The diagnostic challenges of medullary thyroid carcinoma: A practical guide for cytopathologists

Abstract Medullary thyroid carcinoma (MTC) is a rare but potentially aggressive neuroendocrine tumor arising from the thyroid C cells (parafollicular cells) that produce calcitonin, representing 1%–3% of thyroid malignancies but contributing to up to 15% of thyroid cancer‐related deaths. Early detection is critical for improving survival and outcomes because its tumor origin, treatment, and prognosis differ completely from papillary thyroid carcinoma. However, the low incidence of MTC and its variable cytomorphology can pose significant diagnostic challenges for cytopathologists. Referred to as the great mimicker , MTC can resemble various primary and metastatic tumors, complicating its identification, particularly in fine‐needle aspiration (FNA) biopsies. Reported FNA sensitivity for a specific MTC diagnosis varies widely from 12.5% to 88.2%, with a 2014 meta‐analysis estimating an overall sensitivity of 56.5% when including suspicious lesions. False‐negative FNA results, often caused by misinterpretation of cytologic features or inadequate specimen quality, can lead to delayed or suboptimal treatment. Pathologists must be familiar with MTC's diverse cytopathologic presentation and maintain a low threshold for additional diagnostic tests to ensure an accurate preoperative diagnosis. This review article provides practical guidance on diagnosing MTC, emphasizing cytologic features, ancillary studies, mimickers, and common diagnostic pitfalls, serving as a valuable resource for cytopathologists, general pathologists, and trainees to improve diagnostic accuracy and patient care.