Background: Papillary thyroid cancer (PTC) is the most common differentiated thyroid cancer and is responsible for 80-90% of thyroid cancer cases. Despite typically excellent prognoses, these subclinical low-risk cancers are often treated aggressively by surgical thyroidectomy. Consequently, the objective of this study was to generate a prognostic matrix to be used prior to PTC intervention. Methods: In this study, 80 PTC patients were assessed. Following adjustment for sex, logistic regression analysis showed that BRAFV600E mutation, transforming growth factor beta (TGF-β) expression, age, and tumor size are risk factors that can affect tumor clinical stage (p < 0.05). Based on the results of this analysis, we generated a matrix that incorporated 4 variables: patient age, tumor size, BRAFV600E mutation, and TGF-β expression. Results: We observed that the corresponding area under curve was as high as 0.91. The sensitivity and specificity of the model were 94.74 and 83.61%, respectively. These values are significantly higher than those generated from single indexes. Conclusion: As a result of this analysis, it is hoped that the resultant matrix can be utilized during clinical diagnosis and treatment prior to thyroid nodule surgery.

Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, Zhang Y, Bai Y, Zhu C, Guo GL, Rothman N, Zhang Y: International patterns and trends in thyroid cancer incidence. Cancer Causes Control 2009;20:525-531.
Davies L, Welch H: Current thyroid cancer trends in the united states. JAMA Otolaryngol Head Neck Surg 2014;140:317-322.
Kweon SS, Shin MH, Chung IJ, Kim YJ, Choi JS: Thyroid cancer is the most common cancer in women, based on the data from population-based cancer registries, South Korea. Jpn J Clin Oncol 2013;43:1039-1046.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. Nature 2002;417:949-954.
Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373-6379.
Kim SJ, Lee KE, Myong JP, Park JH, Jeon YK, Min HS, Park SY, Jung KC, Koo do H, Youn YK: BRAF V600E mutation is associated with tumor aggressiveness in papillary thyroid cancer. World J Surg 2012;36:310-317.
Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O'Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Clifton-Bligh R, Tallini G, Holt EH, Sýkorová V: Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 2015;33:42-50.
Ito Y, Yoshida H, Kihara M, Kobayashi K, Miya A, Miyauchi A: BRAF(V600E) mutation analysis in papillary thyroid carcinoma: is it useful for all patients? World J Surg 2014;38:679-687.
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 2013;139:1164-1170.
Kilfoy BA, Devesa SS, Ward MH, Zhang Y, Rosenberg PS, Holford TR, Anderson WF: Gender is an age-specific effect modifier for papillary cancers of the thyroid gland. Cancer Epidemiol Biomarkers Prev 2009;18:1092-1100.
Riesco-Eizaguirre G, Gutiérrez-Martinez P, GarciaCabezas MA, Nistal M, Santisteban P: The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer 2006;13:257-269.
Grubeck-Loebenstein B, Buchan G, Sadeghi R, Kissonerghis M, Londei M, Turner M, Pirich K, Roka R, Niederle B, Kassal H: Transforming growth factor β regulates thyroid growth. Role in the pathogenesis of nontoxic goiter. J Clin Invest 1989;83:764-770.
Pardali K, Moustakas A: Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 2007;1775:21-62.
Bravo SB, Pampín S, Cameselle-Teijeiro J, Carneiro C, Domínguez F, Barreiro F, Alvarez CV: TGF-β-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-κB activation. Oncogene 2003;22:7819-7830.
Costamagna E, Garcia B, Santisteban P: The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-β repression of the sodium/iodide symporter gene. J Biol Chem 2004;279:3439-3446.
Kimura ET, Kopp P, Zbaeren J, Zbaeren J, Asmis MA, Ruchti C, Maciel RMB, Studer H: Expression of transforming growth factor β1, β2, and β3 in multinodular goiters and differentiated thyroid carcinomas: a comparative study. Thyroid 1999;9:119-125.
Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, Larin A, Savchenko V, Francis GL, de la Chapelle A, Saji M, Ringel MD: Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci U S A 2007;104:2803-2808.
Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, Santisteban P: The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res 2009;69:8317-8325.
American Joint Committee on Cancer: Thyroid; in Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller CG, Morrow M (eds): AJCC Cancer Staging Manual. New York, NY, Springer, 2002, pp. 77-87.
Wang Y, Ji M, Wang W, Miao Z, Hou P, Chen X, Xu F, Zhu G, Sun X, Li Y, Condouris S, Liu D, Yan S, Pan J, Xing M: Association of the T1799A BRAF mutation with tumor extrathyroidal invasion, higher peripheral platelet counts, and over expression of PDGF-B in papillary thyroid cancer. Endocr Relat Cancer 2008;15:183-190.
Robin X, Turck N, Hainard A, Tibertu N, Lisacek F, Sanchez J, Müller M: pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77.
Brito JP, Morris JC, Montori VM: Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumours. BMJ 2013;347:f4706.
Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE: BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003;88:5399-5404.
Kim KH, Kang DW, Kim SH, Seong IO, Kang DY: Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 2004;45:818-821.
Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S: Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 2003;88:4393-4397.
Tufano RP, Teixeira GV, Bishop J, Carson KA, Xing M: BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine (Baltimore) 2012;91:274-286.
Cappola AR, Mandel SJ: Molecular testing in thyroid cancer: BRAF mutation status and mortality. JAMA 2013;309:1529-1530.
Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O'Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Tufano RP, Pai SI, Zeiger MA, Westra WH, Clark DP, Clifton-Bligh R, Sidransky D, Ladenson PW, Sykorova V: Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 2013;309:1493-1501.
Huang FJ, Fang WY, Ye L, Zhang XF, Shen LY, Han RL, Wei Q, Fei XC, Chen X, Wang WQ, Wang S, Ning G: BRAF mutation correlates with recurrent papillary thyroid carcinoma in Chinese patients. Curr Oncol 2014;21:e740-e747.
Brace MD, Wang J, Petten M, Bullock MJ, Makki F, Trites J, Taylor SM, Hart RD: Differential expression of transforming growth factor-beta in benign vs. papillary thyroid cancer nodules; a potential diagnostic tool? J Otolaryngol Head Neck Surg 2014;43:22.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2015:1:1-133.
Moon S, Song YS, Kim YA: Effects of coexistent BRAF V600E and TERT promoter mutations on poor clinical outcomes in papillary thyroid cancer: a meta-analysis. Thyroid 2017;27:651-660.
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