CONTEXT: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. OBJECTIVE: To study whether BRAF V600E affected LNM-associated mortality in PTC. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. RESULTS: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. CONCLUSIONS: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

Biomedical Research Institute Alberto Sols Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid Madrid Spain

Cancer Molecular Pathology of School of Medicine Griffith University Gold Coast Australia

Ciberonc Health Institute Carlos 3 Madrid Spain

Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University Qingdao China

Department of Endocrinology and Nutrition Hospital Universitario La Paz and Hospital Universitario de Móstoles Madrid Spain

Department of Medicine Endocrinology Unit University of Padua Padua Italy

Department of Medicine University of Perugia Perugia Italy

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Division of Endocrinology and Metabolism IRCCS Istituto Auxologico Italiano Milan and Department of Pathophysiology and Transplantation University of Milan Italy

Endocrine Surgical Unit University of Sydney Sydney Australia

Endocrine Unit Department of Clinical and Experimental Medicine University of Pisa Pisa Italy

Laboratory for Cellular and Molecular Thyroid Research Division of Endocrinology Diabetes and Metabolism Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA

Maria Sklodowska Curie National Institute of Oncology Gliwice Branch Gliwice Poland

University of Pittsburgh School of Medicine Pittsburgh PA USA

Veneto Institute of Oncology IRCCS Padua Italy

J Clin Endocrinol Metab. 2022 Jun 16;107(7):e3103-e3104. doi: 10.1210/clinem/dgac135. PubMed

J Clin Endocrinol Metab. 2022 May 17;107(6):e2638-e2639. doi: 10.1210/clinem/dgac127. PubMed

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