Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS)

Abstract

Background: The Bethesda System for Reporting Thyroid Cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The "atypia of undetermined significance/follicular lesion of undetermined significance" (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS at a comprehensive cancer center.

Methods: The management of 541 AUS/FLUS thyroid nodule patients treated at Memorial Sloan-Kettering Cancer Center between 2008 and 2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology.

Results: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% [CI 22.4-31.3]. Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% [CI 33.1-42.8]. Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age (p<0.0001), increasing nodule size (p<0.0001), and nodule hypervascularity (p=0.032).

Conclusions: In patients presenting to a comprehensive cancer center, malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules in some practice settings may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration.

Figures

FIG. 1.

Flow schematic of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) thyroid nodule patients managed between 2008 and 2011. Malignancy rates shown are specific to the targeted AUS/FLUS nodule, excluding incidental cancers or concurrent nodules.

FIG. 2.

Repeat fine-needle aspiration (FNA) results after initial AUS/FLUS diagnosis. A second (consecutive) AUS/FLUS diagnosis was found in 38.5% of patients, while 42.7% of repeat FNAs were benign. AUS/FLUS, Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (Bethesda Category III); SFN, suspicious for neoplasm (Bethesda Category IV); SFM, suspicious for malignancy (Bethesda Category V).

FIG. 3.

Histologic outcomes for AUS/FLUS patients triaged to surgery. AUS/FLUS nodules with a malignant diagnosis most commonly harbored papillary thyroid carcinoma. CA, cancer; diff., differentiated.

FIG. 4.

Adjusted malignancy risk of thyroid nodules by Bethesda classification. The incidence of malignancy for AUS/FLUS observed is higher than that estimated by the Bethesda System for Reporting Thyroid Cytopathology, and falls within the range where surgical intervention is recommended (Bethesda Category IV). *Conservative estimate assuming all observed/nonsurgical patients are benign. †Aggressive estimate considering only nodules triaged to surgery. MSKCC, Memorial Sloan-Kettering Cancer Center; SFN, suspicious for neoplasm; SFM, suspicious for malignancy.