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and cement in- jections), SBRT, or intensity modulated radiotherapy are the most frequently used techniques. The main principle of thesetechniques is to selectively treat the lesion, be minimally invasive, and be well tolerated with relatively few side ef- fects. The indications and the feasibility of each techniquedepend on the location and the size of the lesion to be treated. Experience with metastases from thyroid cancer is scarce, and most available data have been obtained in patients withmetastases from nonthyroid cancers. SBRT allows for delivering high radiation doses in few fractions to the target tumoral lesion with a high degree of precision, minimizing the radiation of normal surroundingtissue. It has been used in several trials to treat brain, liver, lung, and bone metastases. For patients with few (one to three) brain metastases, SBRT is as effective as surgery and can be repeated in case of appearance of new brain lesions. It
is usually well tolerated, and brain necrosis that occurred in less than 10% of cases isusually limited and had no clinical consequences. The patientoutcome depends mostly on the progression rate of extra- cerebral lesions (1015). Data on lung and liver metastases are available only in ret- rospective studies on low numbers of patients and with a me- dian follow-up of less than 1 year in most cases and in one prospective study (1016). This study included patients withmany different primary tumors, including 10% of the patients having thyroid cancer. They showed a local control rate ranging from 63% to 98% in lung lesions and from 57% to 100% inliver lesions, with a cumulative dose delivered ranging from 20 to 75 Gy in 5–15 fractions. The local tumor control seems to be long lasting with complete response ranging from 70% to 90%at 2–3 years. Furthermore, rare ( <3%) grade 3–4 toxicities
(pneumonitis, pleural effusion, intestinal complications) were reported (1017). These toxicities are much less common that those associated with percutaneous treatment modalities. Thelocal control rate seems to be dose-related, but the optimal protocol for SBRT is still not established. Concerning bone lesions, radiotherapy plays an important role because it can complement surgery in case of incomplete resection or be used alone for pain relief or palliation. In many cases, usual radiotherapy can be given. However, themajor limitation of radiotherapy in spine lesions is the cu- mulative dose to the spinal cord. SBRT compared to standardradiotherapy demonstrated a higher efﬁcacy on tumor control and for limiting radiation to the spinal cord, especially in patients who need to be re-irradiated. A local tumor controlrate of bone lesions for SBRT ranging from 88% to 100% wasreported especially for lesions that were previously surgically resected, with a pain relief rate of 30%–83%. SBRT protocols differed
among studies, with a maximum of 30 Gy admin-istrated in one to ﬁve fractions but a single dose of 12.5–15 Gy seems to achieve similar results (1018). Spinal myelop- athy or vertebral fractures are the most important side effects,especially in case of large-volume lesions. Percutaneous thermal ablation is aimed at destroying tumor foci by increasing (RFA) or decreasing (cryoablation) tem-peratures sufﬁciently to induce irreversible cellular damages. RFA is performed for liver, lung, and bone tumor foci. Clinical trials showed high efﬁcacy of RFA for liver lesions, especially from colorectal cancer with long-term local diseasecontrol ranging from 40% to 80%, depending on lesion size, and a prolonged overall survival in treated patients (1019,1020). In a total of 100 lung lesions including primary lung tu- mors and metastases, RFA was both efﬁcient and well tol- erated, with a complete tumor control rate of 93% at 18 months (1021). A multicenter prospective trial
on 183 lungmetastases from cancer other than colorectal showed a complete response rate of 88% at 1 year and an overall sur- vival of 92% and 64% at 1 year and at 2 years, respectively(1022). Recurrence occurs more frequently in lesions >3c m and can be detected early after ablation (within 3 months) by 18FDG PET/CT (824,1016). Cases of delayed recurrence have also been reported, and long-term follow-up is needed.RFA may be considered for lung lesions <3 cm of diameter, without soft tissue or mediastinum invasion and without contact with large vessels. Furthermore, repeated treatmentscan be performed on the same lesion and multiple lesions can be treated in the same patient. RFA or cryoablation of bone lesions showed promising results with rapid (1–7 days) and long-lasting pain control(1023,1024). Cryoablation is a safe technique to treat or to stabilize bone lesions, is frequently associated with ce- mentoplasty to consolidate the bone
and avoid subsequentcomplications, and can treat larger lesions than RFA. Local disease control was achieved in the few reported cases of lung and bone metastases from thyroid cancer treatedby thermal ablation (883,1016,1025). The association of cryoablation and cementoplasty seems promising in purely lytic bone metastases from thyroid cancer. Furthermore, inthree patients with liver metastases from thyroid cancer (two MTC and one FTC) RFA was feasible and reduced local symptoms (1026). Multidisciplinary treatment for metasta-ses from thyroid cancer especially for bone metastases—including, for example, thermal ablation (RFA or cryoabla- tion) and/or cementoplasty associated with systemic treatment (RAI, bone-directed agents, or chemotherapy)—can improvethe patient’s quality of life by reducing pain and prolonging time to skeletal events, delaying initiation of systemic treat- ment, and even improving patient survival (1027). The toxicity of thermal ablation is generally low, but pneumothorax or pleural effusion was observed in up to 50% of RFA procedures for lung
lesions, but it rarely requiredfurther treatments. Local pain or transient neurological deﬁcit or vertebral fracture can occur in case of ablation of boneATA THYROID NODULE/DTC GUIDELINES 83
lesions (5%–6%), and intestinal perforation, abdominal pain, or intraperitoneal bleeding was observed following ablation of liver lesions (1021,1028). Published experience using thermal ablation and stereo- tactic radiation in thyroid cancer patients is limited, and recommendations are currently based on more robust evi- dence in other solid tumors. Randomized prospective studiescomparing the efﬁcacy and tolerability of these different techniques are lacking, and their choice in clinical practice is based on local experience, lesion location as well as patientstatus and preference. [C39] Treatment of brain metastases &RECOMMENDATION 94 While surgical resection and stereotactic EBRT are the mainstays of therapy for CNS metastases, RAI can be considered if CNS metastases concentrate RAI. If RAI isbeing considered, stereotactic EBRT and concomitant glu- cocorticoid therapy are recommended prior to RAI therapy to minimize the effects of a potential TSH-induced increasein tumor size and RAI-induced inﬂammatory response. (Weak recommendation, Low-quality evidence) Brain metastases typically occur in
older patients with more advanced disease and are associated with a poorprognosis (933). Surgical resection and stereotactic EBRT are the mainstays of therapy (933,1029,1030). There are few data showing efﬁcacy of RAI. Stereotactic radiation therapyis preferred to whole-brain radiation because life expectancy in patients with brain metastases may be prolonged, and stereotactic radiation induces less short- and long-term tox-icity compared with whole-brain radiation (fatigue, head- ache, cognitive decline, and behavioral changes), and it may be effective even in patients with multiple brain lesions. [C40] Who should be considered for clinical trials? &RECOMMENDATION 95 Patients should be considered for referral to participate inprospective therapeutic clinical trials based upon speciﬁceligibility requirements for given studies and the likeli- hood that the patient may or may not beneﬁt from study participation. Clinicians considering referral of patients fortrials should review available treatment options and eli- gibility criteria, preferably through discussions with trial center personnel and
review of trial materials at the web-site www.clinicaltrials.org. (Strong recommendation, Moderate-quality evidence) A therapeutic clinical trial is a systematic investigation of the effectiveness and safety of a potential new or modiﬁed treatment or combination of treatments, potentially includingmedications, surgery, radiation therapy, and/or other novel or revised approaches. A broad variety of such trials may exist at any given time, which can generally be identiﬁed throughonline databases such as www.clinicaltrials.org, best supple- mented with direct contact with the institutions conducting trials of particular interest so as to ensure trial availability andpatient eligibility. There is limited evidence that enrollment into clinical trials is associated with lower overall cancer- speciﬁc mortality for patients with common cancers, evenwithin contexts in which approved and ‘‘standard of care’’ therapies already exist (1031). The reasons for this association are unclear, but there is no evidence to suggest that trial par-ticipation is deleterious to patient outcomes, and it
may bebeneﬁcial. Participation in a clinical trial should be considered in any situation wherein there exists no effective or proven standard of care, or when a standard of care is being comparedwith a promising new or investigational therapy. Adjuvant therapy trials may be appropriate for patients at high risk for disease recurrence following primary treatment who wish topursue aggressive therapy. For patients with RAI-refractory carcinoma that is locally advanced or metastatic, clinical trials may be appropriate in the setting of disease that is consideredprogressive by RECIST criteria, especially if progression oc-curred after use of an approved kinase inhibitor such as len- vatinib or sorafenib, and/or if approved therapies are otherwise unaffordable to a speciﬁc patient. Patients demonstrated tohave speciﬁc therapeutically targetable tumor alterations, such asBRAF mutations or PAX8/PPAR corALK rearrangements, can also be considered for trials testing therapies speciﬁcallytargeting these alterations. However, given the indolent nature of metastatic disease in
most patients, therapeutic clinical trial participation should not be considered for patients with stable,asymptomatic metastatic disease unless agents with signiﬁcant likelihood of complete remission, prolongation of survival, or biologic impact such as redifferentiation that could sensitize todeﬁnitive therapy are available (see section [C37]). [C41] What is the role of systemic therapy (kinase inhibitors, other selective therapies, conventional chemotherapy, bisphosphonates, denosumab)in treating metastatic DTC? Systemic therapeutics of several types in selected clinical contexts appear to provide clinical beneﬁt in treating meta- static DTC (1032). Beneﬁt has been demonstrated in the formof improved progression-free survival (delay in time to dis-ease progression or death) in three randomized, double- blinded, placebo-controlled clinical trials: vandetanib (1033), sorafenib (1013), and lenvatinib (1034). Beneﬁt has also beendemonstrated in the form of induced durable tumor regres- sion (1035–1037). However, randomized clinical trial data are not yet avail- able to address many additional critical questions, including effects of systemic
therapies of various types on survival and quality of life, or to address critical issues of optimal patientselection/inclusion/exclusion criteria for therapy and dura- tion of treatment. To date, no clinical trial has demonstrated an overall survival advantage or improved quality of life from use of any therapyin RAI-refractory DTC (1013,1034). Consequently, thera- peutic decisions are presently based upon the convergence of expert opinion and patient preference/philosophy, thus em-phasizing the critical need to address the above questions de- ﬁnitively through clinical trials. It is therefore important to involve highly skilled clinicians familiar with RAI-refractorydisease and these systemic therapies in decision-making until deﬁnitive guidelines can be developed based upon more rig- orous data. As a guide, evidence-based recommendations withexpert consensus have been recently published (953). It should also be highlighted that, broadly construed, sys- temic therapy encompasses not only more recently emerging84 HAUGEN ET AL.
‘‘targeted’’ approaches, but also historical ‘‘mainstay’’ therapies including TSH suppression and RAI. Although more ‘‘novel’’ approaches have attracted attention recently, itis important to optimally apply fundamental approaches. Inthis regard, therapeutic RAI should also be used to optimal effect prior to the initiation of more recent/novel therapies. To accomplish this requires attention to detail, includingensuring adequate TSH stimulation, patient adherence to low-iodine pre-RAI therapy dietary restrictions, and avoid- ance of proximal preceding iodine contamination from IVcontrast agents, with veriﬁcation by urinary iodine concen- tration measurements in selected cases. In this context, oc- casional patients previously declared ‘‘RAI-refractory’’ caninstead be found to have RAI-responsive disease when suchdetails are attended to if previously neglected. Also important is the consideration of alternatives to the use of systemic therapy, such as the application of surgery orother localized approaches (including radiation therapy or thermal ablation approaches). In patients in whom the threats imposed by cancer are
more localized, directed approachesmay have greater potential to control localized disease and symptoms compared to systemic therapies, especially given the absence of data to indicate survival beneﬁt or improvedquality of life from the application of systemic therapies in advanced RAI-refractory DTC. It is also critically important to ensure that the disease prompting therapy represents metastatic thyroid cancer. Inparticular, because pulmonary nodules attributable to benign causes are common, the presence of pulmonary nodules does not in and of itself justify the application of systemic therapy.Thus, in cases of diagnostic uncertainty in which the result would have deﬁnitive therapeutic implications, biopsy is re- quired, especially when Tg levels are low/unhelpful (such asin the presence of anti-Tg antibodies). Conversely, stable, asymptomatic pulmonary nodules of a few millimeters in size likely do not justify invasive assessment or systemic therapy. The introduction of systemic therapy requires that both the clinician and the patient agree that
clinical beneﬁts are ex- pected to exceed risks for that individual patient. The prob- lem in this determination, however, is that it is often verydifﬁcult to precisely deﬁne such risks and beneﬁts because they vary greatly depending upon patient context and they are often poorly articulated in the literature. It is also critical toweigh not just risks of death and injury, but also risks of systemic therapies on quality of life, especially as viewed by a particular patient considering treatment. Hence, the deci-sion is not based solely on beneﬁts and risks of therapy, but also on patient value judgments. Issues of risks and beneﬁts are reviewed in this context in conjunction with each thera-peutic modality below. Finally, it is important that the in-volved care team (physicians, physician assistants, nurse practitioners, nurses) be experienced in the use and man- agement of toxicities associated with these therapies. [C42] Kinase inhibitors &RECOMMENDATION 96
(A) Kinase inhibitor therapy should be considered in RAI- refractory DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease nototherwise amenable to local control using other approaches.Kinase inhibitors that are FDA approved for differentiated thyroid carcinoma or other available kinase inhibitors (pref- erably within the context of therapeutic clinical trials) can beconsidered since the impact of these agents on overall sur-vival and quality of life remains to be deﬁned. (Weak recommendation, Moderate-quality evidence)(B) Patients who are candidates for kinase inhibitor ther- apy should be thoroughly counseled on the potential risks and beneﬁts of this therapy as well as alternative thera-peutic approaches including best supportive care. Appro- priate informed consent should be obtained and documented in the medical record prior to initiation of anytherapy, regardless of whether the patient is being treatedin the context of a clinical trial. (Strong recommendation, Low-quality evidence) Cytotoxic chemotherapy has historically produced disap- pointing
results in patients with DTC (1038). Kinase inhibi- tors, many of which share the common target of the VEGF receptor (VEGFR) (e.g., sorafenib, pazopanib, sunitinib,lenvatinib, axitinib, cabozantinib, and vandetanib), have re- cently emerged as highly promising therapies for metastatic RAI-refractory DTC (1032). Kinase inhibitors, however, areassociated with numerous adverse effects including diarrhea,fatigue, induced hypertension (requiring initiation of anti- hypertensive therapy in about half of all previously normo- tensive individuals), hepatotoxicity, skin changes, nausea,increased LT 4dosage requirement, changes in taste, and weight loss. These potential side effects have high proba- bility of negatively impacting quality of life and/or neces-sitating dosage reductions in many patients and treatment discontinuation in up to 20% of patients. Furthermore, these agents are also associated wit h more serious and potentially fatal risks including of thrombosis, bleeding, heart failure, hepatotoxicity, gastrointestinal tract ﬁstula formation, and intestinal perforation (1039). Overall, the risk of therapy-related death in cancer patien
ts treated with oral kinase in- hibitors is about 1.5%–2% (RR =2.23, p<0.023, compared with randomized placebo treated control cancer patients) based upon meta-analysis of results from 10 recently pub-lished randomized trials conducted in several cancers (1039). In the setting of thyroid cancer, lenvatinib (now approved in the United States for use in RAI-refractoryDTC) was associated with severe toxicities in 75% of pa- tients and therapy-attributed mortality in 2.3% of patients (1034). While risk of drug-related death is relatively low,the knowledge of potentially fatal therapeutic outcomesshould prompt considerable restraint in the use of kinase inhibitors, especially in patients who are asymptomatic and/ or with stable or slowly progressive disease and in patientswho can otherwise be effectively treated using directed therapies. Three randomized placebo-controlled clinical trials (phase 2, vandetanib; phase 3, sorafenib and lenvatinib) had been published by the time of the writing of these guidelines, each demonstrating delayed time to
disease progression amongkinase inhibitor–treated patients relative to those treated with a placebo (1013,1033,1034). On this basis, sorafenib and lenvatinib were approved for use in the United States and theEuropean Union for patients with advanced RAI-refractoryATA THYROID NODULE/DTC GUIDELINES 85
DTC. Sorafenib or vandetanib treatment were each associ- ated with progression-free survival prolonged by 5 months, with<15% objective response rates, but with no improve- ment on overall survival demonstrated to date. Assessmentscomparing sorafenib to placebo outcomes demonstrated overall lower quality of life among sorafenib-treated patients relative to those treated with placebo, despite improvedprogression-free survival. Lenvatinib therapy was associated with longer prolonged median progression-free survival by 14.7 months compared with placebo, with a RECIST re-sponse rate of 65%, with some complete responses also re- ported. Despite these very encouraging results and regulatory approval, however, no statistically signiﬁcant impact oflenvatinib (or any other kinase inhibitor) therapy on overallsurvival has yet been observed (1034). However, survival data in this context, where all three randomized and placebo- controlled DTC trials allowed crossover of placebo-treatedpatients to kinase inhibitor, must be interpreted with great caution. The crossover trial designs effectively ‘‘contami- nated’’ overall survival data, with
many placebo-treated pa-tients later crossing over to receive open-label kinase inhibitor. Hence, the absence of a proven effect of kinase inhibitors on overall survival in these trials can best be in-terpreted as indicating that, among study populations, a delay in initiation of kinase inhibitor therapy until observation of RECIST disease progression among initially placebo-treatedpatients did not adversely affect overall survival. Additional VEGFR-directed kinase inhibitors including axitinib, pazopanib, cabozantinib, and sunitinib also have activity in metastatic DTC based upon phase 2 therapeutictrials (1035–1037). No multi-arm comparison ‘‘superiority’’ phase 3 trial data in DTC are available to inform decision- making with regard to selection among available and mostlysimilarly targeted kinase inhibitors. Recent regulatory ap- proval in DTC and more abundant outcome data in response to lenvatinib and sorafenib therapy in DTC (1013,1034,1040–1043) prompt prominent consideration of either len- vatinib or sorafenib as a ﬁrst-line therapy. Despite encouraging trial results, the extent to
which any kinase inhibitor may prolong overall survival and in whichcontexts remains undeﬁned. In some situations, however, the decision to initiate kinase inhibitor therapy is straightfor- ward. For example, patients with oxygen dependence at-tributable to DTC lung metastases are not only adversely affected by their cancers, but also imminently threatened. Such patients have potential to gain symptomatic bene-ﬁt even in the absence of deﬁnite extension of life. At the other extreme, many patients with metastatic DTC are asymptomatic from their cancers and are not expected to bethreatened by their cancers in the foreseeable future. Thesepatients should remain on TSH-suppressive treatment as their primary therapeutic intervention rather than be exposed to kinase inhibitor therapy. For patients with disease betweenthese two extremes, it is critical that risks and beneﬁts of therapy, anticipated side effects, goals, patient context, and the therapeutic philosophy of each particular patient bethoroughly vetted so as to best individualize
therapy. This decision is ideally made within the context of specialized centers with comprehensive knowledge of the natural his-tory of the disease and of the effects of available therapies. As a general ‘‘expert consensus’’ guideline, structurally progressive, symptomatic, and/or imminently threateningDTC (wherein disease progression is expected to requireintervention and/or to produce morbidity or mortality in <6 months) that is RAI refractory and not amenable to satis- factory control using directed approaches (e.g., surgery,radiation therapy, thermal ablation) should prompt consid- eration of kinase inhibitor therapy. Speciﬁc characteristics impacting decision-making for starting such therapy areoutlined in Table 16. Patients who are candidates for kinase inhibitor ther- apy should be thoroughly counseled with regard not only to Table 16.Factors to Review When Considering Kinase Inhibitor Therapya Factors favoring kinase inhibitor therapy Factors discouraging kinase inhibitor therapy Imminently threatening disease progression expected to require intervention and/or to produce morbidity or mortality in <6 months
(e.g., pulmonary lesions or lymphadenopathy likely to rapidly invade airways, produce dyspnea, or cause bronchial obstruction). Symptomatic disease (e.g., exertional dyspnea, painful unresectable adenopathy), not adequately addressable using directed therapy. Diffuse disease progression as opposed to focal pro- gression (e.g., in multiple lung metastases, as opposed to a few growing lesions)Comorbidity including /C15Active or recent intestinal disease (e.g., diverticu- litis, inﬂammatory bowel disease, recent bowelresection) /C15Liver disease /C15Recent bleeding (e.g., ulcer/GI bleed) or coagulo- pathy /C15Recent cardiovascular event(s) (e.g., CVA, MI) /C15Recent tracheal radiation therapy (this is associated with increased risks of aerodigestive ﬁstula withkinase inhibitor therapy) /C15Cachexia/low weight/poor nutrition /C15Poorly controlled hypertension /C15Prolonged QTc interval/history of signiﬁcant ar- rhythmia (includes ventricular and bradyarrhythmias) /C15Untreated brain metastases (controversial) /C15Recent suicidal ideation (suicide has been reported in depressed patients receiving TKIs) Life expectancy based upon other comorbidities estimated to be too brief to justify systemic therapy aBone metastases are often poorly
responsive to kinase inhibitor therapy (see Bone-Directed Agents in section [C47]). GI, gastrointestinal; CVA, cerebrovascular accident; MI, myocardial infarction; TKI, tyrosine kinase inhibitor.86 HAUGEN ET AL.
potential beneﬁts, but also about potential side effects and risks of therapy and alternative therapeutic approaches in- cluding best supportive care, as should be the case with anymedical therapeutic decision-making (1044). Such extensiveand comprehensive discussions are particularly important to undertake in the context of kinase inhibitor therapy because of the high probability of side effects of these agents andbecause of their presently uncertain effects on patient overall survival and quality of life (1045). Another critical and complex question often faced in treating patients with kinase inhibitor therapy centers on when treatment should be discontinued once initiated. In general, therapy should be continued so long as net beneﬁtexceeds net detriment. In case of slow RECIST diseaseprogression after signiﬁcant tumor response, treatment may be maintained so long as overall disease control is maintained providing that toxicities are manageable. Progression rateshould be taken into account, and when global progression is rapid, therapy should
be discontinued. However, there are times when focal/oligometastatic disease progression ame-nable to directed therapies is noted. In such instances, su- perimposed loco-regional therapies in the setting of maintained systemic therapy can sometimes be in the bestinterest of a particular patient. For instance, in the setting of regressed lung metastases and yet progression at a solitary bone site, maintained systemic therapy with superimposeddirected radiation therapy may be reasonable. [C43] Patients for whom ﬁrst-line kinase inhibitor therapy fails &RECOMMENDATION 97 Patients who have disease progression while on initial kinase inhibitor therapy without prohibitive adverse ef- fects should be considered for second-line kinase inhibitor therapy. Ideally, such therapy should be undertaken withinthe context of therapeutic clinical trials. (Weak recommendation, Low-quality evidence) DTC patients who progress through ﬁrst-line line kinase inhibitor therapy commonly respond to a second similarly targeted agent, and thus they should be considered candidates for second-line kinase inhibitor therapy (1014,1046). Hence,the
selection of an agent for initial therapy may be less criticalin some senses because many patient will go on to receive several kinase inhibitors over their disease courses. In the near future, other treatment modalities, such as RAI re-sensitization therapy, immunotherapy, or drugs directed to other targets, may also offer additional therapeutic options. [C44] Management of toxicities from kinase inhibitor therapy &RECOMMENDATION 98 Proactive monitoring and timely intervention in response to emergent toxicities are critical components of man- agement in patients receiving kinase inhibitor therapy. (Strong recommendation, Low-quality evidence) Patients treated with kinase inhibitors are subject to many potential toxicities that can negatively impact quality of lifeor even be fatal; as a consequence, great care must be taken not only in selecting appropriate patients for therapy, but also in monitoring patients once they are receiving kinase inhib-itor therapy (1044). Some toxicities (e.g., fatigue, diarrhea,gastrointestinal symptoms, cutaneous effects) will be symp-
tomatic and can be more easily addressed upon close com- munication with patients. However, there are also moreserious potential toxicities that might not be expected to immediately lead to patient symptoms (e.g., hepatotoxicity, prolonged QTc) that require proactive screening (Table 17). Hypertension and hepatotoxicity are especially important to serially monitor and rapidly address. Cardiotoxicity is also im- portant to be aware of and to monitor according to patient riskfactors, agent used, and induced symptoms/signs. In particular,sunitinib induces a decreased cardiac ejection fraction in about 20% of treated patients (1047). Furthermore, kinase inhibitors can induce QTc prolongation that should prompt careful con-sideration of coadministered drugs and periodic electrocardi- ography. Also important is that kinase inhibitor half-life is long; consequently, severe toxicities should prompt complete cessa-tion of kinase inhibitor therapy for an adequate amount of time to allow drug levels to decline before resumption at a lower dosage. Serum TSH level frequently
increases during kinase in- hibitor therapy; this should lead to frequent TSH assessment in conjunction with therapy initiation and upon therapy ces- sation, with responsive modiﬁcations thyroid hormone ther-apy where indicated. [C45] Other novel agents &RECOMMENDATION 99 Agents without established efﬁcacy in DTC should be used primarily within the context of therapeutic clinical trials. (Strong recommendation, Low-quality evidence) A variety of novel agents have been and/or are being tested as candidate therapeutics in progressive metastatic RAI- refractory DTC (1032,1048). At the time of the writing of these guidelines, however, only kinase inhibitors have shown suf-ﬁcient promise to consider use other than within the context of therapeutic clinical trials. Agents of particular interest for further testing include BRAF kinase inhibitors because PTCfrequently harbors the constitutively activating BRAF V600E mutation and the inhibitors have already shown efﬁcacy and been approved for use in BRAF mutant melanoma (1049– 1051). Inhibitors of MEK kinase
and other signaling pathwaysare also of considerable investigational interest. In addition, promising initial results in response to use of kinase inhibition to ‘‘resensitize’’ RAI-refractory tumors to RAI have been re-ported (1052). Data developed to date, however, do not yet favor the use of these novel approaches over use of VEGFR- directed kinase inhibitors unless within the context of thera-peutic clinical trials or alternatively when used as ‘‘salvage’’ therapies after disease progression has occurred despite prior VEGFR-directed kinase inhibitor therapy. [C46] Cytotoxic chemotherapy &RECOMMENDATION 100 Cytotoxic chemotherapy can be considered in RAI- refractory DTC patients with metastatic, rapidly progressive,ATA THYROID NODULE/DTC GUIDELINES 87
symptomatic, and/or imminently threatening disease not otherwise amenable to control through other approaches, including kinase inhibitors. Too few data exist to recom- mend speciﬁc cytotoxic regimens, and use within the contextof a therapeutic clinical trial is preferred. (Weak recommendation, Low-quality evidence) Although doxorubicin was approved for use in thyroid cancer by the US FDA in 1974 and has some utility in ana-plastic thyroid cancer, cytotoxic chemotherapy has histori- cally produced disappointing results when used to treat RAI- refractory DTC (1038). Cytotoxic chemotherapy, however,may have selective beneﬁt in patients unresponsive to kinase inhibitors and perhaps also in some patients with poorly differentiated thyroid cancer (1053). Data are limited andprimarily anecdotal. [C47] Bone-directed agents &RECOMMENDATION 101 Bisphosphonate or denosumab therapy should be consid- ered in patients with diffuse and/or symptomatic bone metastases from RAI-refractory DTC, either alone orconcomitantly with other systemic therapies. Adequate renal function (bisphosphonates) and calcium level (bi- sphosphonates and
denosumab) should be documentedprior to each dose, and dental evaluation should take place before initial use.(Strong recommendation, Moderate-quality evidence) Metastatic bone disease represents a particularly chal- lenging clinical problem in patients with RAI-refractoryDTC, especially given the high rate of multiple skeletal- related events in patients following detection of an initial bone lesion (1054). Patients with a small number of threat-ening and/or symptomatic bone lesions are generally besttreated with focal approaches such as radiation therapy and/ or surgery and/or thermoablation. Many patients, however, suffer from diffuse progression of bone metastases that arenot amenable to effective control using focal therapies alone. In such patients, focal therapy to symptomatic lesions or le- sions at high risk of complications may be beneﬁcial andshould be performed before initiation of systemic treatment. Unfortunately, kinase inhibitors appear to be less effective in controlling bone metastatic disease in comparison to dis-ease at other soft tissue sites such as
lungs and lymph nodes.Progression of bone metastases while on kinase inhibitor therapy commonly occurs despite maintained beneﬁt with respect to disease at other metastatic sites. Hence, kinaseinhibitor therapy cannot be relied upon to control diffuse bone metastases in many patients with RAI-refractory DTC. In other solid tumors, bone-di rected therapeu tics including bisphosphonates (especially zoledronic acid) and the RANK ligand–directed agent denosumab have been shown to delay time to occurrence of subseque nt skeletal-related adverse events (fracture, pain, neurologic complications) and to improve symptoms, and these agents may provide beneﬁts for patientsTable 17.Potential Toxicities and Recommended Screening or Monitoring Approaches in Patients Started on Kinase Inhibitor Therapy Toxicity Recommended screening/monitoring Hypertension Frequent blood pressure monitoring, most critical during the ﬁrst 8 weeks of therapy; if hypertension is induced, therapy should be individualized to patientresponse /C15Note: effective and expeditious management of hypertension is critical - andmay reduce potential for cardiotoxicity. If
antihypertensive therapy isneeded, calcium channel blockers (e.g., amlodipine) may be most effective. Cutaneous/mucocutaneous toxicities Careful patient reporting of rash/mouth sores, patient awareness and education related to increased potential for photosentization/sunburn. Hepatotoxicity Serial assessment of alanine serum transferase (AST), alkaline phosphatase and bilirubin - most critical during the ﬁrst 8 weeks of therapy /C15Note: dose reduction of kinase inhibitor therapy is commonly required due to hepatic toxicity Cardiotoxicity ECG pretherapy and frequently during therapy /C15Hold (or do not initiate) kinase inhibitor therapy if QTc >480 ms Echocardiogram: elective, but recommended in any patient with cardiac history and especially important in patient with hypertension, symptoms consistent with congestive heart failure or coronary artery disease and inpatients receiving sunitinib Hypothyroidism TSH should be assessed frequently, with levothyroxine dosage altered in response to rising TSH if observed Nephrotoxicity Serial serum creatinine, urine analysis with protein determination, Hematological toxicities Serial CBC/diff Pancreatitis Serial amylase Teratogenicity
Pretherapy pregnancy testing and effective contraception in women and men of childbearing potential CBC, complete blood count; ECG, electrocardiography.88 HAUGEN ET AL.
with diffuse bone metastases (1055,1056). The determination of beneﬁts across several tumor types suggests that they may be broadly generalizable, prompti ng FDA approval for their gen- eral use in patients with solid tumor bone metastases. Two smallstudies have suggested beneﬁt from bisphosphonates speciﬁ- cally within the context of DTC bone metastases (951,1057). Risks of bisphosphonates and RANK ligand–directed agents include hypocalcemia, which can be severe, prompt- ing the recommended concomitant use of supplemental cal- cium and vitamin D therapy. Moreover, these agents alsomoderately increase the risk of nonhealing oral lesions and jaw osteonecrosis; thus, candidates for this therapy should undergo dental/oral surgical evaluation prior to their initia-tion so as to minimize these risks (1055). Recent studies have overall shown equivalence or superi- ority of denosumab to zoledronic acid in delaying bone- related adverse events in several solid tumors, with similarrisk of jaw osteonecrosis, greater incidence of hypocalcemia, and less
nephrotoxicity (1058). However, no thyroid-speciﬁc data related to the efﬁcacy of denosumab have yet beenpublished. If the patient’s renal function is impaired, there is sometimes justiﬁcation for beginning with RANK ligand– directed/denosumab therapy because this agent seems toproduce fewer adverse renal effects, albeit the oral/jaw ef- fects are similar to bisphosphonates in magnitude. Expert consensus is that bone-directed therapy should be strongly considered in patients with multiple progressingand/or symptomatic bone metastases, likely best beginning with bisphosphonate/zoledronic acid (assuming calcium and renal function permit). Candidates for such therapy should becleared by their dentist/oral surgeon prior to therapy initia- tion; in addition, calcium and vitamin D therapy should be ongoing in conjunction with any intended bone-directed ther-apeutic. In general, there is consensus that the administration of zoledronic acid therapy every 3 months (rather than every month) is a reasonable initial approach in terms of dosing in-terval, but randomized trial data are unavailable
to deﬁnitivelyclarify this issue. Expert consensus is that bone-directed ther- apy should be used in the setting of diffuse bone metastases even if kinase inhibitor therapy is intended or ongoing. [D1] DIRECTIONS FOR FUTURE RESEARCH [D2] Optimizing molecular markers for diagnosis, progno- sis, and therapeutic targets Signiﬁcant progress has been made over the last several years in understanding the genetic mechanisms of thyroid cancer and creating molecular tests for cancer diagnosis inthyroid nodules. This process is currently going through anaccelerated phase, which is expected to continue into the future. The Cancer Genome Atlas (TCGA) and work from multiple research laboratories led to the identiﬁcation ofmutations and other driver genetic alterations in more than 90% of thyroid cancers, making it one of the best charac- terized human cancers from a genetic standpoint (1059). TheTCGA focused only on PTC. Moreover, next-generation sequencing technologies may allow detection of most of these alterations in
a limited cell sample obtained by FNA.Progress in identifying mutational, other genetic (gene ex- pression, miRNA), and epigenetic markers of thyroid cancer is expected to result in a signiﬁcantly improved accuracy ofcancer detection in thyroid nodules as compared to the cur- rently available clinical tests. If such progress continues, it is expected that future molecular tests will be able to predict therisk of cancer in thyroid nodules with high accuracy, dra-matically reducing the uncertainty of indeterminate FNA cytology. Furthermore, as the cost of next-generation se- quencing of human DNA continues to decrease and the an-alytical tools become more efﬁcient, it should be expected that the cost of molecular testing will decrease, enabling cost- efﬁcient utilization of testing. Molecular markers are expected to have a signiﬁcant im- pact on cancer prognostication. While the BRAF status can be considered as a relatively sensitive prognostic markerfor papillary cancer, it cannot be used in
isolation for tumorprognostication. However, recent results obtained by broad tumor genotyping show that several speciﬁc molecular sig- natures (such as presence of several driver mutations, TP53 mutation, TERT mutation in isolation or in combination with BRAF ) are found in a small fraction of well-differentiated papillary and follicular cancers and appear to be associatedwith more aggressive tumor behavior. It is expected that these molecular signatures will be conﬁrmed and perhaps further improved in additional studies and will offer a more speciﬁcdetection of well-differentiated thyroid cancers that have high risks of tumor recurrence and cancer-related mortality. Furthermore, research may identify how such data may in-form therapeutic decision-making (e.g., surgical extent [ifany], treatment with multi-kinase and speciﬁc kinase inhib- itors or their combination). Discoveries of new gene muta- tions/rearrangements involved in the pathogenesis of thyroidcancer, such as those of ALK andNTRK3 , are expected to offer new effective therapeutic targets. Finally, new
thera- peutic approaches to target genes commonly mutated inthyroid cancer, such as the RAS genes, are in development and expected to enter clinical trials in the future. Prospective long-term outcome studies, ideally in the form of RCTs, willbe needed to deﬁne the optimal surgical and postsurgicalmanagement of patients based on these molecular signatures. Such research may enable personalized, evidence-based care of patients with thyroid cancer across the disease trajectory. [D3] Active surveillance of DTC primary tumors Our Japanese colleagues have provided compelling data that an active surveillance management approach to papil- lary microcarcinoma is a safe and effective alternative to immediate surgical resection in properly selected patients(143,149). Unfortunately, no clinical features or molecular abnor- mality in isolation can reliably differentiate the relativelysmall number of PTMC patients destined to develop clini-cally signiﬁcant progression from the larger population of people that harbor indolent PTMCs that will not cause sig- niﬁcant disease. Therefore,
additional studies are needed toidentify speciﬁc risk factors that would favor surgical re- section over active surveillance. Furthermore, additional studies are needed to deﬁne important management issues that arise during an active surveillance follow-up approach. These issues include the frequency of US evaluations required during follow-up, op-timal TSH goals, the potential role of serum Tg in follow-up, and speciﬁc indications for surgical intervention (e.g., what measurements should be used to deﬁne a clinically signiﬁcantATA THYROID NODULE/DTC GUIDELINES 89
increase in the size of the primary tumor, what constitutes clinically signiﬁcant lymph node metastases). Finally, studies that examine decision-making and ac- ceptability of an active surveillance approach to thyroidcancer in patients, family members, and clinicians are re- quired to better understand how to implement this novel management approach outside of Japan. These studies shouldideally be performed in the context of an Institutional Review Board–approved clinical trial. [D4] Improved risk stratiﬁcation While the AJCC/UICC TNM staging provides valuable information with regard to disease-speciﬁc mortality, studiesare needed to determine if inclusion of additional prognosticvariables into the AJCC staging system could improve its predictive ability. Potential variables for consideration in- clude the speciﬁc histology (well-differentiated thyroidcancer versus poorly differentiated thyroid cancer), molecu- lar proﬁle, size and location of distant metastases (pulmonary metastases versus bone metastases versus brain metastases),functional status of the metastases (RAI avid versus 18FDG- PET avid), and effectiveness of initial
therapy (completeness of resection; effectiveness of RAI, external beam radiation,or other systemic therapies). Furthermore, additional studies will be required to deter- mine if there is any signiﬁcant incremental beneﬁt of addingthese speciﬁc prognostic variables to the 2009 Initial RiskStratiﬁcation system. Since the response to therapy dynamic (ongoing) risk stratiﬁcation systems were primarily optimized and validatedon DTC patients that had total thyroidectomy and RAI remnant ablation or adjuvant therapy, additional studies are needed to reﬁne the deﬁnitions of excellent, biochemical incomplete,structural incomplete, and indeterminate responses in patients treated with total thyroidectomy without RAI ablation and in patients treated with less than total thyroidectomy (602). Fur-thermore, additional studies are needed to deﬁne what types ofcross-sectional/functional imaging are required to rule out structural disease in order to classify a patient as having a biochemical incomplete response to therapy (based on initialrisk, serum Tg, signs/symptoms, or other imaging results). Another area of signiﬁcant research
interest centers on iden- tifying speciﬁc clinical situations in which the molecular ﬁnd-ings provide clinically meaningful information that goes beyond what is predicted by standard clinico-pathological staging. Molecular ﬁndings that provide these types of prognostic in-formation or guide optimal initial/ongoing treatment decisions have the potential to signiﬁcantly alter clinical management. [D5] Improving our understanding of the risks and beneﬁts of DTC treatments and optimal implementation/utilization In achieving a better understanding of the risks and ben- eﬁts of DTC treatments (such as extent of primary surgery orsecondary surgery for recurrence, RAI ablation/treatment, and thyroid hormone suppressive therapy), more prospective long-term outcome research is needed, and in particular,RCTs. In the case of relatively uncommon adverse effects of treatments, prospective surveillance research is also needed. Vaisman and colleagues (633) are conducting a prospective,nonrandomized study to determine which patients with low- to intermediate-risk DTC should receive RAI remnant abla- tion based on the postoperative
stimulated serum Tg level.Longer-term follow-up and randomized multicenter studies are needed to determine how this commonly used biomarker can be applied to decision-making in a majority of patientswith low- to intermediate-risk DTC. Prospective collection ofdata on quality of life and related outcomes (when relevant) is also needed in DTC trials. Using an evidence-based approach to knowledge synthesis (systematic reviews, meta-analyses,and clinical practice guidelines) of data can also enable evidence-informed clinical practice. Barriers to dissemination and implementation of clinical practice guideline recommen-dations need to be overcome. Evidence-based guidelines may need to be formally adapted to various practice settings to enable their implementation. Important gaps in patient-directed knowledge translation have been recently identiﬁedby thyroid cancer patients and survivors (1060,1061). The development of plain language educational materials, in- cluding decision aids or other decision support tools would behelpful for use as adjuncts in physician counseling of patients about diagnostic and treatment options. Decision
aids and other decision support have been associated with improve-ment in patients’ medical knowledge and reducing decisional conﬂict, in general oncology (1062,1063), with a recent RCT demonstrating beneﬁts of a decision aid in thyroid cancersurvivors considering RAI remnant ablation (1064). [D6] Issues with measurement of Tg and anti-Tg anti- bodies Current methodologies for both Tg and anti-Tg antibodies remain problematic in many ways that hopefully will be overcome in the future. For Tg assays, these include interfer-ence with Tg measurement by the presence of anti-Tg and heterophile antibodies and the use of a host of different methods with varying results in terms of sensitivity or detec-tion limits. Assay calibration or standardization may be suc- cessful only if the same certiﬁed reference standard is employed, which currently is CRM-457. While more ‘‘ultra-sensitive’’ Tg assays have been developed, we need to deter-mine the true clinical signiﬁcance or utility of measurable levels below
0.2 ng/mL (either on suppression or after TSH stimulation) as indicating evidence of residual disease or out-come. Recently developed mass spectrometry–based assays have offered some promise, but are yet to be validated (806). Competitive immunoassays have not provided an alternative inview of their unpredictability (771). In regard to anti-Tg an- tibodies, we need to better characterize the various epitopes of interfering antibodies to better understand their effect in dif-ferent sera in order to interpret the associated spectrum of results obtained for measurable Tg. We will need to do better than approximating Tg levels by the ratio of ICMA Tg to Tgmeasured by competitive immunoassay (1065). Authoritativebodies such as the National Academy of Clinical Biochemistry should consider mandating speciﬁc methodology rather than recommending general guidance. It remains to be seen whetherthe future standard might entail adoption of a modiﬁed ICMA, radioimmunoassay, or mass spectrometry methodology. [D7] Management of metastatic cervical adenopathy
de- tected on US With the advent of improved technology, increased utili- zation, and specialized operator experience, US imaging can identify small-volume metastatic cervical lymph nodes. From the surgical pathology literature analyzing specimens90 HAUGEN ET AL.
from prophylactic lateral and central neck dissections with normal preoperative cervical lymph node sonography, up to 90% of patients with papillary cancers <1 cm have metastatic level VI lymph nodes and up to 40% have metastatic lateralneck lymph nodes (359,1066,1067). Yet, in the absence of these dissections, this is not the observed clinical loco- regional recurrence rate for these patients. It should not besurprising then, that during extended surveillance, US will be able to detect small-volume metastatic disease that may represent a stable reservoir of residual cancer. On the otherhand, grossly involved metastatic lymph nodes were at one time minimally invaded by metastatic thyroid cancer. The challenge is to differentiate between low-volume metastaticdisease that progresses with potential clinical consequences,and that which remains stable. To date, only one study has addressed this question, and no sonographic, pathologic, de- mographic, or molecular feature predicted outcome (849). Inaddition, it is unclear if growth
itself is a harbinger of de- creased survival. Therefore, observational studies using stan- dardized US scanning protocols are ﬁrst required to deﬁne themagnitude of this scenario and deﬁne predictors of disease progression. Subsequently, randomized controlled interven- tional trials could be designed to address change in outcome,such as development of additional loco-regional disease, ap- pearance of distant metastases, or disease-speciﬁc survival. [D8] Novel therapies for systemic RAI-refractory disease Over the years, a wide variety of agents have been used in preclinical (valproic acid, trichostatin, depsipeptide, 5- azacytidine, arsenic tri-oxide) and clinical (retinoids, thiazoli-dinediones) models to ‘‘redifferentiate’’ thyroid cancer cells in order to restore RAI avidity. While these agents showed limited clinical effectiveness, the observation that oncogenic activationof the MAP kinase pathway was associated with down- regulation of the genes involved in iodine metabolism sug- gested an alternative, targeted approach to redifferentiationtherapy. Recently, two proof-of-principle pilot clinical trialshave conﬁrmed that targeted blockade
of the MAP kinase pathway can result in clinically relevant restoration of RAI avidity in a substantial percentage of RAI-refractory thyroidcancer patients (1052,1068). In the ﬁrst trial, 1 month of the MEK inhibitor selumetinib increased RAI uptake in 12 of 20 iodine-refractory thyroid cancer patients, with structural tumorshrinkage seen in ﬁve of the eight patients that achieved lesional dosimetry high enough to warrant RAI therapy (1052). In the second trial, 1 month of the BRAF inhibitor dabrabenib restoredRAI avidity on diagnostic WBS in 6 of 10 RAI-refractory pa- tients, resulting in structural responses in two patients and a decrease in serum Tg in four patients (1068). While the primaryfocus of current redifferentiation trials has been in the setting ofRAI-refractory distant metastases, future studies are needed to deﬁne the role of redifferentiation therapy in the high-risk ad- juvant therapy setting and in the RAI-responsive metastaticdisease setting in an effort to enhance
the tumoricidal effect of RAI before the tumors become RAI refractory. Efforts to develop additional and further improved sys- temic therapeutic approaches to RAI-refractory metastatic DTC presently involve a wide a variety of approaches. First, the question arises as to whether kinase inhibitors with al-ready demonstrated clinical activity in DTC can be made more effective as single agents. For example, based upon data indicating strong correlation between achieved pazopaniblevels and extent of clinical response in DTC, indicating absence of response to pazopanib therapy in the lowest quintile of pazopanib drug levels, one clinical trial is pres-ently examining the feasibility and potential beneﬁts of in-dividualization of pazopanib therapy with the goal of achieving target drug levels in the highest achievable fraction of patients, in hopes of improving the fraction of patientsbeneﬁting (NCT01552356). Another study is examining the differential impacts of continuous versus intermittent pazo- panib dosing in thyroid cancer (NCT01813136). Generally
predicated upon identiﬁcation of synergistic interactions in preclinical models, several studies are exam- ining the question of whether therapy combining severalagents may improve outcomes in thyroid cancer. Althoughthe majority of combinatorial studies assess effects of mul- tiple coadministered small molecule therapeutics, several are using kinase inhibitors in combination with RAI in efforts toenhance RAI avidity and clinical efﬁcacy in the context of RAI-refractory disease (e.g., NCT00970359). Still other tri- als are focusing on novel nontraditional therapies, includingengineered candidate virotherapeutics (e.g., NCT01229865). Alternatively, another active area of investigation involves efforts to therapeutically target speciﬁc alterations (mutations,translocation) found in thyroid cancers to individualize ther- apy and thereby potentially improve outcomes in the process; one such recent example is the use of the BRAF V600Einhibitor vemurafenib in BRAFV600EPTC (NCT01286753), with many additional mutation-speciﬁc therapeutic trials under devel- opment or underway. Finally, immunotherapy including checkpoint inhibitors (e.g., PD-1/PD-L1) has shown promise in other cancers
(1069–1071) and is being investigated in advanced RAI- refractory thyroid cancer. [D9] Survivorship care The American Cancer Society estimates that there will be 62,450 new cases of thyroid cancer diagnosed in 2015, butonly 1950 deaths from thyroid cancer (www.cancer.org/cancer/ thyroidcancer/detailedguide/thyroid-cancer-key-statistics). Ac- cording to SEER database statistics, there are more than600,000 people living with thyroid cancer in the United States alone (seer.cancer.gov/statfacts/html/thyro.html). Despite these large numbers of patients living with thyroid cancer, there isonly a modest amount of peer-reviewed literature studying thyroid cancer survivors. The majority of the literature involving thyroid cancer survivors relates directly to the short- and long-term effects of thyroid cancer therapies: surgery, RAI, and lifetime thyroid hormone therapy. There is very little information regarding theimpact of the diagnosis itself or the effect of living with per-sistent disease such as Tg-positive, scan-negative thyroid cancer. A thoughtful and comprehensive analysis of thyroid cancer survivors will likely require both qualitative
studieswith in-depth interviews of survivors that will represent as many demographics of thyroid cancer patients as possible. Additionally, or as a next step, the development and/or utili-zation of a validated survey type instrument needs to be de- veloped. This instrument would be designed to assess the quality of life of thyroid cancer survivors in a more quantita-tive manner, allowing for rigorous statistical analyses, and will help identifying areas to target that may improve the lives of thyroid cancer survivors (1072).ATA THYROID NODULE/DTC GUIDELINES 91
Further research also needs to be performed in addressing patient and survivor care needs throughout the active treat- ment and survivorship trajectory, including issues such asidentiﬁcation and management of treatment-related side ef-fects (1060,1061), psychosocial distress (1060,1061), per- sistent fatigue (1073,1074), ﬁnancial impact (12), and cancer-related worry (1075). ACKNOWLEDGMENTS The task force wishes to thank Ms. Bobbi Smith, Executive Director, ATA, and Ms. Sharleene Cano, Assistant to theTaskforce, for their constant help and support, as well as Ms. Vicki Wright (Division of Endocrinology, University of Color- ado School of Medicine) for her assistance in manuscriptpreparation. We thank Dr. Joshua Klopper (Division of En-docrinology, University of Colorado School of Medicine) on behalf of the CAC Quality Of Life Task Force for the contri- bution of the Survivorship Care section [D9]. We also thank Dr.Irwin Klein (North Shore University Hospital, Manhasset, New York) for his input on TSH targets for long-term thyroid hor-
mone therapy (Table 15). We would like to thank the ATAmembers who responded to our survey in preparation for this iteration of the guidelines as well as manuscript review prior to journal submission, and the leadership of ThyCa: ThyroidCancer Survivors’ Association, Inc. and Thyroid Cancer Canadawho provided written feedback on our survey. A.M.S. holds a Cancer Care Ontario Health Services Research Chair, which enabled protected time for research and contribution to theseguidelines. These guidelines were funded by the ATA without support from any commercial sour ces. The patient organization, ThyCa: Thyroid Cancer Survivors’ Association, Inc., contributed an unrestricted educational grant toward the development of the thyroid nodules and differentiated thyroid cancer guidelines. The following groups reviewed and endorsed the ﬁnal document: American Association of Clinical Endocrinologists; American Association of Endocrine Surgeons; American Head and Neck Society; Asia Oceania Thyroid Association (AOTA);British Society of Nuclear Medicine; Canadian Association ofOtolaryngology Head and
Neck Surgery; The Endocrine So- ciety; Endocrine Society of Australia; European Thyroid As- sociation; International Association of Endocrine Surgeons;International Federation of Head and Neck Oncologic Societie; Japanese Thyroid Association; Latin American Thyroid So- ciety; Society of Surgical Oncology; Ukrainian Association ofEndocrine Surgeons. DISCLAIMER It is our goal in formulating these guidelines, and the ATA’s goal in providing support for the development of theseguidelines, that they assist in the clinical care of patients and share what we believe is current, rational, and optimal medical practice. In some circumstances, it may be apparent that thelevel of care recommended may be best provided in limited centers with speciﬁc expertise. Finally, it is not the intent of these guidelines to replace individual decision-making, thewishes of the patient or family, or clinical judgment. AUTHOR DISCLOSURE STATEMENT These guidelines were funded by the ATA without support from any commercial sources.K.C.B., G.M.D., F.P., G.A.R., A.M.S., and K.S.
have no signiﬁcant ﬁnancial or competing interests to disclose. B.R.H. has received grant/research support from Veracyte and Genzyme, as well as a one-time speaker honorarium fromGenzyme. E.K.A. has received research support from Asura- gen, Veracyte, and Novo Nordisk. He has been a consultant for NPS Pharmaceuticals, Genzyme, and Veracyte as well as onthe Scientiﬁc Advisory Board for Asuragen. S.J.M. has re- ceived grant/research support from Veracyte and Asuragen. She has been on the scientiﬁc advisory committee for Asuragenand has been a CME speaker for Genzyme. Y.N. has been a consultant for Quest Diagnostics. His institution, UPMC, has a service agreement with CBLPath to provide molecular testingfor various tumors. M.S. has received grant/research supportfrom Genzyme, Bayer, AstraZeneca, Exelixis, and Eisai. He has been a consultant for Genzyme, Bayer, AstraZeneca, Ex- elixis, and Eisai. S.I.S. has received grant/research supportfrom Genzyme and the National Cancer Institute. He is a consultant for Veracyte, Exelixis,
Bayer, AstraZeneca, Eisai, Genzyme, Novo Nordisk, and Eli Lilly. He has received hon-oraria from Onyx, and he has ﬁduciary responsibility as Chairman of International Thyroid Oncology Group. J.A.S. has received one-time speaker honorarium from Exelixis and is amember/ATA representative on the Data Monitoring Com- mittee for the Medullary Thyroid Cancer Registry called for by the FDA and funded by NovoNordisk, Astra Zeneca, Glax-oSmithKline, and Eli Lilly. D.L.S. has received grant/researchsupport from Astra-Zeneca. R.M.T. is a consultant for Gen- zyme, Novo Nordisk, AstraZeneca, Bayer/Onyx, and Veracyte. L.W. has been a consultant for Asuragen, Interpace Diag-nostics, Eisei, and IBSA. He has received speaker honoraria from Genzyme. E.K.A. and R.M.T. received consulting payments through stock options from Veracyte. This has been reviewed and discussed with the Ethics Committee and reviewed by the ATA Board. E.K.A. and R.M.T. were recused from reviewand approval of the molecular markers sections. They di-vested these stock options prior
to submission of this docu- ment for journal review. REFERENCES 1. Vander JB, Gaston EA, Dawber TR 1968 The signiﬁ- cance of nontoxic thyroid nodules. Final report of a 15- year study of the incidence of thyroid malignancy. Ann Intern Med 69:537–540. 2. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA 1977 The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 7:481–493. 3. Tan GH, Gharib H 1997 Thyroid incidentalomas: man- agement approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 126: 226–231. 4. Guth S, Theune U, Aberle J, Galach A, Bamberger CM 2009 Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. EurJ Clin Invest 39:699–706. 5. Hegedus L 2004 Clinical practice. The thyroid nodule. N Engl J Med 351:1764–1771. 6. Mandel SJ
2004 A 64-year-old woman with a thyroid nodule. JAMA 292:2632–2642. 7. Sherman SI 2003 Thyroid carcinoma. Lancet 361:501–511.92 HAUGEN ET AL.
8. Siegel R, Ma J, Zou Z, Jemal A 2014 Cancer statistics, 2014. CA Cancer J Clin 64:9–29. 9. Davies L, Welch HG 2014 Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 140:317–322. 10. Leenhardt L, Bernier MO, Boin-Pineau MH, Conte DB, Mare´chaud R, Niccoli-Sire P, Nocaudie M, Orgiazzi J, Schlumberger M, We ´meau JL, Cherie-Challine L, De Vathaire F 2004 Advances in diagnostic practices affect thyroid cancer incidence in France. Eur J Endocrinol 150:133–139. 11. Brito JP, Al Nofal A, Montori V, Hay ID, Morris JC III 2015 The impact of subclinical disease and mechanismof detection on the rise in thyroid cancer incidence: a population-based study in Olmsted County, Minnesota during 1935 through 2012. Thyroid 25:999–1007. 12. Aschebrook-Kilfoy B, Schechter RB, Shih YC, Kaplan EL, Chiu BC, Angelos P, Grogan RH 2013 The clinical and economic burden of a sustained increase in thyroid cancer
incidence. Cancer Epidemiol Biomarkers Prev 22:1252–1259. 13. Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, Braverman LE, Clark OH, McDougall IR, Ain KV, Dorfman SG 1996 Treatment guidelines for patients with thyroid nodules and well- differentiated thyroid cancer. American Thyroid Asso- ciation. Arch Intern Med 156:2165–2172. 14. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, Dinauer CA, Hamilton J, Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson GB, Yamashita S 2015 Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid 25:716–759. 15. Lewis MH, Gohagan JK, Merenstein DJ 2007 The lo- cality rule and the physician’s dilemma: local medical practices vs the national standard of care. JAMA 297:2633–2637. 16. Harrison MB, Graham ID, van den Hoek J, Dogherty EJ, Carley ME, Angus V 2013 Guideline adaptation and implementation planning: a prospective observational study. Implement Sci 8:49–63. 17. Carlson
RW, Larsen JK, McClure J, Fitzgerald CL, Venook AP, Benson AB III, Anderson BO 2014 Inter- national adaptations of NCCN Clinical Practice Guide- lines in Oncology. J Natl Compr Canc Netw 12:643–648. 18. Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedus L, Vitti P 2010 American Association of Clinical Endocrinologists, Associazione Medici En- docrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 16:468–475. 19. Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard BG, Gilbert J, Harrison B, Johnson SJ, Giles TE, Moss L, Lewington V, Newbold K, Taylor J, Thakker RV, Watkinson J, Williams GR 2014 Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf) 81 Suppl 1: 1–122. 20. Leenhardt L, Erdogan MF, Hegedus L, Mandel SJ, Paschke R, Rago T, Russ G 2013 2013 European Thy-
roid Association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur Thyroid J2:147–159.21. Silberstein EB, Alavi A, Balon HR, Clarke SE, Divgi C, Gelfand MJ, Goldsmith SJ, Jadvar H, Marcus CS, Martin WH, Parker JA, Royal HD, Sarkar SD, Stabin M, Waxman AD 2012 The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0. J Nucl Med 53:1633–1651. 22. Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, Oyen WJ, Tennvall J, Bombardieri E 2008 Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 35: 1941–1959. 23. Takami H, Ito Y, Okamoto T, Onoda N, Noguchi H, Yoshida A 2014 Revisiting the guidelines issued by the Japanese Society of Thyroid Surgeons and Japan Asso- ciation of Endocrine Surgeons: a gradual move towardsconsensus between Japanese and Western practice in the management of thyroid carcinoma.
World J Surg 38:2002–2010. 24. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM 2006 Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16:109–142. 25. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM 2009 Revised American Thyroid Association man- agement guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:1167– 1214. 26. Qaseem A, Snow V, Owens DK, Shekelle P 2010 The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med 153:194–199. 27. Schunemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, Williams JW Jr, Kunz R, Craig J, Montori VM, Bossuyt P, Guyatt GH 2008 Grading quality of evidence and
strength of recommendations for diagnostic tests and strategies. BMJ 336:1106–1110. 28. Brozek JL, Akl EA, Jaeschke R, Lang DM, Bossuyt P, Glasziou P, Helfand M, Uefﬁng E, Alonso-Coello P, Meerpohl J, Phillips B, Horvath AR, Bousquet J, Guyatt GH, Schunemann HJ 2009 Grading quality of evidence and strength of recommendations in clinical practice guidelines: part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies. Allergy 64:1109–1116. 29. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Lijmer JG, Moher D, Rennie D, de Vet HC 2003 Towards complete and accurate re- porting of studies of diagnostic accuracy: the STARD Initiative. Ann Intern Med 138:40–44. 30. Leung AN, Bull TM, Jaeschke R, Lockwood CJ, Boiselle PM, Hurwitz LM, James AH, McCullough LB, Menda Y, Paidas MJ, Royal HD, Tapson VF, Winer-Muram HT, Chervenak FA, Cody DD, McNitt-Gray MF, Stave CD, Tuttle
BD 2011 An ofﬁcial American Thoracic So- ciety/Society of Thoracic R adiology clinical practice guideline: evaluation of suspected pulmonary embo- lism in pregnancy. Am J Respir Crit Care Med 184: 1200–1208. 31. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeﬂang MM, Sterne JA, Bossuyt PM 2011 QUADAS-2: a revised tool for the quality as- sessment of diagnostic accuracy studies. Ann Intern Med 155:529–536.ATA THYROID NODULE/DTC GUIDELINES 93
32. Marqusee E, Benson CB, Frates MC, Doubilet PM, Larsen PR, Cibas ES, Mandel SJ 2000 Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med 133:696–700. 33. Hagag P, Strauss S, Weiss M 1998 Role of ultrasound- guided ﬁne-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid 8:989–995. 34. Charkes ND 2006 On the prevalence of familial non- medullary thyroid cancer in multiply affected kindreds. Thyroid 16:181–186. 35. Capezzone M, Marchisotta S, Cantara S, Busonero G, Brilli L, Pazaitou-Panayiotou K, Carli AF, Caruso G, Toti P, Capitani S, Pammolli A, Pacini F 2008 Familialnon-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity. Endocr Relat Cancer 15:1075–1081. 36. Moses W, Weng J, Kebebew E 2011 Prevalence, clini- copathologic features, and somatic genetic mutation proﬁle in familial versus sporadic nonmedullary thyroid cancer. Thyroid 21:367–371. 37. Ito Y, Kakudo K, Hirokawa M,
Fukushima M, Yabuta T, Tomoda C, Inoue H, Kihara M, Higashiyama T, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Miyauchi A 2009 Biological behavior and prognosis of familial papillary thyroid carcinoma. Surgery 145:100–105. 38. Park YJ, Ahn HY, Choi HS, Kim KW, Park do J, Cho BY 2012 The long-term outcomes of the second generation of familial nonmedullary thyroid carcinoma are more ag- gressive than sporadic cases. Thyroid 22:356–362. 39. Mazeh H, Benavidez J, Poehls JL, Youngwirth L, Chen H, Sippel RS 2012 In patients with thyroid cancer of follicular cell origin, a family history of nonmedullary thyroid cancer in one ﬁrst-degree relative is associated with more aggressive disease. Thyroid 22:3–8. 40. Robenshtok E, Tzvetov G, Grozinsky-Glasberg S, Shraga- Slutzky I, Weinstein R, Lazar L, Serov S, Singer J, Hirsch D, Shimon I, Benbassat C 2011 Clinical characteristics and outcome of familial nonmedullary thyroid cancer: a retrospective
controlled study. Thyroid 21:43–48. 41. Richards ML 2010 Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid 20:707–713. 42. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, Horowitz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF Jr, Boice JD Jr 1997 Solid cancers after bone marrow transplantation. N Engl J Med336:897–904. 43. Pacini F, Vorontsova T, Demidchik EP, Molinaro E, Agate L, Romei C, Shavrova E, Cherstvoy ED, Ivash- kevitch Y, Kuchinskaya E, Schlumberger M, Ronga G, Filesi M, Pinchera A 1997 Post-Chernobyl thyroid car- cinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France. J Clin Endocrinol Metab 82:3563–3569. 44. Gharib H, Papini E 2007 Thyroid nodules: clinical im- portance, assessment, and treatment. Endocrinol Metab Clin North Am 36:707–35, vi. 45. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC, Franklyn JA 2006
Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by ﬁne-needle aspiration. J Clin Endocrinol Metab 91:4295–4301. 46. Haymart MR, Repplinger DJ, Leverson GE, Elson DF, Sippel RS, Jaume JC, Chen H 2008 Higher serum thyroidstimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J Clin Endocrinol Metab 93:809–814. 47. Repplinger D, Bargren A, Zhang YW, Adler JT, Haymart M, Chen H 2008 Is Hashimoto’s thyroiditis a risk factor for papillary thyroid cancer? J Surg Res 150:49–52. 48. Suh I, Vriens MR, Guerrero MA, Grifﬁn A, Shen WT, Duh QY, Clark OH, Kebebew E 2010 Serum thyro-globulin is a poor diagnostic biomarker of malignancy in follicular and Hu ¨rthle-cell neoplasms of the thyroid. Am J Surg 200:41–46. 49. Lee EK, Chung KW, Min HS, Kim TS, Kim TH, Ryu JS, Jung YS, Kim SK, Lee
YJ 2012 Preoperative serum thyroglobulin as a useful predictive marker to differen- tiate follicular thyroid cancer from benign nodules in indeterminate nodules. J Korean Med Sci 27:1014–1018. 50. Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F 2004 Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89:163–168. 51. Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ, Yang JH, Chung JH 2001 Routine measurement of serum calcitonin is useful for early detection of medul- lary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid 11:73–80. 52. Niccoli P, Wion-Barbot N, Caron P, Henry JF, de Micco C, Saint Andre JP, Bigorgne JC, Modigliani E, Conte- Devolx B 1997 Interest of routine measurement of
serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 82:338–341. 53. Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, Crocetti U, Attard M, Maranghi M, Tor- lontano M, Filetti S 2007 Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive pa- tients with thyroid nodules. J Clin Endocrinol Metab 92:450–455. 54. Chambon G, Alovisetti C, Idoux-Louche C, Reynaud C, Rodier M, Guedj AM, Chapuis H, Lallemant JG, Lalle- mant B 2011 The use of preoperative routine measurement of basal serum thyrocalcitonin in candidates for thyroid- ectomy due to nodular thyroid disorders: results from 2733consecutive patients. J Clin Endocrinol Metab 96:75–81. 55. Colombo C, Verga U, Mian C, Ferrero S, Perrino M, Vicentini L, Dazzi D, Opocher G, Pelizzo MR, Beck- Peccoz P, Fugazzola L 2012 Comparison
of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. J Clin Endocrinol Metab 97: 905–913. 56. Karga H, Giagourta I, Papaioannou G, Doumouchtsis K, Polymeris A, Thanou S, Papamichael K, Zerva C 2011 Changes in risk factors and Tumor Node Metastasis stage of sporadic medullary thyroid carcinoma over 41 years, before and after the routine measurements of serum calcitonin. Metabolism 60:604–608. 57. Cheung K, Roman SA, Wang TS, Walker HD, Sosa JA 2008 Calcitonin measurement in the evaluation of thy- roid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab 93: 2173–2180.94 HAUGEN ET AL.
58. Gagel RF, Hoff AO, Cote GE 2005 Medullary thyroid carcinoma. In: Braverman L, Utiger R (eds) Werner and Ingbar’s The Thyroid. Lippincott Williams and Wilkins, Philadelphia, PA, pp 967–988. 59. Diazzi C, Madeo B, Taliani E, Zirilli L, Romano S, Granata AR, De Santis MC, Simoni M, Cioni K, Carani C, Rochira V 2013 The diagnostic value of calcitonin measurement in wash-out ﬂuid from ﬁne-needle aspira- tion of thyroid nodules in the diagnosis of medullary thyroid cancer. Endocr Pract 19:769–779. 60. Soelberg KK, Bonnema SJ, Brix TH, Hegedus L 2012 Risk of malignancy in thyroid incidentalomas detected by 18F-ﬂuorodeoxyglucose positron emission tomogra-phy: a systematic review. Thyroid 22:918–925. 61. Chen W, Parsons M, Torigian DA, Zhuang H, Alavi A 2009 Evaluation of thyroid FDG uptake incidentally identiﬁed on FDG-PET/CT imaging. Nucl Med Commun 30:240–244. 62. Nishimori H, Tabah R, Hickeson M, How J 2011 In- cidental thyroid ‘‘PETomas’’: clinical signiﬁcance
and novel description of the self-resolving variant of focal FDG-PET thyroid uptake. Can J Surg 54:83–88. 63. Hall TL, Layﬁeld LJ, Philippe A, Rosenthal DL 1989 Sources of diagnostic error in ﬁne needle aspiration of the thyroid. Cancer 63:718–725. 64. Alexander EK, Heering JP, Benson CB, Frates MC, Doubilet PM, Cibas ES, Marqusee E 2002 Assessment of nondiagnostic ultrasound-guided ﬁne needle aspira- tions of thyroid nodules. J Clin Endocrinol Metab 87: 4924–4927. 65. Smith-Bindman R, Lebda P, Feldstein VA, Sellami D, Goldstein RB, Brasic N, Jin C, Kornak J 2013 Risk of thyroid cancer based on thyroid ultrasound imaging char- acteristics: results of a population-based study. JAMA In- tern Med 173:1788–1796. 66. Brito JP, Gionfriddo MR, Al NA, Boehmer KR, Leppin AL, Reading C, Callstrom M, Elraiyah TA, Prokop LJ, Stan MN, Murad MH, Morris JC, Montori VM 2014 The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic
review and meta-analysis. J Clin Endocrinol Metab 99:1253–1263. 67. Langer JE, Agarwal R, Zhuang H, Huang SS, Mandel SJ 2011 Correlation of ﬁndings from iodine 123 scan and ultrasonography in the recommendation for thyroid ﬁne- needle aspiration biopsy. Endocr Pract 17:699–706. 68. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A 1998 Diagnostic accuracy of conventional versus sonography-guided ﬁne-needle aspiration biopsy of thyroid nodules. Thyroid 8:15–21. 69. Carmeci C, Jeffrey RB, McDougall IR, Nowels KW, Weigel RJ 1998 Ultrasound-guided ﬁne-needle aspira- tion biopsy of thyroid masses. Thyroid 8:283–289. 70. Kwak JY, Han KH, Yoon JH, Moon HJ, Son EJ, Park SH, Jung HK, Choi JS, Kim BM, Kim EK 2011 Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratiﬁcation of cancer risk. Radiology 260:892–899. 71. Moon WJ, Jung SL, Lee JH, Na DG, Baek JH, Lee YH, Kim J, Kim HS,
Byun JS, Lee DH 2008 Benign and malignant thyroid nodules: US differentiation—mul- ticenter retrospective study. Radiology 247:762–770. 72. Moon HJ, Kwak JY, Kim MJ, Son EJ, Kim EK 2010 Can vascularity at power Doppler US help predict thyroid malignancy? Radiology 255:260–269.73. Salmaslioglu A, Erbil Y, Dural C, Issever H, Kapran Y, Ozarmagan S, Tezelman S 2008 Predictive value of so- nographic features in preoperative evaluation of malig- nant thyroid nodules in a multinodular goiter. World J Surg 32:1948–1954. 74. Papini E, Guglielmi R, Bianchini A, Crescenzi A, Tac- cogna S, Nardi F, Panunzi C, Rinaldi R, Toscano V, Pa- cella CM 2002 Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 87:1941–1946. 75. Gul K, Ersoy R, Dirikoc A, Korukluoglu B, Ersoy PE, Aydin R, Ugras SN, Belenli OK, Cakir B 2009 Ultra- sonographic evaluation of thyroid nodules: comparisonof ultrasonographic, cytological,
and histopathological ﬁndings. Endocrine 36:464–472. 76. Cappelli C, Pirola I, Cumetti D, Micheletti L, Tironi A, Gandossi E, Martino E, Cherubini L, Agosti B, Castellano M, Mattanza C, Rosei EA 2005 Is the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules a sonographic criteria for recommending ﬁne-needle aspi- ration cytology? Clin Endocrinol (Oxf) 63:689–693. 77. Frates MC, Benson CB, Doubilet PM, Kunreuther E, Contreras M, Cibas ES, Orcutt J, Moore FD Jr, Larsen PR, Marqusee E, Alexander EK 2006 Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J Clin En- docrinol Metab 91:3411–3417. 78. Moon HJ, Sung JM, Kim EK, Yoon JH, Youk JH, Kwak JY 2012 Diagnostic performance of gray-scale US and elastography in solid thyroid nodules. Radiology 262: 1002–1013. 79. Kim DS, Kim JH, Na DG, Park SH, Kim E, Chang KH, Sohn CH, Choi YH 2009 Sonographic features of
fol- licular variant papillary thyroid carcinomas in compari- son with conventional papillary thyroid carcinomas. J Ultrasound Med 28:1685–1692. 80. Park YJ, Kim JA, Son EJ, Youk JH, Kim EK, Kwak JY, Park CS 2014 Thyroid nodules with macrocalciﬁcation: sonographic ﬁndings predictive of malignancy. Yonsei Med J 55:339–344. 81. Cappelli C, Castellano M, Pirola I, Cumetti D, Agosti B, Gandossi E, Agabiti Rosei E 2007 The predictive value of ultrasound ﬁndings in the management of thyroid nodules. QJM 100:29–35. 82. Jeh SK, Jung SL, Kim BS, Lee YS 2007 Evaluating the degree of conformity of papillary carcinoma and follic-ular carcinoma to the reported ultrasonographic ﬁndings of malignant thyroid tumor. Korean J Radiol 8:192–197. 83. Machens A, Holzhausen HJ, Dralle H 2005 The prog- nostic value of primary tumor size in papillary and fol- licular thyroid carcinoma. Cancer 103:2269–2273. 84. Nam-Goong IS, Kim HY, Gong G, Lee HK, Hong SJ, Kim WB,
Shong YK 2004 Ultrasonography-guided ﬁne- needle aspiration of thyroid incidentaloma: correlation with pathological ﬁndings. Clin Endocrinol (Oxf) 60: 21–28. 85. Henrichsen TL, Reading CC, Charboneau JW, Donovan DJ, Sebo TJ, Hay ID 2010 Cystic change in thyroid carcinoma: prevalence and estimated volume in 360 carcinomas. J Clin Ultrasound 38:361–366. 86. Lee MJ, Kim EK, Kwak JY, Kim MJ 2009 Partially cystic thyroid nodules on ultrasound: probability of malignancy and sonographic differentiation. Thyroid 19: 341–346.ATA THYROID NODULE/DTC GUIDELINES 95
87. Kim DW, Lee EJ, In HS, Kim SJ 2010 Sonographic dif- ferentiation of partially cystic thyroid nodules: a pro- spective study. AJNR Am J Neuroradiol 31:1961–1966. 88. Bonavita JA, Mayo J, Babb J, Bennett G, Oweity T, Macari M, Yee J 2009 Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules can be left alone? AJR Am J Roentgenol 193:207–213. 89. Horvath E, Majlis S, Rossi R, Franco C, Niedmann JP, Castro A, Dominguez M 2009 An ultrasonogram re- porting system for thyroid nodules stratifying cancer risk for clinical management. J Clin Endocrinol Metab 94: 1748–1751. 90. Tae HJ, Lim DJ, Baek KH, Park WC, Lee YS, Choi JE, Lee JM, Kang MI, Cha BY, Son HY, Lee KW, Kang SK 2007 Diagnostic value of ultrasonography to distin- guish between benign and malignant lesions in the management of thyroid nodules. Thyroid 17:461–466. 91. Shimura H, Haraguchi
K, Hiejima Y, Fukunari N, Fuji- moto Y, Katagiri M, Koyanagi N, Kurita T, Miyakawa M, Miyamoto Y, Suzuki N, Suzuki S, Kanbe M, Kato Y, Murakami T, Tohno E, Tsunoda-Shimizu H, Yamada K, Ueno E, Kobayashi K, Kobayashi T, Yokozawa T, Ki- taoka M 2005 Distinct diagnostic criteria for ultrasono- graphic examination of papillary thyroid carcinoma: a multicenter study. Thyroid 15:251–258. 92. Russ G, Royer B, Bigorgne C, Rouxel A, Bienvenu- Perrard M, Leenhardt L 2013 Prospective evaluation of thyroid imaging reporting and data system on 4550 nodules with and without elastography. Eur J Endocrinol 168:649–655. 93. Cheng SP, Lee JJ, Lin JL, Chuang SM, Chien MN, Liu CL 2013 Characterization of thyroid nodules using the proposed thyroid imaging reporting and data system (TI- RADS). Head Neck 35:541–547. 94. Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, Morita S, Kobayashi K, Miyauchi A 2007 Ultra-
sonographic evaluation of thyroid nodules in 900 pa- tients: comparison among ultrasonographic, cytological, and histological ﬁndings. Thyroid 17:1269–1276. 95. Ito Y, Miyauchi A, Kihara M, Higashiyama T, Ko- bayashi K, Miya A 2014 Patient age is signiﬁcantly re- lated to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid 24:27–34. 96. Hamming JF, Goslings BM, van Steenis GJ, van Ra- venswaay CH, Hermans J, van de Velde CJ 1990 The value of ﬁne-needle aspiration biopsy in patients withnodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds. Arch Intern Med 150:113–116. 97. Rago T, Santini F, Scutari M, Pinchera A, Vitti P 2007 Elastography: new developments in ultrasound for pre- dicting malignancy in thyroid nodules. J Clin Endocrinol Metab 92:2917–2922. 98. Azizi G, Keller J, Lewis M, Puett D, Rivenbark K, Malchoff C 2013 Performance of elastography for the evaluation of thyroid nodules: a
prospective study. Thyroid 23:734–740. 99. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, Vielh P, DeMay RM, Sidawy MK, Frable WJ 2008 Diagnostic terminology and morphologic cri- teria for cytologic diagnosis of thyroid lesions: a syn- opsis of the National Cancer Institute Thyroid Fine- Needle Aspiration State of the Science Conference. Di- agn Cytopathol 36:425–437.100. Crippa S, Mazzucchelli L, Cibas ES, Ali SZ 2010 The Bethesda System for reporting thyroid ﬁne-needle aspi- ration specimens. Am J Clin Pathol 134:343–344. 101. Theoharis CG, Schoﬁeld KM, Hammers L, Udelsman R, Chhieng DC 2009 The Bethesda thyroid ﬁne-needle as- piration classiﬁcation system: year 1 at an academic in- stitution. Thyroid 19:1215–1223. 102. Luu MH, Fischer AH, Pisharodi L, Owens CL 2011 Improved preoperative deﬁnitive diagnosis of papillary thyroid carcinoma in FNAs prepared with both ThinPrep and conventional smears compared with FNAs preparedwith ThinPrep alone. Cancer Cytopathol 119:68–73. 103. Bongiovanni
M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW 2012 The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. Acta Cytol 56: 333–339. 104. Nayar R, Ivanovic M 2009 The indeterminate thyroid ﬁne-needle aspiration: experience from an academic center using terminology similar to that proposed in the 2007 National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Cancer 117: 195–202. 105. Ohori NP, Schoedel KE 2011 Variability in the atypia of undetermined signiﬁcance/follicular lesion of undeter- mined signiﬁcance diagnosis in the Bethesda System for Reporting Thyroid Cytopathology: sources and recom- mendations. Acta Cytol 55:492–498. 106. Cibas ES, Baloch ZW, Fellegara G, LiVolsi VA, Raab SS, Rosai J, Diggans J, Friedman L, Kennedy GC, Kloos RT, Lanman RB, Mandel SJ, Sindy N, Steward DL, Zeiger MA, Haugen BR, Alexander EK 2013 A pro- spective assessment deﬁning the limitations of thyroid nodule pathologic evaluation. Ann Intern Med 159: 325–332.
107. Nishino M, Wang HH 2014 Should the thyroid AUS/ FLUS category be further stratiﬁed by malignancy risk? Cancer Cytopathol 122:481–483. 108. Crothers BA, Henry MR, Firat P 2010 Nondiagnostic/ unsatisfactory. In: Ali SZ, Cibas ES (eds) The Bethesda System for Reporting Thyroid Cytopathology. Springer, pp 5–14. 109. Baloch ZW, Tam D, Langer J, Mandel S, LiVolsi VA, Gupta PK 2000 Ultrasound-guided ﬁne-needle aspiration biopsy of the thyroid: role of on-site assessment and multiple cytologic preparations. Diagn Cytopathol 23: 425–429. 110. Braga M, Cavalcanti TC, Collaco LM, Graf H 2001 Efﬁcacy of ultrasound-guided ﬁne-needle aspiration bi- opsy in the diagnosis of complex thyroid nodules. J Clin Endocrinol Metab 86:4089–4091. 111. Redman R, Zalaznick H, Mazzaferri EL, Massoll NA 2006 The impact of assessing specimen adequacy and number of needle passes for ﬁne-needle aspiration biopsy of thyroid nodules. Thyroid 16:55–60. 112. Orija IB, Pineyro M, Biscotti C, Reddy SS, Hamrahian AH
2007 Value of repeating a nondiagnostic thyroid ﬁne-needle aspiration biopsy. Endocr Pract 13:735–742. 113. Wu HH, Rose C, Elsheikh TM 2012 The Bethesda sys- tem for reporting thyroid cytopathology: an experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy. Diagn Cytopathol 40:399–403. 114. Layﬁeld LJ, Abrams J, Cochand-Priollet B, Evans D, Gharib H, Greenspan F, Henry M, LiVolsi V, Merino M,96 HAUGEN ET AL.
Michael CW, Wang H, Wells SA 2008 Post-thyroid FNA testing and treatment options: a synopsis of the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol 36:442–448. 115. Singh RS, Wang HH 2011 Timing of repeat thyroid ﬁne- needle aspiration in the management of thyroid nodules. Acta Cytol 55:544–548. 116. Lubitz CC, Nagarkatti SS, Faquin WC, Samir AE, Hassan MC, Barbesino G, Ross DS, Randolph GW, Gaz RD, Stephen AE, Hodin RA, Daniels GH, Parangi S 2012 Diagnostic yield of nondiagnostic thyroid nodules is not altered by timing of repeat biopsy. Thyroid 22: 590–594. 117. Choi YS, Hong SW, Kwak JY, Moon HJ, Kim EK 2012 Clinical and ultrasonographic ﬁndings affecting nondiagnostic results upon the second ﬁne needle as- piration for thyroid nodules. Ann Surg Oncol 19: 2304–2309. 118. Moon HJ, Kwak JY, Choi YS, Kim EK 2012 How to manage thyroid nodules with two
consecutive non- diagnostic results on ultrasonography-guided ﬁne-needle aspiration. World J Surg 36:586–592. 119. Na DG, Kim JH, Sung JY, Baek JH, Jung KC, Lee H, Yoo H 2012 Core-needle biopsy is more useful than repeat ﬁne-needle aspiration in thyroid nodules read as nondiagnostic or atypia of undetermined signiﬁcance by the Bethesda system for reporting thyroid cytopathology. Thyroid 22:468–475. 120. Nam SY, Han BK, Ko EY, Kang SS, Hahn SY, Hwang JY, Nam MY, Kim JW, Chung JH, Oh YL, Shin JH 2010 BRAFV600Emutation analysis of thyroid nodules needle aspirates in relation to their ultrasongraphic classiﬁca- tion: a potential guide for selection of samples for mo- lecular analysis. Thyroid 20:273–279. 121. Yip L, Nikiforova MN, Carty SE, Yim JH, Stang MT, Tublin MJ, LeBeau SO, Hodak SP, Ogilvie JB, Niki- forov YE 2009 Optimizing surgical treatment of papil- lary thyroid carcinoma associated with BRAF mutation. Surgery 146:1215–1223. 122. Cantara S, Capezzone
M, Marchisotta S, Capuano S, Busonero G, Toti P, Di SA, Caruso G, Carli AF, Brilli L, Montanaro A, Pacini F 2010 Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab 95:1365–1369. 123. Renshaw AA, Pinnar N 2007 Comparison of thyroid ﬁne-needle aspiration and core needle biopsy. Am J Clin Pathol 128:370–374. 124. Yeon JS, Baek JH, Lim HK, Ha EJ, Kim JK, Song DE, Kim TY, Lee JH 2013 Thyroid nodules with initially nondiagnostic cytologic results: the role of core-needle biopsy. Radiology 268:274–280. 125. Deleted. 126. Hatada T, Okada K, Ishii H, Ichii S, Utsunomiya J 1998 Evaluation of ultrasound-guided ﬁne-needle aspiration biopsy for thyroid nodules. Am J Surg 175:133–136. 127. Deleted. 128. Cesur M, Corapcioglu D, Bulut S, Gursoy A, Yilmaz AE, Erdogan N, Kamel N 2006 Comparison of palpation- guided ﬁne-needle aspiration biopsy to ultrasound-
guided ﬁne-needle aspiration biopsy in the evaluation of thyroid nodules. Thyroid 16:555–561. 129. Chehade JM, Silverberg AB, Kim J, Case C, Mooradian AD 2001 Role of repeated ﬁne-needle aspiration ofthyroid nodules with benign cytologic features. Endocr Pract 7:237–243. 130. Orlandi A, Puscar A, Capriata E, Fideleff H 2005 Re- peated ﬁne-needle aspiration of the thyroid in benign nodular thyroid disease: critical evaluation of long-term follow-up. Thyroid 15:274–278. 131. Oertel YC, Miyahara-Felipe L, Mendoza MG, Yu K 2007 Value of repeated ﬁne needle aspirations of the thyroid: an analysis of over ten thousand FNAs. Thyroid 17:1061–1066. 132. Erdogan MF, Kamel N, Aras D, Akdogan A, Baskal N, Erdogan G 1998 Value of re-aspirations in benign nod- ular thyroid disease. Thyroid 8:1087–1090. 133. Illouz F, Rodien P, Saint-Andre JP, Triau S, Laboureau- Soares S, Dubois S, Vielle B, Hamy A, Rohmer V 2007 Usefulness of repeated ﬁne-needle cytology in the follow-up of
non-operated thyroid nodules. Eur J En- docrinol 156:303–308. 134. Tee YY, Lowe AJ, Brand CA, Judson RT 2007 Fine- needle aspiration may miss a third of all malignancy in palpable thyroid nodules: a comprehensive literature re- view. Ann Surg 246:714–720. 135. Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H 2009 Accuracy of ﬁne-needle aspiration biopsy for pre- dicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg 144:649–655. 136. Kuru B, Gulcelik NE, Gulcelik MA, Dincer H 2010 The false-negative rate of ﬁne-needle aspiration cytology for diagnosing thyroid carcinoma in thyroid nodules. Lan- genbecks Arch Surg 395:127–132. 137. Wharry LI, McCoy KL, Stang MT, Armstrong MJ, Le- Beau SO, Tublin ME, Sholosh B, Silbermann A, Ohori NP, Nikiforov YE, Hodak SP, Carty SE, Yip L 2014 Thyroid nodules ( >/=4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg 38:614–621. 138. Yoon JH,
Kwak JY, Moon HJ, Kim MJ, Kim EK 2011 The diagnostic accuracy of ultrasound-guided ﬁne- needle aspiration biopsy and the sonographic differences between benign and malignant thyroid nodules 3 cm or larger. Thyroid 21:993–1000. 139. Porterﬁeld JR Jr, Grant CS, Dean DS, Thompson GB, Farley DR, Richards ML, Reading CC, Charboneau JW, Vollrath BK, Sebo TJ 2008 Reliability of benign ﬁne needle aspiration cytology of large thyroid nodules. Surgery 144:963–968. 140. Nou E, Kwong N, Alexander LK, Cibas ES, Marqusee E, Alexander EK 2014 Determination of the optimal time interval for repeat evaluation after a benign thyroid nodule aspiration. J Clin Endocrinol Metab 99:510–516. 141. Mazzaferri EL 2007 Management of low-risk differen- tiated thyroid cancer. Endocr Pract 13:498–512. 142. Hay ID 2007 Management of patients with low-risk papillary thyroid carcinoma. Endocr Pract 13:521–533. 143. Sugitani I, Toda K, Yamada K, Yamamoto N, Ikenaga M, Fujimoto Y 2010 Three distinctly different
kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J Surg 34: 1222–1231. 144. Yu XM, Wan Y, Sippel RS, Chen H 2011 Should all papillary thyroid microcarcinomas be aggressively trea- ted? An analysis of 18,445 cases. Ann Surg 254:653– 660. 145. Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH 2003 Papillary microcarcinoma of the thyroid—prog-ATA THYROID NODULE/DTC GUIDELINES 97