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Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma

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Abstract

Thymic squamous cell carcinoma (TSC) presents distinct immunohistochemical features with its expression of CD5 and CD117, both of which are rarely expressed in squamous cell carcinoma in other organs. We found insulinoma-associated-1 (INSM1) expression in some TSCs; thus, a series of thymic tumors were examined retrospectively. Using surgically resected thymic tumors (TSC, n = 35; thymic atypical carcinoid [TAC], n = 4; and thymoma, n = 112) and non-neoplastic thymic tissue (n = 26), we evaluated immunohistochemically the expressions of INSM1, ASCL1, SOX2, NE markers (synaptophysin, chromogranin A, and CD56), and conventional TSC markers (CD5 and CD117). INSM1 was expressed in 22 TSCs (63%), whereas the positive frequencies of synaptophysin, chromogranin A, and CD56 were limited to 13, 10, and 1 cases, respectively. The discordance was highly contrasted with concordantly positive TACs. INSM1 and NE makers were rarely expressed in thymomas. INSM1 expression in TSCs was also associated with CD5 expression, which was significantly less frequent in INSM1-negative TSCs. INSM1, ASCL1, and SOX2 expressions were correlated with one another, but none of the single transcription factors or their combinations is associated with NE expression. The non-neoplastic medullary thymic epithelium was dispersedly positive for INSM1, particularly around Hassall’s corpuscles. Despite positive INSM1, a significant decrease in the frequency of NE maker expression may present as a diagnostic pitfall in TSCs. Furthermore, the discordance, which was inherent in the non-neoplastic thymic epithelium, might be a characteristic feature in TSCs.

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References

  1. Brierley JD, Gospodarowicz MK, Wittekind CH (2017) Inter-national union against cancer TNM classification of malignant tumours, 8th edn. Wiley-Blackwell, Hoboken

  2. WHO Classification of Tumours Editorial Board (2021) Thoracic Tumours, WHO Classification of Tumours, vol 5, 5th edn. International Agency for Research on Cancer, Lyon, pp 81–82

  3. Baine MK, Hsieh MS, Lai WV, Egger JV, Jungbluth AA, Daneshbod Y, Beras A, Spencer R, Lopardo J, Bodd F, Montecalvo J, Sauter JL, Chang JC, Buonocore DJ, Travis WD, Sen T, Poirier JT, Rudin CM, Rekhtman N (2020) SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15:1823–1835. https://doi.org/10.1016/j.jtho.2020.09.009

    Article  CAS  Google Scholar 

  4. Chen C, Breslin MB, Lan MS (2015) INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma. Oncotarget 6:36700–36712. https://doi.org/10.18632/oncotarget.5485

    Article  Google Scholar 

  5. Chen C, Notkins AL, Lan MS (2019) Insulinoma-associated-1: from neuroendocrine tumor marker to cancer therapeutics. Mol Cancer Res 17:1597–1604. https://doi.org/10.1158/1541-7786.MCR-19-0286

    Article  CAS  Google Scholar 

  6. Dorfman DM, Shahsafaei A, Chan JKC (1997) Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5 immunoreactivity. Am J Surg Pathol 21:936–940

    Article  CAS  Google Scholar 

  7. Fujino K, Motooka Y, Hassan WA, Ali Abdalla MO, Sato Y, Kudoh S, Hasegawa K, Niimori-Kita K, Kobayashi H, Kubota I, Wakimoto J, Suzuki M, Ito T (2015) Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am J Pathol 185:3164–3177. https://doi.org/10.1016/j.ajpath.2015.08.018

    Article  CAS  Google Scholar 

  8. Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807. https://doi.org/10.1200/JCO.2003.11.069

    Article  CAS  Google Scholar 

  9. Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G (2011) Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol 29:4820–4827. https://doi.org/10.1200/JCO.2011.36.0487

    Article  CAS  Google Scholar 

  10. Khawaja MR, Nelson RP Jr, Miller N, Badve SS, Loehrer E, Czader M, Perkins SM, Kesler K, Loehrer PJ Sr (2012) Immune-mediated diseases and immunodeficiencies associated with thymic epithelial neoplasms. J Clin Immunol 32:430–437. https://doi.org/10.1007/s10875-011-9644-1

    Article  CAS  Google Scholar 

  11. Kuji S, Watanabe R, Sato Y, Iwata T, Hirashima Y, Takekuma M, Ito I, Abe M, Nagashio R, Omae K, Aoki D, Kameya T (2017) A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: analysis of 37 cases. Gynecol Oncol 144:384–390. https://doi.org/10.1016/j.ygyno.2016.11.020

    Article  CAS  Google Scholar 

  12. Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF (2019) Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 32:100–109. https://doi.org/10.1038/s41379-018-0122-7

    Article  CAS  Google Scholar 

  13. Nonaka D, Henley JD, Chiriboga L, Yee H (2007) Diagnostic utility of thymic epithelial markers CD205 (DEC205) and Foxn1 in thymic epithelial neoplasms. Am J Surg Pathol 31:1038–1044. https://doi.org/10.1097/PAS.0b013e31802b4917

    Article  Google Scholar 

  14. Roden AC, Ahmad U, Cardillo G, Girard N, Jain D, Marom EM, Marx A, Moreira AL, Nicholson AG, Rajan A, Shepherd AF, Simone CB 2nd, Strange CD, Szolkowska M, Truong MT, Rimner A (2022) Thymic carcinomas-a concise multidisciplinary update on recent developments from the thymic carcinoma working group of the International Thymic Malignancy Interest Group. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17:637–650. https://doi.org/10.1016/j.jtho.2022.01.021

    Article  CAS  Google Scholar 

  15. Rooper LM, Bishop JA, Westra WH (2018) INSM1 is a sensitive and specific marker of neuroendocrine differentiation in head and neck tumors. Am J Surg Pathol 42:665–671. https://doi.org/10.1097/PAS.0000000000001037

    Article  Google Scholar 

  16. Rooper LM, Sharma R, Li QK, Illei PB, Westra WH (2017) INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol 41:1561–1569. https://doi.org/10.1097/PAS.0000000000000916

    Article  Google Scholar 

  17. Rosenbaum JN, Guo Z, Baus RM, Werner H, Rehrauer WM, Lloyd RV (2015) INSM1: a novel immunohistochemical and molecular marker for neuroendocrine and neuroepithelial neoplasms. Am J Clin Pathol 144:579–591. https://doi.org/10.1309/AJCPGZWXXBSNL4VD

    Article  CAS  Google Scholar 

  18. Sakane T, Sakamoto Y, Masaki A, Murase T, Okuda K, Nakanishi R, Inagaki H (2021) Mutation profile of thymic carcinoma and thymic neuroendocrine tumor by targeted next-generation sequencing. Clin Lung Cancer 22:92-99 e94. https://doi.org/10.1016/j.cllc.2020.11.010

    Article  CAS  Google Scholar 

  19. Schirosi L, Nannini N, Nicoli D, Cavazza A, Valli R, Buti S, Garagnani L, Sartori G, Calabrese F, Marchetti A, Buttitta F, Felicioni L, Migaldi M, Rea F, Di Chiara F, Mengoli MC, Rossi G (2012) Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 23:2409–2414. https://doi.org/10.1093/annonc/mdr626

    Article  CAS  Google Scholar 

  20. Strobel P, Hartmann E, Rosenwald A, Kalla J, Ott G, Friedel G, Schalke B, Kasahara M, Tomaru U, Marx A (2014) Corticomedullary differentiation and maturational arrest in thymomas. Histopathology 64:557–566. https://doi.org/10.1111/his.12279

    Article  Google Scholar 

  21. Tanigawa M, Nakayama M, Taira T, Hattori S, Mihara Y, Kondo R, Kusano H, Nakamura K, Abe Y, Ishida Y, Okabe Y, Hisaka T, Okuda K, Fujino K, Ito T, Kawahara A, Naito Y, Yamaguchi R, Akiba J, Akagi Y, Yano H (2018) Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor. Med Mol Morphol 51:32–40. https://doi.org/10.1007/s00795-017-0167-6

    Article  CAS  Google Scholar 

  22. Tenjin Y, Matsuura K, Kudoh S, Usuki S, Yamada T, Matsuo A, Sato Y, Saito H, Fujino K, Wakimoto J, Ichimura T, Kohrogi H, Sakagami T, Niwa H, Ito T (2020) Distinct transcriptional programs of SOX2 in different types of small cell lung cancers. Lab Invest 100:1575–1588. https://doi.org/10.1038/s41374-020-00479-0

    Article  CAS  Google Scholar 

  23. Toriyama A, Mori T, Sekine S, Yoshida A, Hino O, Tsuta K (2014) Utility of PAX8 mouse monoclonal antibody in the diagnosis of thyroid, thymic, pleural and lung tumours: a comparison with polyclonal PAX8 antibody. Histopathology 65:465–472. https://doi.org/10.1111/his.12405

    Article  Google Scholar 

  24. Tsai HK, Hornick JL, Vivero M (2020) INSM1 expression in a subset of thoracic malignancies and small round cell tumors: rare potential pitfalls for small cell carcinoma. Mod Pathol 33:1571–1580. https://doi.org/10.1038/s41379-020-0517-0

    Article  CAS  Google Scholar 

  25. Tsuchida M, Umezu H, Hashimoto T, Shinohara H, Koike T, Hosaka Y, Eimoto T, Hayashi JI (2008) Absence of gene mutations in KIT-positive thymic epithelial tumors. Lung Cancer 62:321–325. https://doi.org/10.1016/j.lungcan.2008.03.035

    Article  Google Scholar 

  26. Wang M, Abi-Raad R, Baldassarri R, Adeniran AJ, Cai G (2021) Expression of insulinoma-associated protein 1 in non-small cell lung cancers: a diagnostic pitfall for neuroendocrine tumors. Hum Pathol 115:104–111. https://doi.org/10.1016/j.humpath.2021.06.006

    Article  CAS  Google Scholar 

  27. Weissferdt A, Moran CA (2016) Neuroendocrine differentiation in thymic carcinomas: a diagnostic pitfall: an immunohistochemical analysis of 27 cases. Am J Clin Pathol 145:393–400. https://doi.org/10.1093/ajcp/aqv095

    Article  CAS  Google Scholar 

  28. Yamada Y, Simon-Keller K, Belharazem-Vitacolonnna D, Bohnenberger H, Kriegsmann M, Kriegsmann K, Hamilton G, Graeter T, Preissler G, Ott G, Roessner ED, Dahmen I, Thomas RK, Strobel P, Marx A (2021) A tuft cell-like signature is highly prevalent in thymic squamous cell carcinoma and delineates new molecular subsets among the major lung cancer histotypes. J Thorac Oncol 16:1003–1016. https://doi.org/10.1016/j.jtho.2021.02.008

    Article  CAS  Google Scholar 

  29. Yamada Y, Sugimoto A, Hoki M, Yoshizawa A, Hamaji M, Date H, Haga H, Marx A (2022) POU2F3 beyond thymic carcinomas: expression across the spectrum of thymomas hints to medullary differentiation in type A thymoma. Virchows Archiv : an international journal of pathology 480:843–851. https://doi.org/10.1007/s00428-021-03229-9

    Article  CAS  Google Scholar 

  30. Zhang T, Liu WD, Saunee NA, Breslin MB, Lan MS (2009) Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest. J Biol Chem 284:5574–5581. https://doi.org/10.1074/jbc.M808843200

    Article  CAS  Google Scholar 

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Funding

This work was supported partly by Grants-in-Aid for Scientific Research (B), JSPS (20H03461), and the National Cancer Center Research and Development Fund (A-3).

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Authors and Affiliations

  1. Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan

    Jumpei Kashima, Taiki Hashimoto, Akihiko Yoshida & Yasushi Yatabe

  2. Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Jumpei Kashima & Tetsuo Ushiku

  3. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Yasushi Goto & Yuichiro Ohe

  4. Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan

    Shun-ichi Watanabe

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  1. Jumpei Kashima
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Contributions

Conceptualization: JK and YY; sample preparation and clinical information: TH, AY, YG, YO, and SW; analysis and investigation: JK and YY; writing—original draft preparation: JK and YY; writing—review and editing: TH, AY, YG, TU, YO, and SW; supervision: TU.

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Correspondence to Yasushi Yatabe.

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This study was approved by the institutional review board as a part of a larger comprehensive study (NCC IRB No. 2010–077), which are in accordance with the ethical standards of the institutional and/or national research committee and with the declaration of Helsinki.

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Kashima, J., Hashimoto, T., Yoshida, A. et al. Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma. Virchows Arch 481, 893–901 (2022). https://doi.org/10.1007/s00428-022-03437-x

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