The value of molecular diagnostics for indeterminate thyroid nodules.

Abstract

In current clinical practice, fine-needle aspiration biopsy (FNAB) of thyroid nodules will result in indeterminate cytology (atypia of undetermined significance [AUS] or follicular lesion of undetermined significance [FLUS], follicular neoplasm [FN] or suspicious for FN, and suspicious for malignancy) in 15–30% of patients (1). Despite a low risk of malignancy, diagnostic surgery is often necessary in determining a final pathology. However, recent advances in molecular diagnostics may potentially aid clinicians by identifying certain patients in whom surgery can be safely avoided. Two novel molecular tests have become commercially available in the past several years. The gene-expression classifier (GEC) (Afirma; Veracyte, Inc) is based on an expression profile of 142 gene mRNA, which gained prominence after the large industry-sponsored multicenter validation study by Alexander et al (2) on a total study sample of 265 samples of indeterminate nodules from 49 participating centers. This study demonstrated high sensitivity (92%) and high negative predictive value (93%), but low specificity (52%) and positive predictive value (PPV; 47%) for the GEC. Subset analyses of nodules with AUS/FLUS and FN cytology demonstrate a similar diagnostic performance. Given these findings, the GEC has been proposed as a “rule-out” test; that is, nodules with indeterminate cytology and a benign GEC result could be managed by close observation, rather than proceeding to diagnostic surgery. However, diagnostic performance was less favorable for nodules with “suspicious for malignancy” cytology, and therefore these nodules should not undergo GEC testing and should rather proceed directly to surgery. Another molecular diagnostic test has been developed based on the presence of point mutations of BRAF and RAS, and rearrangements of RET/PTC and PAX8/PPAR . Contrary to the GEC, the gene mutation panel (miRInform; Asuragen Inc) was shown to have high specificity (96–99%) and PPV (87–95%), but low sensitivity (57–63%) and negative predictive value (72– 94%) for indeterminate nodules in a study of FNAB samples from 513 nodules at a single academic center (3). This mutation panel can be used as a “rule-in” approach; that is, indeterminate nodules with positive markers can proceed directly to a total thyroidectomy due to the high probability of malignancy, rather than a two-stage operation. The utility of these new tests is recognized because they have been included in the 2013–14 revisions of the National Comprehensive Cancer Network guidelines on thyroid carcinoma (4). In this issue of the JCEM, McIver et al (5) have reported their results on the use of a GEC in the management of patients with indeterminate thyroid nodules based on cytopathology at a large tertiary academic institution. Importantly, FNAB cytopathology was determined by their specialized thyroid cytopathologists, rather than undergoing an initial “screening” process by Thyroid Cytology Partners, as is otherwise required by Veracyte (the manufacturer of the GEC) in clinical practice. In their study, the GEC was offered to all patients with AUS/FLUS or FN cytology. Patients with a benign GEC classification were managed observantly (n 16), whereas those with a “suspicious” result were offered surgery (n 44). Among these 60 patients, only 36 (60%) underwent surgery (four with benign GEC, and 32 with suspicious GEC). The overall prevalence of malignancy in these patients was 16% (6 of