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Architectural Subtyping of Three-Dimensional Cell Groups in Bethesda III Thyroid Cytology: Distinguishing Spherules
Asiye Şafak Bulut1, Sevdenur Özdüzgün Polat2
1Department of Pathology, Bilkent City Hospital, Ankara, Turkiye.
Objective:
Risk stratification of indeterminate thyroid nodules, particularly Bethesda III, remains a major diagnostic challenge in thyroid cytology. We evaluated whether architectural subtyping of three-dimensional (3D) follicular cell groups provides additional diagnostic information in indeterminate thyroid cytology.
Methods:
A total of 107 thyroid fine-needle aspiration (FNA) cases (97 Bethesda III and 10 Bethesda IV) with histopathological follow-up were retrospectively analysed. Cytology smears were examined for 3D follicular groups, which were classified as spherules or cell clusters based on defined morphologic criteria. Ancillary cytologic features were also recorded. Conventional multivariable statistical analyses and receiver operating characteristic analyses were performed to assess diagnostic performance.
Results:
Among Bethesda III cases, spherules were mostly found in non-neoplastic lesions and were not associated with malignancy, demonstrating a strong negative predictive value. In contrast, cell clusters were significantly associated with neoplastic outcomes (p < 0.001) and were identified as an independent predictor of neoplasia (OR: 8.03, 95% CI: 2.90-22.18). Absence of colloid and presence of isolated cells were also associated with neoplastic outcomes. A morphology-based scoring scheme showed a strong association with histopathological outcome (AUC: 0.895 for malignancy). Although the number of Bethesda IV cases was limited, concordant trends were observed.
Conclusions:
Architectural subtyping of 3D follicular groups represents a practical and reproducible method for risk stratification in Bethesda III thyroid cytology. True spherules strongly favour benignity, whereas cell clusters are associated with increased risk of neoplasia. Combined assessment of architectural and background cytologic features may facilitate the interpretation of indeterminate thyroid nodules, particularly where molecular testing is not readily available.
