Abstract
Purpose
Nuclear protein in testis (NUT) carcinoma is an uncommon malignant cancer characterized by NUTM1 rearrangement. We aimed to investigate the clinicopathological and molecular features and immunotherapy of pulmonary NUT carcinoma.
Methods
Immunohistochemistry (IHC) for NUT (C52B1) and programmed cell death ligand 1 (PD-L1: 22C3) and fluorescence in situ hybridization (FISH) for NUTM1 break and BRD4–NUTM1 fusion were performed on six pulmonary NUT carcinoma samples.
Results
The 6 pulmonary NUT carcinoma samples were obtained from 5 males and 1 female, with ages ranging from 31 to 73 years (average, 46 years). Five tumors occurred in the lobes, with one in the trachea. Pathologically, all cases showed primitive-appearing round to epithelioid cells growing in nests and sheets. Squamous differentiation and abrupt keratinization were observed. All tumors expressed the NUT protein and p63, and 4 tumors showed focal synaptophysin, but PD-L1 expression was not observed. All cases displayed NUTM1 rearrangement, 5 had BRD4–NUTM1 fusion, and one had an unknown partner. Three patients presented regional lymph node involvement at diagnosis. Five patients underwent intensive radiation and/or chemotherapy. Furthermore, 2 patients (1 and 2) received a combination of PD-L1 inhibitor and chemotherapy. Patient 1 exhibited a poor response and soon showed tumor progression and metastasis; however, patient 2 responded remarkably and achieved pathologic complete response (pCR) without uncontrollable adverse events. The overall survival time was 2.9 months.
Conclusions
Pulmonary NUT carcinoma exhibits poorly differentiated morphological features with diffuse NUT staining, low PD-L1 expression, and NUTM1 rearrangement. Despite its poor prognosis, it presents a diverse response to immunotherapy. Immune checkpoint inhibitors (ICIs) need to be further explored in NUT carcinoma.
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The original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author.
References
Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP et al (2016) Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17:883–895. https://doi.org/10.1016/S1470-2045(16)30098-5
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R et al (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919–1929. https://doi.org/10.1056/NEJMoa1709937
Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC et al (2012) Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 18:5773–5779. https://doi.org/10.1158/1078-0432.CCR-12-1153
Cavalieri S, Stathis A, Fabbri A, Sonzogni A, Perrone F, Tamborini E et al (2017) Uncommon somatic mutations in metastatic NUT midline carcinoma. Tumori 103:e5–e8. https://doi.org/10.5301/tj.5000685
Chatzopoulos K, Boland JM (2021) Update on genetically defined lung neoplasms: NUT carcinoma and thoracic SMARCA4-deficient undifferentiated tumors. Virchows Arch 478:21–30. https://doi.org/10.1007/s00428-020-03011-3
Chau NG, Ma C, Danga K, Al-Sayegh H, Nardi V, Barrette R et al (2019) An anatomical site and genetic-based prognostic model for patients with nuclear protein in testis (NUT) midline carcinoma: analysis of 124 patients. JNCI Cancer Spectr 4:pkz094. https://doi.org/10.1093/jncics/pkz094
Chen M, Yang J, Lv L, Li Y, Tang Y, Liu W et al (2021) Comprehensive genetic profiling of six pulmonary nuclear protein in testis carcinomas with a novel micropapillary histological subtype in two cases. Hum Pathol 115:56–66. https://doi.org/10.1016/j.humpath.2021.02.004
Chen M, Zhao S, Liang Z, Wang W, Zhou P, Jiang L (2022) NUT carcinoma of the parotid gland: report of two cases, one with a rare ZNF532-NUTM1 fusion. Virchows Arch 480:887–897. https://doi.org/10.1007/s00428-021-03253-9
Cho YA, Choi YL, Hwang I, Lee K, Cho JH, Han J (2020) Clinicopathological characteristics of primary lung nuclear protein in testis carcinoma: a single-institute experience of 10 cases. Thorac Cancer 11:3205–3212. https://doi.org/10.1111/1759-7714.13648
Davis A, Mahar A, Wong K, Barnet M, Kao S (2021) Prolonged disease control on nivolumab for primary pulmonary NUT carcinoma. Clin Lung Cancer 22:e665–e667. https://doi.org/10.1016/j.cllc.2020.10.016
Elegbede AA, Gibson AJ, Fung AS, Cheung WY, Dean ML, Bebb DG et al (2021) A real-world evaluation of atezolizumab plus platinum-etoposide chemotherapy in patients with extensive-stage SCLC in Canada. JTO Clin Res Rep 2:100249. https://doi.org/10.1016/j.jtocrr.2021.100249
Evans AG, French CA, Cameron MJ, Fletcher CD, Jackman DM, Lathan CS et al (2012) Pathologic characteristics of NUT midline carcinoma arising in the mediastinum. Am J Surg Pathol 36:1222–1227. https://doi.org/10.1097/PAS.0b013e318258f03b
French C (2014) NUT midline carcinoma. Nat Rev Cancer 14:149–150. https://doi.org/10.1038/nrc3659
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA (2003) BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63:304–307
Grayson AR, Walsh EM, Cameron MJ, Godec J, Ashworth T, Ambrose JM et al (2014) MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33:1736–1742. https://doi.org/10.1038/onc.2013.126
Gupta R, Mumaw D, Antonios B, Anusim N, Dhulipalla SP, Stender M et al (2022) NUT midline lung cancer: a rare case report with literature review. AME Case Rep. https://doi.org/10.21037/acr-21-35
Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB et al (2009) Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol 33:984–991. https://doi.org/10.1097/PAS.0b013e318198d666
He M, Chernock R, Zhou S, Gondim M, Dehner LP, Pfeifer JD (2020) Tumor mutation burden and checkpoint immunotherapy markers in NUT midline carcinoma. Appl Immunohistochem Mol Morphol 28:495–500. https://doi.org/10.1097/PAI.0000000000000781
Hung YP, Chen AL, Taylor MS, Huynh TG, Kem M, Selig MK et al (2021) Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor-1 and neuroendocrine markers. Histopathology 78:896–904. https://doi.org/10.1111/his.14306
Joel S, Weschenfelder F, Schleussner E, Hofmann GO, Weschenfelder W (2020) NUT midline carcinoma in a young pregnant female: a case report. World J Surg Oncol 18:290. https://doi.org/10.1186/s12957-020-02065-6
Jung M, Kim S, Lee JK, Yoon SO, Park HS, Hong SW et al (2019) Clinicopathological and preclinical findings of NUT carcinoma: a multicenter study. Oncologist 24:e740–e748. https://doi.org/10.1634/theoncologist.2018-0477
Lee JK, Louzada S, An Y, Kim SY, Kim S, Youk J et al (2017) Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma. Ann Oncol 28:890–897. https://doi.org/10.1093/annonc/mdw686
Lee S, Shim HS, Ahn BC, Lim SM, Kim HR, Cho BC et al (2021) Efficacy and safety of atezolizumab, in combination with etoposide and carboplatin regimen, in the first-line treatment of extensive-stage small-cell lung cancer: a single-center experience. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-021-03052-w
Li X, Shi H, Zhang W, Bai C, He M, Ta N et al (2021) Immunotherapy and targeting the tumor microenvironment: current place and new insights in primary pulmonary NUT carcinoma. Front Oncol 11:690115. https://doi.org/10.3389/fonc.2021.690115
Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z et al (2020) Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol 31:310–317. https://doi.org/10.1016/j.annonc.2019.10.021
Maruyama N, Hikiishi A, Suginaka M, Furukawa K, Ogawa K, Nakamura N et al (2018) Nuclear protein in testis carcinoma of the thorax. Intern Med 57:3169–3173. https://doi.org/10.2169/internalmedicine.0434-17
Pan M, Chang JS (2020) Durable complete remission of PD-L1 positive NUT carcinoma treated with concurrent chemotherapy and radiation. Perm J 25:1–3. https://doi.org/10.7812/TPP/20.093
Pezzuto F, Fortarezza F, Mammana M, Pasello G, Pelosi G, Rea F et al (2020) Immunohistochemical neuroendocrine marker expression in primary pulmonary NUT carcinoma: a diagnostic pitfall. Histopathology 77:508–510. https://doi.org/10.1111/his.14166
Riess JW, Rahman S, Kian W, Edgerly C, Heilmann AM, Madison R et al (2021) Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors. Transl Oncol 14:101184. https://doi.org/10.1016/j.tranon.2021.101184
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D et al (2019) KEYNOTE-426 investigators. pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116–1127. https://doi.org/10.1056/NEJMoa1816714
Sholl LM, Nishino M, Pokharel S, Mino-Kenudson M, French CA, Janne PA et al (2015) Primary pulmonary NUT midline carcinoma: clinical, radiographic, and pathologic characterizations. J Thorac Oncol 10:951–959. https://doi.org/10.1097/JTO.0000000000000545
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB et al (2015) WHO panel. The 2015 world Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 10:1243–1260. https://doi.org/10.1097/JTO.0000000000000630
Wang S, Chen R, Tang Y, Yu Y, Fang Y, Huang H et al (2020) Comprehensive genomic profiling of rare tumors: routes to targeted therapies. Front Oncol 10:536. https://doi.org/10.3389/fonc.2020.00536
Wang S, Fang Y, Jiang N, Xing S, Li Q, Chen R et al (2021) Comprehensive genomic profiling of rare tumors in China: routes to immunotherapy. Front Immunol 25(12):631483. https://doi.org/10.3389/fimmu.2021.631483
Xie XH, Wang LQ, Qin YY, Lin XQ, Xie ZH, Liu M et al (2020) Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma. Orphanet J Rare Dis 15:183. https://doi.org/10.1186/s13023-020-01449-x
Xie M, Fu X, Wang W (2021) Clinicopathological and molecular characterizations of pulmonary NUT midline carcinoma. Cancer Med 10:5757–5764. https://doi.org/10.1002/cam4.4096
Yang X, Wang D, Lin J, Yang X, Zhao H (2020) Atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Lancet Oncol 21:e412. https://doi.org/10.1016/S1470-2045(20)30430-7
Zhang Y, Han K, Dong X, Hou Q, Li T, Li L et al (2021) Case report and literature review: primary pulmonary NUT-midline carcinoma. Front Oncol 11:700781. https://doi.org/10.3389/fonc.2021.700781
Zhou J, Duan M, Jiao Q, Chen C, Xing A, Su P et al (2022) Primary thyroid NUT carcinoma with high PD-L1 expression and novel massive IGKV gene fusions: a case report with treatment implications and literature review. Front Oncol 11:778296. https://doi.org/10.3389/fonc.2021.778296
Funding
This study was supported by the Sichuan University 1.3.5 Project for Disciplines of Excellence-Clinical Research Incubation (No. 2019HXFH002).
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MC collected the patients, performed the experiments, and wrote the paper; YZ performed the immunohistochemistry experiments; XC and WW performed the histopathological examinations; and LJ organized and modified the paper. All authors were involved in analyzing the study data and commenting on the manuscript. All authors approved the final manuscript.
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Chen, M., Chen, X., Zhang, Y. et al. Clinical and molecular features of pulmonary NUT carcinoma characterizes diverse responses to immunotherapy, with a pathologic complete response case. J Cancer Res Clin Oncol 149, 6361–6370 (2023). https://doi.org/10.1007/s00432-023-04621-5
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DOI: https://doi.org/10.1007/s00432-023-04621-5