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Intrathyroid thymic carcinoma: clinicopathological features and whole exome sequencing analysis

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Abstract

Intrathyroid thymic carcinoma (ITC) is a rare malignant tumour. We present nine cases of ITC that were analysed by immunohistochemical staining, of which five were analysed using whole exome sequencing (WES). These cases included six women and three men with an age range of 31–66 years. The average postoperative follow-up term was 37.8 months (range, 7–95 months), and all patients survived well except for one case with lung metastasis. Microscopically, ITC showed solid islands of tumour cells separated by fibrous connective tissue containing lymphocytes and other inflammatory cells. Tumour cells strongly expressed Ckpan (AE1/AE3), P63, and CD117. And all cases but one were positive for CD5. The median value of Ki-67 was 32% (range 10–60%). We observed partial positivity of Syn and CgA in only one case. ITC shares morphological and immunohistochemical similarities with thymic squamous cell carcinoma. In situ hybridization of EBER showed negative results. All cases were microsatellite stable, and the tumour mutational burden of the 5 cases was all < 1 mutations/Mb. WES showed higher mutation rates for N4BP1 (2/5), and many genetic alterations were related to the NF-kB signalling pathway, which is crucial for insight into the molecular mechanisms of the occurrence and development of ITC.

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Data availability

The original data generated by the next generation sequencing in this experiment cannot be shared in the public database because of patient privacy. The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Miyauchi A, Kuma K, Matsuzuka F, Matsubayashi S, Kobayashi A, Tamai H, Katayama S (1985) Intrathyroidal epithelial thymoma: an entity distinct from squamous cell carcinoma of the thyroid. World J Surg 9(1):128–135. https://doi.org/10.1007/BF01656263

    Article  CAS  PubMed  Google Scholar 

  2. Bai Y, Kakudo K, Jung CK (2020) Updates in the pathologic classification of thyroid neoplasms: a review of the World Health Organization classification. Endocrinol Metab 35(4):696–715. https://doi.org/10.3803/EnM.2020.807

    Article  Google Scholar 

  3. Dong W, Zhang P, Li J, He L, Wang Z, Zhang T, Shao L, Zhang H (2018) Outcome of thyroid carcinoma showing thymus-like differentiation in patients undergoing radical resection. World J Surg 42(6):1754–1761. https://doi.org/10.1007/s00268-017-4339-2

    Article  PubMed  Google Scholar 

  4. Tahara I, Oishi N, Mochizuki K, Oyama T, Miyata K, Miyauchi A, Hirokawa M, Katoh R, Kondo T (2020) Identification of recurrent TERT promoter mutations in intrathyroid thymic carcinomas. Endocr Pathol 31(3):274–282. https://doi.org/10.1007/s12022-020-09635-0

    Article  CAS  PubMed  Google Scholar 

  5. Ito Y, Miyauchi A, Hirokawa M, Kihara M, Onoda N, Miya A (2022) Clinicopathological features and outcomes of intrathyroidal thymic carcinoma: a single institution study. Endocr J. https://doi.org/10.1507/endocrj.EJ22-0141

  6. Alifano M, Boudaya MS, Dinu C, Kadiri H, Regnard JF (2006) Carcinoma showing thymus-like elements invading the trachea. J Thorac Cardiov Sur 132(1):191–192. https://doi.org/10.1016/j.jtcvs.2006.03.020

    Article  Google Scholar 

  7. Kakudo K, Bai Y, Ozaki T, Homma K, Ito Y, Miyauchi A (2013) Intrathyroid epithelial thymoma (ITET) and carcinoma showing thymus-like differentiation (CASTLE): CD5-positive neoplasms mimicking squamous cell carcinoma of the thyroid. Histol Histopathol. 28(5):543–556. https://doi.org/10.14670/HH-28.543

    Article  PubMed  Google Scholar 

  8. Sun YH, Xu J, Li M (2018) Intrathyroid thymic carcinoma: report of two cases with pathologic and immunohistochemical studies. Int J Clin Exp Patho 11(10):5139–5143

    Google Scholar 

  9. Ito Y, Miyauchi A, Nakamura Y, Miya A, Kobayashi K, Kakudo K (2007) Clinicopathologic significance of intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation: a collaborative study with Member Institutes of The Japanese Society of Thyroid Surgery. Am J Clin Pathol 127(2):230–236. https://doi.org/10.1309/VM7E52B6U9Q729DQ

    Article  PubMed  Google Scholar 

  10. Suzuki A, Hirokawa M, Takada N, Higuchi M, Tanaka A, Hayashi T, Kuma S, Miyauchi A (2018) Utility of monoclonal PAX8 antibody for distinguishing intrathyroid thymic carcinoma from follicular cell-derived thyroid carcinoma. Endocr J 65(12):1171–1175. https://doi.org/10.1507/endocrj.EJ18-0282

    Article  CAS  PubMed  Google Scholar 

  11. Ren WH, Dong K, Huang XZ, Zhu YL (2019) Intrathyroidal thymic carcinoma exhibiting neuroendocrine differentiation: case report with cytomorphology, immunocytochemistry, and review of the literature focusing on cytology. Diagn Cytopathol 47(11):1197–1202. https://doi.org/10.1002/dc.24281

    Article  PubMed  Google Scholar 

  12. Zheng ZG, Sun WY (2021) Clinicopathological features of intrathyroid thymic carcinoma. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 43(1):42–46. https://doi.org/10.3881/j.issn.1000-503X.12609

  13. Veits L, Mechtersheimer G, Steger C, Freitag J, Mikuz G, Schmid KW, Hofmann W, Schirmacher P, Hartmann A, Rieker RJ (2011) Chromosomal imbalances in carcinoma showing thymus-like elements (CASTLE). Virchows Arch 459(2):221–226. https://doi.org/10.1007/s00428-011-1117-7

    Article  PubMed  Google Scholar 

  14. Veits L, Schupfner R, Hufnagel P, Penzel R, Freitag J, Strobel P, Kern MA, Schroder S, Neuhold N, Schmid KW, Schirmacher P, Hartmann A, Rieker RJ (2014) KRAS, EGFR, PDGFR-alpha, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE). Diagn Pathol 9:116. https://doi.org/10.1186/1746-1596-9-116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rajeshwari M, Singh V, Nambirajan A, Mridha AR, Jain D (2018) Carcinoma showing thymus like elements: report of a case with EGFR T790M mutation. Diagn Cytopathol. 46(5):413–418. https://doi.org/10.1002/dc.23859

    Article  PubMed  Google Scholar 

  16. Wong E, Tetter N, Tzankov A, Muller L (2018) CASTLE tumor of the parotid: first documented case, literature review, and genetic analysis of the cancer. Head Neck-J Sci Spec 40:E1–E4. https://doi.org/10.1002/hed.24985

    Article  Google Scholar 

  17. Ishikawa T, Ogawa T, Nakanome A, Yamauchi Y, Usubuchi H, Shiihara M, Yoshida T, Okamura Y, Kinoshita K, Katori Y, Furukawa T (2021) Whole exome sequencing and establishment of an organoid culture of the carcinoma showing thymus-like differentiation (CASTLE) of the parotid gland. Virchows Arch 478(6):1149–1159. https://doi.org/10.1007/s00428-020-02981-8

    Article  CAS  PubMed  Google Scholar 

  18. Cal S, Lopez-Otin C (2015) ADAMTS proteases and cancer. Matrix Biol 44–46:77–85. https://doi.org/10.1016/j.matbio.2015.01.013

    Article  CAS  PubMed  Google Scholar 

  19. Shi H, Sun L, Wang Y, Liu A, Zhan X, Li X, Tang M, Anderton P, Hildebrand S, Quan J, Ludwig S, Moresco E, Beutler B (2021) N4BP1 negatively regulates NF-kappaB by binding and inhibiting NEMO oligomerization. Nat Commun 12(1):1379. https://doi.org/10.1038/s41467-021-21711-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lin C, Song W, Bi X, Zhao J, Huang Z, Li Z, Zhou J, Cai J, Zhao H (2014) Recent advances in the ARID family: focusing on roles in human cancer. Oncotargets Ther 7:315–324. https://doi.org/10.2147/OTT.S57023

    Article  CAS  Google Scholar 

  21. Zhu Y, Yan C, Wang X, Xu Z, Lv J, Xu X, Yu W, Zhou M, Yue L (2022) Pan-cancer analysis of ARID family members as novel biomarkers for immune checkpoint inhibitor therapy. Cancer Biol Ther 23(1):104–111. https://doi.org/10.1080/15384047.2021.2011643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bhatia N, Herter JR, Slaga TJ, Fuchs SY, Spiegelman VS (2002) Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB. Oncogene 21(10):1501–1509. https://doi.org/10.1038/sj.onc.1205311

    Article  CAS  PubMed  Google Scholar 

  23. Kim TY, Siesser PF, Rossman KL, Goldfarb D, Mackinnon K, Yan F, Yi X, MacCoss MJ, Moon RT, Der CJ, Major MB (2015) Substrate trapping proteomics reveals targets of the betaTrCP2/FBXW11 ubiquitin ligase. Mol Cell Biol 35(1):167–181. https://doi.org/10.1128/MCB.00857-14

    Article  CAS  PubMed  Google Scholar 

  24. Wang L, Feng W, Yang X, Yang F, Wang R, Ren Q, Zhu X, Zheng G (2018) Fbxw11 promotes the proliferation of lymphocytic leukemia cells through the concomitant activation of NF-kappaB and beta-catenin/TCF signaling pathways. Cell Death Dis 9(4):427. https://doi.org/10.1038/s41419-018-0440-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nogai H, Wenzel SS, Hailfinger S, Grau M, Kaergel E, Seitz V, Wollert-Wulf B, Pfeifer M, Wolf A, Frick M, Dietze K, Madle H, Tzankov A, Hummel M, Dorken B, Scheidereit C, Janz M, Lenz P, Thome M, Lenz G (2013) IkappaB-zeta controls the constitutive NF-kappaB target gene network and survival of ABC DLBCL. Blood 122(13):2242–2250. https://doi.org/10.1182/blood-2013-06-508028

    Article  CAS  PubMed  Google Scholar 

  26. Fujita M, Enomoto T, Haba T, Nakashima R, Sasaki M, Yoshino K, Wada H, Buzard GS, Matsuzaki N, Wakasa K, Murata Y (1997) Alteration of p16 and p15 genes in common epithelial ovarian tumors. Int J Cancer 74(2):148–155. https://doi.org/10.1002/(sici)1097-0215(19970422)74:2%3c148::aid-ijc2%3e3.0.co;2-z

    Article  CAS  PubMed  Google Scholar 

  27. Lamperska K, Karezewska A, Kwiatkowska E, Mackiewicz A (2002) Analysis of mutations in the p16/CDKN2A gene in sporadic and familial melanoma in the Polish population. Acta Biochim Pol 49(2):369–376

    Article  CAS  PubMed  Google Scholar 

  28. Lee TJ, Bae JJ, Lee JS, Lee SY, Kim HJ, Kim SK, Lee JY, Lee TY (2000) Abrogation of the p16-Rb pathway in Korean hepatocellular carcinomas. Hepatogastroenterology 47(36):1663–1668

    CAS  PubMed  Google Scholar 

  29. Ishii H, Tsujikawa T, Oishi N, Kinouchi A, Sakamoto K, Mitsuda J, Ogi H, Itoh K, Kondo T, Hirano S, Sakurai D (2022) Genomic and immune microenvironment profiling in a case of metastatic intrathyroid thymic carcinoma. Clin Case Rep 10(7):e6050. https://doi.org/10.1002/ccr3.6050

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424(6950):801–805. https://doi.org/10.1038/nature01802

    Article  CAS  PubMed  Google Scholar 

  31. Ye R, Liu D, Guan H, AiErken N, Fang Z, Shi Y, Zhang Y, Wang S (2021) AHNAK2 promotes thyroid carcinoma progression by activating the NF-kappaB pathway. Life Sci 286:120032. https://doi.org/10.1016/j.lfs.2021.120032

    Article  CAS  PubMed  Google Scholar 

  32. Erinjeri NJ, Nicolson NG, Deyholos C, Korah R, Carling T (2018) Whole-exome sequencing identifies two discrete druggable signaling pathways in follicular thyroid cancer. J Am Coll Surgeons 226(6):950–959. https://doi.org/10.1016/j.jamcollsurg.2018.01.059

    Article  Google Scholar 

  33. Pacifico F, Leonardi A (2010) Role of NF-kappaB in thyroid cancer. Mol Cell Endocrinol 321(1):29–35. https://doi.org/10.1016/j.mce.2009.10.010

    Article  CAS  PubMed  Google Scholar 

  34. Suster D, Pihan G, Mackinnon AC, Suster S (2018) Poorly differentiated nonkeratinizing squamous cell carcinoma of the thymus: clinicopathologic and molecular genetic study of 25 cases. Am J Surg Pathol 42(9):1224–1236. https://doi.org/10.1097/PAS.0000000000001101

    Article  PubMed  Google Scholar 

  35. Gurizzan C, Zamparini M, Volante M, Tovazzi V, Amoroso V, Consoli F, Petrelli F, Grisanti S, Bossi P, Berruti A (2021) Outcome of patients with intrathyroidal thymic carcinoma: a pooled analysis. Endocr Relat Cancer 28(8):593–604. https://doi.org/10.1530/ERC-21-0123

  36. Gao R, Jia X, Ji T, Feng J, Yang A, Zhang G (2018) Management and prognostic factors for thyroid carcinoma showing thymus-like elements (CASTLE): a case series study. Front Oncol 8:477. https://doi.org/10.3389/fonc.2018.00477

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No.55, Section 4, Renmin South Road, Chengdu, 610041, China

    Jiayu Li, Yunzhu Li, Qiong Liao & Yang Liu

  2. Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China

    Run Xiang

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Contributions

QL and YL contributed to the study conception and design. Material preparation, data collection, and analysis were performed by JYL, RX, and YZL. The first draft of the manuscript was written by JYL, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qiong Liao or Yang Liu.

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The present study was approved by the Ethics Committees of Sichuan Cancer Hospital & Institute (Chengdu, China). Written informed consent was provided by all patients prior to the study start.

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The authors declare no competing interests.

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Run Xiang is the co-first author.

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Li, J., Xiang, R., Li, Y. et al. Intrathyroid thymic carcinoma: clinicopathological features and whole exome sequencing analysis. Virchows Arch 482, 813–822 (2023). https://doi.org/10.1007/s00428-023-03536-3

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