Endocrine Pathology

, Volume 28, Issue 2, pp 103–111 | Cite as

Frequent BRAF V600E and Absence of TERT Promoter Mutations Characterize Sporadic Pediatric Papillary Thyroid Carcinomas in Japan

  • Naoki Oishi
  • Tetsuo Kondo
  • Tadao Nakazawa
  • Kunio Mochizuki
  • Tomohiro Inoue
  • Kazunari Kasai
  • Ippei Tahara
  • Tomonori Yabuta
  • Mitsuyoshi Hirokawa
  • Akira Miyauchi
  • Ryohei KatohEmail author


Pediatric papillary thyroid carcinoma (PTC) has unique features but requires further genetic investigation. Moreover, there has been increasing concern about the risk for pediatric PTC in Japan after the Fukushima accident. This study aims to evaluate the frequencies of BRAF and TERT promoter mutations and to examine their significance in non-radiation-associated pediatric PTCs in Japan. We enrolled 81 pediatric PTC patients aged ≤20 years. The control group included 91 adult PTCs from patients >20 years old. BRAF and TERT mutations were analyzed by allele-specific-PCR and/or Sanger sequencing. Compared with adult PTCs, pediatric PTCs exhibited larger tumor size, more frequent lymph node metastasis, and less classical histology. The prevalence of BRAF V600E in pediatric PTCs was 54% and significantly lower than that in adults of 85%. In the pediatric PTCs, BRAF V600E was positively associated with older age, classical histology, and the lymph node metastasis but independent from other clinicopathological factors. TERT mutations were identified in 13% of adults and in none of the pediatric PTCs. In conclusion, pediatric PTCs are characterized by more advanced clinicopathological features, lower BRAF V600E frequency, and absence of TERT mutation. The BRAF V600E frequency in this study is similar to the reported BRAF V600E frequency in the ultrasonographically screened pediatric PTCs in Fukushima.


Papillary thyroid carcinoma Pediatric Adult Mutation BRAF TERT 



We thank Ms. Wakaba Iha, Ms. Miyuki Ito, Ms. Mikiko Yoda, and Mr. Yoshihito Koshimizu for technical support and Ms. Kayoko Kono for executive assistance.

Compliance with Ethical Standards


This study was funded by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number 25293087 and 90,623,661).

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures in this study were in accordance with the ethical standards of the institutional research committee. For this type of study, formal consent is not required.

Supplementary material

12022_2017_9470_MOESM1_ESM.pdf (113 kb)
ESM 1 (PDF 113 kb.)


  1. 1.
    Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol 21 Suppl 2:S37-S43, 2008.CrossRefPubMedGoogle Scholar
  2. 2.
    LiVolsi VA. Papillary thyroid carcinoma: an update. Mod Pathol 24 Suppl 2(S2):S1–S9, 2011.CrossRefPubMedGoogle Scholar
  3. 3.
    Giuffrida D, Scollo C, Pellegriti G, Lavenia G, Iurato MP, Pezzin V, et al. Differentiated thyroid cancer in children and adolescents. J Endocrinol Invest 25:18–24, 2011.CrossRefGoogle Scholar
  4. 4.
    Nikiforova MN, Ciampi R, Salvatore G, Santoro M, Gandhi M, Knauf JA, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 209:1–6, 2004.CrossRefPubMedGoogle Scholar
  5. 5.
    Penko K, Livezey J, Fenton C, Patel A, Nicholson D, Flora M, et al. BRAF mutations are uncommon in papillary thyroid cancer of young patients. Thyroid 15:320–325, 2005.CrossRefPubMedGoogle Scholar
  6. 6.
    Rosenbaum E, Hosler G, Zahurak M, Cohen Y, Sidransky D, Westra WH. Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma. Mod Pathol 18:898–902, 2005.CrossRefPubMedGoogle Scholar
  7. 7.
    Ito Y, Kihara M, Takamura Y, Kobayashi K, Miya A, Hirokawa M, et al. Prognosis and prognostic factors of papillary thyroid carcinoma in patients under 20 years. Endocr J 59:539–545, 2012.CrossRefPubMedGoogle Scholar
  8. 8.
    Sassolas G, Hafdi-Nejjari Z, Ferraro A, Decaussin-Petrucci M, Rousset B, Borson-Chazot F, et al. Oncogenic alterations in papillary thyroid cancers of young patients. Thyroid 22:17–26, 2012.CrossRefPubMedGoogle Scholar
  9. 9.
    Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF, Hunt JP. BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. Laryngoscope 124:E389-E393, 2014.CrossRefPubMedGoogle Scholar
  10. 10.
    Henke LE, Perkins SM, Pfeifer JD, Ma C, Chen Y, DeWees T, et al. BRAF V600E mutational status in pediatric thyroid cancer. Pediatr Blood Cancer 61:1168–1172, 2014CrossRefPubMedGoogle Scholar
  11. 11.
    Cordioli MICV, Moraes L, Cury AN, Cerutti JM. Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma? Endocr Relat Cancer 22:R311–324, 2015.CrossRefPubMedGoogle Scholar
  12. 12.
    Nikiforov YE, Erickson LA, Nikiforova MN, Caudill CM, Lloyd R V. Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior. Am J Surg Pathol 25:1478–1484, 2001.CrossRefPubMedGoogle Scholar
  13. 13.
    Sheu S-Y, Schwertheim S, Worm K, Grabellus F, Schmid KW. Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements. Mod Pathol 20:779–787, 2007.CrossRefPubMedGoogle Scholar
  14. 14.
    Pillai S, Gopalan V, Smith R a, Lam AK-Y. Diffuse sclerosing variant of papillary thyroid carcinoma-an update of its clinicopathological features and molecular biology. Crit Rev Oncol Hematol 94:64–73, 2014CrossRefPubMedGoogle Scholar
  15. 15.
    Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306, 2006.CrossRefPubMedGoogle Scholar
  16. 16.
    Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13:184–199, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    The Cancer Genome Atral Research Network. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 159:676–690, 2014.CrossRefGoogle Scholar
  18. 18.
    Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 7:569–580, 2011.CrossRefPubMedGoogle Scholar
  19. 19.
    Kumagai A, Namba H, Saenko V a., Ashizawa K, Ohtsuru A, Ito M, et al. Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab 89:4280–4284, 2004.CrossRefPubMedGoogle Scholar
  20. 20.
    Onder S, Ozturk Sari S, Yegen G, Sormaz IC, Yilmaz I, Poyrazoglu S, et al. Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF V600E Harboring Pediatric Papillary Thyroid Carcinomas. Endocr Pathol 27:153–161, 2016CrossRefPubMedGoogle Scholar
  21. 21.
    Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther 10:385–394, 2011.CrossRefPubMedGoogle Scholar
  22. 22.
    Landa I, Ganly I, Chan T a., Mitsutake N, Matsuse M, Ibrahimpasic T, et al. Frequent Somatic TERT Promoter Mutations in Thyroid Cancer: Higher Prevalence in Advanced Forms of the Disease. J Clin Endocrinol Metab 98:E1562–1566, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu T, Wang N, Cao J, Sofiadis A, Dinets A, Zedenius J, et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene. 33:4978–4984, 2014.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer.20:603–610, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Alzahrani AS, Qasem E, Murugan AK, Al-Hindi HN, AlKhafaji D, Almohanna M, et al. Uncommon TERT Promoter Mutations in Pediatric Thyroid Cancer. Thyroid. 26:235–241, 2016.CrossRefPubMedGoogle Scholar
  26. 26.
    Cardis E, Howe G, Ron E, Bebeshko V, Bogdanova T, Bouville A, et al. Cancer consequences of the Chernobyl accident: 20 years on. J Radiol Prot. 26(2):127–40, 2006.CrossRefPubMedGoogle Scholar
  27. 27.
    Mitsutake N, Fukushima T, Matsuse M, Rogounovitch T, Saenko V, Uchino S, et al. BRAFV600E mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl. Sci Rep 16976, 2015Google Scholar
  28. 28.
    Nagataki S, Takamura N. A review of the Fukushima nuclear reactor accident: radiation effects on the thyroid and strategies for prevention. Curr Opin Endocrinol Diabetes Obes 21:384–393, 2014.CrossRefPubMedGoogle Scholar
  29. 29.
    LiVolsi VA, Albores-Saavedra J, Asa SL, Baloch ZW, Sobrinho-Simões M, Wenig B et al. Papillary carcinoma, in DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds): Pathology and genetics of tumours of endocrine organs. Lyon: IARC; 2004. pp 57–66.Google Scholar
  30. 30.
    Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer 72:777–783, 1995.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Warden DW, Ondrejka S, Lin J, Durkin L, Bodo J, Hsi ED. Phospho-ERK(THR202/Tyr214) is overexpressed in hairy cell leukemia and is a useful diagnostic marker in bone marrow trephine sections. Am J Surg Pathol 37:305–308, 2013CrossRefPubMedGoogle Scholar
  32. 32.
    Oishi N, Kondo T, Mochizuki K. Localized Langerhans cell histiocytosis of the thymus with BRAF V600E mutation : a case report with immunohistochemical and genetic analyses. Hum Pathol 45:1302–1305, 2014CrossRefPubMedGoogle Scholar
  33. 33.
    Xu B, Yoshimoto K, Miyauchi A, Kuma S, Mizusawa N, Hirokawa M, et al. 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. 199:58–67, 2003.CrossRefPubMedGoogle Scholar
  34. 34.
    Kwon MJ, Rho Y-S, Jeong JC, Shin HS, Lee JS, Cho SJ, et al. Cribriform-morular variant of papillary thyroid carcinoma: a study of 3 cases featuring the PIK3CA mutation. Hum Pathol 46:1180–1188, 2015CrossRefPubMedGoogle Scholar
  35. 35.
    Song YS, Lim JA, Park YJ. Mutation Profile of Well-Differentiated Thyroid Cancer in Asians. Endocrinol Metab 30:252–262, 2015.CrossRefGoogle Scholar
  36. 36.
    Finkelstein A, Levy GH, Hui P, Prasad A, Virk R, Chhieng DC, et al. Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct. Histopathology 60:1052–1059, 2012.CrossRefPubMedGoogle Scholar
  37. 37.
    Koperek O, Kornauth C, Capper D, Berghoff AS, Asari R, Niederle B, et al. Immunohistochemical detection of the BRAF V600E-mutated protein in papillary thyroid carcinoma. Am J Surg Pathol 36:844–850, 2012.CrossRefPubMedGoogle Scholar
  38. 38.
    Virk RK, Theoharis CG a, Prasad A, Chhieng D, Prasad ML. Morphology predicts BRAFV600E mutation in papillary thyroid carcinoma: an interobserver reproducibility study. Virchows Arch 464:435–442, 2014.CrossRefPubMedGoogle Scholar
  39. 39.
    Li C, Lee KC, Schneider EB, Zeiger MA. BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab. 97:4559–4570, 2012.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lim JY, Hong SW, Lee YS, Kim B-W, Park CS, Chang H-S, et al. Clinicopathologic implications of the BRAF(V600E) mutation in papillary thyroid cancer: a subgroup analysis of 3130 cases in a single center. Thyroid 23:1423–1430, 2013CrossRefPubMedGoogle Scholar
  41. 41.
    Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493–1501, 2013CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ito Y, Yoshida H, Maruo R, Morita S, Takano T, Hirokawa M, et al. BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr J 56:89–97, 2009CrossRefPubMedGoogle Scholar
  43. 43.
    Gouveia C, Can NT, Bostrom A, Grenert JP, van Zante A, Orloff LA. Lack of association of BRAF mutation with negative prognostic indicators in papillary thyroid carcinoma: the University of California, San Francisco, experience. JAMA Otolaryngol Head Neck Surg 139:1164–1170, 2013CrossRefPubMedGoogle Scholar
  44. 44.
    Li C, Aragon Han P, Lee KC, Lee LC, Fox AC, Beninato T, et al. Does BRAF V600E Mutation Predict Aggressive Features in Papillary Thyroid Cancer? Results From Four Endocrine Surgery Centers. J Clin Endocrinol Metab. 98:3702–3712, 2013CrossRefPubMedGoogle Scholar
  45. 45.
    Cheng S, Serra S, Mercado M, Ezzat S, Asa SL. A High-Throughput Proteomic Approach Provides Distinct Signatures for Thyroid Cancer Behavior. Clin Cancer Res 17:2385–2394, 2011CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Naoki Oishi
    • 1
  • Tetsuo Kondo
    • 1
  • Tadao Nakazawa
    • 1
  • Kunio Mochizuki
    • 1
  • Tomohiro Inoue
    • 1
  • Kazunari Kasai
    • 1
  • Ippei Tahara
    • 1
  • Tomonori Yabuta
    • 2
  • Mitsuyoshi Hirokawa
    • 3
  • Akira Miyauchi
    • 2
  • Ryohei Katoh
    • 1
    Email author
  1. 1.Department of PathologyUniversity of YamanashiYamanashiJapan
  2. 2.Department of SurgeryKuma HospitalKobeJapan
  3. 3.Department of Diagnostic PathologyKuma HospitalKobeJapan

Personalised recommendations