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SPECIAL ARTICLE 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,2Keith C. Bible,3Gerard M. Doherty,4Susan J. Mandel,5 Yuri E. Nikiforov,6Furio Pacini,7Gregory W. Randolph,8Anna M. Sawka,9Martin Schlumberger,10 Kathryn G. Schuff,11Steven I. Sherman,12Julie Ann Sosa,13David L. Steward,14 R. Michael Tuttle,15and 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 ofthese disorders were revised in 2009, signiﬁcant scientiﬁc advances have occurred in the ﬁeld. The aim of theseguidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relatingto 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 onknowledge synthesis methods, including electronic database searching, review and selection of relevant cita- tions, 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 ofevidence and grading strength of recommendations for therapeutic interventions. We developed a similarlyformatted system to appraise the quality of such studies and resultant recommendations. The guideline panelhad complete editorial independence from the ATA. Competing interests of guideline task force members wereregularly 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. Re- commendations
regarding the initial management of thyroid cancer include those relating to screening forthyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy,and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management 1University of Colorado School of Medicine, Aurora, Colorado. 2Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. 3The Mayo Clinic, Rochester, Minnesota. 4Boston Medical Center, Boston, Massachusetts. 5Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 6University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 7The University of Siena, Siena, Italy. 8Massachusetts Eye and Ear Inﬁrmary, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 9University 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, 2016ªAmerican Thyroid Association ªMary Ann Liebert, Inc. DOI: 10.1089/thy.2015.0020 1
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, considerationfor 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, contemporaryoptimal 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 detectthyroid nodules in 19%–68% of randomly selected individ- uals, with higher frequencies in women and the elderly (3,4). The clinical importance of thyroid nodules rests with the needto 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, com- prises the vast majority ( >90%) of all thyroid cancers (7). In the United States, approximately 63,000 new cases of thyroidcancer were predicted to be diagnosed in 2014 (8) comparedwith 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 theentire change has been attributed to an increase in the inci- dence of papillary thyroid cancer (PTC). Moreover, 25% of the new thyroid cancers diagnosed in 1988–1989 were £1c m 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 diag-nosis 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 re-ported the doubling of thyroid cancer incidence from 2000 to2012 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 willbecome the third most common cancer in women at a cost of $19–21 billion in the United States (12). Optimization of long- term health outcomes and education about potential prognosisfor individuals with thyroid neoplasms is critically important. In 1996, the American Thyroid Association (ATA) pub- lished treatment guidelines for patients with thyroid nodulesand DTC (13). Over the last 15–20 years, there have beenmany 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 researchfunding 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 con-ﬂicting ﬁndings of older studies present a signiﬁcant chal- lenge to modern-day medical decision-making in many aspects of thyroid neoplasia. Although they are not a speciﬁcfocus of these guidelines, we recognize that feasibility and cost considerations of various diagnostic and therapeutic optionsalso 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 bestavailable evidence (and its limitations), relating to the dia- gnosis 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. Amajor 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 appropriatelytreating and monitoring those patients at higher risk. Theseguidelines should not be interpreted as a replacement for clinical judgement and should be used to complement in- formed, shared patient–health care provider deliberation oncomplex 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 differ-ences in practice settings present barriers to meaningful im- plementation of the recommendations of these guidelines, interested physicians or groups (in or outside of the UnitedStates) may consider adapting the guidelines using estab- lished methods (16,17) (ADAPTE Collaboration, 2009; www.g-i-n.net). The ADAPTE Collaboration is an interna-tional group of researchers, guideline developers, and guide-line implementers who aim to promote the development and use of clinical practice guidelines through the adaption of existing guidelines. Because
our primary focus was review-ing the quality of evidence related to health outcomes and diagnostic testing, we decided a priori not to focus on eco- nomic resource implications in these guidelines. As part ofour 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 ClinicalEndocrinologists, Associazione Medici Endocrinologi, and the European Thyroid Association (18), the British Thyroid Association and The Royal College of Physicians (19), andthe National Comprehensive Cancer Network (www.nccn .org). The European Thyroid Association has published con- sensus guidelines for postoperative US in the management ofDTC (20). The Society for Nuclear Medicine and Molecular Imaging (21) and the European Association of Nuclear Med- icine have also published guidelines for radioiodine (RAI)therapy of DTC (22). The Japanese Society of Thyroid Sur- geons and the Japanese Association of Endocrine Surgeons2 HAUGEN ET AL.
have recently revised guidelines on treatment of patients with thyroid tumors (23). Given the existing controversies in theﬁeld, differences in critical appraisal approaches for existing evidence, and differences in clinical practice patterns across geographic regions and physician specialties, it should not besurprising that the organizational guidelines are not in com-plete agreement for all issues. Such differences highlight the importance of clarifying evidence uncertainties with future high quality clinical research. METHODS ATA Thyroid Nodules and Differentiated Thyroid Cancer guidelines were published in 2006 (24) and revised in 2009(25). Because of the rapid growth of the literature on this topic, plans for revising the guidelines within approximately4 years of publication were made at the inception of the project. A task force chair was appointed by the ATA Pre- sident with approval of the Board. A task force of specialistswith complementary expertise (endocrinology, surgery, nu-clear medicine, radiology, pathology, oncology, molecular diagnostics, and epidemiology)
was appointed. In order to have broad specialty and geographic representation, as wellas fresh perspectives, one-third of the task force is replaced for each iteration of the guidelines, per ATA policy. Upon discussion among the panel members and the Chair with otherChairs of other ATA guideline committees, the American College of Physicians’ (ACP) Grading System was adoptedTable 1.Interpretation of the American College of Physicians’ Guideline Grading System (for Therapeutic Interventions) Recommendation Clarity of risk/beneﬁt Implications Strong recommendation Beneﬁts clearly outweigh harms and burdens,or vice versa.Patients: Most would want course of action; a person should request discussion if an intervention is not offered. Clinicians: Most patients should receive the recommended course of action. Policymakers: The recommendation can be adopted as policy in most circumstances. Weak recommendation Beneﬁts closely balanced with harms and burdens.Patients: Many would want course of action, but some may not; the decision may depend on individual circumstances. Clinicians:
Different choices will be appropriate for different patients; the management decision should be consistent with patients’ preferences and circumstances. Policymakers: Policymaking will require careful consideration and stakeholder input. No recommendation Balance of beneﬁts and risks cannot be determined.Decisions based on evidence cannot be made. Table 2.Recommendations (for Therapeutic Interventions) Based on Strength of Evidence Recommendation and evidence quality Description of supporting evidenceaInterpretation Strong recommendation High-quality evidence RCT without important limitations or overwhelming evidence fromobservational studiesCan apply to most patients in most circumstances without reservation Moderate-quality evidence RCT with important limitations or strong evidence fromobservational studiesCan apply to most patients in most circumstances without reservation Low-quality evidence Observational studies/case studies May change when higher-quality evidence becomes available Weak recommendation High-quality evidence RCT without important limitations or overwhelming evidence from observational studiesBest action may differ based on circumstances or patients’ values Moderate-quality evidence RCT with important limitations or strong evidence from observational
studiesBest action may differ based on circumstances or patients’ values Low-quality evidence Observational studies/case studies Other alternatives may be equally reasonable Insufﬁcient Evidence is conﬂicting, of poor quality, or lackingInsufﬁcient evidence to recommend for or against aThis description of supporting evidence refers to therapy, therapeutic strategy, or prevention studies. The description of supporting evidence is different for diagnostic accuracy studies. RCT, randomized controlled trial.ATA THYROID NODULE/DTC GUIDELINES 3
for use in these guidelines, relating to critical appraisal and recommendations on therapeutic interventions (26) (Tables 1 and 2). An important component of these guidelines wasjudged to be critical appraisal of studies of diagnostic tests;however, the ACP Guideline Grading System is not designed for this purpose. We reviewed a number of appraisal systemsfor diagnostic tests, but some of the complexity and the time- consuming nature of some systems limited their feasibility for implementation in our group (27–31). We drafted, re-vised, and piloted the use of a newly developed diagnostictest appraisal system that was acceptable to panel members. This system included consideration of the followingTable 3.Interpretation of the American Thyroid Association Guideline Grading System for Diagnostic Tests RecommendationAccuracy of diagnostic information versus risks and burden of testingaImplications Strong recommendationKnowledge of the diagnostic test result clearly outweighs risks and burden of testingor vice versa.Patients: In the case of an accurate test for
which beneﬁts outweigh risks/burden, most would want the diagnostic to be offered (with appropriate counseling). A patient shouldrequest discussion of the test if it is not offered. In contrast,for a test in which risks and burden outweigh the beneﬁts, most patients should not expe ct the test to be offered. Clinicians: I nt h ec a s eo fa na c c u r a t et e s tf o rw h i c h beneﬁts outweigh risks/bur den, most patients should be offered the diagnostic test (and provided relevant counseling). Counseling about the test should include a discussion of the risks, beneﬁts, and uncertainties relatedto testing (as applicable), as well as the implications of thetest result. In contrast, for a test in which risks and burden outweigh the perceived beneﬁt s, most patients should not be offered the test, or if the test is discussed, the rationaleagainst the
test should, for the particular clinical situation, be explained. Policymakers: In the case of an accurate test for which beneﬁts outweigh risks/burden, availability of thediagnostic test should be adopted in health policy. In contrast, for a test in which risks and burden outweigh the perceived beneﬁts, some restrictions oncircumstances for test use may need to be considered. Weak recommendationKnowledge of the diagnostic test result is closely balancedwith risks and burden of testing.Patients: Most would want to be informed about the diagnostic test, but some would not want to seriouslyconsider undergoing the test; a decision may depend on the individual circumstances (e.g., risk of disease, comorbidities, or other), the practice environment,feasibility of optimal execution of the test, andconsideration of other available options. Clinicians: Different choices will be appropriate for different patients, and counseling about the test (ifbeing considered) should include a discussion of therisks, beneﬁts, and uncertainties related to testing (as
applicable), as well as the implications of the test result. The decision to perform the test should includeconsideration of the patients’ values, preferences, feasibility, and the speciﬁc circumstances. Counseling the patient on why the test may be helpful or not, inher/his speciﬁc circumstance, may be very valuable inthe decision-making process. Policymakers: Policymaking decisions on the avail- ability of the test will require discussion and stake-holder involvement. No recommendation Balance of knowledge of the diagnostic test result cannotbe determined.Decisions on the use of the test based on evidence from scientiﬁc studies cannot be made. aFrequently in these guidelines, the accuracy of the diagnosis of thyroid cancer (relative to a histologic gold standard) was the diagnostic outcome unless otherwise speciﬁed. However, prognostic, disease staging, or risk stratiﬁcation studies were also included in the gradingscheme of diagnostic studies. For disease staging systems, the implication for use would be on the part of the
clinician, in reporting resultsin the medical record and communicating them to the patient (at the applicable time point in disease or follow-up trajectory), as opposed tooffering a speciﬁc choice of staging/risk stratiﬁcation system to the patient.4 HAUGEN ET AL.
methodologic elements: consecutive recruitment of patients representative of clinical practice, use of an appropriate ref- erence gold standard, directness of evidence (e.g., target population of interest, testing procedures representative ofclinical practice, and relevant outcomes), precision of diag- nostic accuracy measures (e.g., width of conﬁdence intervals for estimates such as sensitivity, speciﬁcity), and consistencyof results among studies using the same test (Tables 3 and 4). In the majority of circumstances (unless otherwise speciﬁed), the outcome of interest for the diagnostic test was the diag-nosis of thyroid cancer (relative to a histologic gold stan- dard). However, prognostic studies were also graded using the diagnostic study critical appraisal framework. In terms ofstrength of recommendation for use of diagnostic studies, wemodeled our approach on the ACP system for therapeutic studies, as previously described, but the target outcome wasthe accuracy in establishing a deﬁnitive diagnosis, largely relating to the diagnosis of new or recurrent malignancy
(unless otherwise speciﬁed). Diagnostic tests or risk stratiﬁ- cation systems used for estimation of prognosis were alsoappraised using the diagnostic test grading system. An im- portant limitation of our diagnostic test appraisal system is that it does not speciﬁcally examine the clinical utility of atest in improving long-term health outcomes by execution of the test as part of an intended therapeutic strategy (unless speciﬁcally noted). However, as much as possible, we tried toseparate recommendations on the diagnostic accuracy of a test from therapeutic management based on the test result, with the latter grading being more rigorous and based onlonger term outcomes (whenever possible). It is important tonote that according to our diagnostic test grading system, a body of well-executed nonrandomized diagnostic accuracyTable 4.Recommendations (for Diagnostic Interventions) Based on Strength of Evidence Recommendation and evidence quality Methodologic quality of supporting evidence Interpretation Strong recommendation High-quality evidence Evidence from one or more
well-designed nonrandomized diagnostic accuracy studies (i.e., observational—cross-sectional or cohort) or systematic reviews/meta-analyses of suchobservational studies (with no concern aboutinternal validity or external generalizability of the results)Implies the test can be offered to most patients in most applicable circumstances without reservation. Moderate-quality evidence Evidence from nonrandomized diagnostic accuracy studies (cross-sectional or cohort), with one or morepossible limitations causing minor concern about internal validity or external generalizability of the resultsImplies the test can be offered to most patients in mostapplicable circumstances without reservation. Low-quality evidence Evidence from nonrandomized diagnostic accuracy studies with one or more important limitations causing serious concern about internal validity or external generalizability of the resultsImplies the test can be offered to most patients in most applicable circumstances, but the utilization of thetest may change when higher-quality evidence becomes available. Weak recommendation High-quality evidence Evidence from one or more well-designed nonrando- mized diagnostic accuracy studies (i.e., observational—cross-sectional or cohort)or
systematic reviews/meta-analyses of such ob-servational studies (with no concern about internal validity or external generalizability of the results)The degree to which the di- agnostic test is seriously considered may differ de-pending on circumstancesor patients’ or societal values. Moderate-quality evidence Evidence from nonrandomized diagnostic accuracy studies (cross-sectional or cohort), with one or more possible limitations causing minor concern about internal validity or external generalizability of theresultsThe degree to which the diag- nostic test is seriously con- sidered may differ depending on individual patients’/practice circumstances orpatients’ or societal values. Low-quality evidence Evidence from nonrandomized diagnostic accuracy studies with one or more important limitationscausing serious concern about internal validity orexternal generalizability of the results.Alternative options may be equally reasonable. Insufﬁcient Evidence may be of such poor quality, conﬂicting, lacking (i.e., studies not done), or not externallygeneralizable to the target clinical population such that the estimate of the true effect of the test is
uncertain and does not permit a reasonableconclusion to be made.Insufﬁcient evidence exists to recommend for or againstroutinely offering the diag- nostic test.ATA THYROID NODULE/DTC GUIDELINES 5
studies could be considered high-quality evidence; yet, a therapeutic strategy incorporating the use of the diagnostic test would require one or more well-executed randomizedcontrolled trials (RCTs) to be considered high-quality evi-dence. In developing and applying our diagnostic test critical appraisal system, we considered American societal values, relating to the importance of informing patients about po-tentially helpful tests developed for their clinical situation (with counseling on relevant limitations) and the role of patients in informed, shared decision-making relating todiagnostic and therapeutic strategies. Such input was based on thoughtful consideration of stakeholder input, including input from physician stakeholders who were committeemembers. Because this was a preliminary pilot utilization ofthis diagnostic test critical appraisal system by our group, we have labeled recommendations using this system in the manuscript (diagnostic test recommendation). Moreover, weanticipate that the future iterations of these guidelines will likely incorporate further reﬁnements to the system, or even possible adoption of
another system, if it is superior andfeasible to execute by contributing physicians. Prior to initiating the reviews, all task force members were provided written and verbal group advice on conductingelectronic literature searches, critical appraisal of articles, and rationale for formulating strength of recommendations from a panel member with epidemiology and systematic re-view expertise (via e-mail documents, a teleconferencemeeting on February 21, 2012). For each question, a primary reviewer performed a literature search, appraised relevant literature, generated recommendations, accompanying text,and a relevant bibliography. This was then reviewed by the secondary reviewer, revised as needed, and presented for review by the entire panel. Feedback and suggestions forrevisions from the Chair and panel members were obtained via e-mail, regularly scheduled teleconferences, and face-to- face meetings held in conjunction with scientiﬁc meetings.Once the manuscript was drafted, all suggestions for revi-sions were regularly reviewed by all panel members in the form of a tracked changes
draft manuscript and teleconfer- ences. The draft document continued to be revised until nofurther suggestions for further revisions were requested byany panel members. Thus, general consensus on acceptability of recommendations and manuscript text was achieved, with the fundamental understanding that not all recommendationsmay be feasible in all practice settings. Formal stakeholder input in development of these guide- lines was sought from ATA membership in an online surveydistributed in October 2011. Thyroid cancer survivor group leadership input was sought from three North American thyroid cancer groups via e-mail correspondence in Januaryto March of 2012. We also reviewed any letters, editorials, orreviews of the 2009 iteration of the guidelines (25) that were collected by the current Chair of the committee. Pre- publication verbal feedback on some of the key guidelinerecommendations was receive d at a formal Satellite Sym- posium held in conjunction with the Endocrine Society meeting in Chicago on June 19,
2014. The guideline man-uscript was reviewed and approved by the ATA Board of Directors, then made available to the ATA membership for review and comments in September 2014. Substantivecomments were received from 33 members representing endocrinology, surgery, pathology, and nuclear medicine. Feedback and suggestions were formally discussed by thepanel, and revisions were made to the manuscript prior tojournal submission. The organization of management guide- line recommendations is shown in Table 5. The medical opinions expressed here are those of the au- thors, and the committee had complete editorial indepen- dence from the ATA in writing the guidelines. No funding was received by individual committee members from theATA or industry for work on these guidelines. Competing interests of all committee members were reviewed at incep- tion of the group, yearly, and upon completion of theguidelines and are included with this document. Table 5.Organization of the 2015 ATA Guidelines for Thyroid Nodules
and Differentiated Thyroid Cancer Page Location key Sections and subsections Itema 10 [A1] THYROID NODULE GUIDELINES 10 [A2] What is the role of thyroid cancer screening in people with familial follicular cell–derived DTC?bR1b 10 [A3] What is the appropriate laboratory and imaging evaluation for patients with clinically or incidentally discovered thyroidnodules? 10 [A4] Serum thyrotropin measurement R2 11 [A5] Serum thyroglobulin measurement R311 [A6] Serum calcitonin measurement R411 [A7] [18F]Fluorodeoxyglucose positron emission tomography bR5b 12 [A8] Thyroid sonography R612 [A9] US for FNA decision-making R712 [A10] Recommendations for diagnostic FNA of a thyroid nodule based on sonographic pattern cR8cF1c,F 2c,T 6c 16 [A11] What is the role of FNA, cytology interpretation, and molecular testing in patients with thyroid nodules?cR9c,F 1c,T 7c 17 [A12] Nondiagnostic cytology R10 17 [A13] Benign cytology R11 18 [A14] Malignant cytology R1219 [A15] Indeterminate cytology (AUS/FLUS, FN, SUSP)c (continued )6 HAUGEN ET AL.
Table 5. (Continued ) Page Location key Sections and subsections Itema 19 [A16] What are the principles of the molecular testing of FNA samples?bR13–14 21 [A17] AUS/FLUS cytologycR15c 22 [A18] Follicular neoplasm/suspicious for follicular neoplasm cytologycR16c 23 [A19] Suspicious for malignancy cytologycR17c 23 [A20] What is the utility of18FDG -PET scanning to predict malignant or benign disease when FNA cytology is indeterminate (AUS/FLUS, FN, SUSP)?bR18b 23 [A21] What is the appropriate operation for cytologically indeterminate thyroid nodules?cR19–20c 25 [A22] How should multinodular thyroid glands (i.e., two or more clinically relevant nodules) be evaluated for malignancy?R21–22 25 [A23] What are the best methods for long-term follow-up of patients with thyroid nodules? 25 [A24] Recommendations for initial follow-up of nodules with benign FNA cytologycR23A–Cc 25 [A25] Recommendation for follow-up of nodules with two benign FNA cytology resultsbR23Db 26 [A26] Follow-up for nodules that do not meet FNA criteriabR24b 27 [A27] What is
the role of medical or surgical therapy for benign thyroid nodules?R25–29 27 [A28] How should thyroid nodules in pregnant women be managed? 27 [A29] FNA for thyroid nodules discovered during pregnancy R30 28 [A30] Approaches to pregnant patients with malignant or indeterminate cytologyR31 28 [B1] DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT GUIDELINES 29 [B2] Goals of initial therapy of DTC29 [B3] What is the role of preoperative staging with diagnostic imaging and laboratory tests? 29 [B4] Neck imaging—ultrasound R32 F3, T6, T8b 30 [B5] Neck imaging—CT/MRI/PETcR33c 31 [B6] Measurement of serum Tg and anti-Tg antibodies R34 31 [B7] Operative approach for a biopsy diagnostic for follicular cell–derived malignancycR35c 33 [B8] Lymph node dissection R36–37, F335 [B9] Completion thyroidectomy R38 35 [B10] What is the appropriate perioperative approach to voice and parathyroid issues?b 35 [B11] Preoperative care communicationbR39b 35 [B12] Preoperative voice assessmentbR40–41b,T 9b 36 [B13] Intraoperative voice and parathyroid managementbR42–43b 37
[B14] Postoperative carebR44–45b 37 [B15] What are the basic principles of histopathologic evaluation of thyroidectomy samples?bR46b 40 [B16] What is the role of postoperative staging systems and risk stratiﬁcation in the management of DTC? 40 [B17] Postoperative staging R47 40 [B18] AJCC/UICC TNM staging T10 41 [B19] What initial stratiﬁcation system should be used to estimate the risk of persistent/recurrent disease?cR48c, T11b, T12c 43 [B20] Potential impact of speciﬁc clinico-pathologic features on the risk estimates in PTCb 44 [B21] Potential impact of BRAFV600Eand other mutations on risk of estimates in PTCb 45 [B22] Potential impact of postoperative serum Tg on risk estimatesb 46 [B23] Proposed modiﬁcations to the 2009 ATA initial risk stratiﬁcation systembT12c 46 [B24] Risk of recurrence as a continuum of riskbF4b 46 [B25] How should initial risk estimates be modiﬁed over time?bR49 47 [B26] Proposed terminology to classify response to therapy and clinical (continued )ATA THYROID NODULE/DTC
GUIDELINES 7
Table 5. (Continued ) Page Location key Sections and subsections Itema implicationsb 47 [B27] Excellent response: no clinical, biochemical, or structural evidence of disease after initial therapy (remission, NED)bT13b 50 [B28] Biochemical incomplete response: abnormal Tg values in the absence of localizable diseasebT13b 51 [B29] Structural incomplete response: persistent or newly identiﬁed loco- regional or distant metastasesbT13b 52 [B30] Indeterminate response: biochemical or structural ﬁndings that cannot be classiﬁed as either benign or malignant (acceptable response)bT13b 52 [B31] Using risk stratiﬁcation to guide disease surveillance and therapeutic management decisionsb 53 [B32] Should postoperative disease status be considered in decision- making for RAI therapy for patients with DTC?R50 53 [B33] Utility of postoperative serum Tg in clinical decision-making 54 [B34] Potential role of postoperative US in conjunction with postoperative serum Tg in clinical decision-making 54 [B35] Role of postoperative radioisotope diagnostic scanning in clinical decision-making 55 [B36] What is the role
of RAI (including remnant ablation, adjuvant therapy, or therapy persistent disease) after thyroidectomy inthe primary management of differentiated thyroid cancer?R51 T14 58 [B37] What is the role of molecular marker status in therapeutic RAI decision-making?bR52b 58 [B38] How long does thyroid hormone need to be withdrawn in preparation for RAI remnant ablation/treatment or diagnosticscanning?R53 59 [B39] Can rhTSH (Thyrogen) be used as an alternative to thyroxine withdrawal for remnant ablation or adjuvant therapy inpatients who have undergone near-total or totalthyroidectomy?R54 60 [B40] What activity of 131I should be used for remnant ablation or adjuvant therapy?cR55–56c 63 [B41] Is a low-iodine diet necessary before remnant ablation? R57 63 [B42] Should a posttherapy scan be performed following remnant ablation or adjuvant therapy?R58 64 [B43] Early management of DTC after initial therapy 64 [B44] What is the appropriate degree of initial TSH suppression? R59 65 [B45] Is there a role for adjunctive external
beam radiation or chemotherapy? 65 [B46] External beam radiation R6065 [B47] Systemic adjuvant therapy R61 65 [C1] DTC: LONG-TERM MANAGEMENT AND ADVANCED CANCER MANAGEMENT GUIDELINES 65 [C2] What are the appropriate features of long-term management? 66 [C3] What are the criteria for absence of persistent tumor (excellent response)? 66 [C4] What are the appropriate methods for following patients after initial therapy? 66 [C5] What isthe role of serum Tg measurement inthe follow-up of DTC?cR62–63c 66 [C6] Serum Tg measurement and clinical utility 68 [C7] Anti-Tg antibodies68 [C8] What is the role of serum Tg measurement in patients who have not undergone RAI remnant ablation?R64 69 [C9] What is the role of US and other imaging techniques (RAI SPECT/CT, CT, MRI, PET-CT) during follow-up? 69 [C10] Cervical ultrasonography R65 69 [C11] Diagnostic whole-body RAI scans R66–6770 [C12] 18FDG-PET scanning R68 71 [C13] CT and MRIbR69b 72 [C14] Using ongoing risk stratiﬁcation
(response to therapy) to guide disease long-term surveillance and therapeutic managementdecisionsb (continued )8 HAUGEN ET AL.
Table 5. (Continued ) Page Location key Sections and subsections Itema 72 [C15] What is the role of TSH suppression during thyroid hormone therapy in the long-term follow-up of DTC?cR70c T15b 74 [C16] What is the most appropriate management of DTC patients with metastatic disease? 74 [C17] What is the optimal directed approach to patients with suspected structural neck recurrence?R71 74 [C18] Nodal size threshold 75 [C19] Extent of nodal surgery 75 [C20] Ethanol injectionb 75 [C21] Radiofrequency or laser ablationb 75 [C22] Other therapeutic optionsb 76 [C23] What is the surgical management of aerodigestive invasion? R72 76 [C24] How should RAI therapy be considered for loco-regional or distant metastatic disease? 76 [C25] Administered activity of131I for loco-regional or metastatic diseasecR73c 77 [C26] Use of rhTSH (Thyrogen) to prepare patients for131I therapy for loco-regional or metastatic diseaseR74–75 77 [C27] Use of lithium in131I therapy R76 77 [C28] How should distant
metastatic disease to various organs be treated? 78 [C29] Treatment of pulmonary metastases R77–7878 [C30] RAI treatment of bone metastases R7979 [C31] When should empiric RAI therapy be considered for Tg-positive, RAI diagnostic scan–negative patients?R80–82 79 [C32] What is the management of complications of RAI therapy? R83–85 80 [C33] How should patients who have received RAI therapy be monitored for risk of secondary malignancies?R86 80 [C34] What other testing should patients receiving RAI therapy undergo? R87 80 [C35] How should patients be counseled about RAI therapy and pregnancy, breastfeeding, and gonadal function?R88–90 81 [C36] How is RAI-refractory DTC classiﬁed? bR91b 82 [C37] Which patients with metastatic thyroid cancer can be followed without additional therapy?bR92b 82 [C38] What is the role for directed therapy in advanced thyroid cancer?cR93c 84 [C39] Treatment of brain metastases R94 84 [C40] Who should be considered for clinical trials?bR95b 84 [C41] What is the role of
systemic therapy (kinase inhibitors, other selective therapies, conventional chemotherapy, bisphosphonates) in treating metastatic DTC?c 85 [C42] Kinase inhibitorsbR96b, T16b 87 [C43] Patients for whom ﬁrst-line kinase inhibitor therapy failsbR97b 87 [C44] Management of toxicities from kinase inhibitor therapybR98b, T17b 87 [C45] Other novel agentsbR99 87 [C46] Cytotoxic chemotherapy R10088 [C47] Bone-directed agentscR101c 89 [D1] DIRECTIONS FOR FUTURE RESEARCH 89 [D2] Optimizing molecular markers for diagnosis, prognosis, and therapeutic targets 89 [D3] Active surveillance of DTC primary tumors 90 [D4] Improved risk stratiﬁcation90 [D5] Improving our understanding of the risks and beneﬁts of DTC treatments and optimal implementation/utilization 90 [D6] Issues with measurement of Tg and anti-Tg antibodies 90 [D7] Management of metastatic cervical adenopathy detected on US91 [D8] Novel therapies for systemic RAI-refractory disease 91 [D9] Survivorship care aF, ﬁgure; R, recommendation; T, table. bNew section/recommendation. cSubstantially changed recommendation compared with 2009. ATA, American Thyroid Association; AUS/FLUS, atypia of undetermined
signiﬁcance/follicular lesion of undetermined signiﬁcance; CT, computed tomography; DTC, differentiated thyroid cancer; FN, follicular neoplasm; FNA, ﬁne-needle aspiration;18FDG-PET, [18F]ﬂuorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; NED, no evidence of disease; PET, positron emission tomography; RAI, radioactive iodine (radioiodine); rhTSH, recombinant human thyrotropin; SPECT/CT, single photon emissioncomputed tomography–computed tomography; SUSP, suspicious for malignancy; Tg, thyroglobulin; TSH, thyrotropin; US, ultrasound.ATA THYROID NODULE/DTC GUIDELINES 9
[A1] THYROID NODULE GUIDELINES A thyroid nodule is a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding thyroid pa- renchyma. Some palpable lesions may not correspond to distinct radiologic abnormalities (32). Such abnormalities do not meetthe strict deﬁnition for thyroid nodules. Nonpalpable nodules detected on US or other anatomic imaging studies are termed incidentally discovered nodules or ‘‘incidentalomas.’’ Non-palpable nodules have the same risk of malignancy as do so-nographically conﬁrmed palpable nodules of the same size (33). Generally, only nodules >1 cm should be evaluated, since they have a greater potential to be clinically signiﬁcant cancers.Occasionally, there may be nodules <1 cm that require further evaluation because of clinical symptoms or associated lymph- adenopathy. In very rar e cases, some nodules <1c ml a c kt h e s e sonographic and clinical warning signs yet may nonetheless cause future morbidity and mortality. This remains
highly un- likely, and given the unfavorable cost/beneﬁt considerations,attempts to diagnose and treat all such small thyroid cancers in an effort to prevent exceedingly rare outcomes is deemed to cause more harm than good. In general, the guiding clinicalstrategy acknowledges that most thyroid nodules are low risk,and many thyroid cancers pose minimal risk to human health and can be effectively treated. [A2] What is the role of thyroid cancer screening in people with familial follicular cell–derived DTC? &RECOMMENDATION 1 Screening people with familial follicular cell–derived DTC may lead to an earlier diagnosis of thyroid cancer, but the panel cannot recommend for or against US screening since there is no evidence that this would lead to reducedmorbidity or mortality. (No recommendation, Insufﬁcient evidence) Screening programs for patients at risk of oncological disease are usually advocat ed based on the following evi- dence: (a) a clear demonstration that the patient is indeed
at risk; (b) demonstration that screening allows the detection of the disease at an earlier sta ge; (c) early diagnosis has an impact on subsequent ou tcome, both recurrence and survival. Family members of patients with nonmedullary DTC may be considered at risk based on epidemiological evidence showingthat 5%–10% of DTCs have a familial occurrence. However, in most of the pedigrees only two members are affected. There is controversy on whether two family members are sufﬁcient todeﬁne a real familial disease rather than a fortuitous association. The probability estimates reported by Charkes (34) suggests that when only two ﬁrst-degree family members are affected, theprobability that the disease is sporadic is 62%. This probability decreases when the number of affected family members is three or more. In contrast, the study by Capezzone et al. (35), which was statistically adjusted to minimize risk of ‘‘insufﬁcientfollow-up bias,’’ demonstrates that even when only two
family members are affected, the disease displays the features of ‘‘ge- netic anticipation’’ (occurrence of the disease at an earlier ageand with more aggressive presentation in the subsequent gener- ation compared with the ﬁrst generation), which is considered good evidence for a distinct clinical entity possibly representingtrue familial disease. Appearance of the disease at an earlier age has also been found by Moses et al. (36). More advanced disease at presentation and slightly worse outcomes have been reportedin familial cases by Capezzone et al. (35). More frequent mul- ticentricity has been reported by Ito et al. (37), but disease-free and overall survival were similar to sporadic cases. In the study by Park et al. (38), familial follicular cell–derived DTC patients with parent–offspring relationship were found to have a higher recurrence rate compared with sporadic cases and the second generation had even higher rates compared with the ﬁrst gen-eration. Mazeh et
al. (39) found that familial DTC patients had more aggressive disease compared with sporadic cases re- gardless of the number of family members affected. In contrast,Robenshtok et al. (40) found that staging at diagnosis and out- comes were not different in familial DTC patients compared with sporadic DTC patients. Syndromes associated with DTC (e.g., PTEN [phosphatase and tensin homolog] hamartoma tu-mor syndrome [Cowden’s disease], familial adenomatous polyposis [FAP], Carney complex, multiple endocrine neopla- sia [MEN] 2, Werner syndrome/progeria) in a ﬁrst-degree rel-ative, warrant screening based on various components of that syndrome (41). It is not possible to speculate on the impact of screening in preventing or reducing recurrence and deaths, since no in- terventional screening programs have ever been reported in at-risk family members. Patients with familial DTC shouldhave a careful history and directed neck examination as a partof routine health maintenance. One should also consider thyroid cancer syndromes as
noted above (41). [A3] What is the appropriate laboratory and imaging evaluation for patients with clinically or incidentally discovered thyroid nodules? [A4] Serum thyrotropin measurement &RECOMMENDATION 2 (A) Serum thyrotropin (TSH) should be measured during the initial evaluation of a patient with a thyroid nodule. (Strong recommendation, Moderate-quality evidence) (B) If the serum TSH is subnormal, a radionuclide (pref- erably123I) thyroid scan should be performed. (Strong recommendation, Moderate-quality evidence) (C) If the serum TSH is normal or elevated, a radionuclide scan should not be performed as the initial imaging evaluation. (Strong recommendation, Moderate-quality evidence) With the discovery of a thyroid nodule, a complete history and physical examination focusing on the thyroid gland and adjacent cervical lymph nodes should be performed. Perti-nent historical factors predicting malignancy include a his- tory of childhood head and neck radiation therapy, total body radiation for bone marrow transplantation (42), exposure toionizing radiation from fallout in
childhood or adolescence (43), familial thyroid carcinoma, or thyroid cancer syndrome (e.g., PTEN hamartoma tumor syndrome [Cowden’s dis-ease], FAP, Carney complex, Werner syndrome/progeria, or MEN 2, a risk for medullary thyroid cancer [MTC]) in a ﬁrst- degree relative, rapid nodule growth, and/or hoarseness.10 HAUGEN ET AL.
Pertinent physical ﬁndings suggesting possible malignancy include vocal cord paralysis, cervical lymphadenopathy, and ﬁxation of the nodule to surrounding tissue. With the discovery of a thyroid nodule >1 cm in any di- ameter, a serum TSH level should be obtained. If the serum TSH is subnormal, a radionuclide thyroid scan should be obtained to document whether the nodule is hyperfunctioning(‘‘hot,’’ i.e., tracer uptake is greater than the surrounding normal thyroid), isofunctioning (‘‘warm,’’ i.e., tracer uptake is equal to the surrounding thyroid), or nonfunctioning(‘‘cold,’’ i.e., has uptake less than the surrounding thyroid tissue) (44). Since hyperfunctioning nodules rarely harbor malignancy, if one is found that corresponds to the nodule inquestion, no cytologic evaluation is necessary. If overt orsubclinical hyperthyroidism is present, additional evaluation is required. A higher serum TSH level, even within the upper part of the reference range, is associated with increased riskof malignancy in a thyroid nodule, as well
as more advanced stage thyroid cancer (45,46). [A5] Serum thyroglobulin measurement &RECOMMENDATION 3 Routine measurement of serum thyroglobulin (Tg) forinitial evaluation of thyroid nodules is not recommended. (Strong recommendation, Moderate-quality evidence) Serum Tg levels can be elevated in most thyroid diseases and are an insensitive and nonspeciﬁc test for thyroid cancer (47–49). [A6] Serum calcitonin measurement &RECOMMENDATION 4 The panel cannot recommend either for or against routinemeasurement of serum calcitonin in patients with thyroid nodules. (No recommendation, Insufﬁcient evidence) The utility of serum calcitonin has been evaluated in a series of prospective, nonrandomized studies (50–54). These data suggest that the use of routine serum calcitonin forscreening may detect C-cell hyperplasia and MTC at an earlier stage, and overall survival consequently may be improved. However, most studies relied on pentagastrinstimulation testing to increase speciﬁcity. This drug is not available in the United States, Canada, and some other countries, and there remain
unresolved issues of sensitivity,speciﬁcity, assay performance, cut-offs using calcium stim-ulation (55), and cost effectiveness. Two retrospective stud- ies have shown improved survival in patients diagnosed with MTC after routine calcitonin testing compared with historicalcontrols (53,56), but they were unable to show a decreased number of MTC-related deaths. A cost-effectiveness analysis suggested that calcitonin screening would be cost effective inthe United States (57). However, prevalence estimates of MTC in this analysis included patients with C-cell hyper- plasia and microMTC, which have uncertain clinical signif-icance. Based on the retrospective nature of the survival data,unresolved issues of assay performance, lack of availability of pentagastrin in North America, and potential biases in thecost-effective analysis, the task force cannot recommend for or against the routine measurement of serum calcitonin as a screening test in patients with thyroid nodules, although therewas not uniform agreement on this recommendation. Therewas, however, agreement that serum calcitonin may be considered
in the subgroup of patients in whom an elevated calcitonin may change the diagnostic or surgical approach(i.e., patients considered for less than total thyroidectomy, patients with suspicious cytology not consistent with PTC). If the unstimulated serum calcitonin determination has beenobtained and the level is greater than 50–100 pg/mL, a diag- nosis of MTC is common (58). There is emerging evidence that a calcitonin measure- ment from a thyroid nodule ﬁne-needle aspiration (FNA)washout may be helpful in the preoperative evaluation of patients with a modestly elevated basal serum calcitonin (20–100 pg/mL) (59). [A7] [18F]Fluorodeoxyglucose positron emission tomography scan &RECOMMENDATION 5 (A) Focal [18F]ﬂuorodeoxyglucose positron emission to- mography (18FDG-PET) uptake within a sonographically conﬁrmed thyroid nodule conveys an increased risk ofthyroid cancer, and FNA is recommended for those nod-ules‡1 cm. (Strong recommendation, Moderate-quality evidence) B) Diffuse 18FDG-PET uptake, in conjunction with so- nographic and clinical evidence of chronic lymphocyticthyroiditis, does not require
further imaging or FNA. (Strong recommendation, Moderate-quality evidence) 18FDG-PET is increasingly performed during the evalua- tion of patients with both malignant and nonmalignant ill-ness. While18FDG-PET imaging is not recommended for the evaluation of patients with newly detected thyroid nodules or thyroidal illness, the incidental detection of abnormalthyroid uptake may nonetheless be encountered. Importantly, incidental18FDG-PET uptake in the thyroid gland can be either focal or diffuse. Focal18FDG-PET uptake in the thy- roid is incidentally detected in 1%–2% of patients, while an additional 2% of patients demonstrate diffuse thyroid uptake (60–62). Focal thyroid uptake most often corresponds to a clinically relevant thyroid nodule, and US examination is thus rec- ommended to deﬁne thyroid anatomy. Importantly, focal 18FDG-PET uptake increases malignancy risk in an affected nodule, and therefore clinical evaluation and FNA of nodules ‡1 cm is recommended.18FDG-PET positive thyroid nodules <1 cm that do not meet FNA criteria (see Recommendation 8) can
be monitored similarly to thyroid nodules with high-risk sonographic patterns that do not meet FNA criteria (see Rec- ommendation 24A). A recent meta-analysis conﬁrmed thatapproximately one in three ( *35%)18FDG-PET positive thyroid nodules proved to be cancerous (60), with higher mean maximum standardized uptake value in malignantcompared to benign nodules (6.9 vs. 4.8, p<0.001). In con- trast, diffuse thyroid uptake most often represents benign disease corresponding to inﬂammatory uptake in the settingATA THYROID NODULE/DTC GUIDELINES 11
of Hashimoto’s disease or other diffuse thyroidal illness. However, if detected, diffuse18FDG-PET uptake in the thyroid should also prompt sonographic examination to en-sure there is no evidence of clinically relevant nodularity.Most patients with diffuse 18FDG-PET uptake demonstrate diffuse heterogeneity on sonographic examination, and no further intervention or FNA is required. It is appropriate toevaluate thyroid function in these patients. [A8] Thyroid sonography &RECOMMENDATION 6 Thyroid sonography with survey of the cervical lymphnodes should be performed in all patients with known orsuspected thyroid nodules. (Strong recommendation, High-quality evidence) Diagnostic thyroid/neck US should be performed in all patients with a suspected thyroid nodule, nodular goiter, orradiographic abnormality suggesting a thyroid nodule inci- dentally detected on another imaging study (e.g., computed tomography [CT] or magnetic resonance imaging [MRI]or thyroidal uptake on 18FDG-PET scan) (www.aium.org/ resources/guidelines/thyroid.pdf). Thyroid US can answer the following questions: Is there truly a nodule that corre-sponds to an identiﬁed abnormality?
How large is the nodule? What is the nodule’s pattern of US imaging characteristics? Is suspicious cervical lymphadenopathy present? Is the nodulegreater than 50% cystic? Is the nodule located posteriorly inthe thyroid gland? These last two features might decrease the accuracy of FNA biopsy performed with palpation (63,64). Ultrasound should evaluate the following: thyroid paren- chyma (homogeneous or heterogeneous) and gland size; size, location, zand sonographic characteristics of any nodule(s); the presence or absence of any suspicious cervical lymphnodes in the central or lateral compartments. The US report should convey nodule size (in three dimensions) and location (e.g., right upper lobe) and a description of the nodule’s so-nographic features including composition (solid, cystic pro-portion, or spongiform), echogenicity, margins, presence and type of calciﬁcations, and shape if taller than wide, and vascularity. The pattern of sonographic features associatedwith a nodule confers a risk of malignancy, and combined with nodule size, guides
FNA decision-making (65,66) (see Recommendation 8). In the subset of patients with low serum TSH levels who have undergone radionuclide thyroid scintigraphy suggesting nodu- larity, US should also be performed to evaluate both the pres-ence of nodules concordant with the hyperfunctioning areas on the scan, which do not require FNA, as well as other nonfunc- tioning nodules that meet sonographic criteria for FNA (67). [A9] US for FNA decision-making &RECOMMENDATION 7 FNA is the procedure of choice in the evaluation of thyroid nodules, when clinically indicated. (Strong recommendation, High-quality evidence) FNA is the most accurate and cost-effective method for evaluating thyroid nodules. Retrospective studies have reportedlower rates of both nondiagnostic and false-negative cytology from FNA procedures performed using US guidance compared to palpation (68,69). Therefore, for nodules with a higherlikelihood of either a nondiagnostic cytology ( >25%–50% cystic component) (64) or sampling error (difﬁcult to palpate or posteriorly located nodules),
US-guided FNA is preferred. If the diagnostic US conﬁrms the presence of a predominantlysolid nodule corresponding to what is palpated, the FNA may be performed using palpation or US guidance. [A10] Recommendations for diagnostic FNA of a thyroid nodule based on sonographic pattern Figure 1 provides an algorithm for evaluation and man- agement of patients with thyroid nodules based on sono-graphic pattern and FNA cytology, which is discussed in subsequent sections. &RECOMMENDATION 8 I. Thyroid nodule diagnostic FNA is recommended for (Fig. 2, Table 6): (A) Nodules ‡1 cm in greatest dimension with high sus- picion sonographic pattern. (Strong recommendation, Moderate-quality evidence) (B) Nodules ‡1 cm in greatest dimension with intermedi- ate suspicion sonographic pattern. (Strong recommendation, Low-quality evidence) (C) Nodules ‡1.5 cm in greatest dimension with low sus- picion sonographic pattern. (Weak recommendation, Low-quality evidence)II. Thyroid nodule diagnostic FNA may be considered for (Fig. 2, Table 6): (D) Nodules
‡2 cm in greatest dimension with very low suspicion sonographic pattern (e.g., spongiform). Ob- servation without FNA is also a reasonable option. (Weak recommendation, Moderate-quality evidence) III. Thyroid nodule diagnostic FNA is not required for (Fig. 2, Table 6): (E) Nodules that do not meet the above criteria. (Strong recommendation, Moderate-quality evidence)(F) Nodules that are purely cystic.(Strong recommendation, Moderate-quality evidence) Thyroid US has been widely used to stratify the risk of malignancy in thyroid nodules, and aid decision-making about whether FNA is indicated. Studies consistently reportthat several US gray scale features in multivariate analyses are associated with thyroid cancer, the majority of which are PTC. These include the presence of microcalciﬁcations,nodule hypoechogenicity compared with the surrounding thyroid or strap muscles, irregular margins (deﬁned as either inﬁltrative, microlobulated, or spiculated), and a shape tallerthan wide measured on a transverse view. Features with the highest speciﬁcities (median >90%) for thyroid cancer are
microcalciﬁcations, irregular margins, and tall shape,12 HAUGEN ET AL.
although the sensitivities are signiﬁcantly lower for any single feature (70–77). It is important to note that poorly deﬁnedmargins, meaning the sonographic interface between the nod-ule and the surrounding thyroid parenchyma is difﬁcult to de- lineate, are not equivalent to irregular margins. An irregular margin indicates the demarcation between nodule and paren-chyma is clearly visible but demonstrates an irregular, inﬁl- trative or spiculated course. Up to 55% of benign nodules are hypoechoic compared to thyroid parenchyma, making nodulehypoechogenicity less speciﬁc. In addition, subcentimeter be- nign nodules are more likely to be hypoechoic than larger nodules (71). Multivariable analyses conﬁrm that the proba-bility of cancer is higher for nodules with either microlobulatedmargins or microcalciﬁcations than for hypoechoic solid nod- ules lacking these features (70). Macrocalciﬁcations within a nodule, if combined with microcalciﬁcations, confer the samemalignancy risk as microcalciﬁcations alone (70,74). However, the presence of this type of intranodular macrocalciﬁcation alone is
not consistently associated with thyroid cancer (78). Onthe other hand, a nodule that has interrupted peripheral calci- ﬁcations, in association with a soft tissue rim outside the cal- ciﬁcation, is highly likely to be malignant, and the associatedpathology may demonstrate tumor invasion in the area of dis- rupted calciﬁcation (79,80). In a recent study where 98% of the cancers were PTC, intranodular vascularity did not have independent predictivevalue for malignancy in multivariate logistic regression model including gray-scale features (72). Two other studies and ameta-analysis with higher proportions of follicular thyroidcancer (FTC) (10%–22%) have shown that intranodular vas- cularity was correlated with malignancy (66,74,81). FTC ex- hibits other differences in sonographic features compared toPTC. These tumors are more likely to be iso- to hyperechoic, noncalciﬁed, round (width greater than anterioposterior di- mension) nodules with regular smooth margins (82). Similarly,the follicular variant of papillary cancer (FVPTC) is also more likely than conventional
PTC to have this same appearance as FTC (79). Distant metastases are rarely observed arising fromfollicular cancers <2 cm in diameter, which therefore justiﬁes a higher size cutoff for hyperechoic nodules (83). The vast majority (82%–91%) of thyroid cancers are solid (70,73,75,77,84). Of 360 consecutively surgically removedthyroid cancers at the Mayo clinic, 88% were solid or mini- mally cystic ( <5%), 9% were <50% cystic, and only 3% were more than 50% cystic (85). Therefore, FNA decision-makingfor partially cystic thyroid nodules must be tempered by their lower malignant risk. In addition, evidence linking sonographic features with malignancy in this subgroup ofnodules is less robust, originating from univariate rather than multivariate analyses. Ho wever, an eccentric rather than concentric position of the solid component along thecyst wall, an acute rather than obtuse angle interface of the FIG. 1. Algorithm for evaluation and management of patients with thyroid nodules based on US
pattern and FNA cytology. R, recommendation in text.ATA THYROID NODULE/DTC GUIDELINES 13
FIG. 2. ATA nodule sonographic patterns and risk of malignancy. Table 6.Sonographic Patterns, Estimated Risk of Malignancy, and Fine-Needle Aspiration Guidance for Thyroid Nodules Sonographic pattern US featuresEstimated risk of malignancy, %FNA size cutoff (largest dimension) High suspicion Solid hypoechoic nodule or solid hypoechoic component of a partially cystic nodulewith one or more of the following features: irregular margins (inﬁltrative, microlobu- lated), microcalciﬁcations, taller than wideshape, rim calciﬁcations with small extru-sive soft tissue component, evidence of ETE>70–90 aRecommend FNA at ‡1c m Intermediate suspicion Hypoechoic solid nodule with smooth mar- gins without microcalciﬁcations, ETE, or taller than wide shape10–20 Recommend FNA at ‡1c m Low suspicion Isoechoic or hyperechoic solid nodule, or partially cystic nodule with eccentric solidareas, without microcalciﬁcation, irregular margin or ETE, or taller than wide shape.5–10 Recommend FNA at ‡1.5 cm Very low suspicion Spongiform or partially cystic nodules with- outany of the sonographic features de- scribed
in low, intermediate, or high suspicion patterns<3 Consider FNA at ‡2c m Observation without FNAis also a reasonable option Benign Purely cystic nodules (no solid component) <1 No biopsy b US-guided FNA is recommended for cervical lymph nodes that are sonographically suspicious for thyroid cancer (see Table 7). aThe estimate is derived from high volume centers, the overall risk of malignancy may be lower given the interobserver variability in sonography. bAspiration of the cyst may be considered for symptomatic or cosmetic drainage. ETE, extrathyroidal extension. 14
solid component and cyst, and the presence of micro- calciﬁcations consistently confer a higher risk of malignancy (85–87). Other ﬁndings such as lobulated margins or increasedvascularity of the solid portion are risk factors that are not asrobust (86,87). However, a spongiform appearance of mixed cystic solid nodules is strongly correlated with benignity (66,70,71,88). A spongiform appearance is deﬁned as the ag-gregation of multiple microcystic components in more than 50% of the volume of the nodule (71). Spongiform and other mixed cystic solid nodules may exhibit bright reﬂectors on USimaging, caused by colloid crystals or posterior acoustic en- hancement of the back wall of a microcystic area. These may be confused with microcalciﬁcations by less proﬁcient sono-graphers, and a recent meta-analysis conﬁrmed that operatorexperience is correlated with accurate evaluation of internal calciﬁcations (66). Therefore, because of potential for mis- classiﬁcation, FNA may still be considered for nodules inter-preted as spongiform, but
with a higher size cutoff. Lastly, pure cysts, although rare ( <2% of thyroid lesions), are highly likely to be benign (66,89,90). Given the nuances in sonographic appearances of different thyroid cancer histologies, as well as the challenges posed by partially cystic nodules, some authors have suggested riskstratiﬁcation based upon a constellation of sonographic fea- tures (89–91). In the absence of sonographically suspicious cervical lymph nodes, features associated with the highestrisk for thyroid cancer can be used to triage smaller nodulesfor ﬁne-needle biopsy, whereas nodules with sonographic appearance suggesting lower risk might be considered for ﬁne-needle biopsy at a larger size as determined by maximaldiameter (Figs. 1 and 2, Table 6). The sonographic appearance for the vast majority of thyroid nodules can be generally classiﬁed in the following categories of US patterns, whichcombine several individual sonographic characteristics. Since the interobserver variability in reporting individual charac- teristics is moderate even within
controlled studies (72), theuse of patterns exhibiting correlated sonographic features ismore robust. Two recent studies have reported substantial interobserver correlation for identiﬁcation for nodule sono- graphic patterns (multirater kappa statistics >0.6) (92,93). High suspicion [malignancy risk >70%–90% (89,90,94)]. High suspicion of malignancy is warranted with a solid hy-poechoic nodule or a solid hypoechoic component in a par- tially cystic nodule with one or more of the following features: irregular margins (speciﬁcally deﬁned as inﬁltra-tive, microlobulated, or spiculated), microcalciﬁcations, tal- ler than wide shape, disrupted rim calciﬁcations with small extrusive hypoechoic soft tissue component, or evidence ofextrathyroidal extension (Fig. 2, Table 6). A nodule demon-strating this US pattern is highly likely to be a PTC. Nodules with the high suspicion pattern and measuring ‡1 cm should undergo diagnostic ﬁne-needle biopsy to refute or conﬁrmmalignancy. However, in the absence of evidence of extra- thyroidal extension, metastatic cervical lymph nodes, or distant metastases,
micropapillary thyroid cancers ( <1 cm) often have an indolent course, but this may depend upon patient age (95). Although no distant metastases or deaths occurred in a recent observational series of 1235 Japanesepatients with biopsy-proven PTC, tumor growth and new appearance of lymph node metastases occurred more fre- quently in patients younger than 40 years of age comparedwith those over age 60 (5.9% vs. 2.2% for size increase; 5.3% vs. 0.4% for new nodal metastases, p<0.05). Thus although a sonographically suspicious subcentimeter thyroid nodulewithout evidence of extrathyroidal extension or sono-graphically suspicious lymph nodes may be observed with close sonographic follow-up of the nodule and cervical lymph nodes, rather than pursuing immediate FNA, patientage and preference may modify decision-making (95). Intermediate suspicion [malignancy risk 10%–20% (89,90,94)]. Intermediate suspicion of malignancy is at- tached to a hypoechoic solid nodule with a smooth regular margin, but without microcalciﬁcations, extrathyroidal ex-tension, or taller
than wide shape (Fig. 2, Table 6). Thisappearance has the highest sensitivity (60%–80%) for PTC, but a lower speciﬁcity than the preceding high suspicion pattern, and ﬁne-needle biopsy should be considered for thesenodules ‡1 cm to refute malignancy. Low suspicion [malignancy risk 5%–10% (89,90,94)]. Isoechoic or hyperechoic solid nodule, or partially cystic nodule with eccentric uniformly solid areas without micro- calciﬁcations, irregular margin or extrathyroidal extension,or taller than wide shape prompts low suspicion for malig- nancy (Fig. 2, Table 6). Only about 15%–20% of thyroid cancers are iso- or hyperechoic on US, and these are generallythe follicular variant of PTC or FTCs (71). Fewer than 20% ofthese nodules are partially cystic. Therefore, these appear- ances are associated with a lower probability of malignancy and observation may be warranted until the size is ‡1.5 cm. Very low suspicion [ £3% (66,89,90,94)]. Spongiform or partially cystic nodules without any of the sonographic
featuresdescribed in the low, intermediate, or high suspicion patterns have a low risk of malignancy ( <3%). If FNA is performed, the nodule should be at least 2 cm. Observation without FNA mayalso be considered for nodules ‡2 cm (Fig. 2, Table 6). Benign [ £1% (89,90,94)]. Purely cystic nodules are very unlikely to be malignant, and ﬁne-needle biopsy is not indi-cated for diagnostic purposes (Fig. 2, Table 6). Aspiration with or without ethanol ablation may be considered as a therapeutic intervention if a cyst is large and symptomatic;cytology should be performed if aspiration is done. Sonographic evaluation of the anterior cervical lymph node compartments (central and lateral) should be performedwhenever thyroid nodules are detected. If US detects cervical lymph nodes that are sonographically suspicious for thyroid cancer (Table 7), FNA of the suspicious lymph node shouldbe performed for cytology and washout for Tg measurementif indicated. In addition, this scenario
also warrants US- guided FNA of a subcentimeter nodule that is likely to rep- resent the primary tumor based upon sonographic features. Although there are several known clinical risk factors for thyroid cancer in patients with thyroid nodules including immobility with swallowing, pain, cough, voice change,growth, lymphadenopathy, and a history of childhood radi- ation therapy (either therapeutic, such as cranial radiation in childhood leukemia, or for benign conditions, such as en-larged thymus or tonsils) or familial thyroid cancer (96), these have not been incrementally included in multivariate analyses of gray-scale sonographic features and thyroidATA THYROID NODULE/DTC GUIDELINES 15
cancer risk. However, given the higher pretest likelihood of thyroid cancer associated with these clinical risk factors,FNA can be considered at lower size cutoffs for all of thesonographic appearances described above. Ultrasound elastography (USE) has similarly been investi- gated for its ability to modify thyroid cancer risk assessmentamong clinically relevant thyroid nodules. Elastography is a measurement of tissue stiffness. Performance requires an US machine, as well as an elastography computational modulethat most often must be purchased separately. An initial pro- spective study of 92 selected, nonrandomized patients sug- gested positive and negative predictive values (NPVs) near100% (97). However, more recently, larger trials have reportedsubstantially different results. Moon and colleagues retro- spectively studied 703 thyroid nodules in comparison to gray- scale US (78). Performance of USE was inferior to that ofgray-scale US assessment. The largest prospective study of 706 patients with 912 thyroid nodules was recently published by Azizi et al.
(98). In this study, the positive predictive value (PPV) of USE was only 36%, comparable to that of micro- calciﬁcations. The NPV of USE was 97% in a population with cancer prevalence of 9%. Thus, while USE holds promise as ameans by which to noninvasively assess cancer risk, its per- formance is highly variable and operator dependent. Perhaps most importantly, USE can only be effectively applied to solidnodules, thus excluding its utility for cystic or partially cysticnodules. Furthermore, to be amenable to direct pressure and determination of tissue strain, the index nodule must notoverlap with other nodules in the anterioposterior plane. Obese patients, those with multinodular goiters and coalescent nod- ules, or patients in whom the nodule is posterior or inferior arenot candidates for USE. Thus, at present, USE cannot bewidely applied to all thyroid nodules in a similar fashion to gray-scale or Doppler US examination. The committee therefore believes
USE (when available) may prove to be ahelpful tool for preoperative risk assessment in those patients in whom accurate assessment can be performed. However, the committee cannot presently recommend its universal use orwidespread adoption. Importantly, the ability to perform (or not perform) USE should not modify the recommendation for traditional gray-scale sonographic evaluation. Finally, while most thyroid nodules meeting the preceding sonographic patterns and sizes should undergo FNA, we acknowledge that a conservative approach of active surveil- lance management may be appropriate as an alternative toFNA in selected patients. These may include patients with very low-risk tumors (e.g., no clinical or radiographic evi- dence of invasion or metastases), patients at high surgicalrisk, or those with a relatively short life span expectancy in whom the beneﬁts of intervention may be unrealized. [A11] What is the role of FNA, cytology interpretation, and molecular testing in patients with thyroid nodules? &RECOMMENDATION 9 Thyroid
nodule FNA cytology should be reported using diagnostic groups outlined in the Bethesda System forReporting Thyroid Cytopathology. (Strong recommendation, Moderate-quality evidence) To address a signiﬁcant variability in the reporting of cy- tological ﬁndings in thyroid FNA samples, the 2007 NationalCancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference provided consensus recommenda- tions known as the Bethesda System for Reporting ThyroidCytopathology (99,100). The Bethesda system recognizes six diagnostic categories and provides an estimation of cancer risk within each category based upon literature review and expertTable 7.Ultrasound Features of Lymph Nodes Predictive of Malignant Involvementa SignReported sensitivity, %Reported speciﬁcity, % Microcalciﬁcations 5–69 93–100 Cystic aspect 10–34 91–100 Peripheral vascularity 40–86 57–93 Hyperechogenicity 30–87 43–95Round shape 37 70 aAdapted with permission from the European Thyroid Associa- tion guidelines for cervical ultrasound (20). Table 8.The Bethesda System for Reporting Thyroid Cytopathology: Diagnostic Categories and Risk of Malignancya Diagnostic categoryEstimated/predicted risk of malignancy by
the Bethesda system, %aActual risk of malignancy in nodules surgically excised, % median (range)b Nondiagnostic or unsatisfactory 1–4 20 (9–32) Benign 0–3 2.5 (1–10) Atypia of undetermined signiﬁcance or follicular lesion of undeterminedsigniﬁcance5–15 14 (6–48) Follicular neoplasm or suspicious for a follicular neoplasm15–30 25 (14–34) Suspicious for malignancy 60–75 70 (53–97) Malignant 97–99 99 (94–100) aAs reported in The Bethesda System by Cibas and Ali (1076). bBased on the meta-analysis of eight studies reported by Bongiovanni et al. (103). The risk was calculated based on the portion of nodules in each diagnostic category that underwent surgical excision and likely is not representative of the entire population, particularly ofnondiagnostic and benign diagnostic categories.16 HAUGEN ET AL.
opinion (Fig. 1, Table 8). These categories are (i) nondiagnostic/ unsatisfactory; (ii) benign; (iii) atypia of undetermined signiﬁ- cance/follicular lesion of undetermined signiﬁcance (AUS/FLUS); (iv) follicular neoplasm/suspicious for follicular neo-plasm (FN/SFN), a category tha t also encompasses the diag- nosis of Hu ¨rthle cell neoplasm/suspicious for Hu ¨rthle cell neoplasm; (v) suspicious for malignancy (SUSP), and (vi)malignant. Recent studies that applied the criteria and termi- nology of the Bethesda System to a large series of patients have shown a relatively good conc ordance in reporting FNA cytol- ogy, with 89%–95% of samples being satisfactory for inter- pretation and 55%–74% reported as deﬁnitively benign and 2%–5% as deﬁnitively malignant (101–104). The remainingsamples are cytologically indeterminate, including AUS/FLUSin 2%–18% of nodules, FN in 2%–25%, and SUSP in 1%–6%. In these studies, the probability of malignancy for each Be- thesda category demonstrated signiﬁcant variability, but wasoverall compatible with the range predicted by the
Bethesda System, with the exception of the AUS/FLUS diagnosis, for which the risk of malignant outcome in some studies was sig-niﬁcantly higher than predicted (Table 8) (103,105). Recently, a blinded prospective evaluatio n of inter-observer concordance using Bethesda classiﬁcation was performed. These data con-ﬁrm an inherent limitation to the reproducibility of interpreting any cytology specimen (106). Specimens diagnosed as AUS/ FLUS and SUSP were associated with the highest discordancerates. Some studies suggest that the AUS/FLUS category shouldbe further subdivided into AUS with cytologic atypia (higher risk for malignancy) and FLUS with architectural atypia (lower risk for malignancy), but this has not yet been widely adopted(107). Nonetheless, classiﬁcation using the Bethesda system has proven highly beneﬁcial, allowing practitioners to speak with the same terminology and better convey malignant risk. Therisk of malignancy in each of the six diagnostic categories should be independently deﬁned at each cytology center or institution to guide
clinicians on risk estimates and help chooseappropriate molecular testing for patients with indeterminatecytology. [A12] Nondiagnostic cytology &RECOMMENDATION 10 (A) For a nodule with an initial nondiagnostic cytologyresult, FNA should be repeated with US guidance and, ifavailable, on-site cytologic evaluation (Strong recommendation, Moderate-quality evidence)(B) Repeatedly nondiagnostic nodules without a high suspicion sonographic pattern require close observation or surgical excision for histopathologic diagnosis (Weak recommendation, Low-quality evidence)(C) Surgery should be considered for histopathologic di- agnosis if the cytologically nondiagnostic nodule has ahigh suspicion sonographic pattern, growth of the nodule (>20% in two dimensions) is detected during US surveil- lance, or clinical risk factors for malignancy are present (Weak recommendation, Low-quality evidence) Nondiagnostic or unsatisfactory FNA biopsies are those that fail to meet the established quantitative or qualitativecriteria for cytologic adequacy (i.e., the presence of at least six groups of well-visualized follicular cells, each group containing at least 10 well-preserved epithelial cells, pref-erably
on a single slide) (99,108). Although an FNA speci-men found to have abundant colloid and few epithelial cells may be considered nondiagnostic by the above criteria, this is also likely a benign biopsy. After an initial nondiagnosticcytology result, repeat FNA with US guidance and, if avail- able, on-site cytologic evaluation, will substantially increase the rate of specimen adequacy (109–113). It has been sug-gested that repeat FNA should be performed no sooner than 3 months after the initial FNA to prevent false-positive inter- pretation due to biopsy-induced reactive/reparative changes(114). Two recent studies have questioned the necessity for a3-month waiting period after the ﬁrst FNA because they did not ﬁnd a correlation between the diagnostic yield/accuracy of repeated FNA and the waiting time between the procedures(115,116). A 3-month waiting period after a nondiagnostic biopsy is likely not necessary. If clinical and US features are suspicious for malignancy, a shorter waiting period may
beappropriate. Repeat FNA with US guidance will yield a di- agnostic cytology specimen in 60%–80% of nodules, partic- ularly when the cystic component is <50% (64,112,117). Nodules with larger cystic portion have a higher chance to yield nondiagnostic samples on the initial and repeated FNA. Most nodules with a nondiagnostic cytology interpretation are benign. In large series of patients classiﬁed based on theBethesda System, nondiagnostic samples constituted 2%–16% of all FNA samples, of which 7%–26% were eventually resected (101–103). The frequency of malignancy among all initiallynondiagnostic samples was 2%–4% and among those non- diagnostic samples that were eventually resected was 9%–32%. Sonographic features are also useful for identifying which nodules with repeat nondiagnostic FNA cytology results are more likely to be malignant. Of 104 nodules with two non- diagnostic cytology results, thyroid cancer was found in 25%of those with microcalciﬁcations, irregular margins, a tallerthan wide shape, or hypoechogenicity, but in
only 4% lacking these features (118). In some studies, the use of thyroid core-needle biopsy (119) and molecular testing for BRAF (120,121) or a panel of muta- tions (122) helped to facilitate appropriate management of these patients, although the full clinical impact of these approachesfor nodules with nondiagnostic cytology remains unknown. Some studies have found that core biopsy offers a higher ade- quacy rate, but may be less sensitive for the detection of pap-illary cancer (123,124). Mutational testing may be informative in samples considered inadequate by qualitative criteria (i.e., due to poor preparation or poor staining of cells) but is unlikelyto be contributory in samples with insufﬁcient quantity of cells. [A13] Benign cytology &RECOMMENDATION 11 If the nodule is benign on cytology, further immediatediagnostic studies or treatment are not required (Strong recommendation, High-quality evidence) Accurate FNA cytology diagnosis depends upon a num- ber of factors including the skill of the
operator, FNA tech- nique, specimen preparation, and cytology interpretation.ATA THYROID NODULE/DTC GUIDELINES 17
Ultrasound-guided FNA with real-time visualization of needle placement in the target nodule decr eases the false-negative rate of a benign cytology diagnosis (68,69,126,128). Although pro-spective studies are lacking, malignancy rates of only 1%–2%have been reported in large retro spective series that analyzed the utility of systematic repeat FNA in nodules with prior benign cytology results (129–133). A pooled analysis of 12 studies byTeeet al. (134) showed that of 4055 patients with benign cy- tology who underwent surgery, the rate of malignancy was 3.2%. Studies have also attempted to correlate nodule size with accuracy of FNA cytology. Several surgical series have re- ported higher malignancy rates in nodules >3–4 cm, but these suffer from both selection bias (only a subset of patients un-derwent preoperative FNA) and potential sampling error (FNAperformed by palpation) (135,136). A recent study evaluated the accuracy of FNA and US features in patients with thyroid nodules ‡4 cm
(137). This was a single-center study in which the practice is to offer thyroidectomy or lobectomy to all pa- tients with nodules ‡4 cm. The investigators identiﬁed thyroid cancer in 22% of 382 nodules. A subset of thyroid nodulesunderwent preoperative FNA, and of the 125 cytologically benign nodules, 10.4% were malignant on ﬁnal histopathology. The investigators further showed that individual US char-acteristics were not predictive for malignancy, although they did not look at sonographic patterns. Two other recent reports of consecutive US-guided FNA evaluations in over1400 nodules >3 cm with initial benign cytology followed for a mean of 3 years conﬁrmed a lower false-negative rate of<1.5% (138,139). Interestingly, in both these studies 66% of the missed cancers were found in nodules with highsuspicion sonographic pattern, despite initial benign cytol- ogy. A recent retrospective study analyzed the long-term follow-up of 2010 cytologically benign nodules from 1369patients. Over a mean follow-up of
8.5 years 18 false- negative malignancies were detected. However, no deaths attributable to thyroid cancer were identiﬁed in this cohort.These data conﬁrm that an initially benign FNA confersnegligible mortality risk during long-term follow-up despite a low but real risk of false negatives in this cytologic cate- gory (140). Based on the evidence, it is still unclear if pa-tients with thyroid nodules ‡4 cm and benign cytology carry a higher risk of malignancy and should be managed differ- ently than those with smaller nodules. Follow-up for patients with benign cytology is discussed in section [A24] and Recommendation 23. [A14] Malignant cytology &RECOMMENDATION 12 If a cytology result is diagnostic for primary thyroid ma- lignancy, surgery is generally recommended. (Strong recommendation, Moderate-quality evidence) A cytology diagnostic for a primary thyroid malignancy will almost always lead to thyroid surgery. However, an ac- tive surveillance management approach can be considered as an alternative to
immediate surgery in (A) patients with very low risk tumors (e.g., papillary microcarcinomas without clinically evident metasta- ses or local invasion, and no convincing cytologicevidence of aggressive disease),(B) patients at high surgical risk because of comorbid conditions, (C) patients expected to have a relatively short remaining life span (e.g., serious cardiopulmonary disease, othermalignancies, very advanced age), or (D) patients with concurrent medical or surgical issues that need to be addressed prior to thyroid surgery. Following thyroid surgery for papillary thyroid micro- carcinoma (PTMC), deﬁned as a tumor 1 cm or less in size, disease-speciﬁc mortality rates have been reported to be <1%, loco-regional recurrence rates are 2%–6%, and distant recurrence rates are 1%–2% (141,142). It is quite likely that these excellent outcomes are more related to the indolent nature of the disease rather than to the effectiveness oftreatment, since two prospective clinical studies of activesurveillance from Japan reported similar clinical
outcomes in 1465 patients with biopsy-proven PTMC that were not sur- gically removed and were followed for up to 15 years (av-erage 5–6 years, range 1–17 years) (95,143). In the study by Itoet al. (95), observation was offered to 1235 patients with PTMC that did not have (i) location adjacent to the trachea oron the dorsal surface of the lobe close to the recurrent la- ryngeal nerve, (ii) FNA ﬁndings suggestive of high-grade malignancy; (iii) presence of regional lymph node metasta-ses; or (iv) signs of progression during follow-up. Of those,most patients showed stable tumor size on average follow-up of 60 months (range 18–227 months), whereas 5% showed tumor enlargement ( >3 mm) by US on 5-year follow-up, and 8% on 10-year follow-up. Furthermore, 1.7% and 3.8% of patients at 5-year and 10-year follow-up showed evidence for lymph node metastases. Of 1235 patients, 191 underwentsurgical treatment after observation, including those with
tumor enlargement and new lymph node metastases. These patients have been followed an average of 75 months (range1–246 months) after the surgical intervention. Only one of the patients treated with surgery after observation developed tumor recurrence. In the study by Sugitani et al. (143), 230 patients with asymptomatic PTMC were followed for 5 yearson average. Of those patients, tumor size enlargement was observed in 7%, and 1% developed apparent lymph node metastasis. Seven percent of patients underwent surgery after1–12 years of follow-up, and no recurrences were identiﬁed in those on limited follow-up, suggesting that the delayed surgery did not affect the outcome. A more recent study byIto and colleagues followed 1235 patients with PTMC under active surveillance for an average of 60 months (95). Only 43 patients (3.5%) had clinical progression of disease by theirstated criteria (tumor growing to >12 mm or appearance of new lymph node metastases). Interestingly, the
younger pa- tients ( <40 years old) had an 8.9% rate of clinical progres- sion, while those 40–60 years old had a 3.5% rate ofprogression and those >60 years old had the lowest rate of clinical progression (1.6%). Despite the evidence that cautious observation is a safe and effective alternative to immediate surgical resection, very few PTMC patients outside of those two centers in Japan are given the option of an active surveillance approach. This is in part dueto reports in the literature of a small percentage of patients with PTMC presenting with clinically signiﬁcant regional or distant metastases (141,142,144). Unfortunately, no clinical features(145–151) can reliably differentiate the relatively small number18 HAUGEN ET AL.
of PTMC patients destined to develop clinically signiﬁcant progression from the larger population of people that harbor indolent PTMCs that will not cause signiﬁcant disease. Similarly, well-known thyroid cancer oncogenes, such as BRAF , when taken in isolation, are not able to speciﬁcally identify the microcarcinomas that will progress and spread outside of the thyroid. The prevalence of BRAFV600Emuta- tions in PTMC with lymph node metastases and tumor re- currence is higher than PTMC without LN metastases or recurrence, and in some studies the presence of a BRAF mu- tation was associated with lymph node metastasis from PTMC on multivariate analysis (150,152,153). These studies showed that although the presence of a BRAFV600Emutation identiﬁes 65%–77% of patients with PTMC that develop lymph nodemetastases, the BRAF status taken in isolation has a low PPV for detecting PTMC with extrathyroidal spread and therefore has a limited role for guiding patient management. However,recent data
suggest that speciﬁc molecular proﬁles, such as the coexistence of BRAF with other oncogenic mutations (such as PIK3CA ,AKT1 ),TERT promoter, or TP53 mutations may serve as more speciﬁc markers of less favorable outcome of PTC. Therefore, it is likely that ﬁnding of one of these genetic proﬁles in a small tumor would suggest that it represents anearly stage of a clinically relevant PTC (154–157). Future studies are expected to establish the impact of molecular pro- ﬁling involving multiple mutations or other genetic alterationson clinical management of patients with PTMC. [A15] Indeterminate cytology (AUS/FLUS, FN, SUSP) * [A16] What are the principles of the molecular testing of FNA samples? Molecular markers may be classiﬁed according to intended use; that is, diagnostic (classiﬁcation of a disease state),prognostic, or predictive purposes (providing information on the estimated probability of therapeutic beneﬁt or harm of a speciﬁc therapy) (158). Furthermore, companion use of pre-dictive
molecular markers involves the identiﬁcation of patientsubgroups in which a therapeutic intervention is proven to be either beneﬁcial or harmful, with intended implications for appropriate clinical stratiﬁcation of therapies (158). Validationstudies of molecular marker tests may include examination of (a) analytic validity (including test accuracy and reproduc- ibility in ascertaining the molecular event), (b) clinical validity(the performance of the test in distinguishing different groups of patients, based on biology or expected disease outcome, including measures of sensitivity and speciﬁcity or predictivevalues), and (c) clinical utility (examination of the test’s ability to improve outcomes, with direct clinical decision-making implications) (158). Furthermore, an NCCN Tumor MarkerTask Force has indicated that the clinical utility of a moleculartest should be founded in strong evidence proving that use of the marker ‘‘improves patient outcomes sufﬁciently to justify its incorporation into routine clinical practice.’’ {The principal proposed use of molecular markers in indeterminate thyroid FNA specimens
is diagnostic (ruling out or in the presence of thyroid malignancy),with the implication of a companion use to informdecision-making on primary surgical treatment (i.e., the decision to perform surgery and if so, the extent of surgery). However, the focus of this section is restrictedto the clinical validity of molecular testing of indeter- minate FNA specimens. It is important to note that long- term outcome data on companion use of molecularmarker status to guide therapeutic decision-making is currently lacking, and therefore we do not know if im- plementation of molecular marker use in routine clinicalpractice would result in a signiﬁcant overall beneﬁt inhealth outcomes in patients with thyroid nodules. Sur- gical decision-making on indeterminate FNA specimens is reviewed in another section of these guidelines, with somereference to molecular mark er testing (if performed). As summarized in a Disease State Commentary from the AACE Thyroid Scientiﬁc Committee and a consensusstatement from the
ATA Surgical Affairs Committee, use o fm o l e c u l a rm a r k e rt e s t i n go ni n d e t e r m i n a t eF N As p e c - imens should not be intended to replace other sources ofinformation or clinical judgment (159,160). The pretest probability of malignancy (based on clinical risk factors, cytology, US ﬁndings), feasibility considerations, andpatient preferences are some additional factors that needto be considered in decision-making related to molecular marker testing of FNA specimens. Because this is a rap- idly evolving ﬁeld of investigation, it will be important toperform interval evaluations of the published evidence to ensure that recommendations remain contemporary. A number of molecular approaches have been studied in the clinical setting of indeterminate FNA cytologic inter- pretation (161). One could surmise that an ideal ‘‘rule-in’’ test would have
a PPV for histopathologically proven ma-lignancy similar to a malignant cytologic diagnosis (98.6%),and an ideal ‘‘rule-out’’ test would have a NPV similar to a benign cytologic diagnosis (96.3%) (predictive value esti- mates based on a recent meta-analysis of performance of theBethesda system) (103), and these would hold true with a reasonable degree of precision and reproducibility. &RECOMMENDATION 13 If molecular testing is being considered, patients should becounseled regarding the potential beneﬁts and limitations of testing and about the possible uncertainties in thetherapeutic and long-term clinical implications of results. (Strong recommendation, Low-quality evidence) The largest studies of preoperative molecular markers in patients with indeterminate FNA cytology have respectivelyevaluated a seven-gene panel of genetic mutations and re- arrangements ( BRAF ,RAS,RET/PTC ,PAX8/PPAR c) (162), a gene expression classiﬁer (167 GEC; mRNA expressionof 167 genes) (163), and galectin-3 immunohistochemistry (cell blocks) (164). These respective studies have been sub- ject to various degrees of
blinding of outcome assessment(162–164). Mutational testing has been proposed for use as a rule-in test because of relatively high reported speciﬁcity (86%–100%)*The ﬁnal draft for the sections (A15–A19) and recommenda- tions (13–17) were revised and approved by a subgroup of seven members of the task force with no perceived conﬂicts or competinginterests in this area. {From the NCCN Biomarkers Compendium (www.nccn.org/ professionals/biomarkers/default.aspx).ATA THYROID NODULE/DTC GUIDELINES 19
and PPV (84%–100%) (105,122,162,165–168). Although BRAFV600Esingle mutation testing has been estimated to have a speciﬁcity of approximately 99% (pooled data from 1117nodules with histopathologic conﬁrmation from multiplestudies), the sensitivity has been deemed to be too low to reliably rule out the presence of malignancy (169). Therefore, mutational panels have been expanded to include multiplemutations/translocations including BRAF ,NRAS ,HRAS ,a n d KRAS point mutations, as well as RET/PTC1 andRET/PTC3 , with or without PAX8/PPAR crearrangements (105,122,162, 165–168) and other gene rearrangements (170). In indeter- minate cytology thyroid nodules, the sensitivity of the seven- gene mutational panel testing is variable, with reports rangingfrom 44% to 100% (162,165,167). The reported variability insensitivity of mutational analysis with the seven-gene panel in indeterminate nodules suggests that traditional limited muta- tion panels may not reliably rule out malignancy with a neg-ative test in this population. Next-generation sequencing of an expanded panel of point mutations, single

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