Sex and Mortality Among Patients with Papillary Thyroid Cancer.

IMPORTANCE

Unlike patient age, which has been a well-established and routinely used primary biological prognostic factor in the risk stratification of papillary thyroid cancer (PTC), the prognostic value of patient sex remains controversial in this common endocrine malignant neoplasm.

OBJECTIVE

To examine PTC-specific mortality risk of sex with respect to patient age and tumor genetics-specifically the status of BRAF V600E and TERT promoter (TERTp) mutations.

DESIGN, SETTING, AND

PARTICIPANTS

This cohort study was conducted among patients with PTC with an overall median (IQR) follow-up time of 51.0 (26.4-109.1) months after initial treatment at 15 centers in 10 countries between 1979 and 2023. Data analysis was completed in December 2025 and examined aggregately for the association of PTC-specific mortality and patient sex with respect to patient age and BRAF V600E and TERTp mutation.

MAIN OUTCOME AND MEASURE: Patient deaths specifically caused by PTC.

RESULTS

The study included 4746 patients with PTC (median [IQR] age, 48 [37-59] years; 3612 women [76.1%]). Male patients, compared with female patients, demonstrated a higher overall PTC-specific mortality (3.7% [42 of 1134] vs 1.7% [60 of 3612]; P < .001). This male sex-associated risk was observed only in patients harboring BRAF V600E or TERTp mutations, not wild-type genes. PTC-specific mortality particularly paralleled the occurrence and accumulation of dual BRAF V600E and TERTp mutations, which all exhibited a patient age-dependent rise, beginning to be prominent around age 45 years and markedly amplified by male sex. A male sex-age synergy index of 1.81 (95% CI, 1.02-3.16) and a male-to-female hazard ratio of 3.07 (95% CI, 1.35-6.97; P = .007) after adjustment for clinicopathologic factors in mortality risk were observed in patients aged 45 years or older with dual mutations.

CONCLUSIONS AND RELEVANCE: This cohort study reconciled previous controversies on the prognostic value of patient sex and establishes male sex as a cardinal mortality risk in PTC in a patient age- and tumor genetic-dependent manner, defining especially male patients aged 45 years and older with dual BRAF V600E and TERTp mutations as having the worst prognosis and supporting integration of patient sex into risk stratification of PTC.