Recognizing Familial Thyroid Neoplasia: The Pathologist's Role in Diagnosis and Management

Thyroid carcinoma is the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) comprising most cases and arising from follicular epithelial cells. Although most follicular cell-derived thyroid carcinomas are sporadic and driven by acquired genetic alterations, a subset reflects an inherited predisposition. Increasing recognition of familial thyroid carcinoma has been prompted by advances in molecular genetics and by heightened awareness of recurring clinicopathologic patterns, including early age at onset, multifocal and bilateral disease, associated benign follicular proliferations, and, in some cases, multiorgan tumor involvement. Awareness of these features is essential, as they may represent the first diagnostic clue to an underlying familial tumor syndrome. The 2022 World Health Organization classification formally recognizes familial thyroid carcinoma and subdivides these tumors into familial medullary thyroid carcinoma and familial nonmedullary thyroid carcinoma (FNMTC). FNMTC comprises a genetically heterogeneous and underrecognized group of follicular-cell-derived neoplasms, most commonly presenting as multifocal PTC, and includes both syndromic forms associated with extra-thyroidal tumors and nonsyndromic forms in which thyroid carcinoma predominates. In contrast, familial medullary thyroid carcinoma arises from parafollicular C cells, often with bilateral tumors and C-cell hyperplasia as a precursor lesion, and is most frequently encountered in the setting of multiple endocrine neoplasia. This review highlights histopathologic features that should prompt consideration of familial thyroid carcinoma and underscores the pathologist's vital role in identifying these entities and facilitating appropriate molecular evaluation and clinical management.