Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as ‘indeterminate’ and they are further subclassified into two categories. BRAF mutation occurs in 40–60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as ‘indeterminate’ were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.

1.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
2.
Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE: Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 2006;30:216–222.
3.
Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA: High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454–1457.
4.
Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Máximo V, Botelho T, Seruca R, Sobrinho-Simões M: BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003;22:4578–4580.
5.
Nikiforova MN, Nikiforov YE: Molecular diagnostics and predictors in thyroid cancer. Thyroid 2009;19:1351–1361.
6.
Gilfillan CP: Review of the genetics of thyroid tumours: diagnostic and prognostic implications. ANZ J Surg 2010;80:33–40.
7.
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.
8.
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.
9.
Horne MJ, Chhieng DC, Theoharis C, Schofield K, Kowalski D, Prasad ML, Hammers L, Udelsman R, Adeniran AJ: Thyroid follicular lesion of undetermined significance: evaluation of the risk of malignancy using the two-tier sub-classification. Diagn Cytopathol DOI: 10.1002/dc.21790.
10.
Adeniran AJ, Theoharis C, Hui P, Prasad ML, Hammers L, Carling T, Udelsman R, Chhieng DC: Reflex BRAF testing in thyroid fine-needle aspiration biopsy with equivocal and positive interpretation: a prospective study. Thyroid 2011;21:717–723.
11.
Mazzaferri EL: Management of a solitary thyroid nodule. N Engl J Med 1993;328:553–559.
12.
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167–1214.
13.
Amrikachi M, Ramzy I, Rubenfeld S, Wheeler TM: Accuracy of fine-needle aspiration of thyroid. Arch Pathol Lab Med 2001;125:484–488.
14.
Yang J, Schnadig V, Logrono R, Wasserman PG: Fine-needle aspiration of thyroid nodules: a study of 4,703 patients with histologic and clinical correlations. Cancer 2007;111:306–315.
15.
Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, Vielh P, DeMay RM, Sidawy MK, Frable WJ: Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425–437.
16.
Rowe LR, Bentz BG, Bentz JS: Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules. Cytojournal 2006;3:10.
17.
Nam SY, Han BK, Ko EY, Kang SS, Hahn SY, Hwang JY, Nam MY, Kim JW, Chung JH, Oh YL, Shin JH: BRAF V600E mutation analysis of thyroid nodules needle aspirates in relation to their ultrasonographic classification: a potential guide for selection of samples for molecular analysis. Thyroid 2010;20:273–279.
18.
Xing M, Tufano RP, Tufaro AP, Basaria S, Ewertz M, Rosenbaum E, Byrne PJ, Wang J, Sidransky D, Ladenson PW: Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. J Clin Endocrinol Metab 2004;89:2867–2872.
19.
Jin L, Sebo TJ, Nakamura N, Qian X, Oliveira A, Majerus JA, Johnson MR, Lloyd RV: BRAF mutation analysis in fine needle aspiration (FNA) cytology of the thyroid. Diagn Mol Pathol 2006;15:136–143.
20.
Domingues R, Mendonça E, Sobrinho L, Bugalho MJ: Searching for RET/PTC rearrangements and BRAF V599E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma. Cytopathology 2005;16:27–31.
21.
Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA, Nikiforov YE, Troncone G, Palombini L, Basolo F, Santoro M: Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 2004;89:5175–5180.
22.
Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M, Weber K, Nikiforova MN: Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94:2092–2098.
23.
Flynn C, Theoharis CG, Chhieng DC, Prasad M, Hui P: Detection of BRAF V600E mutation in papillary thyroid carcinoma by highly sensitive single strand conformation polymorphism analysis. Mod Pathol 2010;23:274A.
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