Familial Non-Medullary Thyroid Carcinoma: Distinct Clinicopathological Features and Prognostic Implications in a Large Cohort of 46,572 Patients

<b>Background:</b> The incidence of thyroid cancer has rapidly increased worldwide, and familial aggregation of the disease has been increasingly recognized. This study aimed to evaluate the prevalence, clinicopathological characteristics, and long-term outcomes of familial non-medullary thyroid cancer (FNMTC) in a large institutional cohort. <b>Methods:</b> Patients with non-medullary thyroid cancer (NMTC) who had undergone surgery were classified as sporadic NMTC (SNMTC) or FNMTC based on family history. Clinicopathological features at diagnosis and surgery were compared, and prognostic outcomes were analyzed in patients with follow-up data. <b>Results:</b> Among the 46,572 NMTC patients, 3829 (8.2%) had FNMTC, and 42,743 (91.8%) had SNMTC. FNMTC was more prevalent in women and occurred at a younger age. Its proportion increased over time, peaking in the 35-59 age group. FNMTC showed higher rates of bilaterality (23.5% vs. 17.5%, <i>p</i> < 0.001), multifocality (39.0% vs. 30.5%, <i>p</i> < 0.001), and central lymph node metastasis (41.5% vs. 38.8%, <i>p</i> = 0.001), despite smaller tumors (0.9 ± 0.7 cm vs. 1.0 ± 0.9 cm, <i>p</i> < 0.001). Recurrence rates were similar between the two groups (1.9% vs. 2.3%, <i>p</i> = 0.1), but overall survival was higher in the FNMTC group (99.6% vs. 98.6%, <i>p</i> < 0.001). Family history, extracapsular extension, lymph node metastasis, and tumor size independently predicted recurrence. Family history significantly impacted recurrence-free survival in the intermediate-to-high-risk group (HR = 1.65, <i>p</i> < 0.001) but not in low-risk patients. <b>Conclusions:</b> FNMTC represents a distinct NMTC subset with more extensive local disease but favorable survival, warranting risk-adapted management, particularly for intermediate-to-high-risk patients.