Diagnosing Thyroid Lesions Through A Morphology-Molecular Lens: Four Case-Based Lessons From 22nd International Congress of Cytology-Florence 2025.

Imaging-driven detection of thyroid nodules has expanded the role of fine-needle aspiration (FNA) while demanding integration of molecular data into routine cytologic assessment. We present four illustrative cases spanning the contemporary diagnostic spectrum: (1) an Atypia of Undetermined Significance (AUS) nodule with dual low-level PTEN mutations managed by active surveillance; (2) an oncocytic follicular neoplasm upgraded to total thyroidectomy by concurrent HRAS and TERT promoter mutations; (3) an oncocytic subtype poorly differentiated thyroid carcinoma (O-PDTC) highlighting subtle high-grade cytologic cues and a distinct genomic profile; and (4) a pediatric poorly differentiated carcinoma harboring a DICER1 hotspot mutation, underscoring age-specific biology and the need for genetic consideration. These cases emphasize that morphology remains foundational, but mutation context, single versus co-alterations, allelic burden, and patient age ultimately direct management. Harmonized reporting that clearly conveys molecular findings is essential to translate limited cytology material into precise, patient-specific care.