Advertisement

Endocrine Pathology

, Volume 28, Issue 1, pp 49–53 | Cite as

TERT Promoter Mutation in an Aggressive Cribriform Morular Variant of Papillary Thyroid Carcinoma

  • Eun Ji Oh
  • Sohee Lee
  • Ja Seong Bae
  • Yourha Kim
  • Sora Jeon
  • Chan Kwon JungEmail author
Article

Abstract

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare thyroid neoplasm characterized by unique morphologic findings and association with familial adenomatous polyposis. The biologic behavior of this variant has been reported to behave similarly to classic PTC. We report a rare sporadic case of CMV-PTC occurring in a 45-year-old female with multiple lymph nodes and bone metastases, which were detected after total thyroidectomy and radioactive iodine remnant ablation. Molecular analyses of primary thyroid and metastatic tumor tissues revealed a telomerase reverse transcriptase (TERT) promoter mutation, but absence of BRAF, KRAS, NRAS, HRAS, and PIK3CA mutations. Over a 4-year follow-up period, structurally identifiable bone metastases were persistent, but serial post-operative serum thyroglobulin levels remained undetectable in the absence of thyroglobulin antibody. The literature was reviewed. This is the first case of aggressive CMV-PTC showing TERT promoter mutation. TERT promoter mutations may help in predicting aggressive clinical behavior in CMV-PTC. Postoperative serum thyroglobulin measurement may have no impact on clinical decision-making in this type of tumor.

Keywords

Papillary thyroid carcinoma Cribriform-morular variant Telomerase reverse transcriptase Biomarker 

Notes

Acknowledgments

This research was supported by a grant (2013R1A2A2A01068570) of Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future planning, Republic of Korea. The authors gratefully acknowledge the use of the services and facilities of the Catholic Cancer Research Institute at the Catholic University of Korea.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Harach HR, Williams GT, Williams ED (1994) Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histopathology 25 (6):549–561CrossRefPubMedGoogle Scholar
  2. 2.
    Tomoda C, Miyauchi A, Uruno T, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Kuma S, Kuma K, Kakudo K (2004) Cribriform-morular variant of papillary thyroid carcinoma: clue to early detection of familial adenomatous polyposis-associated colon cancer. World J Surg 28 (9):886–889CrossRefPubMedGoogle Scholar
  3. 3.
    Jung CK, Choi YJ, Lee KY, Bae JS, Kim HJ, Yoon SK, Son YI, Chung JH, Oh YL (2009) The cytological, clinical, and pathological features of the cribriform-morular variant of papillary thyroid carcinoma and mutation analysis of CTNNB1 and BRAF genes. Thyroid 19 (8):905–913. doi: 10.1089/thy.2008.0332 CrossRefPubMedGoogle Scholar
  4. 4.
    Pradhan D, Sharma A, Mohanty SK (2015) Cribriform-morular variant of papillary thyroid carcinoma. Pathol Res Pract 211 (10):712–716. doi: 10.1016/j.prp.2015.04.011 CrossRefPubMedGoogle Scholar
  5. 5.
    Cameselle-Teijeiro J, Menasce LP, Yap BK, Colaco RJ, Castro P, Celestino R, Ruiz-Ponte C, Soares P, Sobrinho-Simoes M (2009) Cribriform-morular variant of papillary thyroid carcinoma: molecular characterization of a case with neuroendocrine differentiation and aggressive behavior. Am J Clin Pathol 131 (1):134–142. doi:  10.1309/AJCP7ULS0VSISBEB CrossRefPubMedGoogle Scholar
  6. 6.
    Cho U, Oh WJ, Bae JS, Lee S, Lee YS, Park GS, Lee YS, Jung CK (2014) Clinicopathological features of rare BRAF mutations in Korean thyroid cancer patients. J Korean Med Sci 29 (8):1054–1060. doi: 10.3346/jkms.2014.29.8.1054 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee SR, Jung CK, Kim TE, Bae JS, Jung SL, Choi YJ, Kang CS (2013) Molecular genotyping of follicular variant of papillary thyroid carcinoma correlates with diagnostic category of fine-needle aspiration cytology: values of RAS mutation testing. Thyroid 23 (11):1416–1422. doi:  10.1089/thy.2012.0640 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bae JS, Kim Y, Jeon S, Kim SH, Kim TJ, Lee S, Kim MH, Lim DJ, Lee YS, Jung CK (2016) Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation. Diagn Pathol 11:21. doi:  10.1186/s13000-016-0458-6 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kwon MJ, Rho YS, Jeong JC, Shin HS, Lee JS, Cho SJ, Nam ES (2015) Cribriform-morular variant of papillary thyroid carcinoma: a study of 3 cases featuring the PIK3CA mutation. Hum Pathol 46 (8):1180–1188. doi:  10.1016/j.humpath.2015.04.010 CrossRefPubMedGoogle Scholar
  10. 10.
    Oh WJ, Lee YS, Cho U, Bae JS, Lee S, Kim MH, Lim DJ, Park GS, Lee YS, Jung CK (2014) Classic papillary thyroid carcinoma with tall cell features and tall cell variant have similar clinicopathologic features. Korean J Pathol 48 (3):201–208. doi:  10.4132/KoreanJPathol.2014.48.3.201 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Giannelli SM, McPhaul L, Nakamoto J, Gianoukakis AG (2014) Familial adenomatous polyposis-associated, cribriform morular variant of papillary thyroid carcinoma harboring a K-RAS mutation: case presentation and review of molecular mechanisms. Thyroid 24 (7):1184–1189. doi:  10.1089/thy.2013.0589 CrossRefPubMedGoogle Scholar
  12. 12.
    Xu B, Yoshimoto K, Miyauchi A, Kuma S, Mizusawa N, Hirokawa M, Sano T (2003) Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene. J Pathol 199 (1):58–67. doi:  10.1002/path.1225 CrossRefPubMedGoogle Scholar
  13. 13.
    Uchino S, Noguchi S, Yamashita H, Yamashita H, Watanabe S, Ogawa T, Tsuno A, Murakami A, Miyauchi A (2006) Mutational analysis of the APC gene in cribriform-morula variant of papillary thyroid carcinoma. World J Surg 30 (5):775–779. doi:  10.1007/s00268-005-0368-3 CrossRefPubMedGoogle Scholar
  14. 14.
    Abbosh PH, Nephew KP (2005) Multiple signaling pathways converge on beta-catenin in thyroid cancer. Thyroid 15 (6):551–561. doi:  10.1089/thy.2005.15.551 CrossRefPubMedGoogle Scholar
  15. 15.
    Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z (2007) Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282 (15):11221–11229. doi:  10.1074/jbc.M611871200 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kurihara K, Shimizu S, Chong J, Hishima T, Funata N, Kashiwagi H, Nagai H, Miyaki M, Fukayama M (2000) Nuclear localization of immunoreactive beta-catenin is specific to familial adenomatous polyposis in papillary thyroid carcinoma. Jpn J Cancer Res 91 (11):1100–1102CrossRefPubMedGoogle Scholar
  17. 17.
    Song YS, Lim JA, Park YJ (2015) Mutation profile of well-differentiated thyroid cancer in Asians. Endocrinol Metab (Seoul) 30 (3):252–262. doi:  10.3803/EnM.2015.30.3.252 CrossRefGoogle Scholar
  18. 18.
    Lyros O, Rafiee P, Nie L, Medda R, Jovanovic N, Otterson MF, Behmaram B, Gockel I, Mackinnon A, Shaker R (2015) Wnt/beta-catenin signaling activation beyond robust nuclear beta-catenin accumulation in nondysplastic Barrett's Esophagus: regulation via Dickkopf-1. Neoplasia 17 (7):598–611. doi:  10.1016/j.neo.2015.07.006 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Samuels Y, Diaz LA, Jr., Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7 (6):561–573. doi:  10.1016/j.ccr.2005.05.014 CrossRefPubMedGoogle Scholar
  20. 20.
    Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, El-Naggar AK, Xing M (2008) Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 93 (8):3106–3116. doi:  10.1210/jc.2008-0273 CrossRefPubMedGoogle Scholar
  21. 21.
    Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE (2009) Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460 (7251):66–72. doi:  10.1038/nature08137 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Smekalova EM, Shubernetskaya OS, Zvereva MI, Gromenko EV, Rubtsova MP, Dontsova OA (2012) Telomerase RNA biosynthesis and processing. Biochemistry (Mosc) 77 (10):1120–1128. doi:  10.1134/S0006297912100045 CrossRefGoogle Scholar
  23. 23.
    Mocellin S, Pooley KA, Nitti D (2013) Telomerase and the search for the end of cancer. Trends Mol Med 19 (2):125–133. doi:  10.1016/j.molmed.2012.11.006 CrossRefPubMedGoogle Scholar
  24. 24.
    Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, Castro P, Prazeres H, Lima J, Amaro T, Lobo C, Martins MJ, Moura M, Cavaco B, Leite V, Cameselle-Teijeiro JM, Carrilho F, Carvalheiro M, Maximo V, Sobrinho-Simoes M, Soares P (2014) TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 99 (5):E754–E765. doi:  10.1210/jc.2013-3734 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, Pai S, Bishop J (2014) BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 32 (25):2718–2726. doi:  10.1200/JCO.2014.55.5094 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Schuetze D, Hoschar AP, Seethala RR, Assaad A, Zhang X, Hunt JL (2009) The T1799A BRAF mutation is absent in cribriform-morular variant of papillary carcinoma. Arch Pathol Lab Med 133 (5):803-805. doi:  10.1043/1543-2165-133.5.803
  27. 27.
    Rossi ED, Revelli L, Martini M, Taddei A, Pintus C, Panunzi C, Fadda G (2012) Cribriform-morular variant of papillary thyroid carcinoma in an 8-year-old girl: a case report with immunohistochemical and molecular testing. Int J Surg Pathol 20 (6):629-632. doi:  10.1177/1066896912441830
  28. 28.
    Nakazawa T, Celestino R, Machado JC, Cameselle-Teijeiro JM, Vinagre J, Eloy C, Benserai F, Lameche S, Soares P, Sobrinho-Simoes M (2013) Cribriform-morular variant of papillary thyroid carcinoma displaying poorly differentiated features. Int J Surg Pathol 21 (4):379-389. doi:  10.1177/1066896912473355

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Eun Ji Oh
    • 1
  • Sohee Lee
    • 2
  • Ja Seong Bae
    • 2
  • Yourha Kim
    • 3
  • Sora Jeon
    • 3
  • Chan Kwon Jung
    • 1
    Email author
  1. 1.Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  2. 2.Department of Surgery, Seoul St. Mary’s Hosptial, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  3. 3.Department of Biomedicine & Health SciencesThe Catholic University of KoreaSeoulRepublic of Korea

Personalised recommendations