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CASE REPORT
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Primary pulmonary NUT midline carcinoma: An elusive and a rare diagnostic entity


1 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Radiology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
3 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
4 Department of Molecular Diagnostics Radiology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
5 Department of Laboratory, Molecular and Transfusion Services, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Submission27-Dec-2020
Date of Acceptance05-Jan-2021
Date of Web Publication06-Dec-2021

Correspondence Address:
Divya Bansal,
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi - 110 085
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1887_20

 > Abstract 


Nuclear protein in testis (NUT) midline carcinoma is a poorly differentiated tumor, is more common in midline anatomic sites, and involves young adults and children mainly. Primary pulmonary NUT midline carcinoma (NMC) is a rare and poorly defined entity in the prevailing literature. Being a highly aggressive and fatal neoplasm, it gets incumbent for the oncologists and the pathologists to be aware of this entity as it holds distinct management protocol and prognosis. Currently, BET inhibitors (BETi) and histone deactylase inhibitors have shown promising results as targeted therapies in clinical trials in head and neck NMC. We present a case report of NMC of primary pulmonary location in a young male with widespread bony metastasis.

Keywords: Mediastinum, metastasis, nuclear protein in testis midline carcinoma, pulmonary, radiotherapy



How to cite this URL:
Pasricha S, Jajodia A, Sharma A, Bansal D, Batra U, Gupta G, Durga G, Kamboj M, Nathany S, Mehta A. Primary pulmonary NUT midline carcinoma: An elusive and a rare diagnostic entity. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=331846




 > Introduction Top


Nuclear protein in testis (NUT) midline carcinoma (NMC) is an aggressive, uncommon mediastinal malignancy which presents as poorly differentiated carcinoma (PDC) or undifferentiated malignant round cell tumor (MRCT) on histology.[1],[2]

The diagnostic hallmark is defined by chromosomal translocation t (15;19) that fuses NUTM1 (gene on chromosome 15) with bromodomain (BRD) family members, usually BRD3 OR BRD4 gene.[3] The tumor arises at many sites with a predilection for head and neck and mediastinal region although primary pulmonary involvement is exceptionally rare in existing literature.[1],[2] Majority of cases present with locally advanced or widespread metastasis with dismal prognosis.[4]

The pathologist and oncologist should be familiarized with this entity which is often being underrecognized, however carries a distinct prognostic and therapeutic implication. We present a rare case of NMC of primary lung in a young male with widespread bony metastasis.


 > Case Report Top


A 31-year-old male without significant past or addiction history presented with gradually progressing backache and right leg pain for 4 months. The performance status (PS) score was 4.

Routine laboratory investigations were unremarkable. Serum lactate dehydrogenase was elevated (1477 u/l), and serum alpha-fetoprotein and beta-subunit of human chorionic gonadotropin were normal. Magnetic resonance imaging brain and spine revealed multiple altered marrow signal enhancing lesions with associated soft tissue component in calvarial bones, cervical, dorsal, lumbar vertebrae, sacrum, pelvic bones, humerus, and ribs suggestive of metastatic lesions [Figure 1]. Subsequently, positron emission tomography–computed tomography (CT) scan revealed a metabolically active suprahilar soft tissue density mass lesion in the right lung with intrabronchial extension, right paratracheal lymph node, liver, adrenal, and multiple skeletal lesions suggestive of primary lung carcinoma [Figure 2].
Figure 1: (a-d) Magnetic resonance imaging of the brain and spine in a suspected case of lung carcinoma shows a large dural-based mass in the right skull vault (a). Coronal images show large soft tissue mass involving the right acetabular joint with multiple liver lesions (b). (c and d) Sagittal magnetic resonance view of the spine shows multiple vertebral lesions

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Figure 2: (a and b) Axial computed tomography images show heterogeneously enhancing lesion invading the right main bronchus with distal collapse consolidation of subsegmental lung parenchyma. Initially, this was suspected to be a carcinogenic lung mass

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Trucut biopsy from the right iliac blade showed bony trabeculae infiltrated by poorly differentiated malignancy [Figure 3]a comprising of monomorphic round to oval cells with scant cytoplasm, hyperchromatic nucleus, and conspicuous nucleoli, exhibiting significant mitosis [Figure 3]b. Perivascular pseudorosette formation was readily evident [Figure 3]b. Histomorphological features were of undifferentiated MRCT. On immunohistochemistry (IHC), the primary panel revealed diffuse positivity for cytokeratin (CK), CK7 in the tumor cells [Figure 3]c and negativity for synaptophysin, chromogranin, leukocyte common antigen (LCA), NKX2.2, and HMB45. The Ki-67 index was 60%–70%. The findings were suggestive of metastatic PDC and ruled out differential diagnosis of lymphoma, malignant melanoma, Ewing's sarcoma, and neuroendocrine carcinoma. Subsequently, p40 and TTF 1 negativity largely ruled out squamous cell carcinoma and adenocarcinoma, respectively.
Figure 3: (a) Bone biopsy infiltrated by a tumor with predominantly small blue round cell morphology (H and E; ×100). (b) Monomorphic round to oval cells with perivascular pseudorosette formation (H and E; ×400). (c) Cytokeratin 7 immunoexpression in tumor cells (DAB; ×400). (d) Nuclear protein in testis nuclear immunoexpression in tumor cells (DAB; ×400)

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In view of young age, large pulmonary mass, and disseminated metastatic disease espoused with MRCT morphology, it provoked us to rule out NMC of lung and subsequently NUT IHC was positive [Figure 3]d; hence, the final diagnosis of NMC of lung was rendered. No targeted driver mutation was identified for ALK-1, ROS-1, and EGFR. The PD-L1 immunoexpression showed tumor proportion score of <1%.

The case was discussed in the multispecialty tumor board; after explaining the prognosis and palliative intent of treatment to the patient, he was subjected to palliative radiotherapy (RT) comprising 20 Gray/5 fractions (conventional) for the whole pelvis, L2–L4 vertebrae, D10 vertebrae, and left shoulder. There was a significant symptomatic relief in pain after RT; however, subsequently, the patient was lost to follow-up.


 > Discussion Top


NMC with t (15;19) is a PDC with aggressive clinical course and poor prognosis.[1],[2],[4] Although it is a well-recognized entity in head and neck region,[5] especially nasal cavity and paranasal sinuses, the clinicopathological and radiological features are not well defined in pulmonary/mediastinal region due to paucity or underrecognition of this entity.

Sholl et al.[2] reported largest series of nine patients of primary pulmonary NMC with available clinicoradiographic and pathological features for eight cases. The median age was 30 years (range, 21–68) and single patient was a chronic smoker. Marked regional lymphadenopathy was seen in all cases and bone involvement was seen in three patients. CK was expressed in all cases. TTF1 expression was seen focally in two cases, while p63 was positive in all cases (scattered to diffuse). None of the eight cases showed expression of specific neuroendocrine markers: synaptophysin and chromogranin except for single case with focal synaptophysin expression. All the cases showed NUT protein nuclear positivity by IHC and NUT gene rearrangement by fluorescence in situ hybridization (FISH). The median overall survival (OS) was 2.2 months. Xie et al.[6] also reported a series of seven patients with a median age of 31 years presenting with advanced stage and poor PS score. The median OS of patients with lung masses was 2.75 months in spite of receiving multiple lines of therapy.[6]

As per the prevailing literature, the histopathological diagnostic features of NMC are not characteristic. The common morphology is PDC with abrupt and focal squamous differentiation with or without keratinization.[7] In the absence of squamous and epithelioid features, it may be construed as undifferentiated malignancy or MRCT including differentials such as lymphoma, Ewing's sarcoma, melanoma, or undifferentiated round cell sarcoma.[1],[2] The present case also shows features of MRCT without any epithelial or squamoid differentiation, however showed pseudorosettes. On IHC, besides CK, all other lineage markers (LCA, NKX 2.2, HMB-45) were negative. It was the constellation of clinicoradiological and pathological features that prompted us to rule out NMC.

NMC was initially diagnosed by FISH and reverse transcription-polymerase chain reaction; however, recently, specific monoclonal antibody against NUT (Clone: C52B1) had shown 100% specificity and 87% sensitivity.[8] Evans et al.[1] screened 114 cases of mediastinal malignancy with NUT IHC; four (3.5%) cases were positive for NUT out of which only 1 showed CK positive and the remaining 3 cases were CK negative.

In terms of survival, the median OS of the largest series of NMC including all sites was 6.7 months.[9] Currently, there are no standard guidelines for the treatment of NMC. Since overwhelming majority of the patients present with advanced stage disease, chemotherapy and/or RT is the mainstay of treatment. Immunotherapy and new drugs such as BETi and histone deacetylase inhibitors are being explored in clinical trials for NMC.[10]

To conclude, NMC is a highly aggressive malignancy which can present as pulmonary or thoracic mass. Knowing this entity is essential to suspect this diagnosis for undifferentiated MRCT or PDC in germane of clinical context. Hence, a timely recognition can enable an appropriate patient counseling and consideration to enroll for targeted therapy for NMC.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to acknowledge Ms. Sangeeta Arora and Mr. Arvind Bhuker for their technical assistance in performing immunohistochemical stain.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Evans AG, French CA, Cameron MJ, Fletcher CD, Jackman DM, Lathan CS, et al. Pathologic characteristics of NUT midline carcinoma arising in the mediastinum. Am J Surg Pathol 2012;36:1222-7.  Back to cited text no. 1
    
2.
Sholl LM, Nishino M, Pokharel S, Mino-Kenudson M, French CA, Janne PA, et al. Primary pulmonary NUT midline carcinoma: Clinical, radiographic, and pathologic characterizations. J Thorac Oncol 2015;10:951-9.  Back to cited text no. 2
    
3.
French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, Thyne ME, 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;27:2237-42.  Back to cited text no. 3
    
4.
Huang QW, He LJ, Zheng S, Liu T, Peng BN. An overview of molecular mechanism, clinicopathological factors, and treatment in NUT carcinoma. Biomed Res Int 2019;2019:1018439.  Back to cited text no. 4
    
5.
Napolitano M, Venturelli M, Molinaro E, Toss A. NUT midline carcinoma of the head and neck: current perspectives. Onco Targets Ther 2019;12:3235-44.  Back to cited text no. 5
    
6.
Xie XH, Wang LQ, Qin YY, Lin XQ, Xie ZH, Liu M, et al. Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma. Orphanet J Rare Dis 2020;15:183.  Back to cited text no. 6
    
7.
Stelow EB, Bellizzi AM, Taneja K, Mills SE, Legallo RD, Kutok JL, et al. NUT rearrangement in undifferentiated carcinomas of the upper aerodigestive tract. Am J Surg Pathol 2008;32:828-34.  Back to cited text no. 7
    
8.
Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, et al. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol 2009;33:984-91.  Back to cited text no. 8
    
9.
Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC, et al. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 2012;18:5773-9.  Back to cited text no. 9
    
10.
French CA, Rahman S, Walsh EM, Kühnle S, Grayson AR, Lemieux ME, et al. NSD3-NUT fusion oncoprotein in NUT midline carcinoma: Implications for a novel oncogenic mechanism. Cancer Discov 2014;4:928-41.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

 
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