Diagnostic uncertainty remains a significant challenge in thyroid pathology, particularly for general anatomical pathologists who encounter these specimens infrequently or practice in resource-limited settings. Both thyroid cytology and histology are susceptible to false positive and false negative interpretations due to sampling limitations, inflammatory and treatment-related mimics and the absence of absolute diagnostic thresholds for key features such as papillary thyroid carcinoma nuclear changes. A practical, structured framework is presented to improve diagnostic confidence in routine practice for the most common thyroid tumours. Emphasis is placed on integrating clinical context, radiologic risk stratification and standardized reporting systems including the Bethesda System for Reporting Thyroid Cytopathology and the WHO classification of thyroid tumours. Key areas of interobserver variability are highlighted, together with common sources of diagnostic discordance between imaging, cytology and histology.
