Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.

Fei Wang Shihua Zhao and Yangang Wang The Affiliated Hospital of Qingdao University Qingdao People's Republic of China; Fei Wang Xiaopei Shen Guangwu Zhu Rengyun Liu and Mingzhao Xing Johns Hopkins University School of Medicine Baltimore MD; David Viola and Rossella Elisei University of Pisa Pisa; Efisio Puxeddu University of Perugia Perugia; Laura Fugazzola and Carla Colombo Istituto Auxologico Italiano Istituto di Recovero e Cura a Carattere Scientifico and University of Milan Milan; Caterina Mian University of Padua; Federica Vianello Veneto Institute of Oncology IRCCS Padua Italy; Barbara Jarzab and Agnieszka Czarniecka Maria Sklodowska Curie Institute Oncology Center Gliwice Poland; Alfred K Lam Griffith University Gold Coast Queensland; Christine J O'Neill Mark S Sywak and Roderick Clifton Bligh University of Sydney Sydney New South Wales Australia; Linwah Yip University of Pittsburgh Pittsburgh PA; Garcilaso Riesco Eizaguirre Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco Eizaguirre and Pilar Santisteban Biomedical Research Institute Alberto Sols and Health Institute Carlos 3 Madrid Spain; and Bela Bendlova and Vlasta Sýkorová Institute of Endocrinology Prague Czech Republic

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