Mutational Testing and its Utility in Thyroid Cancer Management: The Need for Something More

Abstract

nodules are found to be benign at histology [1]. For this reason, ancillary diagnostic approaches for such nodules are needed. Genetic markers hold great promise in improving the accuracy of FNAC in patients with thyroid nodules. The last decade has seen advances in the understanding of the molecular basis of thyroid cancer, leading to the identifica­ tion of genetic alterations with a pathogenetic role, and thus these are the best candidates for thyroid cancer biomarkers. The thymine to adenine substitution at nucleo­ tide position 1799 of BRAF (BRAFV600E), con­ stitutes 98–99% of all BRAF mutations found in thyroid cancer [2]. Other alterations include a single point mutation at position 601, inframe insertions or deletions surrounding codon 600, and the AKAP9–BRAF rearrangement [3]. Many studies have focused their attention on the sensitivity and specificity of BRAFV600E as a hallmark of thyroid cancer in different clini­ cal settings [3,4]. The cumulative analysis per­ formed on more than a thousand tumors, with a few exceptions that are probably due to tech­ nical issues, assigns a positive predictive value of 100% to BRAFV600E. Despite the high specificity, the sensitivity of BRAF mutations for cancer is limited. Within thyroid tumors, BRAFV600E is restricted to the PTC histotype. Its prevalence is subjected to the sensitivity of detection methods and regional/ethnical fac­ tors of patients with PTC. While in the Korean population the prevalence of BRAFV600E has been reported to be 83%, its average prevalence worldwide is approximately 50% [5]. Other genetic alterations identified in thyroid cancer are RET–PTC, TRK and PAX8–PPARg rearrangements and RAS point mutations. These mutations not only exhibit a lower sensitivity, but they are also not infrequently Although it remains a rare disease, the incidence of thyroid cancer has been increasing and has almost doubled during the past 20 years in the USA and Europe. The increased incidence is limited to follicular cell­derived cancers, and within this category, the papillary histotype. The introduction of ultrasonography to clinical practice and the large access to this non invasive diagnostic procedure is partly responsible for the increased incidence of thyroid cancer and for its early detection. The result is that, now­ adays, the majority of thyroid cancers are of small size at the time of diagnosis and often less than 1 cm in diameter. The high prevalence of benign nodular goiter and the high incidence of clinically silent subcentimetric thyroid can­ cers raise relevant diagnostic and prognostic issues. Fine­needle aspiration cyto logy (FNAC) is currently the primary means to distinguish between benign and malignant nodules. Although FNAC is the most accurate and cost­ effective method for evaluating thyroid nod­ ules, it is a highly operator­dependent method, its accuracy is assured only by an experienced pathologist and it yields inconclusive results; that is, indeterminate or suspicious for malig­ nancy results, in approximately 20% of cases [1]. These two histo logical categories include follicular adenomas and follicular carcin omas (FTCs), which cannot be distinguished, and papillary carcinomas (PTCs), mostly folli cular variant PTCs that exhibit some cytologic char­ acteristics of malignancy, but not enough to be definitely classified. The number of FNACs performed yearly in Europe is estimated to be in the hundreds of thousands, yielding tens of thousands of inconclusive results. The impos­ sibility to rule out cancer in these nodules imposes a diagnostic thyroidectomy for most of these patients, although the majority of these