Cancer prevalence in the subcategories of the indeterminate class III (AUS/FLUS) of the Bethesda system for thyroid cytology: a meta-analysis

Purpose: The indeterminate cytologic report represents a major challenge in the field of thyroid nodule. The indeterminate class III of the Bethesda classification system (i.e., AUS/FLUS) includes a heterogeneous group of subcategories characterized by doubtful nuclear and/or architectural atypia. The study aim was to conduct a systematic review and meta-analysis to evaluate the rate of malignancy in each subcategory of Bethesda III. Methods: PubMed, CENTRAL, and Scopus databases were searched until April 2020. Original articles reporting data on the subcategories of Bethesda III were included. The histological diagnosis was the reference standard to classify true/false negative and true/false positive cases. Results: The pooled cancer prevalence in each subcategory of Bethesda III was estimated using a random-effects model. Twenty-three papers with 4241 nodules were included. Overall, 1163 (27.4%) were malignant. The cancer rate observed in the subcategories ranged from 15%, in “Hürthle cell aspirates with low risk pattern”, to 44%, in “Focal cytologic atypia”. Conclusions: The overall cancer rate found in the Bethesda III ranged more largely than that originally estimated (10–30%) and varied among any scenarios. These evidence-based data represent a reference for the clinical management of these patients.