INTRODUCTION: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management. METHODS: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months). RESULTS: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC. CONCLUSIONS: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.

Biomedical Research Institute Alberto Sols Consejo Superior De Investigaciones Cientificas and Univeridad Autonoma de Madrid 28029 Madrid Spain; Ciberonc Health Institute Carlos 3 28029 Madrid Spain

Cancer Molecular Pathology of School of Medicine and Menzies Health Institute Queensland Griffith University Gold Coast Australia

Department of Endocrinology and Nutrition Hospital Universitario La Paz and Hospital Universitario De Mostoles 28029 Madrid Spain; Biomedical Research Institute Alberto Sols Consejo Superior De Investigaciones Cientificas and Univeridad Autonoma de Madrid 28029 Madrid Spain; Ciberonc Health Institute Carlos 3 28029 Madrid Spain

Department of Internal Medicine University of Perugia Perugia Italy

Department of Medicine Endocrinology Unit University of Padua Italy

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Division of Endocrine and Metabolic Diseases IRCCS Instituto Auxologico Italiano and Department of Pathophysiology and Transplantation University of Milan Milan Italy

Division of Endocrinology and Metabolism Department of Internal Medicine Korea University College of Medicine Seoul 02841 South Korea

Endocrine Surgical Unit The University of Sydney Sydney Australia

Laboratory for Cellular and Molecular Thyroid Research Division of Endocrinology Diabetes and Metabolism Department of Medicine The Johns Hopkins University School of Medicine Baltimore MD 21287 USA

Laboratory for Cellular and Molecular Thyroid Research Division of Endocrinology Diabetes and Metabolism Department of Medicine The Johns Hopkins University School of Medicine Baltimore MD 21287 USA; Division of Endocrinology and Metabolism Department of Internal Medicine Korea University College of Medicine Seoul 02841 South Korea

Maria Sklodowska Curie Institute Oncology Center Gliwice Branch Gliwice Poland

Section of Endocrinology Department of Clinical and Experimental Medicine University of Pisa Pisa Italy

University of Pittsburgh School of Medicine Pittsburgh PA USA

Veneto Institute of Oncology IRCCS Padua Italy

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