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Background: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy., Methods: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed., Results: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria., Conclusions: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery., Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules., Design, Setting, and Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules., Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3)., Main Outcomes and Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules., Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%., Conclusions and Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.

Background: The Bethesda System for Reporting Thyroid Cytopathology is the most widely used classification system for the reporting of thyroid fine-needle aspiration cytology (FNAC) specimens. However, the "atypical" category ("atypia of undetermined significance" [AUS] or "follicular lesion of undetermined significance" [FLUS]) continues to cause diagnostic and therapeutic dilemmas. The objectives of this study were to describe the differential malignancy rates of FNACs diagnosed as AUS/FLUS based on nuclear or architectural atypia and to assess the significance of demographic and ultrasonographic features in predicting malignancy in this category., Methods: A retrospective review was performed of all thyroid FNACs between 2008 and 2014 that were diagnosed as AUS/FLUS at a tertiary referral center in Singapore. Patient demographics, preoperative ultrasonographic features, and follow-up data were collected and correlated with the final histopathologic diagnosis in resected cases., Results: In total, 309 thyroid nodules were diagnosed as AUS/FLUS, and 137 (44%) were surgically excised. Final histology yielded 37 (27%) malignancies. The malignancy rate for nodules that featured nuclear atypia was significantly higher at 36.8% than the rate for nodules that had only architectural atypia at 14.7% (P < .01). After up to 3 repeat FNACs, 67.1% of cases had a more definitive diagnosis. The only predictive sonographic finding for malignancy was irregular margins (P < .01)., Conclusions: The disparity between malignancy risks within the Bethesda "atypical" category suggests that cytologic (nuclear) atypia is significantly more predictive of malignancy than architectural atypia. This supports the substratification of patients according to risk and a corresponding management approach within this category. A sonographic finding of irregular margins is also predictive for malignancy. Cancer Cytopathol 2017;125:245-256. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

BACKGROUND.: A significant number of thyroid fine-needle aspiration cytology (FNAC) cases yield inconclusive results. The recent National Cancer Institute guidelines and those published by other societies are important contributions to standardizing the diagnostic approach. Nevertheless, there are significant issues in the application of guidelines and the evaluation of their clinical efficacy. Data from individual departments can be useful in demonstrating the role of standardized reporting. METHODS.: The authors followed 529 consecutive cases with inconclusive thyroid FNA results that were analyzed in a single laboratory in Western Australia. In that laboratory, standardized reporting in categories has been in place for a decade, and inconclusive cases have been subdivided into indeterminate and atypical groups. Follow-up data was obtained for 341 indeterminate cases (17.2% of total thyroid FNA accessions) and for 188 atypical cases (9.5% of accessions). RESULTS.: In total, 127 nodules with atypical results (67.6%) underwent surgical excision compared with 131 nodules with indeterminate results (38.4%; P < .0001). In 96 excised nodules with atypical results (75.6%), the excised specimens were identified as neoplastic compared with 61 excised nodules with indeterminate results (46.6%; P < .0001). In addition, 31 excised nodules with atypical results (24.4%) had a malignancy proven compared with 17 excised nodules with indeterminate results (13%; P < .05). In addition, 51 of 82 repeat FNAs (62.2%) among patients who had indeterminate results yielded a more specific diagnosis compared with 2 of 9 repeat FNAs (22.2%) among patients who had atypical results (P < .05). CONCLUSIONS.: The routine subcategorization of patients who had inconclusive thyroid FNA reports into indeterminate and atypical groups resulted in statistically significant differences in the likelihood of neoplasia and malignancy. Patients who had indeterminate results were more likely to benefit from repeat FNAC than patients who had atypical results. The current results indicated that patients who fall into these 2 categories are likely to benefit from different clinical management protocols. Cancer Cancer Cytopathol 2010. © 2010 American Cancer Society., (Copyright © 2010 American Cancer Society.)