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 ( TERT p) 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 TERT p 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 TERT p mutations, not wild-type genes. PTC-specific mortality particularly paralleled the occurrence and accumulation of dual BRAF V600E and TERT p 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 TERT p mutations as having the worst prognosis and supporting integration of patient sex into risk stratification of PTC.

Authors

Institutions

Publication Details

Journal
JAMA Network Open
Published
2026-09-29
DOI
https://doi.org/10.1001/jamanetworkopen.2026.35582
Citations
1
Primary Topic
Thyroid Cancer Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
4.47
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

Sex and Mortality Among Patients with Papillary Thyroid Cancer

Norisato Mitsutake, Barbara Jarząb, Luis G. Carvajal‐Carmona, Shuhuang Lin et al.
1 citations
JAMA Network Open
Thyroid Cancer Diagnosis and Treatment
4.47
article

Sex and Mortality Among Patients with Papillary Thyroid Cancer

Norisato Mitsutake, Barbara Jarząb, Luis G. Carvajal‐Carmona, Shuhuang Lin, Mabel Elena Bohórquez L, Aarti Mathur, Miguel Manuel Melo, Chan Kwon Jung, Bayu Brahma, Agnieszka Czarniecka, Caterina Mian, Ana Patricia Estrada-Florez, Tito T. Jesus, Běla Bendlová, Paul W. Ladenson, Mingzhao Xing, Carla Maria Colombo, Laura Fugazzola, Federica Alessandra Vianello, Paula Soares, Roderick John Clifton-Bligh, Ayaka Sako, Michiko Matsuse, Christine J. O’Neill, Vlasta Kuklíková, Zhuo Wang, Young Joo Park, Ying Li, Liufeng Wu
article en
1 citations

Abstract

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 ( TERT p) 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 TERT p 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 TERT p mutations, not wild-type genes. PTC-specific mortality particularly paralleled the occurrence and accumulation of dual BRAF V600E and TERT p 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 TERT p mutations as having the worst prognosis and supporting integration of patient sex into risk stratification of PTC.

JAMA Network OpenVol. 9(9)
The University of Sydney (AU), University of Padua (IT), Seoul National University (KR), Johns Hopkins University (US), Universidade do Porto (PT), University of Milan (IT), Johns Hopkins Medicine (US), John Hunter Hospital (AU), Hospitais da Universidade de Coimbra (PT), Southern University of Science and Technology (CN), University of Tolima (CO), Istituto Oncologico Veneto (IT), National Institute of Oncology (HU), IRCCS Istituto Auxologico Italiano (IT), Institute of Endocrinology (CZ), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Dharmais Cancer Hospital (ID), i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT), The Catholic University of Korea Seoul St. Mary's Hospital (KR), Nagasaki University (JP), Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, University of California, Davis (US), Catholic University of Korea (KR)
Good health and well-being
Openalex Percentile: Top 4%
Thyroid Cancer Diagnosis and Treatment
4.47
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.