD, Lemieux ME, et al. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 2011; 71:2686–2696 14. French CA. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013; 7:11–16 15. Bauer DE, Mitchell CM, Strait K, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 2012; 18:5773–5779 16. French CA. NUT midline carcinoma. Cancer Genet Cytogenet 2010; 203:16–20 17. Shehata BM, Steelman CK, Abramowsky CR, et al. NUT midline carcinoma in a newborn with
multiorgan disseminated tumor and a 2-year-old with a pancreatic/hepatic primary. Pediatr Dev Pathol 2010; 13:481–485 18. Polsani A, Braithwaite AK, Alazraki AL, Abramowsky C, Shehata BM. NUT midline carcinoma: an imaging case series and review of literature. Pediatr Radiol 2012; 42:205–210 19. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Successful treatment of a child with t(15;19)-positive tumor. Pediatr Blood Cancer 2007; 49:1015–1017 20. Teo M, Crotty P, O’Sullivan M, French CA, Walshe JM. NUT midline carcinoma in a young woman. J Clin Oncol 2011; 29:e336–e339 21. Tanaka M, Kato K, Gomi K, et al. NUT midline carcinoma: report of 2 cases suggestive of pulmonary origin. Am J Surg Pathol 2012; 36:381–388 22. 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 23. Wartchow EP, Moore TS, French CA, Mierau GW. Ultrastructural features of NUT midline carcinoma. Ultrastruct Pathol 2012; 36:280–284 24. Haack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol 2009; 33:984–991 25. Stelow EB, French CA. Carcinomas of the upper aerodigestive tract with rearrangement of the nuclear protein of the testis (NUT) gene (NUT midline carcinomas). Adv Anat Pathol 2009; 16:92– 96 26. Rosenbaum DG, Teruya-Feldstein J, Price AP, Meyers P, Abramson S. Radiologic features of NUT midline carcinoma in an adolescent. Pediatr Radiol 2012; 42:249–252 27. Stelow EB. A review of NUT midline carcinoma. Head Neck Pathol 2011; 5:31–35 28. Bruzzi JF, Komaki R, Walsh GL, et al. Imaging of non-small cell lung cancer of the superior sulcus. Part 1. Anatomy, clinical manifestations, and management. RadioGraphics 2008; 28:551–560 29. Vogt FM, Goyen M, Debatin JF. MR angiography of the chest. Radiol Clin North Am 2003; 41:29–41 30. Dall’Armellina E, Hamilton CA, Hundley WG. Assessment of blood flow and valvular heart disease using phase-contrast cardiovascular magnetic resonance. Echocardiography 2007; 24:207–216
31. Rasch C, Keus R, Pameijer FA, et al. The potential impact of CT-MRI matching on tumor volume delineation in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1997; 39:841–848 32. Sakata K, Hareyama M, Tamakawa M, et al. Prognostic factors of nasopharynx tumors investigated by MR imaging and the value of MR imaging in the newly published TNM staging. Int J Radiat Oncol Biol Phys 1999; 43:273–278 33. Steinbach LS, Palmer WE, Schweitzer ME. Special focus session. MR arthrography. RadioGraphics 2002; 22:1223–1246 34. Niederkohr RD, Cameron MJ, French CA. FDG PET/CT imaging of NUT midline carcinoma. Clin Nucl Med 2011; 36:e124–e126 35. Rutt AL, Poulik J, Siddiqui AH, et al. NUT midline carcinoma mimicking tonsillitis in an eightyear-old girl. Ann Otol Rhinol Laryngol 2011; 120:546–549 36. Lee AC, Kwong YI, Fu KH, Chan GC, Ma L, Lau YL. Disseminated mediastinal carcinoma with chromosomal translocation (15;19): a distinctive clinicopathologic syndrome. Cancer 1993; 72:2273–2276 37. 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 a rapidly fatal course. Cancer 2001; 92:1195–1203 38. Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M, Jerkeman M. Midline carcinoma with t(15;19) and BRD 4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. BMC Cancer 2006; 6:69 39. Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Children’s Hospital Boston, and Harvard Medical School. International NUT midline carcinoma registry. www.NMCRegistry.org. Published 2011. Updated December 18, 2013. Accessed June 17, 2014 40. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature 2010; 468:1067–1073 41. GlaxoSmithKline. A study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK525762 in subjects with NUT midline carcinoma (NMC) and other cancers. U. S. National Institutes of Health website. www. clinicaltrials.gov/ct2/show/NCT01587703?term= NMC&rank=1. Published April 3, 2012, Updated May 22, 2014. Accessed June 17, 2014 (Figures start on next page)
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 1—25-year-old man who presented with progressive febrile respiratory illness and shortness of breath, despite antibiotic treatment. A, Initial chest radiograph shows right infrahilar and medial lung base masslike opacity (arrow) with convex lateral margins. Associated small-to-moderate right pleural effusion is also present. B–D, Axial contrast-enhanced chest CT images in soft-tissue (B and C) and lung (D) windows reveal right infrahilar mass (solid arrows, B–D) with extension across fissures (dashed arrow, D) into right middle and lower lobes. Bulky subcarinal lymphadenopathy is also present. E, Follow-up chest CT in lung window completed only 2 weeks later shows significant increase in size of bulky right hilar and mediastinal lymphadenopathy (arrows). Mass now occupies significant portions of right middle and lower lobes. F and G, Contrast-enhanced CT images in soft-tissue windows shows striking heterogeneous enhancement and central necrosis (arrows, F). In addition, there is marked mass effect on bronchovascular structures with more severe narrowing of pulmonary arteries, veins, and right lower lobe bronchi (arrows, G). All features suggest very aggressive neoplasm with high proliferation rate. After lung biopsy confirmed NUT midline carcinoma, patient was treated with two rounds of chemotherapy with carboplatin and paclitaxel. Patient elected to have remainder of his therapy near his home and was consequently lost to follow-up.
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Fig. 2—22-year-old man who presented with productive cough and dyspnea on exertion with no response to antibiotics. A, Initial chest radiograph shows extensive opacification in right hemithorax consisting of lobulated pleural abnormality as well as underlying parenchymal dense consolidation. B and C, Axial (B) and coronal (C) contrast-enhanced CT images in soft-tissue windows show hypoattenuating necrotic masses in mediastinum, right hilum, and right lower lobe (arrows, B), causing inversion of right hemidiaphragm. Mass crosses tissue planes and encases hilar vessels; fat planes with left atrium and pulmonary veins are lost. D, Coronal CT in lung window shows severe narrowing of right main and right lower lobe bronchus with endobronchial tumor extension (arrow). Leftward mediastinal shift is seen. E, Coronal fused PET/CT image shows intense FDG-avid uptake in mass (standardized uptake value, > 12) and several photopenic areas within it due to necrosis. Mediastinal involvement is multicompartmental and extends to left as well. F, Coronal T2-weighted MRI delineates solid lobulated mass in mid-to-lower hemithorax with extensive mediastinal and pericardial invasion. Myocardial tagging sequences (not shown) were done before urgent debulking surgery to delineate any myocardial invasion. G, Coronal contrast-enhanced MRI subtraction image completed 3 weeks after initial imaging and chemotherapy shows enhancing soft tissue within several portions of bulky right lower lobe mass. This sequence along with PET/CT is helpful in differentiating postchemotherapy-related hemorrhage from enhancing viable tumor and has potential to monitor treatment changes. Given severe cardiorespiratory symptoms due to mass effect from tumor, urgent debulking surgery including right pneumonectomy and partial pericardiectomy was planned under cardiopulmonary bypass. H, Gross pathology of right lung shows perihilar tumor that has invaded into lower lobe with surrounding areas of hemorrhage and necrosis. (Courtesy of Seidman M, Brigham and Women’s Hospital, Boston, MA)
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 3—68-year-old woman who presented with night sweats, lower extremity pain, cough, and 40-pound weight loss. A, Initial chest radiograph shows complete opacification of right hemithorax and abrupt cutoff of right main bronchus (arrow). B and C, Axial (B) and coronal (C) contrast-enhanced CT images show large right perihilar mass inseparable from right mediastinal and subcarinal lymphadenopathy. Complete encasement of pulmonary arteries and veins (long arrows, B and C) and complete occlusion of right-sided bronchi (short arrow, C) suggest aggressive tumor. Medially mass abuts esophagus (black arrow, B). Fluid bronchograms are seen secondary to proximal hilar obstructing mass. D, Mass shows intense FDG uptake on PET. Atelectatic right lung shows mild diffuse increased uptake due to postobstructive changes and pneumonitis. Initial biopsy was thought to be consistent with poorly differentiated non–small cell lung cancer. Consequently, patient was treated with multiple rounds of chemoradiation, with little response. Subsequent reevaluation of pathology revealed findings more consistent with NUT midline carcinoma. E and F, Axial CT images obtained 3 weeks after chemoradiation show progressive disease with new pericardial tumor implants (solid arrows, E and F) causing extrinsic compression and mass effect. Urgent video-assisted thoracic surgery pericardial window placement was done. Tumor also obstructs esophagus (black arrow, F) requiring polyethylene glycol tube placement.
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Fig. 4—23-year-old man who presented with persistent sore throat, hoarseness, and dysphagia, which was initially thought to be mononucleosis. Epstein-Barr virus titers were positive. A and B, Axial T1-weighted (A) and T2-weighted (B) MRI scans show infiltrative poorly circumscribed mass (arrows) in right hypopharynx with supraglottic and infraglottic extension. C and D, Coronal STIR (C) and coronal T1-weighted (D) contrast-enhanced MRI scans show bulky bilateral, right greater than left, adenopathy (arrows) with marked central necrosis. Initially, case was misdiagnosed and treated as hypopharyngeal carcinoma. Because of worsening pulmonary and pleural disease, repeat biopsy was completed and confirmed NUT midline carcinoma. Treatment was started with histone deacetylase inhibitor (romidepsin). E and F, Coronal contrast-enhanced CT in soft-tissue (E) and lung (F) windows obtained within 2 weeks of initial presentation show marked disease progression bilaterally with bulky pleural, mediastinal, and hilar tumor. Marked narrowing of right main bronchus is seen (arrow). G, Coronal fused FDG PET/CT shows continued and significant progression of pleural, pulmonary, and mediastinal disease as well as multiple bone metastases (arrows) not appreciated on chest CT.
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 5—29-year-old man who presented with dyspnea, shoulder pain, and hemoptysis. A, Initial chest radiograph shows left lower lobe opacification and moderate left pleural effusion. B and C, Axial (B) and coronal (C) contrast-enhanced chest CT scans reveal large confluent and infiltrative mass in left lower lobe extending up to hilum and causing compression of left main bronchus with associated pleural nodularity. Sampling confirmed NUT midline carcinoma. D, Coronal fused FDG PET/CT shows significant progression of pleural and pulmonary disease and complete loss of left lung aeration. Multiple bony metastases are also seen (arrow). Patient developed bilateral Horner syndrome due to compression of sympathetic chains by mediastinal mass. Treatment was initiated with romidepsin, but patient died within 6 months of diagnosis. E, H and E stain (×400) of patient’s pleural metastasis reveals characteristic monotony of NUT midline carcinoma cells, which are typically small to medium in size. F, Immunohistochemistry for NUT in patient’s bone metastasis shows nuclear speckled staining. This is area where squamous differentiation is apparent. Interestingly, NUT staining typically diminishes in cells undergoing terminal differentiation as can be seen here.
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Cardiopulmonary Imaging Clinical Perspective
Demystifying NUT Midline Carcinoma: Radiologic and Pathologic Correlations of an Aggressive Malignancy Ryan J. Bair 1 Jeffrey F. Chick1 Nikunj R. Chauhan1 Christopher French2 Rachna Madan1 Bair RJ, Chick JF, Chauhan NR, French C, Madan R
OBJECTIVE. NUT midline carcinoma is a rare poorly differentiated aggressive subtype of squamous cell carcinoma. To date, fewer than 100 total cases have been reported. CONCLUSION. Given the rarity of this disease process and lack of pathognomonic imaging findings, a definitive diagnosis based solely on imaging findings alone is untenable. Select cases are used to emphasize the particularly infiltrative and aggressive nature of NUT midline carcinoma, which shows a complete disregard for normal tissue boundaries and rapid progression during brief intervals.
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Keywords: aggressive malignancy, genetic typing, NUT midline carcinoma DOI:10.2214/AJR.13.12401 Received December 14, 2013; accepted after revision February 15, 2014. 1 Department of Radiology, Division of Thoracic Imaging, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. Address correspondence to R. Madan ([email protected]). 2 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
WEB This is a web exclusive article. AJR 2014; 203:W391–W399 0361–803X/14/2034–W391 © American Roentgen Ray Society
UT midline carcinoma is a rare poorly differentiated aggressive subtype of squamous cell carcinoma. This malignancy is commonly found in the midline structures of children and young adults but is increasingly being diagnosed in all age groups. Although the genetic, epigenetic, molecular biologic, and pathologic features of this disease process have been extensively described in the recent literature, the imaging findings have not been adequately illustrated. This article provides a concise review of the current basic science literature and provides insight and detail into the chest radiography, CT, MRI, and PET findings characteristic of NUT midline carcinoma. What Is Unique and Why Is It Important? Background and Genetic Characteristics Originally called thymic carcinomas with t(15;19) translocation, NUT midline carcinoma was first described in Japan in the early 1990s [1, 2]. The term “NUT midline carcinoma” is used because this cancer is defined by rearrangement and translocation of the NUT (NUTM1) gene, and most of these tumors (≈ 90%) arise from midline anatomic sites [3]. This aggressive malignancy is unique because it is defined genetically, differing from other malignancies, which are classified according to their site of origin [4]. In most cases (70%), NUT on chromosome 15 is translocated to BRD4 on chromosome 19, forming a BRD4-NUT
fusion oncogene [5]. In the remaining cases, NUT is fused to the closely related gene BRD3 or to other, yet to be identified, partner genes [4, 6]. Most studies have focused on BRD4-NUT. NUT (nuclear protein in testis) is expressed only in the testes and ciliary ganglion, whereas BRD4 is ubiquitously expressed and plays an important role in chromatin reading and transcriptional elongation [7–11]. The BRD4-NUT fusion protein acts, in part, through aberrant histone acetylation and activation of MYC to promote growth and block cellular differentiation [6, 12, 13]. Although classified as a poorly differentiated squamous cell carcinoma, the NUT midline carcinoma cytogenetic feature of a single translocation and simple karyotype appear more similar to leukemia and lymphoma rather than to squamous cell carcinoma [3]. This contrasts with most solid malignancies because they typically show complex karyotypes and aneuploidy [3]. These dichotomous findings suggest a unique pathologic mechanism through which the NUT midline carcinoma malignant phenotype is obtained [14]. Epidemiology NUT midline carcinoma is an uncommon and highly aggressive malignancy. To date, there have been fewer than 100 total cases reported in the literature [15]. Because institutional resources limit cytogenetic and molecular evaluation, this disease entity is often undiagnosed or misdiagnosed. Given these limitations, the true incidence and preva-
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Bair et al. lence of this malignancy are currently unknown [3, 15, 16]. NUT midline carcinoma does not appear to have a predilection for either sex. The median age at diagnosis is 16 years (range, 0.1–78 years) [4]. Some reports have suggested a bias in diagnosis of these tumors in the younger age group because more tumors are sent for molecular and genetic analysis in children and young adults [15]. Recently, however, the number of reported cases has increased among all ages, suggesting that this is not primarily a pediatric disease, but likely shows a more uniform prevalence among all ages [3, 15]. The two most common sites of disease presentation are the thorax and the head and neck [15]. Other reported locations include the pancreas [17], abdomen [18], bladder [4], and axial skeleton [19]. Clinical Presentation and Outcomes The clinical presentation of NUT midline carcinoma of the thorax includes pleuritic chest pain [20, 21], nonproductive cough [21, 21], shortness of breath [21], and weight loss [22]. NUT midline carcinoma is known to be an aggressive malignancy, with high mortality rates and a median survival of 6.7 months [15]. The reported 1- and 2-year overall survival rates are 30% and 19%, respectively [15]. Patients with metastatic disease or tumor originating from the thorax have the worst overall survival [15]. To date, there is only one known case of curative treatment in NUT midline carcinoma; the patient presented with a large iliac mass and, after definitive chemoradiation therapy, is now free of disease with nearly 14 years of follow-up [19]. Diagnosis: What, How, and Why? Pathologic Features NUT midline carcinoma lacks pathognomonic cytologic and histopathologic features; however, there are certain unique characteristics that should place NUT midline carcinoma high on the differential diagnosis during pathologic evaluation. The cells in NUT midline carcinoma are typically small-to-medium in size with monotonous nuclei that are usually round-to-oval with clear cytoplasm and a uniform appearance [3]. Importantly, these cells may show areas of focal squamous differentiation, indicating that the tumor is predominately undifferentiated and lacking the intermediate differentiation seen in typical squamous cell carcinomas [3, 14, 23].
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Immunohistochemistry The reference standard for diagnosing NUT midline carcinoma is through immunohistochemistry. The diagnosis is obtained when a monoclonal antibody shows nuclear reactivity for NUT [24], with nuclei stained with a speckled distribution [14]. The specificity and sensitivity are 100% and 87%, respectively [24]. Given the high positive predictive value, confirmation with fluorescence in situ hybridization, polymerase chain reaction, or cytogenetic analysis is no longer necessary. Genetic Evaluation As further advancements are being made into the understanding of the genetic and epigenetic characteristics of this disease process, we recommend additional diagnostic evaluation to determine the underlying fusion gene product driving the oncologic process. The gene products include BRD4NUT, BRD3-NUT, and NUT variant. This information may be obtained using fluorescence in situ hybridization, reverse-transcriptase polymerase chain reaction, or conventional cytogenetics [3, 14]. Imaging Characteristics: Infiltrative and Rapidly Aggressive Chest Radiography In our institutional experience, patients generally present with advanced disease, with initial radiographs showing partial or complete opacification of the hemithorax (Figs. 1A, 2A, and 3A). This may be secondary to large effusions; however, an underlying mass should be suspected given the convex margins of the pleural and parenchymal opacities (Fig. 1A) and the presence of an abrupt cutoff of the bronchus (Fig. 3A). Patients may also present with a widened mediastinum, indicating the presence of an underlying mass (Figs. 2A and 4A). NUT midline carcinoma shows extremely rapid disease progression, often presenting as a large opacity and then progressing to complete opacification of the hemithorax within a 2- to 8-week period, highlighting the rapid temporal evolution of this disease. CT On CT, NUT midline carcinoma typically appears as a hypoattenuating heterogeneously enhancing infiltrative mass with poorly defined margins [18, 22]. The tumor usually shows necrosis [18, 25] and occasionally tumoral calcification [18] and has a propensity to invade adjacent structures, including the
heart, pericardium, esophagus, central airways, and vessels within the mediastinum [18, 20, 22]. Given the aggressive nature of the tumor and its proclivity to invade vascular structures and the central airways, contrastenhanced CT of the chest is useful to evaluate these critical structures and provide guidance for urgent debulking surgery if deemed necessary [26] (Fig. 2). Furthermore, radiographs are limited in their ability to differentiate tumor from pleural effusion. Patients with rapidly worsening opacification on chest radiographs may require repeat chest CT examinations to differentiate tumor from effusion and facilitate thoracentesis if necessary. CT features of heterogeneous enhancement of the primary tumor and low attenuation of involved lymph nodes correlate with pathologic evidence of hemorrhage and necrosis (secondary to rapid tumor growth unsupported by the blood supply) on patients’ pathologic specimens after surgical resection in NUT midline carcinoma [26, 27]. The radiographic findings in our institutional series are largely in agreement with the previously reported findings throughout the literature. In contrast, however, we did not find evidence of tumoral calcification in any of the primary or metastatic sites of disease and only rarely noted tumor hemorrhage [18, 26]. Our series powerfully shows the extremely aggressive clinical and radiographic imaging findings associated with NUT midline carcinoma. A number of cases emphasize the particularly infiltrative nature of NUT midline carcinoma, which shows a complete disregard for normal tissue boundaries and rapid progression during brief intervals (Figs. 1, 3, and 4). MRI Contrast-enhanced chest CT is currently considered the standard in the initial staging of NUT midline carcinoma at our institution. MRI plays an adjunctive role to CT and is used when there are findings concerning for chest wall or vascular invasion [28]. In cases with suspected myocardial invasion, cardiac MRI may be used. The use of dark-blood sequences, such as double inversion recovery and HASTE (Fig. 2), offer superior delineation of intracardiac and intravascular tumor extension [29]. Myocardial tagging sequences obtained in multiple planes may confirm myocardial invasion in select cases. Unfortunately, because this process requires patient cooperation to minimize respiratory motion, these types of images may be challenging to obtain in patients with dyspnea secondary to
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma tumor mass effect on bronchovascular structures. Additionally, in patients receiving chemotherapy or radiation, MRI may be used to assess treatment response and disease progression [26]. MRI is superior to CT in differentiating gross tumor extent from tumorrelated hemorrhage, and in detecting bone metastases [22, 30, 31]. Similarly, MRI provides superior soft-tissue delineation compared with CT for evaluation of masses involving the head and neck [32] and musculoskeletal system [33] and should be used in conjunction with CT during radiographic evaluation when NUT midline carcinoma arises in these locations. When NUT midline carcinoma involves the head and neck, MRI may provide information regarding the presence of bone marrow invasion, perineural involvement, and skull base invasion [31]; this information is critical in radiation therapy treatment planning and helps determine the feasibility of surgical resection [31]. This information allows the most appropriate treatment modality to be used for each patient (Fig. 4). The MRI features of these tumors have been described as heterogeneous with predominantly hypointense signal on T1weighted images and hyperintense signal on T2-weighted images. Contrast-enhanced images show in exquisite detail the marked central necrosis in these lesions and also reveal smaller lesions not appreciated on CT [22]. PET/CT After a confirmed diagnosis of NUT midline carcinoma, 18F-FDG PET/CT is considered the imaging modality of choice when assessing for metastatic disease (Figs. 4 and 5). Whole-body scintigraphy has inferior sensitivity and specificity compared with FDG PET/CT in detecting bony metastases [26]. This observation is similar to that seen in other tumors with predominantly lytic appearances on CT, where FDG PET/CT is superior to whole-body scintigraphy. Those authors thought that the differing specificities may be secondary to a lytic process intrinsic to NUT midline carcinoma [26]. FDG PET/CT evaluation may also underestimate the disease burden in both the primary tumor and lymph nodes because areas of necrosis may show FDG avidity inconsistent with the actually metabolic process of the tumor [26]. FDG PET/CT is also very useful in directing percutaneous tissue biopsy to obtain viable tissue, especially if previous biopsies have been inconclusive because of extensive necrosis.
FDG PET/CT shows objective responses to treatment and assesses disease activity over time [26, 34, 35]. This information can provide real-time evaluation of the effectiveness of the current treatment regimen. In a telling case report from the literature, FDG PET/CT after first-line chemotherapy showed a minimal response to therapy; after transitioning to second-line chemotherapy, the subsequent PET/CT showed a favorable response to second-line chemotherapy and a marked decrease in the size and activity of both the patient’s primary and metastatic lesions [34]. Misdiagnoses and Differential Diagnosis on Imaging Given the rarity of this disease process and the lack of pathognomonic imaging findings, a definitive diagnosis based solely on imaging findings alone is untenable. Regardless of the lack of definitive features, NUT midline carcinoma should be included in the differential diagnosis of masses with abnormal clinical presentations, aggressive imaging features, and an accelerated clinical and radiologic course unusual for most solid malignancies [18]. The differential diagnosis is based on the anatomic location of the abnormality, the patient’s age, the presumed tissue of origin, and the observed radiographic findings. For example, in a 40-year-old patient with a rapidly progressive neck mass, NUT midline carcinoma should be added to human papilloma virus–related oropharyngeal cancer, other head and neck malignancies, and lymphoma. Similarly, in patients with mediastinal and pleuroparenchymal disease consistent with primary lung malignancy, NUT midline carcinoma should be included in the differential diagnosis along with non–small cell lung cancer, small cell lung cancer, intrathoracic sarcoma, and lymphoma. A similar differential diagnosis paradigm should also be applied within the pediatric population. Current Treatment Options Because of the rarity of NUT midline carcinoma, a multitude of treatment paradigms have been used in the treatment of this disease, including head-and-neck and non– small cell lung cancer regimens [2, 36, 37], lymphoma regimens [2, 36, 38], and sarcoma regimens [19, 20]. The chemotherapy used in these regimens is nonuniform and contains a multiple of chemotherapeutic agents used alone or in concert, with no effective regi-
men identified to date. To identify effective treatment, a registry for NUT midline carcinoma has been developed to prospectively analyze treatment outcomes [39]. Recent advances in the understanding of the molecular biology of NUT midline carcinoma have found that the BRD4-NUT fusion protein causes aberrant histone acetylation and inhibits cellular differentiation. These discoveries have led to the use of histone deacetylase inhibitors as an additional treatment option [13]. In addition, targeted therapy using direct-acting inhibitors of the BRD3 and BRD4 bromodomains (BET inhibitors) are also under development [40] and there is currently an open phase 1 clinical trial using these inhibitors for NUT midline carcinoma [41]. Conclusion NUT midline carcinoma is a rapidly aggressive and nearly uniformly fatal disease entity initially described just over 20 years ago. Since its discovery, a number of strides in the identification of its genetic make-up, oncologic mechanism, and pathologic features have been elucidated. These advances have led to the development of targeted therapies with the goal of more effectively treating this disease. As treatment options and outcomes continue to improve, it becomes increasingly more important for radiologists to become aware of radiologic features of NUT midline carcinoma, learn to recognize the aggressive imaging characteristics suggestive of NUT midline carcinoma, and subsequently educate other clinicians about this disease. This review serves as a foundation for describing the chest radiography, CT, MRI, and PET findings characteristic of NUT midline carcinoma. References 1. Kees UR, Mulcahy MT, Willoughby ML. Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Am J Pediatr Hematol Oncol 1991; 13:459–464 2. Kubonishi I, Takehara N, Iwata J, et al. Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 1991; 51:3327– 3328 3. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012; 7:247–265 4. French CA, Kutok JL, Faquin WC, et al. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 2004; 22:4135–4139 5. French CA, Miyoshi I, Kubonishi I, Grier HE,
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Bair et al. Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 2003; 63:304–307 6. 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 7. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 2003; 100:8758– 8763 8. Dey A, Ellenberg J, Farina A, et al. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition. Mol Cell Biol 2000; 20:6537–6549 9. Mochizuki K, Nishiyama A, Jang MK, et al. The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 2008; 283:9040–9048 10. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of PTEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 2005; 19:523– 534 11. Yang Z, Yik JH, Chen R, et al. Recruitment of PTEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 2005; 19:535–545 12. 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 13. Schwartz BE, Hofer MD, Lemieux ME, et al. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 2011; 71:2686–2696 14. French CA. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013; 7:11–16 15. Bauer DE, Mitchell CM, Strait K, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 2012; 18:5773–5779 16. French CA. NUT midline carcinoma. Cancer Genet Cytogenet 2010; 203:16–20 17. Shehata BM, Steelman CK, Abramowsky CR, et al. NUT midline carcinoma in a newborn with
multiorgan disseminated tumor and a 2-year-old with a pancreatic/hepatic primary. Pediatr Dev Pathol 2010; 13:481–485 18. Polsani A, Braithwaite AK, Alazraki AL, Abramowsky C, Shehata BM. NUT midline carcinoma: an imaging case series and review of literature. Pediatr Radiol 2012; 42:205–210 19. Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA. Successful treatment of a child with t(15;19)-positive tumor. Pediatr Blood Cancer 2007; 49:1015–1017 20. Teo M, Crotty P, O’Sullivan M, French CA, Walshe JM. NUT midline carcinoma in a young woman. J Clin Oncol 2011; 29:e336–e339 21. Tanaka M, Kato K, Gomi K, et al. NUT midline carcinoma: report of 2 cases suggestive of pulmonary origin. Am J Surg Pathol 2012; 36:381–388 22. 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 23. Wartchow EP, Moore TS, French CA, Mierau GW. Ultrastructural features of NUT midline carcinoma. Ultrastruct Pathol 2012; 36:280–284 24. Haack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol 2009; 33:984–991 25. Stelow EB, French CA. Carcinomas of the upper aerodigestive tract with rearrangement of the nuclear protein of the testis (NUT) gene (NUT midline carcinomas). Adv Anat Pathol 2009; 16:92– 96 26. Rosenbaum DG, Teruya-Feldstein J, Price AP, Meyers P, Abramson S. Radiologic features of NUT midline carcinoma in an adolescent. Pediatr Radiol 2012; 42:249–252 27. Stelow EB. A review of NUT midline carcinoma. Head Neck Pathol 2011; 5:31–35 28. Bruzzi JF, Komaki R, Walsh GL, et al. Imaging of non-small cell lung cancer of the superior sulcus. Part 1. Anatomy, clinical manifestations, and management. RadioGraphics 2008; 28:551–560 29. Vogt FM, Goyen M, Debatin JF. MR angiography of the chest. Radiol Clin North Am 2003; 41:29–41 30. Dall’Armellina E, Hamilton CA, Hundley WG. Assessment of blood flow and valvular heart disease using phase-contrast cardiovascular magnetic resonance. Echocardiography 2007; 24:207–216
31. Rasch C, Keus R, Pameijer FA, et al. The potential impact of CT-MRI matching on tumor volume delineation in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1997; 39:841–848 32. Sakata K, Hareyama M, Tamakawa M, et al. Prognostic factors of nasopharynx tumors investigated by MR imaging and the value of MR imaging in the newly published TNM staging. Int J Radiat Oncol Biol Phys 1999; 43:273–278 33. Steinbach LS, Palmer WE, Schweitzer ME. Special focus session. MR arthrography. RadioGraphics 2002; 22:1223–1246 34. Niederkohr RD, Cameron MJ, French CA. FDG PET/CT imaging of NUT midline carcinoma. Clin Nucl Med 2011; 36:e124–e126 35. Rutt AL, Poulik J, Siddiqui AH, et al. NUT midline carcinoma mimicking tonsillitis in an eightyear-old girl. Ann Otol Rhinol Laryngol 2011; 120:546–549 36. Lee AC, Kwong YI, Fu KH, Chan GC, Ma L, Lau YL. Disseminated mediastinal carcinoma with chromosomal translocation (15;19): a distinctive clinicopathologic syndrome. Cancer 1993; 72:2273–2276 37. 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 a rapidly fatal course. Cancer 2001; 92:1195–1203 38. Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M, Jerkeman M. Midline carcinoma with t(15;19) and BRD 4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy. BMC Cancer 2006; 6:69 39. Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Children’s Hospital Boston, and Harvard Medical School. International NUT midline carcinoma registry. www.NMCRegistry.org. Published 2011. Updated December 18, 2013. Accessed June 17, 2014 40. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature 2010; 468:1067–1073 41. GlaxoSmithKline. A study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK525762 in subjects with NUT midline carcinoma (NMC) and other cancers. U. S. National Institutes of Health website. www. clinicaltrials.gov/ct2/show/NCT01587703?term= NMC&rank=1. Published April 3, 2012, Updated May 22, 2014. Accessed June 17, 2014 (Figures start on next page)
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 1—25-year-old man who presented with progressive febrile respiratory illness and shortness of breath, despite antibiotic treatment. A, Initial chest radiograph shows right infrahilar and medial lung base masslike opacity (arrow) with convex lateral margins. Associated small-to-moderate right pleural effusion is also present. B–D, Axial contrast-enhanced chest CT images in soft-tissue (B and C) and lung (D) windows reveal right infrahilar mass (solid arrows, B–D) with extension across fissures (dashed arrow, D) into right middle and lower lobes. Bulky subcarinal lymphadenopathy is also present. E, Follow-up chest CT in lung window completed only 2 weeks later shows significant increase in size of bulky right hilar and mediastinal lymphadenopathy (arrows). Mass now occupies significant portions of right middle and lower lobes. F and G, Contrast-enhanced CT images in soft-tissue windows shows striking heterogeneous enhancement and central necrosis (arrows, F). In addition, there is marked mass effect on bronchovascular structures with more severe narrowing of pulmonary arteries, veins, and right lower lobe bronchi (arrows, G). All features suggest very aggressive neoplasm with high proliferation rate. After lung biopsy confirmed NUT midline carcinoma, patient was treated with two rounds of chemotherapy with carboplatin and paclitaxel. Patient elected to have remainder of his therapy near his home and was consequently lost to follow-up.
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Fig. 2—22-year-old man who presented with productive cough and dyspnea on exertion with no response to antibiotics. A, Initial chest radiograph shows extensive opacification in right hemithorax consisting of lobulated pleural abnormality as well as underlying parenchymal dense consolidation. B and C, Axial (B) and coronal (C) contrast-enhanced CT images in soft-tissue windows show hypoattenuating necrotic masses in mediastinum, right hilum, and right lower lobe (arrows, B), causing inversion of right hemidiaphragm. Mass crosses tissue planes and encases hilar vessels; fat planes with left atrium and pulmonary veins are lost. D, Coronal CT in lung window shows severe narrowing of right main and right lower lobe bronchus with endobronchial tumor extension (arrow). Leftward mediastinal shift is seen. E, Coronal fused PET/CT image shows intense FDG-avid uptake in mass (standardized uptake value, > 12) and several photopenic areas within it due to necrosis. Mediastinal involvement is multicompartmental and extends to left as well. F, Coronal T2-weighted MRI delineates solid lobulated mass in mid-to-lower hemithorax with extensive mediastinal and pericardial invasion. Myocardial tagging sequences (not shown) were done before urgent debulking surgery to delineate any myocardial invasion. G, Coronal contrast-enhanced MRI subtraction image completed 3 weeks after initial imaging and chemotherapy shows enhancing soft tissue within several portions of bulky right lower lobe mass. This sequence along with PET/CT is helpful in differentiating postchemotherapy-related hemorrhage from enhancing viable tumor and has potential to monitor treatment changes. Given severe cardiorespiratory symptoms due to mass effect from tumor, urgent debulking surgery including right pneumonectomy and partial pericardiectomy was planned under cardiopulmonary bypass. H, Gross pathology of right lung shows perihilar tumor that has invaded into lower lobe with surrounding areas of hemorrhage and necrosis. (Courtesy of Seidman M, Brigham and Women’s Hospital, Boston, MA)
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 3—68-year-old woman who presented with night sweats, lower extremity pain, cough, and 40-pound weight loss. A, Initial chest radiograph shows complete opacification of right hemithorax and abrupt cutoff of right main bronchus (arrow). B and C, Axial (B) and coronal (C) contrast-enhanced CT images show large right perihilar mass inseparable from right mediastinal and subcarinal lymphadenopathy. Complete encasement of pulmonary arteries and veins (long arrows, B and C) and complete occlusion of right-sided bronchi (short arrow, C) suggest aggressive tumor. Medially mass abuts esophagus (black arrow, B). Fluid bronchograms are seen secondary to proximal hilar obstructing mass. D, Mass shows intense FDG uptake on PET. Atelectatic right lung shows mild diffuse increased uptake due to postobstructive changes and pneumonitis. Initial biopsy was thought to be consistent with poorly differentiated non–small cell lung cancer. Consequently, patient was treated with multiple rounds of chemoradiation, with little response. Subsequent reevaluation of pathology revealed findings more consistent with NUT midline carcinoma. E and F, Axial CT images obtained 3 weeks after chemoradiation show progressive disease with new pericardial tumor implants (solid arrows, E and F) causing extrinsic compression and mass effect. Urgent video-assisted thoracic surgery pericardial window placement was done. Tumor also obstructs esophagus (black arrow, F) requiring polyethylene glycol tube placement.
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Fig. 4—23-year-old man who presented with persistent sore throat, hoarseness, and dysphagia, which was initially thought to be mononucleosis. Epstein-Barr virus titers were positive. A and B, Axial T1-weighted (A) and T2-weighted (B) MRI scans show infiltrative poorly circumscribed mass (arrows) in right hypopharynx with supraglottic and infraglottic extension. C and D, Coronal STIR (C) and coronal T1-weighted (D) contrast-enhanced MRI scans show bulky bilateral, right greater than left, adenopathy (arrows) with marked central necrosis. Initially, case was misdiagnosed and treated as hypopharyngeal carcinoma. Because of worsening pulmonary and pleural disease, repeat biopsy was completed and confirmed NUT midline carcinoma. Treatment was started with histone deacetylase inhibitor (romidepsin). E and F, Coronal contrast-enhanced CT in soft-tissue (E) and lung (F) windows obtained within 2 weeks of initial presentation show marked disease progression bilaterally with bulky pleural, mediastinal, and hilar tumor. Marked narrowing of right main bronchus is seen (arrow). G, Coronal fused FDG PET/CT shows continued and significant progression of pleural, pulmonary, and mediastinal disease as well as multiple bone metastases (arrows) not appreciated on chest CT.
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Radiologic and Pathologic Correlation for NUT Midline Carcinoma
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Fig. 5—29-year-old man who presented with dyspnea, shoulder pain, and hemoptysis. A, Initial chest radiograph shows left lower lobe opacification and moderate left pleural effusion. B and C, Axial (B) and coronal (C) contrast-enhanced chest CT scans reveal large confluent and infiltrative mass in left lower lobe extending up to hilum and causing compression of left main bronchus with associated pleural nodularity. Sampling confirmed NUT midline carcinoma. D, Coronal fused FDG PET/CT shows significant progression of pleural and pulmonary disease and complete loss of left lung aeration. Multiple bony metastases are also seen (arrow). Patient developed bilateral Horner syndrome due to compression of sympathetic chains by mediastinal mass. Treatment was initiated with romidepsin, but patient died within 6 months of diagnosis. E, H and E stain (×400) of patient’s pleural metastasis reveals characteristic monotony of NUT midline carcinoma cells, which are typically small to medium in size. F, Immunohistochemistry for NUT in patient’s bone metastasis shows nuclear speckled staining. This is area where squamous differentiation is apparent. Interestingly, NUT staining typically diminishes in cells undergoing terminal differentiation as can be seen here.
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