2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer Bryan R. Haugen,1

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer Bryan R. Haugen,1,* Erik K. Alexander,2 Keith C. Bible,3 Gerard M. Doherty,4 Susan J. Mandel,5 Yuri E. Nikiforov,6 Furio Pacini,7 Gregory W. Randolph,8 Anna M. Sawka,9 Martin Schlumberger,10 Kathryn G. Schuff,11 Steven I. Sherman,12 Julie Ann Sosa,13 David L. Steward,14 R. Michael Tuttle,15 and Leonard Wartofsky16 Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association’s (ATA’s) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management 1 University of Colorado School of Medicine, Aurora, Colorado. 2 Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. 3 The Mayo Clinic, Rochester, Minnesota. 4 Boston Medical Center, Boston, Massachusetts. 5 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 6 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 7 The University of Siena, Siena, Italy. 8 Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 9 University Health Network, University of Toronto, Toronto, Ontario, Canada. 10Institute Gustave Roussy and University Paris Sud, Villejuif, France. 11Oregon Health and Science University, Portland, Oregon. 12University of Texas M.D. Anderson Cancer Center, Houston, Texas. 13Duke University School of Medicine, Durham, North Carolina. 14University of Cincinnati Medical Center, Cincinnati, Ohio. 15Memorial Sloan Kettering Cancer Center, New York, New York. 16MedStar Washington Hospital Center, Washington, DC. *Chair. Authors are listed in alphabetical order and were appointed by ATA to independently formulate the content of this manuscript. None of the scientific or medical content of the manuscript was dictated by the ATA. THYROID Volume 26, Number 1, 2016 ª American Thyroid Association ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2015.0020 1 Harryson of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders. INTRODUCTION Thyroid nodules are a common clinical problem. Epidemiologic studies have shown the prevalence of palpable thyroid nodules to be approximately 5% in women and 1% in men living in iodine-sufficient parts of the world (1,2). In contrast, high-resolution ultrasound (US) can detect thyroid nodules in 19%–68% of randomly selected individuals, with higher frequencies in women and the elderly (3,4). The clinical importance of thyroid nodules rests with the need to exclude thyroid cancer, which occurs in 7%–15% of cases depending on age, sex, radiation exposure history, family history, and other factors (5,6). Differentiated thyroid cancer (DTC), which includes papillary and follicular cancer, comprises the vast majority (>90%) of all thyroid cancers (7). In the United States, approximately 63,000 new cases of thyroid cancer were predicted to be diagnosed in 2014 (8) compared with 37,200 in 2009 when the last ATA guidelines were published. The yearly incidence has nearly tripled from 4.9 per 100,000 in 1975 to 14.3 per 100,000 in 2009 (9). Almost the entire change has been attributed to an increase in the incidence of papillary thyroid cancer (PTC). Moreover, 25% of the new thyroid cancers diagnosed in 1988–1989 were £1 cm compared with 39% of the new thyroid cancer diagnoses in 2008–2009 (9). This tumor shift may be due to the increasing use of neck ultrasonography or other imaging and early diagnosis and treatment (10), trends that are changing the initial treatment and follow-up for many patients with thyroid cancer. A recent population-based study from Olmsted County reported the doubling of thyroid cancer incidence from 2000 to 2012 compared to the prior decade as entirely attributable to clinically occult cancers detected incidentally on imaging or pathology (11). By 2019, one study predicts that PTC will become the third most common cancer in women at a cost of $19–21 billion in the United States (12). Optimization of longterm health outcomes and education about potential prognosis for individuals with thyroid neoplasms is critically important. In 1996, the American Thyroid Association (ATA) published treatment guidelines for patients with thyroid nodules and DTC (13). Over the last 15–20 years, there have been many advances in the diagnosis and therapy of both thyroid nodules and DTC, but clinical controversy exists in many areas. A long history of insufficient peer-reviewed research funding for high-quality clinical trials in the field of thyroid neoplasia may be an important contributing factor to existing clinical uncertainties (12). Methodologic limitations or conflicting findings of older studies present a significant challenge to modern-day medical decision-making in many aspects of thyroid neoplasia. Although they are not a specific focus of these guidelines, we recognize that feasibility and cost considerations of various diagnostic and therapeutic options also present important clinical challenges in many clinical practice settings. AIM AND TARGET AUDIENCE Our objective in these guidelines is to inform clinicians, patients, researchers, and health policy makers about the best available evidence (and its limitations), relating to the diagnosis and treatment of adult patients with thyroid nodules and DTC. These guidelines should not be applied to children (<18–20 years old); recent ATA guidelines for children with thyroid nodules and DTC were published in 2015 (14). This document is intended to inform clinical decision-making. A major goal of these guidelines is to minimize potential harm from overtreatment in a majority of patients at low risk for disease-specific mortality and morbidity, while appropriately treating and monitoring those patients at higher risk. These guidelines should not be interpreted as a replacement for clinical judgement and should be used to complement informed, shared patient–health care provider deliberation on complex issues. It is important to note that national clinical practice guidelines may not necessarily constitute a legal standard of care in all jurisdictions (15). If important differences in practice settings present barriers to meaningful implementation of the recommendations of these guidelines, interested physicians or groups (in or outside of the United States) may consider adapting the guidelines using established methods (16,17) (ADAPTE Collaboration, 2009; ). The ADAPTE Collaboration is an international group of researchers, guideline developers, and guideline implementers who aim to promote the development and use of clinical practice guidelines through the adaption of existing guidelines. Because our primary focus was reviewing the quality of evidence related to health outcomes and diagnostic testing, we decided a priori not to focus on economic resource implications in these guidelines. As part of our review, we identified some knowledge gaps in the field, with associated future research priorities. Other groups have previously developed clinical practice guidelines, including the American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and the European Thyroid Association (18), the British Thyroid Association and The Royal College of Physicians (19), and the National Comprehensive Cancer Network ( .org). The European Thyroid Association has published consensus guidelines for postoperative US in the management of DTC (20). The Society for Nuclear Medicine and Molecular Imaging (21) and the European Association of Nuclear Medicine have also published guidelines for radioiodine (RAI) therapy of DTC (22). The Japanese Society of Thyroid Surgeons and the Japanese Association of Endocrine Surgeo