CONTEXT: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished. OBJECTIVE: To investigate the role of tumor multifocality in clinical outcomes of PTC. METHODS: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation. RESULTS: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database. CONCLUSIONS: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.

Biomedical Research Institute Alberto Sols Spanish Council of Research Consejo Superior de Investigaciones Científicas and Autonomous University of Madrid 28029 Madrid Spain

Cancer Molecular Pathology of School of Medicine and Menzies Health Institute Queensland Griffith University Gold Coast 4222 Australia

Department of Endocrinology and Metabolism Shandong Provincial Hospital Jinan 250021 China

Department of Endocrinology and Metabolism The Affiliated Hospital of Qingdao University Qingdao 266003 China

Department of Endocrinology and Nutrition Hospital La Paz Health Research Institute and Hospital Universitario de Móstoles Department of Endocrinology Hospital Universitario de Móstoles 28029 Madrid Spain

Department of Internal Medicine University of Perugia 06100 Perugia Italy

Department of Medicine Endocrinology Unit University of Padua Padua 35128 Italy

Department of Molecular Endocrinology Institute of Endocrinology Prague 11694 Czech Republic

Department of Surgery Division of Endocrine Surgery University of Pittsburgh School of Medicine Pittsburgh Pennsylvania 15213

Division of Endocrine and Metabolic Diseases IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation University of Milan 20122 Milan Italy

Endocrine Surgical Unit The University of Sydney Sydney 2052 Australia

Endocrine Unit Department of Clinical and Experimental Medicine University of Pisa School of Medicine 56124 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 Maryland 21287

Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology 44 101 Gliwice Poland

Prenatal Diagnosis Center The Affiliated Hospital of Qingdao University Qingdao 266003 China

Veneto Institute of Oncology Instituto di Ricovero e Cura a Carattere Scientifico Padua 35128 Italy

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