The Sex Paradox in Papillary Thyroid Carcinoma: Higher Incidence in Women, Poorer Outcomes in Men, and an Emerging Non-Coding RNA Layer

Background/Objectives: Thyroid cancer, predominantly papillary thyroid carcinoma (PTC), is diagnosed about three times more often in women than in men, yet in several cohorts male sex is associated with worse outcomes after diagnosis. We critically appraised this “female incidence–male outcome paradox” and evaluated non-coding RNA (ncRNA) as a candidate regulatory layer. Methods: We conducted a narrative review with documented search methods and an evidence table, complemented by an exploratory, covariate-adjusted analysis of CD274 and ACTA2 transcripts in The Cancer Genome Atlas thyroid carcinoma cohort (497 tumors; 58 normal samples). Results: Similar prevalence of subclinical PTC at autopsy in both sexes supports detection bias as the main driver of the female excess in incidence. Among diagnosed patients, male sex was associated with cancer-specific mortality in a large registry (adjusted HR 1.46, 95% CI 1.26–1.69) but not in several other cohorts; in a multicenter cohort, this association was confined to BRAF V600E-positive disease. In TCGA, ACTA2 was higher in male tumors after adjustment (fold difference 1.22, 95% CI 1.06–1.41), whereas lower CD274 in men was also present in normal thyroid. Sex-stratified androgen receptor–miR-146b correlations have been reported, but formal tests of sex-dependent effect modification are lacking. Conclusions: The paradox reflects detection-driven differences in incidence and a heterogeneous, mechanistically unresolved outcome association in men. The evidence supports sex-stratified studies with formal interaction testing, not sex-specific management.