2343 ISSN 1479-6694 Future Oncol. (2015) 11(16), 2343–2350 part of 10.2217/FON.15.135 © 2015 Future Medicine Ltd REVIEW The utility of molecular markers in pre-operative assessment of thyroid nodules Parisha Bhatia 1 , Zakaria Y Abd Elmageed 1 , Paul Friedlander 2 , Rizwan Aslam 2 & Emad Kandil* ,1,2 1 Department of Surgery, Tulane University School of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA 2 Department of Otolaryngology, Tulane University School of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA *Author for correspondence: Tel.: +1 504 988 5454; Fax: +1 504 988 7846; ekandil@tulane.edu The pre-operative diagnosis of thyroid tumors is determined by gold standard fne needle aspiration (FNA) biopsy. This has been widely accepted and ofers the most cost-efective approach for evaluation of thyroid nodules. However, its diagnostic accuracy can pose a challenging scenario to surgeons. These diagnostic difculties may subject patients to unnecessary thyroidectomies for benign thyroid nodules. Thus, additional molecular tests are needed to improve the sensitivity and specifcity of FNA. The role of molecular markers is being proposed to predict the type and risk of malignancy to abate the need for diagnostic thyroidectomies. This review discusses their utility and validity in pre-operative diagnosis of thyroid nodules and how these markers can enhance the accuracy of FNA cytology. KEYWORDS • biological markers • cytodiagnosis • genetic markers • immunochemistry • mutations • thyroidectomy • thyroid neoplasms • thyroid nodules Currently, thyroid nodules are being detected in 67% of the general population [1] , and the risk increases with age. A majority of these nodules (>90%) are benign, 50% of which are detected on thyroid ultrasound (US) [1] . According to current American Thyroid Association (ATA) guidelines, nodules presenting with US characteristics suspicious of malignancy are referred for fine needle aspiration (FNA) biopsy [2,3] . FNA, the mainstay of pre-operative assessment of thyroid nodules, can determine the type and risk of malignancy, yielding an accurate diagnosis in 62–85% of thy- roid nodules. That being said, the diagnostic accuracy of FNA varies significantly according to histological subtypes of thyroid neoplasms [4–6] . The inherent limitation of FNA to provide an indeterminate cytological diagnosis in 15–30% of cases raises concerns for malignancy. The Bethesda System for Reporting Thyroid Cytology (TBSRTC) classifies indeterminate cytology as class III: Atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), class IV: follicular neoplasm (FN) and class V: suspi- cious for malignancy. Consequently, to establish a diagnosis in this class of FNA samples, patients undergo an unnecessary operative risk of diagnostic thyroidectomy, where final pathology is deemed malignant in only 5–15% of class III cytology [7,8] . Additionally, the cytological distinction between benign and malignant follicular neoplasm and follicular variant of papillary thyroid carcinoma (PTC) becomes difficult, so that these lesions are again referred for surgical intervention [9,10] . These scenarios warrant a novel test that increases the accuracy of a pre-operative diagnosis, thus avoiding unnecessary thyroidectomies for benign thyroid nodules. With a growing body of evidence, several molecular markers and genetic based assays have been proposed that are being increasingly associ- ated with thyroid cancer [11–15] . These genetic markers are discovered by immunocytochemistry or PCR, while oncogenic mutations such as BRAF V600E , PAX8 /PPAR- γ and RAS point mutation are detected by mutational assay and RNA-based microarray assay. Based on the molecular test, For reprint orders, please contact: reprints@futuremedicine.com