Cytologic, histologic and molecular findings of papillary thyroid carcinoma variants, one institution’s experience

Abstract

Papillary thyroid carcinoma (PTC) has two major types, classic (PTCC) and follicular variant (FVPTC), which correlate with molecular findings and have varying clinical implications. We assessed the cytologic findings and subsequent surgical pathology findings with the molecular mutations in these two groups, including microcarcinomas. Fourty-four patients with PTC resections over a one-year period were retrospectively examined in conjunction with previous cytologic diagnoses. BRAF, NRAS and TERT promoter mutations for the resected specimens were analyzed. Correlation with previous cytology in regard to molecular mutations and tumor size (microcarcinoma) were made. Significantly more BRAF V600E mutations were seen with PTCC, whereas significantly more NRAS mutations were seen with FVPTC. TERT mutations were only seen with PTCC. Molecular studies for thyroid carcninomas are becoming increasingly more common and influence treatment and patient prognosis. BRAF and or TERT mutations are associated with a worse prognosis. NRAS mutations associated with FVPTC and may lead to milder cytologic changes compared to the BRAF- and TERT-driven PTCC.

Keywords

Papillary thyroid carcinoma / follicular variant / BRAF / NRAS / TERT

References

[1] Haddad RI, Nasr C, Bischoff L, Busaidy NL, Byrd D, et al. NCCN guidelines insights: Thyroid carcinoma, version 2.2018. J Natl Compr Canc Netw. 2018 Dec; 16(12):1429-1440. PMid:30545990. https://doi.org/10.6004/jnccn.2018.0089

[2] Bandoh N, Akehane T, Goto T, et al. Targeted next-generation se-quencing of cancer-related genes in thyroid carcinoma: A single institution’s experience. Oncol Lett. 2018 Dec; 16(6):7278-7286. PMid:30546467. https://doi.org/10.3892/ol.2018.9538

[3] Canadas GM, Becerra MP, Casares AM, et al. Relevance of BRAF and NRAS mutations in the primary tumor and metastases of papil-lary thyroid carcinoma. Head Neck. 2016 Dec; 38(12):1772-1779. PMid:27299298. https://doi.org/10.1002/hed.24517

[4] Chen H, Luthra R, Routbort MJ, Patel KP, Cabanillas ME, et al. Molecular profile of advanced thyroid carcinomas by next-generation sequencing: Characterizing tumors beyond diagnosis for targeted therapy. Mol Cancer Ther. 2018 Jul; 17(7):1575-1584. PMid:29695638. https://doi.org/10.1158/1535-7163.MCT-17-0871

[5] Fakhruddin N, Jabbour M, Novy M, et al. BRAF and NRAS mu-tations in papillary thyroid carcinoma and concordance in BRAF mutations between primary and corresponding lymph node metas- tases. Sci Rep. 2017 Jul; 7(1): 4666. PMid:28680105. https://doi.org/10.1038/s41598-017-04948-3

[6] Penna GC, Vaisman F, Vaisman M. Molecular markers involved in tumorigenesis of thyroid carcinoma: Focus on aggressive histiotypes. Cytogenet Genome Res. 2016; 150(3-4):194-207. PMid:28231576. https://doi.org/10.1159/000456576

[7] Kure S, Wada R, Naito Z. Relationship between genetic alter-ations and clinicopathological characteristics of papillary thyroid carcinoma. Med Mol Morphol. 2019 Feb. PMid:30788603. https://doi.org/10.1007/s00795-019-00217-6

[8] Valvo V, Nucera C. Coding molecular determinants of thyroid cancer development and progression. Endocrinol Metab Clin North Am. 2019 Mar; 48(1):37-59. PMid:30717910. https://doi.org/10.1016/j.ecl.2018.10.003

[9] Patel SG, Carty SE, McCoy KL, et al. Preoperative detection of RAS mutation may guide extent of thyroidectomy. Surgery. 2017 Jan; 161(1):168-175. PMid:27863786. https://doi.org/10.1016/j.surg.2016.04.054

[10] Yang J, Gong Y, Yan S, et al. Comparison of the clinicopathological behavior of the follicular variant of papillary thyroid carcinoma and classical papillary thyroid carcinoma: A systematic review and meta- analysis. Mol Clin Oncol. 2015 Jul; 3(4):753-764. PMid:26171175. https://doi.org/10.3892/mco.2015.540

[11] Chem KT, Rosai J. Follicular variant of thyroid papillary carci-noma: a clinicopathologic study of six cases. Am J Surg Pathol. 1977 Jun; 1(2):123-30. https://doi.org/10.1097/00000478-197706000-00003

[12] Henke LE, Pfeifer JD, Baranski TJ, et al. Long-term outcomes of follicular variant vs classic papillary thyroid carcinoma. En-docr Connect. 2018 Dec; 7:12):1226-1235. PMid:30352402. https://doi.org/10.1530/EC-18-0264

[13] Guney G, Tezel GG, Kosemehmetoglu K, et al. Molecular features of follicular variant papillary carcinoma of thyroid: comparison of areas with or without classical nuclear features. Endocr Pathol. 2014 Sep; 25(3):241-7. PMid:24277231. https://doi.org/10.1007/s12022-013-9275-6

[14] Lee SR, Jung CK, Kim TE, et al. Molecular genotyping of follicu-lar variant of papillary thyroid carcinoma correlates with diagnostic category of fine needle aspiration cytology: values of RAS muta-tion testing. Thyroid. 2013 Nov; 23(11):1416-22. PMid:23590130. https://doi.org/10.1089/thy.2012.0640

[15] Hwang TS, Kim WY, Han HS, et al. Preoperative RAS muta-tional analysis is of great value in predicting follicular variant of papillary thyroid carcinoma. Biomed Res Int. 2015; 2015:697068. PMid:25648502. https://doi.org/10.1155/2015/697068

[16] Kim MJ, Won JK, Jung KC, et al. Clinical characteristics of subtypes of follicular variant papillary thyroid carcinoma. Thyroid. 2018 Mar; 28(3):311-318. PMid:29343212. https://doi.org/10.1089/thy.2016.0671

[17] Gandolfi G, Ragazzi M, et al. TERT promoter mutations in papillary thyroid microcarcinomas. Thyroid. 2015 Sep; 25(9):1031-9. PMid:26148423. https://doi.org/10.1089/thy.2015.0101

[18] Rodrigues AC, Penna G, Rodrigues E, et al. The genetics of papillary microcarcinomas of the thyroid: Diagnostic and prognostic impli-cations. Curr Genomics. 2017 Jun; 18(3):244-254. PMid:28659720. https://doi.org/10.2174/1389202918666170105094459

[19] Adeniran AJ, Hui P. Best practice of BRAF V600E mutation test-ing for the diagnosis and management of thyroid cancers. Expert Rev Endocrinol Metab. 2014 Nov; 9(6):571-577. PMid:30736195. https://doi.org/10.1586/17446651.2014.951635

[20] Melo M, Gaspar da Rocha A, Batista R, et al. TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. J Clin Endocrinol Metab. 2017 Jun; 102(6):1898-1907. PMid:28323937. https://doi.org/10.1210/jc.2016-2785

[21] Kowalska A, Walczyk A, Kowalik A, et al. Increase in papillary thy-roid cancer incidence is accompanied by changes in the frequency of the BRAFV600E mutation: A single-institution study. Thyroid. 2016; 26(4):543-551. PMid:26889698. https://doi.org/10.1089/thy.2015.0352

[22] Poller DN, Glaysher S.Molecular pathology and thyroid FNA. Cy-topathology. 2017 Dec; 28(6):475-481. PMid:29165888. https://doi.org/10.1111/cyt.12492

[23] Tallini G, Tuttle RM, Ghossein RA. The history of the follicular vari-ant of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2017 Jan; 102(1):15-22. PMid:25148236. https://doi:10.1210/jc.2014-2611

[24] An JH, Song KH, Kim SK, et al. Ras mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2015 May; 82(5):760-6. PMid:25109485. https://doi.org/10.1111/cen.12579

[25] Crescenzi A, Fulciniti F, Bongiovanni M, et al. Detecting N-RAS Q61R mutated thyroid neoplasias by immunohistochemistry. Endocr Pathol. 2017 Mar; 28(1):71-74. PMid:28064410. https://doi.org/10.1007/s12022-016-9466-z

[26] Rivera M, Ricarte FJ, Knauf J, et al. Molecular genotyping of papil-lary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. 2010 Sep; 23(9):1191-200. PMid:20526288. https://doi.org/10.1038/modpathol.2010.112

[27] Vuong HG, Duong UN, Altibi AM, Ngo HT, Pham TQ, et al. A meta-analysis of prognostic roles of molecular markers in papil-lary thyroid carcinoma. Endocr Connect. 2017 Apr; 6(3):R8-R17. PMid:28219937. https://doi.org/10.1530/EC-17-0010

[28] Proietti A, Sartori C, Macerola E, et al. Low frequency of TERT promoter mutations in a series of well-differentiated follicular-patterned thyroid neoplasms. Virchows Arch. 2017 Dec; 471(6):769-773. PMid:28975450. https://doi.org/10.1007/s00428-017-2236-6

[29] Alzahrani AS, Alsaadi R, Murugan AK, et al. TERT promoter mu-tations in thyroid cancer. Horm Cancer. 2016 Jun; 7(3):165-77. PMid:26902827 https://doi.org/10.1007/s12672-016-0256-3

[30] Kim TH, Kim YE, Ahn S, et al. TERT promoter mutations and long-term survival in patients with thyroid cancer. Endocr Relat Cancer. 2016 Oct; 23(10):813-23. PMid:27528624. https://doi.org/10.1530/ERC-16-0219

[31] Kim TH, Ki CS, Kim HS, et al. Refining dynamic risk stratifica-tion and prognostic groups for differentiated thyroid cancer with TERT promoter mutations. J Clin Endocrinol Metab. 2017 May; 102(5):1757-1764. PMid:28323925. https://doi.org/10.1210/jc.2016-3434

[32] Adeniran AJ, Zhu Z, Gnadhi M, et al. Correlation between ge-netic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006 Feb; 30(2):216-22. PMid:16434896. https://doi.org/10.1097/01.pas.0000176432.73455.1b

[33] Bernaud C, Descotes F, Decaussin PM, et al. TERT promoter muta-tions identify a high-risk group in metastasis-free advanced thyroid carcinoma. Eur J Cancer. 2019 Feb; 108:41-49. PMid:30648628. https://doi.org/10.1016/j.ejca.2018.12.003

[34] Liu Z, Lv T, Xie C, et al. BRAF V600E gene mutation is asso-ciated with bilateral malignancy of papillary thyroid cancer. Am J Med Sci. 2018 Aug; 356(2):130-134. PMid:30219154. https://doi.org/10.1016/j.amjms.2018.04.012

[35] Insilla AC, Proietti A, Borrelli N, et al. TERT promoter mutations and their correlation with BRAF and NRAS mutations in a con-secutive cohort of 145 thyroid cancer cases. Oncol Lett. 2018 Mar; 15(3):2763-2770. https://doi.org/10.3892/ol.2017.7675

[36] Yin DT, Yu K, Lu RQ, et al. Clinicopathological significance of TERT promoter mutation in papillary thyroid carcinomas: a systematic re-view and meta-analysis. Clin Endocrinol (Oxf). 2016 Aug; 85(2):299-305. PMid:26732020 https://doi.org/10.1111/cen.13017

[37] Ren H, Shen Y, Hu D, et al. Co-existence of BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma is associ-ated with tumor aggressiveness, but not with lymph node metasta-sis. Cancer Manag Res. 2018 May; 10:1005-1013. PMid:29760568 https://doi.org/10.2147/CMAR.S159583

[38] Bullock M, Ren Y, O’Neill C, et al. TERT promoter mutations are a major indicator of recurrence and death due to papillary thy-roid carcinomas. Clin Endocrinol (Oxf). 2016 Aug; 85(2):283-90. PMid:26667986. https://doi.org/10.1111/cen.12999

[39] Liu R, Bishop J, Zhu G, et al. Mortality risk stratification by combin-ing BRAF V600E and TERT promoter mutations in papillary thyroid cancer: genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality. JAMA Oncol. 2016 Sep 1. PMid:27581851. https://doi.org/10.1001/jamaoncol.2016.3288

[40] Jin L, Chen E, Dong S, et al. BRAF and TERT promoter muta-tions in the aggressiveness of papillary thyroid carcinoma: A study of 653 patients. Oncotarget. 2016 Apr; 7(14):18346-55. https://doi.org/10.18632/oncotarget.7811

[41] Jin A, Xu J, Wang Y. The role of TERT promoter mutations in post-operative and preoperative diagnosis and prognosis in thyroid cancer. Medicine (Baltimore). 2018 Jul; 97(29): e11548. PMid:30024548. https://doi.org/10.1097/MD.0000000000011548

[42] Liu C, Liu Z, Chen T, et al. TERT promoter mutation and its asso-ciation with clinicopathological features and prognosis of papillary thyroid cancer: A meta-analysis. Sci Rep. 2016 Nov; 6: 36990. PMid:27833153. https://doi.org/10.1038/srep36990z

[43] Moon S, Song YS, Kim YA, et al. Thyroid.2017 May; 27(5):651-660. PMid:28181854. https://doi.org/10.1089/thy.2016.0350

[44] Vuong HG, Altibi AM, Duong UNP, et al. Prognostic implication of BRAF and TERT promoter mutation combination in papillary thy-roid carcinoma-A meta-analysis. Clin Endocrinol (Oxf). 2017 Nov: 87(5):411-417. PMid:28666074. https://doi.org/10.1111/cen.13413