A Novel Risk Stratification System for Thyroid Nodules With Indeterminate Cytology—A Pilot Cohort Study

Abstract

Background: Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations. Methods:We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (X US ), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine TM Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (X GC ). The total risk score (TRS) was the sum of X US and X GC . ROC curves were generated to assess the diagnostic accuracy of X US , X GC, and TRS. Results:The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. BRAFV600E was the most common mutation in papillary TC, PAX8-PPARG fusion was present in NIFTP, pathogenic variants of SLX4, ATM, and NRAS were found in Hürthle cell TC and RET mutations in medullary TC. The diagnostic accuracy of X GC and TRS was significantly higher compared with X US (88 vs. 62.5%, p < 0.001; 85.2 vs. 62.5%, p < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, p < 0.001; 84.6 vs. 34.6%, p < 0.001, respectively) without improved specificity (94.7 vs. 90%, p = 0.55; 85.7 vs. 90%, p = 0.63, respectively).Gomes-Lima et al. Scoring System for Indeterminate Thyroid NodulesConclusion: Molecular testing might not be necessary in ITN with high-risk US pattern (X US = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (X US < 0.9), as it increases the accuracy of TC diagnosis.

Spectrum of thyroid nodules in a tertiary care center in the Kingdom of Bahrain

“…15 Molecular testing has been evolving as an especially useful test for informing decision-making regarding the management of thyroid nodules. 12,22 It has the potential to improve patient care, especially in the setting of indeterminate thyroid nodules, by helping to guide both the need for thyroid surgery and the extent to which it is needed. Our hospital has not yet established molecular testing for thyroid nodules.…”

“…[7][8][9][10] The high prevalence of thyroid nodules makes evidence-based strategies necessary for its exact diagnosis, risk stratification, treatment and follow up. 11,12 Thyroid nodules are usually benign. However, thyroid cancer is one of the most common endocrine malignancies; it is listed as the seventh most common cancer affecting women and as the fifteenth most common cancer experienced by men.…”

“…It is the procedure of choice for identifying patients who require surgical excision. 12 It is a noninvasive and inexpensive assessment that should be performed on all patients with suspected of having a thyroid nodule to confirm the presence of the nodule, to assess suspicious sonographic findings and to exclude the presence of additional nodules and lymphadenopathy.…”

Evolutionary analysis of indeterminate cytology and risk of malignancy in a thyroid nodule unit

“…It is generally reasonable to adopt a conservative approach with ultrasound surveillance and repeat FNA [3,8,16,32]. If available, the study of molecular markers may be a useful tool [3,[33][34][35],…”

VHL tumor suppressor as a novel potential candidate biomarker in papillary thyroid carcinoma

“…Currently, the prognosis of PTC is essentially based on clinical and pathological factors; among them are: the patient's age, tumor size, nodal and distant metastases, extrathyroid spread, and histotype [10,12]. More recent studies suggest that mutational and expressional molecular alterations could be a significant addition to conventional evaluation and a critical addition towards personalized treatment of PTC patients [13][14][15][16].…”