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Revised american thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancerORIGINAL STUDIES, REVIEWS, Volume 19, Number 11, 2009ª Mary Ann Liebert, Inc.
AND SCHOLARLY DIALOG THYROID CANCER AND NODULES Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer David S. Cooper, M.D.1 (Chair)*, Gerard M. Doherty, M.D.,2 Bryan R. Haugen, M.D.,3 Richard T. Kloos, M.D.,4 Stephanie L. Lee, M.D., Ph.D.,5 Susan J. Mandel, M.D., M.P.H.,6 Ernest L. Mazzaferri, M.D.,7 Bryan McIver, M.D., Ph.D.,8 Furio Pacini, M.D.,9 Martin Schlumberger, M.D.,10 Steven I. Sherman, M.D.,11 David L. Steward, M.D.,12 and R. Michael Tuttle, M.D.13 Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becomingincreasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the man-agement of these disorders was published in 2006, a large amount of new information has become available,prompting a revision of the guidelines.
Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic andlevel of evidence according to a modified schema used by the United States Preventative Services Task Force.
Results: The revised guidelines for the management of thyroid nodules include recommendations regardinginitial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needleaspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initialmanagement of thyroid cancer include those relating to optimal surgical management, radioiodine remnantablation, and suppression therapy using levothyroxine. Recommendations related to long-term management ofdifferentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound andserum thyroglobulin as well as those related to management of recurrent and metastatic disease.
Conclusions: We created evidence-based recommendations in response to our appointment as an independenttask force by the American Thyroid Association to assist in the clinical management of patients with thyroidnodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for pa-tients with these disorders.
Thyroid nodules are a common clinical problem. Epi- nodules in 19–67% of randomly selected individuals with demiologic studies have shown the prevalence of palpa- higher frequencies in women and the elderly (3). The clinical ble thyroid nodules to be approximately 5% in women and 1% importance of thyroid nodules rests with the need to exclude in men living in iodine-sufficient parts of the world (1,2). In thyroid cancer which occurs in 5–15% depending on age, sex, contrast, high-resolution ultrasound (US) can detect thyroid radiation exposure history, family history, and other factors *Authors are listed in alphabetical order and were appointed by ATA to independently formulate the content of this manuscript. None of the scientific or medical content of the manuscript was dictated by the ATA.
1The Johns Hopkins University School of Medicine, Baltimore, Maryland.
2University of Michigan Medical Center, Ann Arbor, Michigan.
3University of Colorado Health Sciences Center, Denver, Colorado.
4The Ohio State University, Columbus, Ohio.
5Boston University Medical Center, Boston, Massachusetts.
6University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
7University of Florida College of Medicine, Gainesville, Florida.
8The Mayo Clinic, Rochester, Minnesota.
9The University of Siena, Siena, Italy.
10Institute Gustave Roussy, Paris, France.
11University of Texas M.D. Anderson Cancer Center, Houston, Texas.
12University of Cincinnati Medical Center, Cincinnati, Ohio.
13Memorial Sloan-Kettering Cancer Center, New York, New York.
COOPER ET AL.
(4,5). Differentiated thyroid cancer (DTC), which includes aboutcdp.htm), and developed a series of clinically relevant papillary and follicular cancer, comprises the vast majority questions pertaining to thyroid nodule and thyroid cancer di- (90%) of all thyroid cancers (6). In the United States, approx- agnosis and treatment. These questions were as follows: imately 37,200 new cases of thyroid cancer will be diagnosedin 2009 (7). The yearly incidence has increased from 3.6 per — Questions regarding thyroid nodules 100,000 in 1973 to 8.7 per 100,000 in 2002, a 2.4-fold increase What is the appropriate evaluation of clinically or inci- ( p < 0.001 for trend) and this trend appears to be continuing dentally discovered thyroid nodule(s)? (8). Almost the entire change has been attributed to an in- What laboratory tests and imaging modalities are in- crease in the incidence of papillary thyroid cancer (PTC), which increased 2.9-fold between 1988 and 2002. Moreover, What is the role of fine-needle aspiration (FNA)? 49% of the rising incidence consisted of cancers measuring What is the best method of long-term follow up of pa- 1 cm or smaller and 87% consisted of cancers measuring 2 cm tients with thyroid nodules? or smaller (8). This tumor shift may be due to the increasing What is the role of medical therapy of patients with use of neck ultrasonography and early diagnosis and treat- benign thyroid nodules? ment (9), trends that are changing the initial treatment and How should thyroid nodules in children and pregnant follow-up for many patients with thyroid cancer.
women be managed? In 1996, the American Thyroid Association (ATA) pub- — Questions regarding the initial management of DTC lished treatment guidelines for patients with thyroid nodules What is the role of preoperative staging with diagnostic and DTC (10). Over the last decade, there have been many imaging and laboratory tests? advances in the diagnosis and therapy of both thyroid nodules What is the appropriate operation for indeterminate and DTC. Controversy exists in many areas, including the thyroid nodules and DTC? most cost-effective approach in the diagnostic evaluation of a What is the role of postoperative staging systems and thyroid nodule, the extent of surgery for small thyroid cancers, which should be used? the use of radioactive iodine to ablate remnant tissue following What is the role of postoperative RAI remnant ablation? thyroidectomy, the appropriate use of thyroxine suppression What is the role of thyrotropin (TSH) suppression therapy, and the role of human recombinant thyrotropin (rhTSH). In recognition of the changes that have taken place in Is there a role for adjunctive external beam irradiation or the overall management of these clinically important prob- lems, the ATA appointed a task force to re-examine the currentstrategies that are used to diagnose and treat thyroid nodules — Questions regarding the long term management of DTC and DTC, and to develop clinical guidelines using principles of What are the appropriate features of long-term man- evidence-based medicine. Members of the taskforce included experts in thyroid nodule and thyroid cancer management What is the role of serum thyroglobulin (Tg) assays? with representation from the fields of endocrinology, surgery, What is the role of US and other imaging techniques and nuclear medicine. The medical opinions expressed here during follow-up? are those of the authors; none were dictated by the ATA. The What is the role of TSH suppression in long-term follow- final document was approved by the ATA Board of Directors and endorsed (in alphabetical order) by the American Asso- What is the most appropriate management of patients ciation of Clinical Endocrinologists (AACE), American College with metastatic disease? of Endocrinology, British Association of Head and Neck How should Tg-positive, scan-negative patients be Oncologists (BAHNO), The Endocrine Society, European As- sociation for Cranio-Maxillo-Facial Surgery (EACMFS), Eur- What is the role of external radiation therapy? opean Association of Nuclear Medicine (EANM), European What is the role of chemotherapy? Society of Endocrine Surgeons (ESES), European Society for — What are directions for future research? Paediatric Endocrinology (ESPE), International Association ofEndocrine Surgeons (IAES), and Latin American Thyroid So- The initial ATA guidelines were published in 2006 (16).
Because of the rapid growth of the literature on this topic, Other groups have previously developed guidelines, in- plans for revising the guidelines within 24–36 months of cluding the American Association of Clinical Endocrinologists publication were made at the inception of the project. Re- and the American Association of Endocrine Surgeons (11), the levant articles on thyroid cancer were identified using the British Thyroid Association and The Royal College of Physi- same search criteria employed for the original guidelines (16).
cians (12), and the National Comprehensive Cancer Network Individual task force members submitted suggestions for (13) that have provided somewhat conflicting recommenda- clarification of prior recommendations, as well as new infor- tions due to the lack of high quality evidence from random- mation derived from studies published since 2004. Relevant ized controlled trials. The European Thyroid Association has literature continued to be reviewed through December 2008.
published consensus guidelines for the management of DTC To begin the revision process, a half-day meeting was held (14). The European Association of Nuclear Medicine has also on June 2, 2007. The Task Force was broadened to include recently published consensus guidelines for radioiodine (RAI) European experts and a head and neck surgeon. Three sub- therapy of DTC (15).
sequent half-day meetings were held on October 5, 2007; July The ATA guidelines taskforce used a strategy similar to that 13, 2008; and October 5, 2008, to review these suggestions and employed by the National Institutes of Health for its Consen- for additional comments to be considered. The meeting in July sus Development Conferences (http:==consensus.nih.gov= 2008 also included a meeting with six additional surgeons in REVISED ATA THYROID CANCER GUIDELINES Table 1. Organization of Management Guideline Recommendations, Tables, and Figures for Patients with Thyroid Nodules and Differentiated Thyroid Cancer Sections and subsections THYROID NODULE GUIDELINES Evaluation of Newly Discovered Thyroid Nodules Serum thyroglobulin (Tg) Role of fine-needle aspiration (FNA) Ultrasound (US) with FNA Cytopathological interpretation of FNA samples Nondiagnostic cytology Cytology suggesting papillary thyroid cancer (PTC) Indeterminate cytology Multinodular goiter (MNG)=multiple thyroid nodules Long-Term Follow-Up of Thyroid Nodules Medical therapy for benign thyroid nodules Thyroid nodules in children Thyroid nodules in pregnant women DIFFERENTIATED THYROID CANCER (DTC):INITIAL MANAGEMENT GUIDELINES Goals of Initial Therapy of DTC Preoperative staging of DTC Surgery for nondiagnostic biopsy Surgery for biopsy diagnostic of malignancy Lymph node dissection Completion thyroidectomy Postoperative staging systems Role of postoperative staging AJCC=UICC TNM staging Role of postoperative remnant ablation Preparation for radioiodine (RAI) remnant ablation rhTSH preparation RAI scanning before RAI ablation Radiation doses for RAI ablation Low-iodine diet for RAI ablation Post RAI ablation whole-body RAI scan Post Initial Therapy of DTC Role of TSH suppression therapy Degree of initial TSH suppression required Adjunctive measures External beam irradiation DTC: LONG-TERM MANAGEMENT Appropriate Features of Long-Term Management Appropriate method of follow-up after surgery Criteria for absence of persistent tumor Role of serum Tg assays Whole body RAI scans, US, and other imaging aIf viewing these guidelines on the Web, or in a File, copy the Location Key to the Find or Search Function to navigate rapidly to the desired section.
bR, recommendation; T, table; F, figure.
Table 1. (Continued) Sections and subsections Diagnostic whole-body RAI scans Cervical ultrasound Role of thyroxine suppression of TSH Management of Metastatic Disease Surgery for locoregional metastases Surgery for aerodigestive invasion RAI for local or distant metastatic disease Methods for administering RAI The use of lithium in RAI therapy Metastasis to various organs Pulmonary metastasis Non–RAI-avid pulmonary disease Management of Complications of RAI Therapy Secondary malignancies and leukemia from RAI Other risks to bone marrow from RAI Effects of RAI on gonads and in nursing women Management of Tg Positive, RAI Scan–Negative Patients Patients with a negative post-treatment whole-body scan External beam radiation for metastatic disease DIRECTIONS FOR FUTURE RESEARCH Novel Therapies and Clinical Trials Inhibitors of oncogenic signaling pathways Modulators of growth or apoptosis Angiogenesis inhibitors Better Understanding of the Long-Term Risks of RAI Clinical Significance of Persistent Low-Level Tg The Problem of Tg Antibodies Small Cervical Lymph Node Metastases Improved Risk Stratification Table 2. Strength of Panelists' Recommendations Based on Available Evidence Strongly recommends. The recommendation is based on good evidence that the service or intervention can improve important health outcomes. Evidence includes consistent results from well-designed, well-conducted studies inrepresentative populations that directly assess effects on health outcomes.
Recommends. The recommendation is based on fair evidence that the service or intervention can improve important health outcomes. The evidence is sufficient to determine effects on health outcomes, but the strengthof the evidence is limited by the number, quality, or consistency of the individual studies; generalizability toroutine practice; or indirect nature of the evidence on health outcomes.
Recommends. The recommendation is based on expert opinion.
Recommends against. The recommendation is based on expert opinion.
Recommends against. The recommendation is based on fair evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
Strongly recommends against. The recommendation is based on good evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
Recommends neither for nor against. The panel concludes that the evidence is insufficient to recommend for or against providing the service or intervention because evidence is lacking that the service or interventionimproves important health outcomes, the evidence is of poor quality, or the evidence is conflicting. As a result, thebalance of benefits and harms cannot be determined.
Adapted from the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality (17).
REVISED ATA THYROID CANCER GUIDELINES an effort to produce guidelines related to central neck dis- diffuse or focal thyroidal uptake on 18FDG-PET scan, a se- section that would be as authoritative as possible. The orga- rum TSH level should be obtained. If the serum TSH is nization of management guideline recommendations is subnormal, a radionuclide thyroid scan should be obtained shown in Table 1. It was agreed to continue to categorize the to document whether the nodule is hyperfunctioning (i.e., published data and strength of recommendations using a tracer uptake is greater than the surrounding normal thy- modified schema proposed by the U.S. Preventive Services roid), isofunctioning or ‘ warm' (i.e., tracer uptake is equal to Task Force (17) (Table 2).
the surrounding thyroid), or nonfunctioning (i.e., has uptakeless than the surrounding thyroid tissue). Since hyperfunc- [A1] THYROID NODULE GUIDELINES tioning nodules rarely harbor malignancy, if one is found A thyroid nodule is a discrete lesion within the thyroid that corresponds to the nodule in question, no cytologic gland that is radiologically distinct from the surrounding evaluation is necessary. If overt or subclinical hyperthy- thyroid parenchyma. Some palpable lesions may not corre- roidism is present, additional evaluation is required. Higher spond to distinct radiologic abnormalities (18). Such abnor- serum TSH, even within the upper part of the reference malities do not meet the strict definition for thyroid nodules.
range, is associated with increased risk of malignancy in a Nonpalpable nodules detected on US or other anatomic im- thyroid nodule (26).
aging studies are termed incidentally discovered nodules or‘‘incidentalomas.'' Nonpalpable nodules have the same risk of malignancy as palpable nodules with the same size (19).
Measure serum TSH in the initial evaluation of a patient Generally, only nodules >1 cm should be evaluated, since with a thyroid nodule. If the serum TSH is subnormal, a they have a greater potential to be clinically significant can- radionuclide thyroid scan should be performed using either cers. Occasionally, there may be nodules <1 cm that require technetium 99 mTc pertechnetate or 123I. Recommendation evaluation because of suspicious US findings, associated lymphadenopathy, a history of head and neck irradiation, or ahistory of thyroid cancer in one or more first-degree relatives.
Diagnostic thyroid US should be performed in all However, some nodules <1 cm lack these warning signs yet patients with a suspected thyroid nodule, nodular goiter, or eventually cause morbidity and mortality. These are rare and, radiographic abnormality; e.g., a nodule found incidentally given unfavorable cost=benefit considerations, attempts to on computed tomography (CT) or magnetic resonance im- diagnose and treat all small thyroid cancers in an effort to aging (MRI) or thyroidal uptake on 18FDG-PET scan.
prevent these rare outcomes would likely cause more harm Thyroid US can answer the following questions: Is there than good. Approximately 1–2% of people undergoing 2- truly a nodule that corresponds to the palpable abnormal- deoxy-2[18F]fluoro-d-glucose positron emission tomography ity? How large is the nodule? Does the nodule have benign (18FDG-PET) imaging for other reasons have thyroid nodules or suspicious features? Is suspicious cervical lymphade- discovered incidentally. Since the risk of malignancy in these nopathy present? Is the nodule greater than 50% cystic? Is 18FDG-positive nodules is about 33% and the cancers may be the nodule located posteriorly in the thyroid gland? These more aggressive (20), such lesions require prompt evaluation last two features might decrease the accuracy of FNA bi- (21–23). When seen, diffuse 18FDG uptake is likely related to opsy performed with palpation (27,28). Also, there may underlying autoimmune thyroiditis.
be other thyroid nodules present that require biopsy basedon their size and appearance (18,29,30). As already noted, [A2] What is the appropriate evaluation of clinically FNA is recommended especially when the serum TSH or incidentally discovered thyroid nodule(s)? is elevated because, compared with normal thyroid glands, (See Fig. 1 for algorithm) the rate of malignancy in nodules in thyroid glandsinvolved with Hashimoto's thyroiditis is as least as high or With the discovery of a thyroid nodule, a complete history possibly higher (31,32).
and physical examination focusing on the thyroid gland andadjacent cervical lymph nodes should be performed. Pertinent historical factors predicting malignancy include a history of childhood head and neck irradiation, total body irradiation Thyroid sonography should be performed in all patients for bone marrow transplantation (24), family history of thy- with known or suspected thyroid nodules. Recommenda- roid carcinoma, or thyroid cancer syndrome (e.g., Cowden's syndrome, familial polyposis, Carney complex, multiple en-docrine neoplasia [MEN] 2, Werner syndrome) in a first- [A5] Serum Tg measurement. Serum Tg levels can be ele- degree relative, exposure to ionizing radiation from fallout vated in most thyroid diseases and are an insensitive and in childhood or adolescence (25), and rapid growth and nonspecific test for thyroid cancer (33).
hoarseness. Pertinent physical findings suggesting possiblemalignancy include vocal cord paralysis, lateral cervical lymphadenopathy, and fixation of the nodule to surrounding Routine measurement of serum Tg for initial evaluation of thyroid nodules is not recommended. Recommendationrating: F [A3] What laboratory tests and imaging modalities are [A6] Serum calcitonin measurement. The utility of serum [A4] Serum TSH with US and with or without scan. With calcitonin has been evaluated in a series of prospective, the discovery of a thyroid nodule >1 cm in any diameter or nonrandomized studies (34–37). The data suggest that the COOPER ET AL.
WORKUP OF THYROID NODULE
DETECTED BY PALPATION OR IMAGING
Normal or High TSH History, Physical, TSH 123I or 99Tc Scana Hyperfunctioning Suspicious for PTC Consider 123I Scan Hyperfunctioning Algorithm for the evaluation of patients with one or more thyroid nodules.
aIf the scan does not show uniform distribution of tracer activity, ultrasound may be considered to assess for the presence of a cystic component.
use of routine serum calcitonin for screening may detect of sensitivity, specificity, assay performance and cost- C-cell hyperplasia and medullary thyroid cancer at an effectiveness. A recent cost-effectiveness analysis suggested earlier stage and overall survival may be improved. How- that calcitonin screening would be cost effective in the ever, most studies rely on pentagastrin stimulation test- United States (38). However, the prevalence estimates of ing to increase specificity. This drug is no longer available medullary thyroid cancer in this analysis included patients in the United States, and there remain unresolved issues with C-cell hyperplasia and micromedullary carcinoma, REVISED ATA THYROID CANCER GUIDELINES Table 3. Sonographic and Clinical Features of Thyroid Nodules and Recommendations for FNA Nodule sonographic or clinical features Recommended nodule threshold size for FNA High-risk historya Nodule WITH suspicious sonographic featuresb Nodule WITHOUT suspicious sonographic featuresb Abnormal cervical lymph nodes Microcalcifications present in nodule AND iso- or hyperechoic Mixed cystic–solid nodule WITH any suspicious ultrasound featuresb WITHOUT suspicious ultrasound features Spongiform nodule Purely cystic nodule FNA not indicatede aHigh-risk history: History of thyroid cancer in one or more first degree relatives; history of external beam radiation as a child; exposure to ionizing radiation in childhood or adolescence; prior hemithyroidectomy with discovery of thyroid cancer, 18FDG avidity on PET scanning;MEN2=FMTC-associated RET protooncogene mutation, calcitonin >100 pg=mL. MEN, multiple endocrine neoplasia; FMTC, familial medullarythyroid cancer.
bSuspicious features: microcalcifications; hypoechoic; increased nodular vascularity; infiltrative margins; taller than wide on transverse view.
cFNA cytology may be obtained from the abnormal lymph node in lieu of the thyroid nodule.
dSonographic monitoring without biopsy may be an acceptable alternative (see text) (48).
eUnless indicated as therapeutic modality (see text).
which have an uncertain clinical significance. If the un- neoplasm'' be substituted for ‘‘indeterminate'' (risk of malig- stimulated serum calcitonin determination has been ob- nancy 15–25%) (42).
tained and the level is greater than 100 pg=mL, medullarycancer is likely present (39).
[A8] US for FNA decision making (see Table 3). Various sonographic characteristics of a thyroid nodule have been associated with a higher likelihood of malignancy (43–48).
The panel cannot recommend either for or against the These include nodule hypoechogenicity compared to the routine measurement of serum calcitonin. Recommenda- normal thyroid parenchyma, increased intranodular vascu- larity, irregular infiltrative margins, the presence of micro-calcifications, an absent halo, and a shape taller than the widthmeasured in the transverse dimension. With the exception of [A7] What is the role of FNA biopsy? suspicious cervical lymphadenopathy, which is a specific but accurate and cost-effective method for evaluating thyroid insensitive finding, no single sonographic feature or combi- nodules. Retrospective studies have reported lower rates of nations of features is adequately sensitive or specific to both nondiagnostic and false-negative cytology specimens identify all malignant nodules. However, certain features and from FNA procedures performed via US guidance compared combination of features have high predictive value for ma- to palpation (40,41). Therefore, for nodules with a higher lignancy. Furthermore, the most common sonographic ap- likelihood of either a nondiagnostic cytology (>25–50% cystic pearances of papillary and follicular thyroid cancer differ. A component) (28) or sampling error (difficult to palpate or PTC is generally solid or predominantly solid and hy- posteriorly located nodules), US-guided FNA is preferred (see poechoic, often with infiltrative irregular margins and in- Table 3). If the diagnostic US confirms the presence of a pre- creased nodular vascularity. Microcalcifications, if present, dominantly solid nodule corresponding to what is palpated, are highly specific for PTC, but may be difficult to distinguish the FNA may be performed via palpation or US guidance.
from colloid. Conversely, follicular cancer is more often iso- to Traditionally FNA biopsy results are divided into four cate- hyperechoic and has a thick and irregular halo, but does not gories: nondiagnostic, malignant (risk of malignancy at sur- have microcalcifications (49). Follicular cancers that are <2 cm gery >95%), indeterminate or suspicious for neoplasm, and in diameter have not been shown to be associated with met- benign. The recent National Cancer Institute Thyroid Fine- astatic disease (50).
Needle Aspiration State of the Science Conference proposed a Certain sonographic appearances may also be highly pre- more expanded classification for FNA cytology that adds two dictive of a benign nodule. A pure cystic nodule, although rare additional categories: suspicious for malignancy (risk of ma- (<2% of all nodules), is highly unlikely to be malignant (47). In lignancy 50–75%) and follicular lesion of undetermined sig- addition, a spongiform appearance, defined as an aggregation nificance (risk of malignancy 5–10%). The conference further of multiple microcystic components in more than 50% of the recommended that ‘‘neoplasm, either follicular or Hu¨rthle cell nodule volume, is 99.7% specific for identification of a benign COOPER ET AL.
thyroid nodule (48,51,52). In a recent study, only 1 of 360 (b) Partially cystic nodules that repeatedly yield non- malignant nodules demonstrated this appearance (48) and in diagnostic aspirates need close observation or surgical another report, a spongiform appearance had a negative pre- excision. Surgery should be more strongly considered dictive value for malignancy of 98.5% (52). Elastography is an if the cytologically nondiagnostic nodule is solid. Re- emerging and promising sonographic technique that requires commendation rating: B additional validation with prospective studies (53).
Routine FNA is not recommended for subcentimeter nod- [A11] Cytology suggesting PTC.
ules. However, the presence of a solid hypoechoic nodule withmicrocalcifications is highly suggestive of PTC. Although most micropapillary carcinomas may be incidental findings, a subset If a cytology result is diagnostic of or suspicious for PTC, may be more clinically relevant, especially those >5 mm in surgery is recommended (65). Recommendation rating: A diameter (54). These include nodules that have abnormallymph nodes detected clinically or with imaging at presenta- [A12] Indeterminate cytology (follicular or Hu¨rthle cell neoplasm tion (55,56). Therefore, after imaging a subcentimeter nodule follicular lesion of undetermined significance, atypia). Indetermi- with a suspicious appearance, sonographic assessment of lat- nate cytology, reported as ‘‘follicular neoplasm' or ‘‘Hu¨rthle eral neck and central neck lymph nodes (more limited due to cell neoplasm' can be found in 15–30% of FNA specimens (4) the presence of the thyroid) must be performed. Detection of and carries a 20–30% risk of malignancy (42), while lesions abnormal lymph nodes should lead to FNA of the lymph node.
reported as atypia or follicular lesion of undetermined signifi- Other groups of patients for whom consideration of FNA of a cance are variably reported and have 5–10% risk of malignancy subcentimeter nodule may be warranted include those with a (42). While certain clinical features such as male sex and nodule higher likelihood of malignancy (high risk history): 1) family size (>4 cm) (66), older patient age (67), or cytologic features history of PTC (57); 2) history of external beam radiation ex- such as presence of atypia (68) can improve the diagnostic ac- posure as a child (58); 3) exposure to ionizing radiation in curacy for malignancy in patients with indeterminate cytology, childhood or adolescence (59); 4) history of prior hemi- overall predictive values are still low. Many molecular markers thyroidectomy with discovery of thyroid cancer; and 5) 18FDG- (e.g., galectin-3 (69), cytokeratin, BRAF) have been evaluated to PET–positive thyroid nodules.
improve diagnostic accuracy for indeterminate nodules (70– Mixed cystic–solid nodules and predominantly cystic with 72). Recent large prospective studies have confirmed the ability >50% cystic component are generally evaluated by FNA with of genetic markers (BRAF, Ras, RET=PTC) and protein markers directed biopsy of the solid component (especially the vas- (galectin-3) to improve preoperative diagnostic accuary for cular component.) Cyst drainage may also be performed, es- patients with indeterminate thyroid nodules (69,73,74). Many pecially in symptomatic patients.
of these markers are available for commercial use in referencelaboratories but have not yet been widely applied in clinical RECOMMENDATION 5 (see Table 3) practice. It is likely that some combination of molecular (a) FNA is the procedure of choice in the evaluation of markers will be used in the future to optimize management of thyroid nodules. Recommendation rating: A patients with indeterminate cytology on FNA specimens.
(b) US guidance for FNA is recommended for those nod- Recently, 18FDG-PET scanning has been utilized in an ef- ules that are nonpalpable, predominantly cystic, or fort to distinguish those indeterminate nodules that are be- located posteriorly in the thyroid lobe. Recommenda- nign from those that are malignant (75–78). 18FDG-PET scans appear to have relatively high sensitivity for malignancy butlow specificity, but results vary among studies (79).
[A9] What are the principles of the cytopathological inter- pretation of FNA samples? (a) The use of molecular markers (e.g., BRAF, RAS, [A10] Nondiagnostic cytology. Nondiagnostic biopsies are RET=PTC, Pax8-PPARg, or galectin-3) may be consid- those that fail to meet specified criteria for cytologic adequacy ered for patients with indeterminate cytology on FNA that have been previously established (the presence of at least to help guide management. Recommendation rating: C six follicular cell groups, each containing 10–15 cells derived (b) The panel cannot recommend for or against routine from at least two aspirates of a nodule) (5). After an initial clinical use of 18FDG-PET scan to improve diagnostic nondiagnostic cytology result, repeat FNA with US guidance accuracy of indeterminate thyroid nodules. Recom- will yield a diagnostic cytology specimen in 75% of solid mendation rating: I nodules and 50% of cystic nodules (28). Therefore, such bi-opsies need to be repeated using US guidance (60) and, if available, on-site cytologic evaluation, which may substan- If the cytology reading reports a follicular neoplasm, a 123I tially increase cytology specimen adequacy (61,62). However, thyroid scan may be considered, if not already done, es- up to 7% of nodules continue to yield nondiagnostic cytology pecially if the serum TSH is in the low-normal range. If a results despite repeated biopsies and may be malignant at the concordant autonomously functioning nodule is not seen, time of surgery (63,64).
lobectomy or total thyroidectomy should be considered.
Recommendation rating: C (a) US guidance should be used when repeating the FNA RECOMMENDATION 10 procedure for a nodule with an initial nondiagnostic If the reading is ‘‘suspicious for papillary carcinoma'' or cytology result. Recommendation rating: A ‘‘Hu¨rthle cell neoplasm,'' a radionuclide scan is not needed, REVISED ATA THYROID CANCER GUIDELINES and either lobectomy or total thyroidectomy is re- Nodule growth is not in and of itself pathognomonic of commended, depending on the lesion's size and other risk malignancy, but growth is an indication for repeat biopsy. For factors. Recommendation rating: A mixed cystic–solid nodules, the indication for repeat biopsyshould be based upon growth of the solid component. For [A13] Benign cytology.
nodules with benign cytologic results, recent series reporta higher false-negative rate with palpation FNA (1–3%) RECOMMENDATION 11 (40,84,85) than with US FNA (0.6%) (40). Since the accuracy of If the nodule is benign on cytology, further immediate di- physical examination for nodule size is likely inferior to that of agnostic studies or treatment are not routinely required.
US (30), it is recommended that serial US be used in follow-up Recommendation rating: A of thyroid nodules to detect clinically significant changes insize. There is no consensus on the definition of nodule growth, [A14] How should multinodular thyroid glands or multi- however, or the threshold that would require rebiopsy. Some nodular goiters be evaluated for malignancy? groups suggest a 15% increase in nodule volume, while others multiple thyroid nodules have the same risk of malignancy as recommend measuring a change in the mean nodule diameter those with solitary nodules (18,44). However, one large study (82,86). One reasonable definition of growth is a 20% increase found that a solitary nodule had a higher likelihood of malig- in nodule diameter with a minimum increase in two or more nancy than did a nonsolitary nodule ( p < 0.01), although the dimensions of at least 2 mm. This approximates the 50% in- risk of malignancy per patient was the same and independent crease in nodule volume that was found by Brauer et al. (87) to of the number of nodules (47). A diagnostic US should be be the minimally significant reproducibly recorded change in performed to delineate the nodules, but if only the ‘‘dominant' nodule size. These authors suggested that only volume or largest nodule is aspirated, the thyroid cancer may be missed changes of at least 49% or more can be interpreted as nodule (44). Radionuclide scanning should also be considered in pa- shrinkage or growth and consequently suggest that future tients with multiple thyroid nodules, if the serum TSH is in the investigations should not describe changes in nodule volume low or low-normal range, with FNA being reserved for those <50% as significant. A 50% cutoff for nodule volume reduc- nodules that are shown to be hypofunctioning.
tion or growth, which is used in many studies, appears toappropriate and safe, since the false-negative rate for malig- RECOMMENDATION 12 nant thyroid nodules on repeat FNA is low (88,89).
(a) In the presence of two or more thyroid nodules >1 cm, those with a suspicious sonographic appearance (see RECOMMENDATION 14 text and Table 3) should be aspirated preferentially.
(a) It is recommended that all benign thyroid nodules be Recommendation rating: B followed with serial US examinations 6–18 months (b) If none of the nodules has a suspicious sonographic after the initial FNA. If nodule size is stable (i.e., no appearance and multiple sonographically similar coa- more than a 50% change in volume or <20% increase lescent nodules with no intervening normal paren- in at least two nodule dimensions in solid nodules or chyma are present, the likelihood of malignancy is low in the solid portion of mixed cystic–solid nodules), the and it is reasonable to aspirate the largest nodules only interval before the next follow-up clinical examination and observe the others with serial US examinations.
or US may be longer, e.g., every 3–5 years. Recom- Recommendation rating: C mendation rating: C (b) If there is evidence for nodule growth either by palpation or sonographically (more than a 50% change in volume or RECOMMENDATION 13 A low or low-normal serum TSH concentration may sug- a 20% increase in at least two nodule dimensions with gest the presence of autonomous nodule(s). A technetium a minimal increase of 2 mm in solid nodules or in the 99 mTc pertechnetate or 123I scan should be performed and solid portion of mixed cystic–solid nodules), the FNA directly compared to the US images to determine func- should be repeated, preferably with US guidance. Re- tionality of each nodule commendation rating: B >1–1.5 cm. FNA should then be considered only for those isofunctioning or nonfunctioningnodules, among which those with suspicious sonographic Cystic nodules that are cytologically benign can be moni- features should be aspirated preferentially. Recommenda- tored for recurrence (fluid reaccumulation) which can be seen in 60–90% of patients (90,91). For those patients with subse-quent recurrent symptomatic cystic fluid accumulation,surgical removal, generally by hemithyroidectomy, or per- [A15] What are the best methods for long-term cutaneous ethanol injection (PEI) are both reasonable strate- follow-up of patients with thyroid nodules? gies. Four controlled studies demonstrated a 75–85% success Thyroid nodules diagnosed as benign require follow-up rate after PEI compared with a 7–38% success rate in controls because of a low, but not negligible, false-negative rate of up treated by simple cyst evacuation or saline injection. Success to 5% with FNA (41,80), which may be even higher with was achieved after an average of two PEI treatments. Com- nodules >4 cm (81). While benign nodules may decrease in plications included mild to moderate local pain, flushing, size, they often increase in size, albeit slowly (82). One study dizziness, and dysphonia (90–93).
of cytologically benign thyroid nodules <2 cm followed byultrasonography for about 38 months found that the rate of RECOMMENDATION 15 thyroid nodule growth did not distinguish between benign Recurrent cystic thyroid nodules with benign cytology and malignant nodules (83).
should be considered for surgical removal or PEI based on COOPER ET AL.
compressive symptoms and cosmetic concerns. Recom- performed to evaluate nodule function. Recommendation mendation rating: B [A16] What is the role of medical therapy for benign thyroid If the FNA cytology is consistent with PTC, surgery is re- Evidence from multiple randomized control trials commended. However, there is no consensus about whether and three meta-analyses suggest that thyroid hormone in doses surgery should be performed during pregnancy or after de- that suppress the serum TSH to subnormal levels may result in livery. To minimize the risk of miscarriage, surgery during a decrease in nodule size and may prevent the appearance of pregnancy should be done in the second trimester before new nodules in regions of the world with borderline low iodine 24 weeks gestation (105). However, PTC discovered during intake. Data in iodine-sufficient populations are less compel- pregnancy does not behave more aggressively than that di- ling (94–96), with large studies suggesting that only about agnosed in a similar-aged group of nonpregnant women 17–25% of thyroid nodules shrink more than 50% with le- (104,106). A retrospective study of pregnant women with DTC vothyroxine (LT4) suppression of serum TSH (94–96).
found there to be no difference in either recurrence, or survivalrates, between women operated on during or after their RECOMMENDATION 16 pregnancy (104). Further, retrospective data suggest that Routine suppression therapy of benign thyroid nodules in treatment delays of less than 1 year from the time of thyroid iodine sufficient populations is not recommended. Re- cancer discovery do not adversely affect patient outcome (107).
commendation rating: F Finally, a recent study reported a higher rate of complicationsin pregnant women undergoing thyroid surgery compared RECOMMENDATION 17 with nonpregnant women (108). Some experts recommend Patients with growing nodules that are benign after repeat thyroid hormone suppression therapy for pregnant women biopsy should be considered for continued monitoring or with FNA suspicious for or diagnostic of PTC, if surgery is intervention with surgery based on symptoms and clinical deferred until the postpartum period (109).
concern. There are no data on the use of LT4 in this sub-population of patients. Recommendation rating: I RECOMMENDATION 20 (a) A nodule with cytology indicating PTC discovered early [A17] How should thyroid nodules in children be man- in pregnancy should be monitored sonographically and Thyroid nodules occur less frequently in children if it grows substantially (as defined above) by 24 weeks than in adults. In one study in which approximately 5000 gestation, surgery should be performed at that point.
children aged 11–18 years were assessed annually in the However, if it remains stable by midgestation or if it is southwestern United States, palpable thyroid nodules oc- diagnosed in the second half of pregnancy, surgery may curred in approximately 20 per 1000 children, with an annual be performed after delivery. In patients with more ad- incidence of 7 new cases per 1000 children (97). Some studies vanced disease, surgery in the second trimester is rea- have shown the frequency of malignancy to be higher in sonable. Recommendation rating: C children than adults, in the range of 15–20% (98–100), whereas (b) In pregnant women with FNA that is suspicious for or other data have suggested that the frequency of thyroid can- diagnostic of PTC, consideration could be given to cer in childhood thyroid nodules is similar to that of adults administration of LT4 therapy to keep the TSH in the (101,102). FNA biopsy is sensitive and specific in the diagnosis range of 0.1–1 mU=L. Recommendation rating: C of childhood thyroid nodules (99–101).
[B1] DIFFERENTIATED THYROID CANCER: RECOMMENDATION 18 INITIAL MANAGEMENT GUIDELINES The diagnostic and therapeutic approach to one or more Differentiated thyroid cancer, arising from thyroid follicular thyroid nodules in a child should be the same as it would be epithelial cells, accounts for the vast majority of thyroid can- in an adult (clinical evaluation, serum TSH, US, FNA).
cers. Of the differentiated cancers, papillary cancer comprises Recommendation rating: A about 85% of cases compared to about 10% that have follicularhistology, and 3% that are Hu¨rthle cell or oxyphil tumors (110).
[A18] How should thyroid nodules in pregnant women be In general, stage for stage, the prognoses of PTC and follicular It is uncertain if thyroid nodules discovered in cancer are similar (107,110). Certain histologic subtypes of PTC pregnant women are more likely to be malignant than those have a worse prognosis (tall cell variant, columnar cell variant, found in nonpregnant women (103), since there are no popu- diffuse sclerosing variant), as do more highly invasive variants lation-based studies on this question. The evaluation is the same of follicular cancer. These are characterized by extensive vas- as for a nonpregnant patient, with the exception that a radio- cular invasion and invasion into extrathyroidal tissues or nuclide scan is contraindicated. In addition, for patients with extensive tumor necrosis and=or mitoses. Other poorly dif- nodules diagnosed as DTC by FNA during pregnancy, delay- ferentiated aggressive tumor histologies include trabecular, ing surgery until after delivery does not affect outcome (104).
insular, and solid subtypes (111). In contrast, minimally in-vasive follicular thyroid cancer, is characterized histologically RECOMMENDATION 19 by microscopic penetration of the tumor capsule without For euthyroid and hypothyroid pregnant women with vascular invasion, and carries no excess mortality (112–115).
thyroid nodules, FNA should be performed. For womenwith suppressed serum TSH levels that persist after the first [B2] Goals of initial therapy of DTC trimester, FNA may be deferred until after pregnancy andcessation of lactation, when a radionuclide scan can be The goals of initial therapy of DTC are follows: REVISED ATA THYROID CANCER GUIDELINES 1. To remove the primary tumor, disease that has ex- presenting either colloid or microcalcifications (100%), and tended beyond the thyroid capsule, and involved cer- peripheral vascularity (82%). Of these, the only one with suf- vical lymph nodes. Completeness of surgical resection ficient sensitivity was peripheral vascularity (86%). All of the is an important determinant of outcome, while residual others had sensitivities <60% and would not be adequate to metastatic lymph nodes represent the most common use as single criterion for identification of malignant involve- site of disease persistence=recurrence (116–118).
ment (140). As shown by earlier studies (141,142), the feature 2. To minimize treatment-related morbidity. The extent of with the highest sensitivity was absence of a hilus (100%), but surgery and the experience of the surgeon both play this had a low specificity of only 29%. The location of the lymph important roles in determining the risk of surgical nodes may also be useful for decision-making. Malignant lymph nodes are much more likely to occur in levels III, IV, 3. To permit accurate staging of the disease. Because dis- and VI than in level II (140,142). Figure 2 illustrates the delin- ease staging can assist with initial prognostication, eation of cervical lymph node Levels I through VI.
disease management, and follow-up strategies, accurate Confirmation of malignancy in lymph nodes with a sus- postoperative staging is a crucial element in the man- picious sonographic appearance is achieved by US-guided agement of patients with DTC (121,122).
FNA aspiration for cytology and=or measurement of Tg in the 4. To facilitate postoperative treatment with radioactive needle washout. This FNA measurement of Tg is valid even in iodine, where appropriate. For patients undergoing RAI patients with circulating Tg autoantibodies (143,144).
remnant ablation, or RAI treatment of residual or met- Accurate staging is important in determining the prognosis astatic disease, removal of all normal thyroid tissue is and tailoring treatment for patients with DTC. However, an important element of initial surgery (123). Near total unlike many tumor types, the presence of metastatic disease or total thyroidectomy also may reduce the risk for re- does not obviate the need for surgical excision of the primary currence within the contralateral lobe (124).
tumor in DTC (145). Because metastatic disease may respond 5. To permit accurate long-term surveillance for disease to RAI therapy, removal of the thyroid as well as the primary recurrence. Both RAI whole-body scanning (WBS) and tumor and accessible locoregional disease remains an im- measurement of serum Tg are affected by residual portant component of initial treatment even in metastatic normal thyroid tissue. Where these approaches are utilized for long-term monitoring, near-total or total- As US evaluation is uniquely operator dependent, alter- thyroidectomy is required (125).
native imaging procedures may be preferable in some clinical 6. To minimize the risk of disease recurrence and meta- settings, though the sensitivities of CT, MRI, and PET for the static spread. Adequate surgery is the most important detection of cervical lymph node metastases are all relatively treatment variable influencing prognosis, while radio- low (30–40%) (146). These alternative imaging modalities, as active iodine treatment, TSH suppression, and external well as laryngoscopy and endoscopy, may also be useful in beam irradiation each play adjunctive roles in at least the assessment of large, rapidly growing, or retrosternal or some patients (125–128).
invasive tumors to assess the involvement of extrathyroidaltissues (147,148).
[B3] What is the role of preoperative staging with diag- RECOMMENDATION 21 nostic imaging and laboratory tests? Preoperative neck US for the contralateral lobe and cervical [B4] Neck imaging. Differentiated thyroid carcinoma (central and especially lateral neck compartments) lymph (particularly papillary carcinoma) involves cervical lymph nodes is recommended for all patients undergoing thy- nodes in 20–50% of patients in most series using standard roidectomy for malignant cytologic findings on biopsy. US- pathologic techniques (45,129–132), and may be present even guided FNA of sonographically suspicious lymph nodes when the primary tumor is small and intrathyroidal (133). The should be performed to confirm malignancy if this would frequency of micrometastases may approach 90%, depending change management. Recommendation rating: B on the sensitivity of the detection method (134,135). However,the clinical implications of micrometastases are likely less RECOMMENDATION 22 significant compared to macrometastases. Preoperative US Routine preoperative use of other imaging studies (CT, identifies suspicious cervical adenopathy in 20–31% of cases, MRI, PET) is not recommended. Recommendation rating: E potentially altering the surgical approach (136,137) in as manyas 20% of patients (138,139). However, preoperative US [B5] Measurement of serum Tg. There is limited evidence identifies only half of the lymph nodes found at surgery, due that high preoperative concentrations of serum Tg may pre- to the presence of the overlying thyroid gland (140).
dict a higher sensitivity for postoperative surveillance with Sonographic features suggestive of abnormal metastatic serum Tg (149). Evidence that this impacts patient manage- lymph nodes include loss of the fatty hilus, a rounded rather ment or outcomes is not yet available.
than oval shape, hypoechogenicity, cystic change, calcifica-tions, and peripheral vascularity. No single sonographic fea- RECOMMENDATION 23 ture is adequately sensitive for detection of lymph nodes with Routine preoperative measurement of serum Tg is not re- metastatic thyroid cancer. A recent study correlated the sono- commended. Recommendation rating: E graphic features acquired 4 days preoperatively directly withthe histology of 56 cervical lymph nodes. Some of the most [B6] What is the appropriate operation for indeterminate specific criteria were short axis >5 mm (96%), presence of cystic thyroid nodules and DTC? The goals of thyroid surgery areas (100%), presence of hyperechogenic punctuations re- can include provision of a diagnosis after a nondiagnostic or COOPER ET AL.
Anterior digastric Spinal accessory nerve Cricoid cartilage Lymph node compartments separated into levels and sublevels. Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally oneach side by the carotid sheaths. The level II, III, and IV nodes are arrayed along the jugular veins on each side, borderedanteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes arebounded superiorly by the level of the hyoid bone, and inferiorly by the cricoid cartilage; levels II and IV are above and belowlevel III, respectively. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone,and anterior to the posterior edge of the submandibular gland. Finally, the level V nodes are in the posterior triangle, lateralto the lateral edge of the sternocleidomastoid muscle. Levels I, II, and V can be further subdivided as noted in the figure. Theinferior extent of level VI is defined as the suprasternal notch. Many authors also include the pretracheal and paratrachealsuperior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neckdissection (166).
indeterminate biopsy, removal of the thyroid cancer, staging, RECOMMENDATION 24 and preparation for radioactive ablation and serum Tg moni- For patients with an isolated indeterminate solitary nodule toring. Surgical options to address the primary tumor should who prefer a more limited surgical procedure, thyroid lo- be limited to hemithyroidectomy with or without isthmu- bectomy is the recommended initial surgical approach.
sectomy, near-total thyroidectomy (removal of all grossly vis- Recommendation rating: C ible thyroid tissue, leaving only a small amount [<1 g] of tissueadjacent to the recurrent laryngeal nerve near the ligament of Berry), and total thyroidectomy (removal of all grossly visible RECOMMENDATION 25 thyroid tissue). Subtotal thyroidectomy, leaving >1 g of tissue (a) Because of an increased risk for malignancy, total with the posterior capsule on the uninvolved side, is an inap- thyroidectomy is indicated in patients with indeter- propriate operation for thyroid cancer (150).
minate nodules who have large tumors (>4 cm), whenmarked atypia is seen on biopsy, when the biopsy [B7] Surgery for a nondiagnostic biopsy, a biopsy suspicious for reading is ‘‘suspicious for papillary carcinoma,'' in papillary cancer or suggestive of ‘ follicular neoplasm' (including patients with a family history of thyroid carcinoma, special consideration for patients with other risk factors). Amongst and in patients with a history of radiation exposure.
solitary thyroid nodules with an indeterminate (‘‘follicular Recommendation rating: A neoplasm'' or Hu¨rthle cell neoplasm) biopsy, the risk of (b) Patients with indeterminate nodules who have bilat- malignancy is approximately 20% (151–153). The risk is eral nodular disease, or those who prefer to undergo higher with large tumors (>4 cm), when atypical features bilateral thyroidectomy to avoid the possibility of re- (e.g., cellular pleomorphism) are seen on biopsy, when the quiring a future surgery on the contralateral lobe, biopsy reading is ‘‘suspicious for papillary carcinoma,'' in should also undergo total or near-total thyroidectomy.
patients with a family history of thyroid carcinoma, and in Recommendation rating: C patients with a history of radiation exposure (66,154,155). Forsolitary nodules that are repeatedly nondiagnostic on biopsy, [B8] Surgery for a biopsy diagnostic for malignancy. Near- the risk of malignancy is unknown but is probably closer to 5– total or total thyroidectomy is recommended if the primary thyroid carcinoma is >1 cm (156), there are contralateral REVISED ATA THYROID CANCER GUIDELINES thyroid nodules present or regional or distant metastases are recent consensus conference statement discusses the relevant present, the patient has a personal history of radiation therapy anatomy of the central neck compartment, delineates the no- to the head and neck, or the patient has first-degree family dal subgroups within the central compartment commonly history of DTC. Older age (>45 years) may also be a criterion involved with thyroid cancer, and defines the terminology for recommending near-total or total thyroidectomy even relevant to central compartment neck dissection (173).
with tumors <1–1.5 cm, because of higher recurrence rates in Comprehensive bilateral central compartment node dis- this age group (112,116,122,123,157). Increased extent of pri- section may improve survival compared to historic controls mary surgery may improve survival for high-risk patients and reduce risk for nodal recurrence (174). In addition, se- (158–160) and low-risk patients (156). A study of over 50,000 lective unilateral paratracheal central compartment node patients with PTC found on multivariate analysis that total dissection increases the proportion of patients who appear thyroidectomy significantly improved recurrence and sur- disease free with unmeasureable Tg levels 6 months after vival rates for tumors >1.0 cm (156). When examined sepa- surgery (175). Other studies of central compartment dissec- rately, even patients with 1.0–2.0 cm tumors who underwent tion have demonstrated higher morbidity, primarily recurrent lobectomy, had a 24% higher risk of recurrence and a 49% laryngeal nerve injury and transient hypoparathyroidism, higher risk of thyroid cancer mortality ( p ¼ 0.04 and p < 0.04, with no reduction in recurrence (176,177). In another study, respectively). Other studies have also shown that rates of re- comprehensive (bilateral) central compartment dissection currence are reduced by total or near total thyroidectomy demonstrated higher rates of transient hypoparathyroidism among low-risk patients (122,161,162).
compared to selective (unilateral) dissection with no reduc-tion in rates of undetectable or low Tg levels (178). Although RECOMMENDATION 26 some lymph node metastases may be treated with radioactive For patients with thyroid cancer >1 cm, the initial surgical iodine, several treatments may be necessary, depending upon procedure should be a near-total or total thyroidectomy the histology, size, and number of metastases (179).
unless there are contraindications to this surgery. Thyroidlobectomy alone may be sufficient treatment for small RECOMMENDATION 27* (<1 cm), low-risk, unifocal, intrathyroidal papillary carci- (a) Therapeutic central-compartment (level VI) neck dis- nomas in the absence of prior head and neck irradiation or section for patients with clinically involved central or radiologically or clinically involved cervical nodal metas- lateral neck lymph nodes should accompany total tases. Recommendation rating: A thyroidectomy to provide clearance of disease from thecentral neck. Recommendation rating: B [B9] Lymph node dissection. Regional lymph node metas- (b) Prophylactic central-compartment neck dissection tases are present at the time of diagnosis in 20–90% of patients (ipsilateral or bilateral) may be performed in patients with papillary carcinoma and a lesser proportion of patients with papillary thyroid carcinoma with clinically unin- with other histotypes (129,139). Although PTC lymph node volved central neck lymph nodes, especially for ad- metastases are reported by some to have no clinically impor- vanced primary tumors (T3 or T4). Recommendation tant effect on outcome in low risk patients, a study of the Surveillance, Epidemiology, and End Results (SEER) database (c) Near-total or total thyroidectomy without prophylactic found, among 9904 patients with PTC, that lymph node me- central neck dissection may be appropriate for small tastases, age >45 years, distant metastasis, and large tumor size (T1 or T2), noninvasive, clinically node-negative PTCs significantly predicted poor outcome on multivariate analysis and most follicular cancer. Recommendation rating: C (163). All-cause survival at 14 years was 82% for PTC withoutlymph node and 79% with lymph node metastases ( p < 0.05).
These recommendations (R27a–c) should be interpreted in Another recent SEER registry study concluded that cervical light of available surgical expertise. For patients with small, lymph node metastases conferred an independent risk of de- noninvasive, apparently node-negative tumors, the balance of creased survival, but only in patients with follicular cancer and risk and benefit may favor simple near-total thyroidectomy patients with papillary cancer over age 45 years (164). Also, the with close intraoperative inspection of the central compart- risk of regional recurrence is higher in patients with lymph ment with compartmental dissection only in the presence of node metastases, especially in those patients with multiple obviously involved lymph nodes. This approach may increase metastases and=or extracapsular nodal extension (165).
the chance of future locoregional recurrence, but overall this In many patients, lymph node metastases in the central approach may be safer in less experienced surgical hands.
compartment (166) do not appear abnormal preoperatively Lymph nodes in the lateral neck (compartments II–V), level with imaging (138) or by inspection at the time of surgery.
VII (anterior mediastinum), and rarely in Level I may also be Central compartment dissection (therapeutic or prophylactic) involved by thyroid cancer (129,180). For those patients in can be achieved with low morbidity in experienced hands whom nodal disease is evident clinically, on preoperative US (167–171), and may convert some patients from clinical N0 to and nodal FNA or Tg measurement, or at the time of surgery, pathologic N1a, upstaging patients over age 45 from Ameri- surgical resection may reduce the risk of recurrence and can Joint Committee on Cancer (AJCC) stage I to III (172). A possibly mortality (56,139,181). Functional compartmental *R27a, 27b, 27c, and 28 were developed in collaboration with an ad hoc committee of endocrinologists (David S. Cooper, M.D., Richard T.
Kloos, M.D., Susan J. Mandel, M.D., M.P.H., and R. Michael Tuttle, M.D.), otolaryngology-head and neck surgeons (Gregory Randolph, M.D.,David Steward, M.D., David Terris, M.D. and Ralph Tufano, M.D.), and endocrine surgeons (Sally Carty, M.D., Gerard M. Doherty, M.D.,Quan-Yang Duh, M.D., and Robert Udelsman, M.D., M.B.A.) COOPER ET AL.
en-bloc neck dissection is favored over isolated lymphade- [B13] AJCC=UICC TNM staging. Application of the nectomy (‘‘berry picking'') with limited data suggesting im- AJCC=International Union against Cancer (AJCC=UICC) proved mortality (118,182–184).
classification system based on pTNM parameters and age isrecommended for tumors of all types, including thyroid RECOMMENDATION 28* cancer (121,190), because it provides a useful shorthand Therapeutic lateral neck compartmental lymph node dis- method to describe the extent of the tumor (191) (Table 4). This section should be performed for patients with biopsy- classification is also used for hospital cancer registries and proven metastatic lateral cervical lymphadenopathy.
epidemiologic studies. In thyroid cancer, the AJCC=UICC Recommendation rating: B stage does not take account of several additional independentprognostic variables and may risk misclassification of some [B10] Completion thyroidectomy. Completion thyroidec- patients. Numerous other schemes have been developed in an tomy may be necessary when the diagnosis of malignancy is effort to achieve more accurate risk factor stratification, in- made following lobectomy for an indeterminate or non- cluding CAEORTC, AGES, AMES, U of C, MACIS, OSU, diagnostic biopsy. Some patients with malignancy may re- MSKCC, and NTCTCS systems. (107,116,122,159,192–195).
quire completion thyroidectomy to provide complete These schemes take into account a number of factors identi- resection of multicentric disease (185), and to allow RAI fied as prognostic for outcome in multivariate analysis of therapy. Most (186,187) but not all (185) studies of papillary retrospective studies, with the most predictive factors gener- cancer have observed a higher rate of cancer in the opposite ally being regarded as the presence of distant metastases, the lobe when multifocal (two or more foci), as opposed to uni- age of the patient, and the extent of the tumor. These and other focal, disease is present in the ipsilateral lobe. The surgical risk factors are weighted differently among these systems risks of two-stage thyroidectomy (lobectomy followed by according to their importance in predicting outcome, but no completion thyroidectomy) are similar to those of a near-total scheme has demonstrated clear superiority (195). Each of the or total thyroidectomy (188).
schemes allows accurate identification of the majority (70–85%) of patients at low-risk of mortality (T1–3, M0 patients), RECOMMENDATION 29 allowing the follow-up and management of these patients to Completion thyroidectomy should be offered to those pa- be less intensive than the higher-risk minority (T4 and M1 tients for whom a near-total or total thyroidectomy would patients), who may benefit from a more aggressive manage- have been recommended had the diagnosis been available ment strategy (195). Nonetheless, none of the examined before the initial surgery. This includes all patients with staging classifications is able to account for more than a small thyroid cancer except those with small (<1 cm), unifocal, proportion of the uncertainty in either short-term, disease- intrathyroidal, node-negative, low-risk tumors. Ther- specific mortality or the likelihood of remaining disease free apeutic central neck lymph node dissection should be in- (121,195,196). AJCC=IUCC staging was developed to predict cluded if the lymph nodes are clinically involved.
risk for death, not recurrence. For assessment of risk of re- Recommendation rating: B currence, a three-level stratification can be used: RECOMMENDATION 30 Low-risk patients have the following characteristics: Ablation of the remaining lobe with radioactive iodine has 1) no local or distant metastases; 2) all macroscopic tu- been used as an alternative to completion thyroidectomy mor has been resected; 3) there is no tumor invasion of (189). It is unknown whether this approach results in sim- locoregional tissues or structures; 4) the tumor does not ilar long-term outcomes. Consequently, routine radioactive have aggressive histology (e.g., tall cell, insular, colum- iodine ablation in lieu of completion thyroidectomy is not nar cell carcinoma) or vascular invasion; 5) and, if 131I is recommended. Recommendation rating: D given, there is no 131I uptake outside the thyroid bed onthe first posttreatment whole-body RAI scan (RxWBS)(197–199).
[B11] What is the role of postoperative staging systems Intermediate-risk patients have any of the following: and which should be used? 1) microscopic invasion of tumor into the perithyroidalsoft tissues at initial surgery; 2) cervical lymph node [B12] The role of postoperative staging. Postoperative stag- metastases or 131I uptake outside the thyroid bed on the ing for thyroid cancer, as for other cancer types, is used: 1) to RxWBS done after thyroid remnant ablation (200,201); permit prognostication for an individual patient with DTC; or 3) tumor with aggressive histology or vascular inva- 2) to tailor decisions regarding postoperative adjunctive ther- sion (202–204).
apy, including RAI therapy and TSH suppression, to assess the High-risk patients have 1) macroscopic tumor invasion, patient's risk for disease recurrence and mortality; 3) to make 2) incomplete tumor resection, 3) distant metastases, and decisions regarding the frequency and intensity of follow-up, possibly 4) thyroglobulinemia out of proportion to what directing more intensive follow-up towards patients at highest is seen on the posttreatment scan (205).
risk; and 4) to enable accurate communication regarding apatient among health care professionals. Staging systems also Since initial staging is based on clinico-pathologic factors allow evaluation of differing therapeutic strategies applied to that are available shortly after diagnosis and initial therapy, comparable groups of patients in clinical studies.
the AJCC stage of the patient does not change over time.
*See footnote, page 1179.
REVISED ATA THYROID CANCER GUIDELINES Table 4. TNM Classification System for Differentiated Thyroid Carcinoma Tumor diameter 2 cm or smaller Primary tumor diameter >2 to 4 cm Primary tumor diameter >4 cm limited to the thyroid or with minimal extrathyroidal extension Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels Primary tumor size unknown, but without extrathyroidal invasion No metastatic nodes Metastases to level VI (pretracheal, paratracheal, and prelaryngeal=Delphian lymph nodes) Metastasis to unilateral, bilateral, contralateral cervical or superior mediastinal nodes Nodes not assessed at surgery No distant metastases Distant metastases Distant metastases not assessed Patient age <45 years Patient age 45 years or older T3, N0, M0T1, N1a, M0T2, N1a, M0T3, N1a, M0 T4a, N0, M0T4a, N1a, M0T1, N1b, M0T2, N1b, M0T3, N1b, N0T4a, N1b, M0 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (435).
However, depending on the clinical course of the disease and tained at the time of remnant ablation may facilitate initial response to therapy, the risk of recurrence and the risk of staging by identifying previously undiagnosed disease, es- death may change over time. Appropriate management re- pecially in the lateral neck. Furthermore, from a theoretical quires an ongoing reassessment of the risk of recurrence and point of view, this first dose of RAI may also be considered the risk of disease-specific mortality as new data are obtained adjuvant therapy because of the potential tumoricidal effect on during follow-up (206).
persistent thyroid cancer cells remaining after appropriatesurgery in patients at risk for recurrence or disease specific RECOMMENDATION 31 mortality. Depending on the risk stratification of the indi- Because of its utility in predicting disease mortality, and vidual patient, the primary goal of the first dose of RAI after its requirement for cancer registries, AJCC=UICC staging total thyroidectomy may be 1) remnant ablation (to facilitate is recommended for all patients with DTC. The use of detection of recurrent disease and initial staging), 2) adjuvant postoperative clinico-pathologic staging systems is also re- therapy (to decrease risk of recurrence and disease specific commended to improve prognostication and to plan mortality by destroying suspected, but unproven metastatic follow-up for patients with DTC. Recommendation rating: B disease), or 3) RAI therapy (to treat known persistent disease).
While these three goals are closely interrelated, a clearer un- [B14] What is the role of postoperative RAI remnant derstanding of the specific indications for treatment will im- Postoperative RAI remnant ablation is increas- prove our ability to select patients most likely to benefit from ingly being used to eliminate the postsurgical thyroid rem- RAI after total thyroidectomy, and will also influence our nant (122). Ablation of the small amount of residual normal recommendations regarding choice of administered activity thyroid remaining after total thyroidectomy may facilitate the for individual patients. Supporting the use of RAI as adju- early detection of recurrence based on serum Tg measurement vant therapy, a number of large, retrospective studies show a and=or RAI WBS. Additionally, the posttherapy scan ob- significant reduction in the rates of disease recurrence COOPER ET AL.
(107,159,160,207) and cause-specific mortality (159,160,207– the presence of intrathyroidal vascular invasion, or the find- 209). However, other similar studies show no such benefit, at ing of gross or microscopic multifocal disease. While many of least among the majority of patients with PTC, who are at the these features have been associated with increased risk, there lowest risk for mortality (110,122,162,209–212). In those are inadequate data to determine whether RAI ablation has a studies that show benefit, the advantage appears to be re- benefit based on specific histologic findings, independent of stricted to patients with tumors >1.5 cm, or with residual tumor size, lymph node status, and the age of the patient.
disease following surgery, while lower-risk patients do not Therefore, while RAI ablation is not recommended for all show evidence for benefit (122,159,213). The National Thyroid patients with these higher risk histologic features, the pres- Cancer Treatment Cooperative Study Group (NTCTCSG) re- ence of these features in combination with size of the tumor, port (214) of 2936 patients found after a median follow-up of 3 lymph node status, and patient age may increase the risk of years, that near-total thyroidectomy followed by RAI therapy recurrence or metastatic spread to a degree that is high en- and aggressive thyroid hormone suppression therapy pre- ough to warrant RAI ablation in selected patients. However, dicted improved overall survival of patients with NTCTCSG in the absence of data for most of these factors, clinical judg- stage III and IV disease, and was also beneficial for patients ment must prevail in the decision-making process. For mi- with NTCTCSG stage II disease. No impact of therapy was croscopic multifocal papillary cancer, when all foci are <1 cm, observed in patients with stage I disease. It should be noted recent data suggest that RAI is of no benefit in preventing that the NTCTCSG staging criteria are similar but not iden- tical to the AJCC criteria. Thus, older patients with micro- Nonpapillary histologies (such as follicular thyroid cancer scopic extrathyroidal extension are stage II in the NTCTCSG and Hu¨rthle cell cancer) are generally regarded as higher risk system, but are stage III in the AJCC system. There are recent tumors. Expert opinion supports the use of RAI in almost all data suggesting a benefit of RAI in patients with more of these cases. However, because of the excellent prognosis aggressive histologies (215). There are no prospective ran- associated with surgical resection alone in small follicular domized trials that have addressed this question (209). Un- thyroid cancers manifesting only capsular invasion (without fortunately, many clinical circumstances have not been vascular invasion (so-called ‘‘minimally invasive follicular examined with regard to the efficacy of RAI ablative therapy.
cancer''), RAI ablation may not be required for all patients Table 5 presents a framework for deciding whether RAI is with this histological diagnosis (112).
worthwhile, solely based on the AJCC classification, andprovides the rationale for therapy and the strength of existing RECOMMENDATION 32 evidence for or against treatment.
(a) RAI ablation is recommended for all patients with In addition to the major factors listed in Table 5, several known distant metastases, gross extrathyroidal exten- other histological features may place the patient at higher risk sion of the tumor regardless of tumor size, or primary of local recurrence or metastases than would have been pre- tumor size >4 cm even in the absence of other higher dicted by the AJCC staging system. These include worrisome risk features (see Table 5 for strength of evidence).
histologic subtypes (such as tall cell, columnar, insular, and (b) RAI ablation is recommended for selected patients solid variants, as well as poorly differentiated thyroid cancer), with 1–4 cm thyroid cancers confined to the thyroid, Table 5. Major Factors Impacting Decision Making in Radioiodine Remnant Ablation 1 cm or less, intrathyroidal or microscopic multifocal 1–2 cm, intrathyroidal Conflicting dataa >2–4 cm, intrathyroidal Conflicting dataa Conflicting dataa Any size, any age, minimal extrathyroidal extension Any size with gross extrathyroidal extension No metastatic nodes documented Conflicting dataa Conflicting dataa Distant metastasis present aBecause of either conflicting or inadequate data, we cannot recommend either for or against RAI ablation for this entire subgroup.
However, selected patients within this subgroup with higher risk features may benefit from RAI ablation (see modifying factors in the text).
REVISED ATA THYROID CANCER GUIDELINES who have documented lymph node metastases, or rhTSH (235,236). A prospective randomized study found that other higher risk features (see preceding paragraphs) thyroid hormone withdrawal and rhTSH stimulation were when the combination of age, tumor size, lymph node equally effective in preparing patients for 131I remnant abla- status, and individual histology predicts an interme- tion with 100 mCi with significantly improved quality of life diate to high risk of recurrence or death from thyroid (237). Another randomized study using rhTSH showed that cancer (see Table 5 for strength of evidence for indi- ablation rates were comparable with 50 mCi compared to vidual features). Recommendation rating: C (for se- 100 mCi with a significant decrease (33%) in whole-body ir- lective use in higher risk patients) radiation (238). Finally, a recent study has shown that ablation (c) RAI ablation is not recommended for patients with rates were similar with either withdrawal or preparation with unifocal cancer <1 cm without other higher risk fea- rhTSH using 50 mCi of 131I (239). In addition, short-term re- tures (see preceding paragraphs). Recommendation currence rates have been found to be similar in patients pre- pared with thyroid hormone withdrawal or rhTSH (240).
(d) RAI ablation is not recommended for patients with Recombinant human TSH is approved for remnant ablation in multifocal cancer when all foci are <1 cm in the ab- the United States, Europe, and many other countries around sence other higher risk features (see preceding para- graphs). Recommendation rating: E RECOMMENDATION 34 [B15] How should patients be prepared for RAI ablation? Remnant ablation can be performed following thyroxine Remnant ablation requires TSH stimulation. No withdrawal or rhTSH stimulation. Recommendation rat- controlled studies have been performed to assess adequate levels of endogenous TSH for optimal ablation therapy orfollow-up testing. Noncontrolled studies suggest that a TSH [B17] Should RAI scanning be performed before RAI abla- of >30 mU=L is associated with increased RAI uptake in RAI WBS provides information on the presence of io- tumors (218), while studies using single dose exogenous TSH dine-avid thyroid tissue, which may represent the normal suggest maximal thyrocyte stimulation at TSH levels between thyroid remnant or the presence of residual disease in the 51 and 82 mU=L (219, 220). However, the total area under the postoperative setting. In the presence of a large thyroid rem- TSH curve, and not simply the peak serum TSH concentra- nant, the scan is dominated by uptake within the remnant, tion, is also potentially important for optimal RAI uptake by potentially masking the presence of extrathyroidal disease thyroid follicular cells. Endogenous TSH elevation can be within locoregional lymph nodes, the upper mediastinum, or achieved by two basic approaches to thyroid hormone with- even at distant sites, reducing the sensitivity of disease de- drawal, stopping LT4 and switching to LT3 for 2–4 weeks tection (241). Furthermore, there is an increasing trend to avoid followed by withdrawal of LT3 for 2 weeks, or discontinua- pretherapy RAI scans altogether because of its low impact tion of LT4 for 3 weeks without use of LT3. Both methods of on the decision to ablate, and because of concerns over 131I- preparation can achieve serum TSH levels >30 mU=L in induced stunning of normal thyroid remnants (242) and dis- >90% of patients (220–229). These two approaches have not tant metastases from thyroid cancer (243). Stunning is defined been directly compared for efficiency of patient prepara- as a reduction in uptake of the 131I therapy dose induced by a tion (efficacy of ablation, iodine uptake, Tg levels, disease pretreatment diagnostic activity. Stunning occurs most detection), although a recent prospective study showed no prominently with higher activities (5–10 mCi) of 131I (244), difference in hypothyroid symptoms between these two ap- with increasing time between the diagnostic dose and therapy proaches (230). Other preparative methods have been pro- (245), and does not occur if the treatment dose is given within posed, but have not been validated by other investigators 72 hours of the scanning dose (246). However, the accuracy of (231,232). Children with thyroid cancer achieve adequate low-activity 131I scans has been questioned, and some research TSH elevation within 14 days of LT4 withdrawal (233). A low has reported quantitatively the presence of stunning below the serum Tg level at the time of ablation has excellent negative threshold of visual detection (247). Although comparison predictive value for absence of residual disease, and the risk studies show excellent concordance between 123I and 131I for of persistent disease increases with higher stimulated Tg tumor detection, optimal 123I activity and time to scan after 123I administration are not known (248). Furthermore, 123I is ex-pensive, is not universally available, its short half life (t½ ¼ 13 RECOMMENDATION 33 hours) makes handling this isotope logistically more difficult Patients undergoing RAI therapy or diagnostic testing can (249), and stunning may also occur though to a lesser degree be prepared by LT4 withdrawal for at least 2–3 weeks or than with 131I (245). Furthermore, a recent study showed no LT3 treatment for 2–4 weeks and LT3 withdrawal for 2 difference in ablation rates between patients that had pre- weeks with measurement of serum TSH to determine therapy scans with 123I (81%) compared to those who had timing of testing or therapy (TSH >30 mU=L). Thyroxine received diagnostic scans using 2 mCi of 131I (74%, p > 0.05) therapy (with or without LT3 for 7–10 days) may be re- (250). Alternatively, determination of the thyroid bed uptake, sumed on the second or third day after RAI administration.
without scanning, can be achieved using 10–100 mCi 131I.
Recommendation rating: B RECOMMENDATION 35 [B16] Can rhTSH (Thyrogen) be used in lieu of thyroxine Pretherapy scans and=or measurement of thyroid bed up- withdrawal for remnant ablation? For most patients, including take may be useful when the extent of the thyroid remnant those unable to tolerate hypothyroidism or unable to generate cannot be accurately ascertained from the surgical report an elevated TSH, remnant ablation can be achieved with or neck ultrasonography, or when the results would alter ALGORITHM FOR REMNANT ABLATION:
Initial Follow-Up in Patients with Differentiated Thyroid
Carcinoma in Whom Remnant Ablation is Indicated
One to Three Months after Surgery
Final Surgery is a Total or Near-Total Thyroidectomy Residual Macroscopic Prior to Ablation Neck USb, CT scan Consider Pretherapy Consider PET Scan Diagnostic WBS Using Surgery if Feasible if Expected to Change Residual Disease Management (R35) 30–100 mCi 131Ig 100–200 mCi 131I 5–8 Days Post 131I 6–12 Months with Algorithm for initial follow-up of patients with differentiated thyroid carcinoma.
aEBRT, external beam radiotherapy. The usual indication for EBRT is macroscopic unresectable tumor in a patient older than 45 years; it is not usually recommended for children and adults less than age 45.
bNeck ultrasonography of operated cervical compartments is often compromised for several months after surgery.
cTg, thyroglobulin with anti-thyroglobulin antibody measurement; serum Tg is usually measured by immunometric assay and may be falsely elevated for several weeks by injury from surgery or by heterophile antibodies, although a very highserum Tg level after surgery usually indicates residual disease.
dSome clinicians suspect residual disease when malignant lymph nodes, or tumors with aggressive histologies (as defined in the text) have been resected, or when there is a microscopically positive margin of resection.
erhTSH is recombinant human TSH and is administered as follows: 0.9 mg rhTSH i.m. on two consecutive days, followed by 131I therapy on the third day.
fTHW is levothyroxine and=or triiodothyronine withdrawal.
gSee text for exceptions regarding remnant ablation. The smallest amount of 131I necessary to ablate normal thyroid remnant tissue should be used. DxWBS (diagnostic whole-body scintigraphy) is not usually necessary at this point, but maybe performed if the outcome will change the decision to treat with radioiodine and=or the amount of administered activity.
hRxWBS is posttreatment whole-body scan done 5 to 8 days after therapeutic 131I administration.
iUptake in the thyroid bed may indicate normal remnant tissue or residual central neck nodal metastases.
REVISED ATA THYROID CANCER GUIDELINES either the decision to treat or the activity of RAI that is the neck, lungs, and mediastinum, and the newly discovered administered. If performed, pretherapy scans should uti- disease altered the disease stage in approximately 10% of the lize 123I (1.5–3 mCi) or low-activity 131I (1–3 mCi), with the patients, affecting clinical management in 9–15% (264–266).
therapeutic activity optimally administered within 72 Iodine 131 single photon emission computed tomography hours of the diagnostic activity. Recommendation rating: C (SPECT)=CT fusion imaging may provide superior lesion lo-calization after remnant ablation, but it is still a relatively new [B18] What activity of 131I should be used for remnant imaging modality (267).
Successful remnant ablation is usually defined as an absence of visible RAI uptake on a subsequent diagnostic RECOMMENDATION 39 RAI scan or an undetectable stimulated serum Tg. Activities A posttherapy scan is recommended following RAI rem- between 30 and 100 mCi of 131I generally show similar rates of nant ablation. This is typically done 2–10 days after the successful remnant ablation (251–254) and recurrence rates therapeutic dose is administered, although published data (213). Although there is a trend toward higher ablation rates supporting this time interval are lacking. Recommendation with higher activities (255,256), a recent prospective ran- domized study found no significant difference in the remnantablation rate using 30 or 100 mCi of 131I (257). Furthermore,there are data showing that 30 mCi is effective in ablating the [B21] Postsurgery and RAI therapy remnant with rhTSH preparation (258). In pediatric patients, early management of DTC it is preferable to adjust the ablation activity according to the [B22] What is the role of TSH suppression therapy? patient's body weight (259) or surface area (260).
expresses the TSH receptor on the cell membrane and re-sponds to TSH stimulation by increasing the expression of RECOMMENDATION 36 several thyroid specific proteins (Tg, sodium-iodide sym- The minimum activity (30–100 mCi) necessary to achieve porter) and by increasing the rates of cell growth (268). Sup- successful remnant ablation should be utilized, particularly pression of TSH, using supra-physiologic doses of LT4, is used for low-risk patients. Recommendation rating: B commonly to treat patients with thyroid cancer in an effort todecrease the risk of recurrence (127,214,269). A meta-analysis RECOMMENDATION 37 supported the efficacy of TSH suppression therapy in pre- If residual microscopic disease is suspected or documented, venting major adverse clinical events (RR ¼ 0.73; CI ¼ 0.60– or if there is a more aggressive tumor histology (e.g., tall 0.88; p < 0.05) (269).
cell, insular, columnar cell carcinoma), then higher activi-ties (100–200 mCi) may be appropriate. Recommendation [B23] What is the appropriate degree of initial TSH Retrospective and prospective studies have demonstrated that TSH suppression to below 0.1 mU=L may [B19] Is a low-iodine diet necessary before remnant improve outcomes in high-risk thyroid cancer patients The efficacy of radioactive iodine depends on the (127,270), though no such evidence of benefit has been docu- radiation dose delivered to the thyroid tissue (261). Low- mented in low-risk patients. A prospective cohort study (214) iodine diets (<50 mg=d of dietary iodine) and simple recom- of 2936 patients found that overall survival improved signifi- mendations to avoid iodine contamination have been cantly when the TSH was suppressed to undetectable levels in recommended prior to RAI therapy (261–263) to increase the patients with NTCTCSG stage III or IV disease and suppressed effective radiation dose. A history of possible iodine exposure to the subnormal to undetectable range in patients with (e.g., intravenous contrast, amiodarone use) should be NTCTCSG stage II disease; however, in the latter group there sought. Measurement of iodine excretion with a spot urinary was no incremental benefit from suppressing TSH to unde- iodine determination may be a useful way to identify patients tectable levels. Suppression of TSH was not beneficial in pa- whose iodine intake could interfere with RAI remnant abla- tients with stage I disease. In another study, there was a tion (263). Information about low-iodine diets can be obtained positive association between serum TSH levels and the risk for at the Thyroid Cancer Survivors Association website (www.
recurrent disease and cancer-related mortality (271). Adverse effects of TSH suppression may include the known conse-quences of subclinical thyrotoxicosis, including exacerbation of RECOMMENDATION 38 angina in patients with ischemic heart disease, increased risk A low-iodine diet for 1–2 weeks is recommended for pa- for atrial fibrillation in older patients (272), and increased risk of tients undergoing RAI remnant ablation, particularly for osteoporosis in postmenopausal women (273).
those patients with high iodine intake. Recommendationrating: B RECOMMENDATION 40 Initial TSH suppression to below 0.1 mU=L is re- [B20] Should a posttherapy scan be performed following commended for high-risk and intermediate-risk thyroid remnant ablation? Posttherapy whole-body iodine scanning cancer patients, while maintenance of the TSH at or slightly is typically conducted approximately 1 week after RAI ther- below the lower limit of normal (0.1–0.5 mU=L) is appro- apy to visualize metastases. Additional metastatic foci have priate for low-risk patients. Similar recommendations ap- been reported in 10–26% of patients scanned following high- ply to low-risk patients who have not undergone remnant dose RAI treatment compared with the diagnostic scan ablation, i.e., serum TSH 0.1–0.5 mU=L. Recommendation (264,265). The new abnormal uptake was found most often in COOPER ET AL.
[B24] Is there a role for adjunctive external beam irradiation creased incidence of second tumors in thyroid cancer patients has been recognized (157,281) this elevated risk was not foundto be associated with the use of 131I in another study (282), and [B25] External beam irradiation. External beam irradiation RAI therapy in low-risk patients did not affect median overall is used infrequently in the management of thyroid cancer survival in another (210). Patients with persistent or recurrent except as a palliative treatment for locally advanced, other- disease are offered treatment to cure or to delay future mor- wise unresectable disease (274). There are reports of responses bidity or mortality. In the absence of such options, therapies to among patients with locally advanced disease (275,276) and palliate by substantially reducing tumor burden or prevent- improved relapse-free and cause-specific survival in patients ing tumor growth are utilized, with special attention paid to over age 60 with extrathyroidal extension but no gross re- tumors threatening critical structures.
sidual disease (277). It remains unknown whether external A second goal of long-term follow-up is to monitor thy- beam radiation might reduce the risk for recurrence in the roxine suppression or replacement therapy, to avoid under- neck following adequate primary surgery and=or RAI treat- replacement or overly aggressive therapy (283).
ment in patients with aggressive histologic subtypes (278).
RECOMMENDATION 41 [C3] What is the appropriate method The use of external beam irradiation to treat the primary for following patients after surgery tumor should be considered in patients over age 45 with with or without remnant ablation? grossly visible extrathyroidal extension at the time of sur- See Fig. 4 for an algorithm for the first 6–12 months of gery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whomfurther surgery or RAI would likely be ineffective. The se- [C4] What are the criteria for absence of persistent quence of external beam irradiation and RAI therapy de- In patients who have undergone total or near-total pends on the volume of gross residual disease and the thyroidectomy and thyroid remnant ablation, disease-free likelihood of the tumor being RAI responsive. Re- status comprises all of the following: commendation rating: B 1) no clinical evidence of tumor, [B26] Chemotherapy. There are no data to support the use 2) no imaging evidence of tumor (no uptake outside the of adjunctive chemotherapy in the management of DTC.
thyroid bed on the initial posttreatment WBS, or, if Doxorubicin may act as a radiation sensitizer in some tumors uptake outside the thyroid bed had been present, no of thyroid origin (279), and could be considered for patients imaging evidence of tumor on a recent diagnostic scan with locally advanced disease undergoing external beam ra- and neck US), and 3) undetectable serum Tg levels during TSH suppression and stimulation in the absence of interfering antibodies.
RECOMMENDATION 42 There is no role for the routine adjunctive use of chemo- [C5] What is the role of serum Tg assays in the follow up of therapy in patients with DTC. Recommendation rating: F Measurement of serum Tg levels is an important modality to monitor patients for residual or recurrent disease.
[C1] DTC: LONG-TERM MANAGEMENT GUIDELINES Most laboratories currently use immunometric assays tomeasure serum Tg, and it is important that these assays are [C2] What are the appropriate features calibrated against the CRM-457 international standard. De- of long-term management? spite improvements in standardization of thyroglobuin as- Accurate surveillance for possible recurrence in patients says, there is still a twofold difference between some assays thought to be free of disease is a major goal of long-term (149), leading to the recommendation that measurements in follow-up. Tests with high negative predictive value allow individual patients over time be performed in the same assay.
identification of patients unlikely to experience disease re- Immunometric assays are prone to interference from Tg currence, so that less aggressive management strategies can autoantibodies, which commonly cause falsely low serum be used that may be more cost effective and safe. Similarly, Tg measurements. Radioimmunoassays may be less prone patients with a higher risk of recurrence are monitored more to antibody interference, but are not as widely available, aggressively because it is believed that early detection of re- and their role in the clinical care of patients is uncertain. In current disease offers the best opportunity for effective the absence of antibody interference, serum Tg has a high treatment. A large study (280), found that the residual life degree of sensitivity and specificity to detect thyroid cancer, span in disease-free patients treated with total or near-total especially after total thyroidectomy and remnant ablation, thyroidectomy and 131I for remnant ablation and, in some with the highest degrees of sensitivity noted following thyroid cases, high dose 131I for residual disease, was similar to that in hormone withdrawal or stimulation using rhTSH (284). Serum the general Dutch population. In contrast, the life expectancy Tg measurements obtained during thyroid hormone sup- for patients with persistent disease was reduced to 60% of that pression of TSH, and, less commonly during TSH stimula- in the general population but varied widely depending upon tion, may fail to identify patients with relatively small amounts tumor features. Age was not a factor in disease-specific mor- of residual tumor (197,285,286). Conversely, even TSH- tality when patients were compared with aged matched in- stimulated Tg measurement may fail to identify patients with dividuals in the Dutch population. Treatment thus appears clinically significant tumor, due to anti-Tg antibodies or less safe and does not shorten life expectancy. Although an in- commonly to defective or absent production and secretion of REVISED ATA THYROID CANCER GUIDELINES ALGORITHM for MANAGEMENT of DTC
SIX to TWELVE MONTHS after REMNANT ABLATION
Tg (R43) and Neck US (R48a) US Suspicious for Lymph Biopsy for Cytology Nodes or Nodules >5–8 mm and Tg Wash (R48b/c) If Negative, Monitor Dissection (R50)e Long-Term Follow-up Consider Neck/Chest (R56, 58, 61, 75) Consider Surgery, 131I Therapy, EBRT, Clinical Trial, or Tyrosine Kinase Inhibitor Therapy (R59b, 78b) Longer term follow-up of patients with differentiated thyroid carcinoma.
aTgAb is anti-thyroglobulin antibody usually measured by immunometric assay.
bHeterophile antibodies may be a cause of falsely elevated serum Tg levels (436,437). The use of heterophile blocking tubes or heterophile blocking reagents have reduced, but not completely eliminated this problem. Tg that rises with TSH stimu-lation and falls with TSH suppression is unlikely to result from heterophile antibodies.
cSee text concerning further information regarding levels of Tg at which therapy should be considered.
dTg radioimmunoassay (RIA) may be falsely elevated or suppressed by TgAb. Tg results following TSH stimulation with rhTSH or thyroid hormone withdrawal are invalidated by TgAb in the serum even when Tg is measured by most RIA tests.
TgAb levels often decline to undetectable levels over years following surgery (306). A rising level of TgAb may be an earlyindication of recurrent disease (305).
eSee text for decision regarding surgery versus medical therapy, and surgical approaches to locoregional metastases. FNA confirmation of malignancy is generally advised. Preoperative chest CT is recommended as distant metastases may changemanagement.
COOPER ET AL.
immunoreactive Tg by tumor cells (286). Tg levels should be patients with persistent tumor (285,295–300). However, the interpreted in light of the pretest probability of clinically sig- results of serum Tg measurements made on the same serum nificant residual tumor. An aggressive or poorly differentiated specimen differ among assay methods (149). Therefore, the Tg tumor may be present despite low basal or stimulated Tg; in cutoff may differ significantly among medical centers and contrast, a minimally elevated stimulated Tg may occur in laboratories. Further, the clinical significance of minimally patients at low risk for clinically significant morbidity (287).
detectable Tg levels is unclear, especially if only detected fol- Nevertheless, a single rhTSH-stimulated serum Tg <0.5 ng=mL lowing TSH stimulation. In these patients, the trend in serum in the absence of anti-Tg antibody has an approximately Tg over time will typically identify patients with clinically 98–99.5% likelihood of identifying patients completely free of significant residual disease. A rising unstimulated or stimu- tumor on follow-up (288,289).
lated serum Tg indicates disease that is likely to become clini- Follow-up of low-risk patients who have undergone total cally apparent (294,301).
or near-total thyroidectomy alone without 131I remnant ab- The presence of anti-Tg antibodies, which occur in ap- lation or hemithyroidectomy alone may represent a chal- proximately 25% of thyroid cancer patients (302) and 10% of lenge. A cohort of 80 consecutive patients with very low-risk the general population (303), will falsely lower serum Tg de- papillary thyroid microcarcinoma who had undergone near- terminations in immunometric assays (304). The use of re- total thyroidectomy without postoperative RAI treatment covery assays in this setting to detect significant interference is was studied over 5 years (290). The rhTSH-stimulated serum controversial (201,304). Serial serum anti-Tg antibody quan- Tg levels were 1 ng=mL in 45 patients (56%) and >1 ng=mL tification using the same methodology may serve as an im- in 35 (44%) patients in whom rhTSH-stimulated Tg levels precise surrogate marker of residual normal thyroid tissue or were as high as 25 ng=mL. The diagnostic WBS (DxWBS) tumor (305, 306).
revealed uptake in the thyroid bed but showed no patho-logical uptake in any patient, and thyroid bed uptake corre- RECOMMENDATION 43 lated with the rhTSH-stimulated serum Tg levels ( p < 0.0001).
Serum Tg should be measured every 6–12 months by an Neck ultrasonography identified lymph node metastases immunometric assay that is calibrated against the CRM- in both Tg-positive and Tg-negative patients. The authors 457 standard. Ideally, serum Tg should be assessed in the concluded that for follow-up of this group of patients: 1) same laboratory and using the same assay, during follow- WBS was ineffective in detecting metastases; 2) neck ultra- up of patients with DTC who have undergone total or near sonography as the main surveillance tool was highly sensitive total thyroidectomy with or without thyroid remnant ab- in detecting node metastases; and 3) detectable rhTSH- lation. Thyroglobulin antibodies should be quantitatively stimulated serum Tg levels mainly depended upon the size of assessed with every measurement of serum Tg. Recom- thyroid remnants.
mendation rating: A Initial follow-up for low-risk patients (about 85% of post- operative patients) who have undergone total or near-totalthyroidectomy and 131I remnant ablation should be based RECOMMENDATION 44 mainly on TSH-suppressed Tg and cervical US, followed Periodic serum Tg measurements and neck ultrasonography by TSH-stimulated serum Tg measurements if the TSH- should be considered during follow-up of patients with DTC suppressed Tg testing is undetectable (197,285). However, a who have undergone less than total thyroidectomy, and in Tg assay with a functional sensitivity of 0.1 ng=mL may re- patients who have had a total thyroidectomy but not RAI duce the need to perform TSH-stimulated Tg measurements ablation. While specific cutoff levels during TSH suppres- during the initial follow-up of some patients. In one study of sion or stimulation that optimally distinguish normal re- this assay, a T4-suppressed serum Tg <0.1 ng=mL was only sidual thyroid tissue from persistent thyroid cancer are rarely (2.5%) associated with an rhTSH-stimulated Tg unknown, rising Tg values over time are suspicious for >2 ng=mL; however, 61.5% of the patients had baseline Tg growing thyroid tissue or cancer. Recommendation rating: B elevation >0.1 ng=mL, but only one patient was found to haveresidual tumor (291). In another study of the same assay (292), RECOMMENDATION 45 a TSH-suppressed serum Tg level was >0.1 ng=mL in 14% of (a) In low-risk patients who have had remnant ablation and patients, but the false-positive rate was 35% using an rhTSH- negative cervical US and undetectable TSH-suppressed stimulated Tg cutoff of >2 ng=mL, raising the possibility of Tg within the first year after treatment, serum Tg should unnecessary testing and treatment. The only prospective be measured after thyroxine withdrawal or rhTSH stim- study also documented increased sensitivity of detection of ulation approximately 12 months after the ablation to disease at the expense of reduced specificity (293).
verify absence of disease. Recommendation rating: A Approximately 20% of patients who are clinically free of disease with serum Tg levels <1 ng=mL during thyroid hor- The timing or necessity of subsequent stimulated testing is mone suppression of TSH (285) will have a serum Tg level uncertain for those found to be free of disease, because there is >2 ng=mL after rhTSH or thyroid hormone withdrawal at 12 infrequent benefit in this patient cohort from repeated TSH- months after initial therapy with surgery and RAI. In this pa- stimulated Tg testing (289).
tient population, one third will have identification of persistentor recurrent disease and of increasing Tg levels, and the other (b) Low-risk patients who have had remnant abla- two thirds will remain free of clinical disease and will have tion, negative cervical US, and undetectable TSH- stable or decreasing stimulated serum Tg levels over time (294).
stimulated Tg can be followed primarily with yearly There is good evidence that a Tg cutoff level above 2 ng=mL clinical examination and Tg measurements on thyroid following rhTSH stimulation is highly sensitive in identifying hormone replacement. Recommendation rating: B REVISED ATA THYROID CANCER GUIDELINES [C6] What are the roles of diagnostic whole-body RAI scans, ance providers have usually required documentation that the US, and other imaging techniques during follow-up of DTC? patient had a follicular derived thyroid cancer with sup-pressed or stimulated Tg >10 ng=mL in the setting of a neg- [C7] Diagnostic whole-body RAI scans. There are two main ative DxWBS. Still, the impact of 18FDG-PET imaging on issues that affect the use of DxWBS during follow-up: stun- biochemical cure, survival, or progression-free survival in this ning (described above) and accuracy. A DxWBS is most useful setting are not well defined.
during follow-up when there is little or no remaining normal More recently, publications provide data that support the thyroid tissue. Disease not visualized on the DxWBS, use of 18FDG-PET scanning for indications beyond simple regardless of the activity of 131I employed, may occasionally disease localization in Tg-positive, RAI scan–negative pa- be visualized on the RxWBS images done after larger, thera- tients (315,316).
peutic amounts of 131I (285,307–310). Following RAI ablation, Current additional clinical uses of 18FDG-PET scanning when the posttherapy scan does not reveal uptake outside the thyroid bed, subsequent DxWBS have low sensitivity and areusually not necessary in low-risk patients who are clinically Initial staging and follow-up of high-risk patients with free of residual tumor and have an undetectable serum Tg poorly differentiated thyroid cancers unlikely to con- level on thyroid hormone and negative cervical US centrate RAI in order to identify sites of disease that may be missed with RAI scanning and conventional imaging.
Initial staging and follow-up of invasive or metastatic RECOMMENDATION 46 Hu¨rthle cell carcinoma.
After the first RxWBS performed following RAI remnant As a powerful prognostic tool for identifying which ablation, low-risk patients with an undetectable Tg on patients with known distant metastases are at highest thyroid hormone with negative antithyrogolublin anti- risk for disease-specific mortality.
bodies and a negative US do not require routine DxWBS As a selection tool to identify those patients unlikely to during follow-up. Recommendation rating: F respond to additional RAI therapy.
As a measurement of posttreatment response following RECOMMENDATION 47 external beam irradiation, surgical resection, emboliza- DxWBS, either following thyroid hormone withdrawal tion, or systemic therapy.
or rhTSH, 6–12 months after remnant ablation may be of As can be seen from the list of indications above, low-risk value in the follow-up of patients with high or intermedi- patients are very unlikely to require 18FDG-PET scanning as ate risk of persistent disease (see risk stratification system part of initial staging or follow-up. Additionally, inflamma- under AJCC=UICC TNM staging), but should be done tory lymph nodes, suture granulomas, and increased muscle with 123I or low activity 131I. Recommendation rating: C activity are common causes of false-positive 18FDG-PETfindings. Therefore, cytologic or histologic confirmation is [C8] Cervical ultrasonography. Cervical ultrasonography is required before one can be certain that an 18FDG-positive le- highly sensitive in the detection of cervical metastases in pa- sion represents metastatic disease.
tients with DTC (139,290,312). Recent data suggest that The sensitivity of 18FDG-PET scanning may be marginally measurement of Tg in the needle washout fluid enhances the improved with TSH stimulation (especially in patients with sensitivity of FNA of cervical nodes that are suspicious on US low Tg values), but the clinical benefit of identifying these (313,314). Cervical metastases occasionally may be detected additional small foci is yet to be proven (316).
by neck ultrasonography even when TSH-stimulated serumTg levels remain undetectable (201,296).
(d) In addition to its proven role in the localization of disease in Tg-positive, RAI scan–negative patients,18 RECOMMENDATION 48 FDG-PET scanning may be employed 1) as part of (a) Following surgery, cervical US to evaluate the thyroid initial staging in poorly differentiated thyroid cancers bed and central and lateral cervical nodal compartments and invasive Hu¨rthle cell carcinomas, especially those should be performed at 6–12 months and then periodi- with other evidence of disease on imaging or because cally, depending on the patient's risk for recurrent dis- of elevated serum Tg levels, and 2) as a prognostic tool ease and Tg status. Recommendation rating: B in patients with metastatic disease to identify those (b) If a positive result would change management, ultra- patients at highest risk for rapid disease progression sonographically suspicious lymph nodes greater than and disease-specific mortality, 3) and as an evaluation 5–8 mm in the smallest diameter should be biopsied for of posttreatment response following systemic or local cytology with Tg measurement in the needle washout therapy of metastatic or locally invasive disease. Re- fluid. Recommendation rating: A commendation rating: C (c) Suspicious lymph nodes less than 5–8 mm in largest di- ameter may be followed without biopsy with consider- [C10] What is the role of thyroxine TSH suppression ation for intervention if there is growth or if the node during thyroid hormone therapy in the long-term follow-up of threatens vital structures. Recommendation rating: C A meta-analysis has suggested an association (269) between thyroid hormone suppression therapy and reduction [C9] 18FDG-PET scanning. For many years, the primary of major adverse clinical events. The appropriate degree of clinical application of 18FDG-PET scanning in thyroid cancer TSH suppression by LT4 is still unknown, especially in high- was to localize disease in Tg-positive (>10 ng=mL), RAI scan– risk patients rendered free of disease. One study found that a negative patients (315). When used for this indication, insur- constantly suppressed TSH (0.05 mU=L) was associated with COOPER ET AL.
a longer relapse-free survival than when serum TSH levels small fraction of patients may benefit from radiofrequency were always 1 mU=L or greater, and that the degree of TSH ablation (323), ethanol ablation (324), or chemo-embolization suppression was an independent predictor of recurrence in (325). Additionally, surgical therapy in selected incurable multivariate analysis (270). Conversely, another large study patients is important to prevent complications in targeted found that disease stage, patient age, and 131I therapy inde- areas, such as the central nervous system (CNS) and central pendently predicted disease progression, but that the degree neck compartment. Conversely, watchful waiting may be of TSH suppression did not (127). A third study showed that appropriate for selected patients with stable asymptomatic during LT4 therapy the mean Tg levels were significantly local metastatic disease, and most patients with stable higher when TSH levels were normal than when TSH levels asymptomatic non-CNS distant metastatic disease.
were suppressed (<0.5 mU=L) but only in patients with localor distant relapse (317). A fourth study of 2936 patients found [C12] What is the surgical management of locoregional that overall survival improved significantly when the TSH Surgery is favored for locoregional (i.e., cervical was suppressed to <0.1 mU=L in patients with NTCTCSG lymph nodes and=or soft tissue tumor in the neck) recurrences, stage III or IV disease and to 0.1 to about 0.5 range in patients when distant metastases are not present. Approximately one with NTCTCSG stage II disease; however, there was no in- third to one half of patients may become free of disease in short- cremental benefit from suppressing TSH to undetectable levels term follow-up (288). It is not clear that treatment of locor- in stage II patients and suppression of TSH was of no benefit in egional disease is beneficial in the setting of untreatable distant patients with stage I disease (214). Another recent study found metastases, except for possible palliation of symptoms or pre- that a serum TSH threshold of 2 mU=L differentiated best be- vention of airway or aerodigestive obstruction. Impalpable tween patients free of disease and those with relapse or cancer- metastatic lymph nodes, visualized on US or other anatomic related mortality (271). No prospective studies have been imaging modality, that have survived initial 131I therapy performed examining the risk of recurrence and death from should be considered for resection. Conversely, the benefit to thyroid cancer associated with varying serum TSH levels, removing asymptomatic small (<5–8 mm) metastatic lymph based on the criteria for the absence of tumor at 6–12 months nodes towards improving gross clinical disease recurrences or postsurgery and RAI ablation outlined above in [C3].
disease-specific survival is unproven. When surgery is elected,most surgeons endorse comprehensive or selective ipsilateral RECOMMENDATION 49 compartmental dissection of previously unexplored compart- (a) In patients with persistent disease, the serum TSH ments with clinically significant persistent or recurrent disease should be maintained below 0.1 mU=L indefinitely (i.e., lymph nodes >0.8 cm in diameter,) while sparing vital in the absence of specific contraindications. Recom- structures (e.g., ipsilateral central neck dissection [level VI], mendation rating: B selective neck dissection levels II–IV, or modified neck dissec- (b) In patients who are clinically and biochemically free tion [levels II–V sparing the spinal accessory nerve, the internal of disease but who presented with high risk disease, jugular vein, and sternocleidomastoid muscle] (326) as op- consideration should be given to maintaining TSH- posed to ‘‘berry picking,' limited lymph node resection pro- suppressive therapy to achieve serum TSH levels of cedures, or ethanol ablation (324), because microscopic lymph 0.1–0.5 mU=L for 5–10 years. Recommendation rating: C node metastases are commonly more extensive than would (c) In patients free of disease, especially those at low risk for appear from imaging studies alone (183,327,328). Conversely, recurrence, the serum TSH may be kept within the low compartmental surgical dissections may not be feasible in the normal range (0.3–2 mU=L). Recommendation rating: B setting of compartments that have been previously explored (d) In patients who have not undergone remnant ablation due to extensive scarring, and only a more limited or targeted who are clinically free of disease and have undetect- lymph node resection may be possible.
able suppressed serum Tg and normal neck US, theserum TSH may be allowed to rise to the low normal RECOMMENDATION 50 range (0.3–2 mU=L). Recommendation rating: C (a) Therapeutic comprehensive compartmental lateral and=or central neck dissection, sparing uninvolved [C11] What is the most appropriate management vital structures, should be performed for patients with of DTC patients with metastatic disease? persistent or recurrent disease confined to the neck.
Recommendation rating: B Metastases discovered during follow-up are likely mani- (b) Limited compartmental lateral and=or central com- festations of persistent disease that has survived initial treat- partmental neck dissection may be a reasonable ment. Some patients will have a reduction in tumor burden alternative to more extensive comprehensive dissec- with additional treatments that may offer a survival or palli- tion for patients with recurrent disease within com- ative benefit (318–322). The preferred hierarchy of treatment partments having undergone prior comprehensive for metastatic disease (in order) is surgical excision of locor- dissection and=or external beam radiotherapy. Re- egional disease in potentially curable patients, 131I therapy for commendation rating: C RAI-avid disease, external beam radiation, watchful waitingwith patients with stable or slowly progressive asymptomaticdisease, and experimental trials, especially for patients with [C13] What is the surgical management of aerodigestive significantly progressive macroscopic refractory disease. Ex- For tumors that invade the upper aerodigestive perimental trials may be tried before external beam radiation tract, surgery combined with additional therapy such as 131I in special circumstances, in part because of the morbidity of and=or external beam radiation is generally advised (329,330).
external beam radiation and its relative lack of efficacy. A Patient outcome is related to complete resection of all gross REVISED ATA THYROID CANCER GUIDELINES disease with the preservation of function, with techniques of one method of RAI administration over another ranging from shaving tumor off the trachea or esophagus for (empiric high dose vs. blood and=or body dosimetry superficial invasion, to more aggressive techniques when the vs. lesional dosimetry.) Recommendation rating: I trachea is more deeply invaded (e.g., direct intraluminal in- (b) Empirically administered amounts of 131I exceeding vasion) including tracheal resection and anastomosis (331–333) 200 mCi that often potentially exceed the maximum or laryngopharyngoesophagectomy. Patients who are not tolerable tissue dose should be avoided in patients curable may undergo less aggressive local treatment in cases of over age 70 years. Recommendation rating: A asphyxia or significant hemoptysis, and as a preliminary stepprior to subsequent radical or palliative treatments (330).
No randomized trial comparing thyroid hormone with- drawal therapy to rhTSH-mediated therapy for treatment of RECOMMENDATION 51 metastatic disease has been reported but there is, despite a When technically feasible, surgery for aerodigestive invasive growing body of nonrandomized studies regarding this use disease is recommended in combination with RAI and=or (343–352), one small comparative study that showed the radi- external beam radiotherapy. Recommendation rating: B ation dose to metastatic foci is lower with rhTSH than thatfollowing withdrawal (353). Many of these case reports andseries report disease stabilization or improvement in some [C14] What is the nature of RAI therapy for locoregional or patients following rhTSH-mediated 131I therapy. The use of distant metastatic disease? For regional nodal metastases rhTSH does not eliminate and may even increase the possibility discovered on DxWBS, RAI may be employed, although of rapid swelling of metastatic lesions (348,354–356).
surgery is typically used in the presence of bulky disease ordisease amenable to surgery found on anatomic imaging such as US, CT scanning, or MRI. Radioiodine is also used ad- RECOMMENDATION 53 junctively following surgery for regional nodal disease or There are currently insufficient outcome data to recom- aerodigestive invasion if residual RAI avid disease is present mend rhTSH-mediated therapy for all patients with meta- or suspected.
static disease being treated with 131I. Recommendationrating: D [C15] Dose and methods of administering 131I for locoregional RECOMMENDATION 54 or metastatic disease. Despite the apparent effectiveness of131I therapy in many patients, the optimal therapeutic activity Recombinant human TSH–mediated therapy may be in- remains uncertain and controversial (334). There are three dicated in selected patients with underlying comorbiditiesmaking iatrogenic hypothyroidism potentially risky, in approaches to 131I therapy: empiric fixed amounts, therapydetermined by the upper bound limit of blood and body patients with pituitary disease who are unable to raise their dosimetry, and quantitative tumor dosimetry (335). Dosi- serum TSH, or in patients in whom a delay in therapymight be deleterious. Such patients should be given the metric methods are often reserved for patients with distantmetastases or unusual situations such as renal insufficiency same or higher activity that would have been given had (336,337) or when therapy with rhTSH stimulation is deemed they been prepared with hypothyroidism or a dosime-trically determined activity. Recommendation rating: C necessary. Comparison of outcome among these methodsfrom published series is difficult (334). No prospective ran-domized trial to address the optimal therapeutic approach [C16] Use of lithium in 131I therapy.
Lithium inhibits io- has been published. Arguments in favor of higher activities dine release from the thyroid without impairing iodine up- cite a positive relationship between the total 131I uptake per take, thus enhancing 131I retention in normal thyroid and tumor mass and outcome (225), while others have not con- tumor cells (357). One study (358) found that lithium in- firmed this relationship (338). In the future, the use of 123I or creased the estimated 131I radiation dose in metastatic tumors 131I with modern SPECT=CT or 124I PET-based dosimetry may an average of more than twofold, but primarily in those tu- facilitate whole-body and lesional dosimetry (339,340).
mors that rapidly cleared iodine. On the other hand, another The maximum tolerated radiation absorbed dose (MTRD), more recent study was unable to document any clinical ad- commonly defined as 200 rads (cGy) to the blood, is poten- vantage of lithium therapy on outcome in patients with tially exceeded in a significant number of patients undergoing metastatic disease, despite an increase in RAI uptake in tumor empiric treatment with various amounts of 131I. In one study deposits (359).
(341) 1–22% of patients treated with 131I according to dosim- etry calculations would have theoretically exceeded the RECOMMENDATION 55 MTRD had they been empirically treated with 100–300 mCi of Since there are no outcome data that demonstrate a better 131I. Another study (342) found that an empirically adminis- outcome of patients treated with lithium as an adjunct to131 tered 131I activity of 200 mCi would exceed the MTRD in I therapy, the data are insufficient to recommend lithium 8–15% of patients younger than age 70 and 22–38% of patients therapy. Recommendation rating: I aged 70 years and older. Administering 250 mCi empiricallywould have exceeded the MTRD in 22% of patients younger [C17] How should distant metastatic disease to various than 70 and 50% of patients 70 and older.
organs be treated? The overall approach to treatment of distant metastatic thyroid cancer is based upon the followingobservations and oncologic principles: RECOMMENDATION 52 (a) In the treatment of locoregional or metastatic disease, 1. Morbidity and mortality are increased in patients with no recommendation can be made about the superiority distant metastases, but individual prognosis depends COOPER ET AL.
upon factors including histology of the primary tumor, Macronodular pulmonary metastases may also be treated distribution and number of sites of metastasis (e.g., with RAI if demonstrated to be iodine avid. How many doses brain, bone, lung), tumor burden, age at diagnosis of RAI to give and how often to give it is a decision that must of metastases, and 18FDG and RAI avidity (320,351, be individualized based on the disease response to treatment, the rate of disease progression in between treatments, age of 2. Improved survival is associated with responsiveness to the patient, the presence or absence of other metastatic lesions, surgery and=or RAI (320,351,360–366).
and the availability of other treatment options including 3. In the absence of demonstrated survival benefit, certain clinical trials (360,365).
interventions can provide significant palliation or re-duce morbidity (325,367–369).
RECOMMENDATION 58 4. In the absence of improved survival, palliative benefit, Radioiodine-avid macronodular metastases should be trea- or reduced potential morbidity, the value of empiric ted with RAI and treatment should be repeated when ob- therapeutic intervention is significantly limited by the jective benefit is demonstrated (decrease in the size of the potential for toxicity.
lesions, decreasing Tg), but complete remission is not com- 5. Treatment of a specific metastatic area must be con- mon and survival remains poor. The selection of RAI activity sidered in light of the patient's performance status and to administer can be made empirically (100–200 mCi) or other sites of disease; e.g., 5–20% of patients with dis- estimated by lesional dosimetry or dosimetry to limit whole- tant metastases die from progressive cervical disease body retention to 80 mCi at 48 hours and 200 cGy to the red bone marrow. Recommendation rating: B 6. Longitudinal re-evaluation of patient status and con- tinuing re-assessment of potential benefit and risk of [C19] Non–RAI-avid pulmonary disease. Radioiodine is of intervention is required.
no benefit in patients with non–RAI-avid disease. In the 7. The overall poor outcome of patients with radio- setting of a negative diagnostic RAI scan, micronodular graphically evident or symptomatic metastases that do pulmonary metastases may demonstrate a positive post- not respond to RAI, the complexity of multidisciplinary treatment scan and measurable benefit to RAI therapy, treatment considerations and the availability of pro- whereas this is unlikely in the setting of macronodular me- spective clinical trials should encourage the clinician to tastases. In one study, administration of 200–300 mCi of RAI refer such patients to tertiary centers with particular to 10 patients with pulmonary macrometastases who had negative 3 mCi diagnostic scans was associated with a five-fold increase in the median TSH-suppressed Tg, and deathwas reported in several patients within 4 years of treatment [C18] Treatment of pulmonary metastases. In the manage- (374). Although not specifically limited to pulmonary lesions, ment of the patient with pulmonary metastases, key criteria patients with increasing volumes of 18FDG-avid disease seen for therapeutic decisions include 1) size of metastatic lesions on PET scans were less likely to respond to RAI and more (macronodular typically detected by chest radiography; mi- likely to die during a 3-year follow-up compared with 18FDG- cronodular typically detected by CT; lesions beneath the res- negative patients (375). Another study found that RAI ther- olution of CT); 2) avidity for RAI and, if applicable, response apy of metastatic lesions that were positive on 18FDG-PET to prior RAI therapy; and 3) stability (or lack thereof ) of scanning was of no benefit (376). In other studies of 18FDG- metastatic lesions. Pulmonary pneumonitis and fibrosis are PET imaging, however, insufficient details exist in patients rare complications of high-dose radioactive iodine treatment.
known to have pulmonary metastases to assess the utility of Dosimetry studies with a limit of 80 mCi whole-body reten- this modality to predict treatment response or prognosis tion at 48 hours and 200 cGy to the red bone marrow should (377). A study (378) that retrospectively examined the clinical be considered in patients with diffuse 131I pulmonary uptake course of 400 thyroid cancer patients with distant metastases (371). If pulmonary fibrosis is suspected, then appropriate who had undergone 18FDG-PET scanning found that al- periodic pulmonary function testing and consultation should though age, initial tumor stage, histology, Tg level, RAI up- be obtained. The presence of pulmonary fibrosis may limit the take, and PET outcomes all correlated with survival by ability to further treat metastatic disease with RAI.
univariate analysis, only age and PET results were strongpredictors of survival. There were significant inverse rela- RECOMMENDATION 56 tionships between survival and both the glycolytic rate of the Pulmonary micrometastases should be treated with RAI most active lesion and the number of 18FDG-avid lesions. The therapy, and repeated every 6–12 months as long as disease study found tumors that did not concentrate 18FDG had a continues to concentrate RAI and respond clinically, be- significantly better prognosis after a median follow-up of cause the highest rates of complete remission are reported about 8 years than did tumors that avidly concentrated in these subgroups (360,365,372,373). Recommendation Most studies evaluating systemic therapy for metastatic disease have focused on patients with pulmonary metastases.
RECOMMENDATION 57 Traditional cytotoxic chemotherapeutic agents, such as The selection of RAI activity to administer for pulmonary doxorubicin and cisplatin, are generally associated with no micrometastases can be empiric (100–200 mCi) or estimated more than 25% partial response rates, complete remission has by dosimetry to limit whole-body retention to 80 mCi at been rare, and toxicities from these treatments are consider- 48 hours and 200 cGy to the red bone marrow. Recom- able (379). Doxorubicin monotherapy, which remains the only mendation rating: B treatment for metastatic thyroid carcinoma approved by the REVISED ATA THYROID CANCER GUIDELINES U.S. Food and Drug Administration, is occasionally effective kinase inhibitors should be considered. Recommenda- when dosed appropriately (60–75 mg=m2 every 3 weeks) (380–383), but durable responses are uncommon. Most stud-ies of combination chemotherapy show no increased response [C20] Treatment of bone metastases. In the management of over single agent doxorubicin and increased toxicity (384).
the patient with bone metastases, key criteria for therapeutic Some specialists recommend consideration of single agent decisions include 1) the presence of or the risk for pathologic doxorubicin or paclitaxel, or a combination of these agents, fracture, particularly in a weight-bearing structure; 2) risk for based on limited data in anaplastic thyroid carcinoma (385).
neurologic compromise from vertebral lesions; 3) presence of One recent study evaluated the effect of combination che- pain; 4) avidity of RAI uptake; and 5) potential significant motherapy (carboplatinum and epirubicin) under TSH stim- marrow exposure from radiation arising from RAI-avid pelvic ulation (endogenous or rhTSH) (386), demonstrating an overall rate of complete and partial response of 37%. Thesedata need to be confirmed prior to consideration for general RECOMMENDATION 60 use. Recently published phase II trials suggest that anti- Complete surgical resection of isolated symptomatic me- angiogenic therapies may produce partial response rates of tastases has been associated with improved survival and up to 31% and stabilize another 40–50% of patients with should be considered, especially in patients <45 years old progressive metastatic disease (387–391). Clinical benefit with slowly progressive disease (320,363). Recommenda- lasting at least 24 weeks was observed in about half of patients. The orally available anti-angiogenic tyrosine kinaseinhibitors (axitinib, motesanib, and sorafenib) have numerous RECOMMENDATION 61 common side effects, including hypertension, diarrhea, RAI therapy of iodine-avid bone metastases has been as- fatigue, skin rashes and erythema, and weight loss, and var- sociated with improved survival and should be employed ious drug-specific toxicities have been reported as well. These (320,365), although RAI is rarely curative. The RAI activity side effects, although often mild and responsive to supportive administered can be given empirically (100–200 mCi) or care measures, justify suggesting that treatment with these determined by dosimetry (225). Recommendation rating: B agents should be limited to specialists experienced in theiruse. Similar results are also being reported with use of suni- RECOMMENDATION 62 tinib, but phase II studies are still ongoing. Serum TSH levels When skeletal metastatic lesions arise in locations where may increase with the use of these agents. Serum TSH should acute swelling may produce severe pain, fracture, or neu- be monitored, and the thyroxine dose increased as needed.
rologic complications, external radiation and the concom- Multiple other agents are in clinical trials, targeting pathways itant use of glucocorticoids to minimize potential TSH- involved in angiogenesis, cell cycle regulation, and tumor induced and=or radiation-related tumor expansion should be strongly considered (392). Recommendation rating: C If the patient qualifies for a clinical trial, they should con- sider bypassing traditional chemotherapy and moving di- RECOMMENDATION 63 rectly to clinical trials. However, often patients cannot Painful lesions that cannot be resected can also be treated participate in clinical trials because of the time and expense by several options individually or in combination, includ- required, or failure to meet strict eligibility criteria. Most ing RAI, external beam radiotherapy, intra-arterial embo- available trials can be found listed at www.clinicaltrials.
lization (325,393), radiofrequency ablation (394), periodic gov, www.nci.nih.gov, www.centerwatch.com, or www.
pamidronate or zoledronate infusions (with monitoring for development of possible mandibular osteonecrosis) (369),or verteboplasty or kyphoplasty (395). While many of these RECOMMENDATION 59 modalities have been shown to relieve bone pain in cancer, (a) Evidence of benefit of routine treatment of non–RAI- they have not necessarily been reported to have been used avid pulmonary metastases is insufficient to recom- in thyroid cancer patients. Recommendation rating: C mend any specific systemic therapy. For manypatients, metastatic disease is slowly progressive and RECOMMENDATION 64 patients can often be followed conservatively on TSH- Evidence is insufficient to recommend treatment of suppressive therapy with minimal evidence of radio- asymptomatic, non–RAI-responsive, stable lesions that do graphic or symptomatic progression. For selected not threaten nearby critical structures. Recommendation patients, however, other treatment options need to be considered, such as metastasectomy, endobronchiallaser ablation, or external beam radiation for palliation [C21] Treatment of brain metastases. Brain metastases typ- of symptomatic intrathoracic lesions (e.g., obstructing ically occur in older patients with more advanced disease and or bleeding endobronchial masses), and pleural or are associated with a poor prognosis (351). Surgical resection pericardial drainage for symptomatic effusions. Re- and external beam radiotherapy traditionally have been the ferral for participation in clinical trials should be con- mainstays of therapy (351,396). There are few data showing sidered. Recommendation rating: C efficacy of RAI.
(b) Referral for participation in clinical trials should be considered for patients with progressive or symp- RECOMMENDATION 65 tomatic metastatic disease. For those patients who do Complete surgical resection of CNS metastases should not participate in clinical trials, treatment with tyrosine be considered regardless of RAI avidity, because it is COOPER ET AL.
associated with significantly longer survival. Recommen- tearing (epiphora) but also predisposes to infection. Re- commendation rating: B RECOMMENDATION 66 [C23] What is the risk of second malignancies and leu- CNS lesions that are not amenable to surgery should be kemia from RAI therapy? Most long-term follow-up studies considered for external beam irradiation. Optimally, very variably report a very low risk of secondary malignancies targeted approaches (such as radiosurgery) are employed (bone and soft tissue malignancies, including breast, colo- to limit the radiation exposure of the surrounding brain rectal, kidney, and salivary cancers, and myeloma and leu- tissue. Whole brain and spine irradiation could be consid- kemia) in long-term survivors (157,281). A meta-analysis of ered if multiple metastases are present. Recommendation two large multicenter studies showed that the risk of second malignancies was significantly increased at 1.19 (95% CI:1.04–1.36; p < 0.010), relative to thyroid cancer survivors nottreated with RAI (403). The risk of leukemia was also signif- RECOMMENDATION 67 icantly increased in thyroid cancer survivors treated with If CNS metastases do concentrate RAI, then RAI could be RAI, with a relative risk of 2.5 (95% CI: 1.13–5.53; p < 0.024) considered. If RAI is being considered, prior external beam (403). The risk of secondary malignancies is dose related (157), radiotherapy and concomitant glucocorticoid therapy are with an excess absolute risk of 14.4 solid cancers and of 0.8 strongly recommended to minimize the effects of a poten- leukemias per gigabecquerel of 131I at 10,000 person-years of tial TSH-induced increase in tumor size and the subsequent follow-up. Cumulative 131I activities above 500–600 mCi are inflammatory effects of the RAI (392). Recommendation associated with a significant increase in risk. There appears to be an increased risk of breast cancer in women with thyroidcancer (281,399,404). It is unclear whether this is due to [C22] What is the management of complications screening bias, RAI therapy, or other factors. An elevated risk of breast cancer with 131I was not observed in another study While RAI appears to be a reasonably safe therapy, it is (282). The use of laxatives may decrease radiation exposure of associated with a cumulative dose-related low risk of early- the bowel, and vigorous oral hydration will reduce exposure and late-onset complications such as salivary gland damage, of the bladder and gonads (15).
dental caries (397), nasolacrimal duct obstruction (398), andsecondary malignancies (157,281,399,400). Therefore, it is RECOMMENDATION 71 important to ensure that the benefits of RAI therapy, espe- Because there is no evidence demonstrating a benefit of cially repeated courses, outweigh the potential risks. There is more intensive screening, all thyroid cancer patients should probably no dose of RAI that is completely safe nor is there be encouraged to seek age-appropriate screenings for any maximum cumulative dose that could not be used in cancer according to routine health maintenance recom- selected situations. However, with higher individual and mendations. Patients who receive a cumulative 131I activity cumulative doses there are increased risks of side effects as in excess of 500–600 mCi should be advised that they may have a small excess risk of developing leukemia and solid For acute transient loss of taste or change in taste and sia- tumors in the future. Recommendation rating: C ladentitis, recommended measures to prevent damage to thesalivary glands have included amifostine, hydration, sour [C24] What are other risks to the bone marrow from RAI candies, and cholinergic agents (401), but evidence is insuffi- Published data indicate that when administered cient to recommend for or against these modalities. One re- activities are selected to remain below 200 cGy to the bone cent study suggested sour candy may actually increase marrow, minimal transient effects are noted in white blood salivary gland damage when given within 1 hour of RAI cell and platelet counts (371). However, persistent mild dec- therapy, as compared to its use until 24 hours posttherapy rements in white blood cell count and=or platelets are not (402). For chronic salivary gland complications, such as dry uncommon in patients who have received multiple RAI mouth and dental caries, cholinergic agents may increase therapies. Further, radiation to the bone marrow is impacted salivary flow (401).
by several factors, including renal function.
RECOMMENDATION 68 RECOMMENDATION 72 The evidence is insufficient to recommend for or against Patients receiving therapeutic doses of RAI should have the routine use of preventive measures to prevent salivary baseline CBC and assessment of renal function. Recom- gland damage after RAI therapy. Recommendation rating: I mendation rating: C RECOMMENDATION 69 [C25] What are the effects of RAI on gonadal function and Patients with xerostomia are at increased risk of dental in nursing women? Women about to receive radioactive caries and should discuss preventive strategies with their iodine therapy should first undergo pregnancy testing. Go- dentists. Recommendation rating: C nadal tissue is exposed to radiation from RAI in the blood,urine, and feces. Temporary amenorrhea=oligomenorrhea RECOMMENDATION 70 lasting 4–10 months occurs in 20–27% of menstruating Surgical correction should be considered for nasolacrimal women after 131I therapy for thyroid cancer. Although the outflow obstruction, which often presents as excessive numbers of patients studied are small, long-term rates of in- REVISED ATA THYROID CANCER GUIDELINES fertility, miscarriage, and fetal malformation do not appear to >10 ng=mL. If the 18FDG PET scan is negative, then empiric be elevated in women after RAI therapy (405–407). One large therapy with RAI (100–200 mCi) should be considered to aid retrospective study suggested that pregnancy should be localization or for therapy of surgically incurable disease postponed for 1 year after therapy because of an increase in (Fig. 5). This approach may identify the location of persistent miscarriage rate (408), although this was not confirmed in disease in approximately 50% of patients (307,416) with a another similarly designed study (409). Ovarian damage from wide range of reported success. Some investigators have RAI therapy may result in menopause occurring approxi- reported a fall in serum Tg after empiric RAI therapy in mately 1 year earlier than the general population, but this patients with negative DxWBS (417,418), but there is no ev- result was not associated with cumulative dose administered idence for improved survival with empiric therapy in this or the age at which the therapy was given (410). In men, RAI setting (374,418). On the other hand, Tg levels may decline therapy may be associated with a temporary reduction in without specific therapy during the first years of follow-up sperm counts and elevated serum follicle-stimulating hor- mone (FSH) levels (411,412). Higher cumulative activities When the RxWBS after empiric 131I therapy is negative, (500–800 mCi) in men are associated with an increased risk of 18FDG-PET scanning is indicated if not already obtained. In- persistent elevation of serum FSH levels, but fertility and risks tegrated 18FDG-PET=CT is able to improve diagnostic accu- of miscarriage or congenital abnormalities in subsequent racy of 18FDG-PET in patients with iodine-negative tumors. In pregnancies are not changed with moderate RAI activities a study of 40 such patients, in whom PET and CT images were (*200 mCi) (413,414). Permanent male infertility is unlikely scored blindly, the diagnostic accuracy was 93% for inte- with a single ablative activity of RAI, but theoretically there grated 18FDG-PET=CT and 78% for PET alone ( p < 0.5) (419).
could be cumulative damage with multiple treatments. It has In 74% of the patients with suspicious 18FDG foci, integrated been suggested that sperm banking be considered in men who 18FDG-PET=CT added relevant information to the side-by- may receive cumulative RAI activities 400 mCi (412). Go- side interpretation of PET and CT images by precisely local- nadal radiation exposure is reduced with good hydration, izing the lesions. 18FDG-PET=CT fusion studies led to a frequent micturition to empty the bladder, and avoidance of change of therapy in 48% of the patients. In another study, constipation (415).
18FDG-PET=CT changed the clinical management of 44% of 61patients, including surgery, radiation therapy, or chemo- RECOMMENDATION 73 therapy (420). The rate of PET scan positivity is low (11–13%) Women receiving RAI therapy should avoid pregnancy for in patients with stimulated Tg levels <10 ng=mL (421,422).
6–12 months. Recommendation rating: C Some have argued that 18FDG-PET scanning should be per-formed prior to empiric RAI therapy (423), since tumors thatare 18FDG-PET positive do not generally concentrate RAI RECOMMENDATION 74 (376), and RAI therapy is unlikely to alter the poorer outcome (a) Radioactive iodine should not be given to nursing in such patients (378).
women. Depending on the clinical situation, RAI A cutoff value of Tg above which a patient should be therapy could be deferred until a time when lactating treated with an empiric dose of RAI is difficult to determine, women have stopped breast-feeding for at least 6–8 due in part to the wide variation in available Tg assays (in- weeks. Recommendation rating: B cluding those used in reports suggesting benefit of such (b) Dopaminergic agents might be useful in decreasing therapy) and the differences in Tg levels based on method and breast exposure in recently lactating women, although degree of TSH stimulation or suppression. Recent studies caution should be exercised given the risk of serious have reported primarily on patients with Tg levels after T side effects associated with their routine use to sup- withdrawal of 10 ng=mL or higher, and it has been suggested press postpartum lactation. Recommendation rating: C that a corresponding level after rhTSH stimulation would be5 ng=mL (308,374,416,418,424). A Tg level that is rising may [C26] What is the management of Tg-positive, warrant greater concern for the need for empiric therapy, al- RAI scan–negative patients? though data regarding the appropriate rate of change are If the unstimulated Tg is or becomes detectable, or in- minimal (301). However a detectable but low Tg level at 9–12 creases over time, or if stimulated Tg levels rise to greater months following remnant ablation may not warrant further than 2 ng=mL, imaging of the neck and chest should be performed to search for metastatic disease, typically withneck US and with thin cut (5–7 mm) helical chest CT. Iodi- RECOMMENDATION 75 nated contrast should be avoided if RAI therapy is planned Empiric radioactive iodine therapy (100–200 mCi) might be within the subsequent few months, although intravenous considered in patients with elevated (Tg levels after T contrast may aid in identification of cervical and mediastinal withdrawal of 10 ng=mL or higher, or a level of 5 ng=mL or disease. In addition, for patients with a prior history of higher after rhTSH stimulation) or rising serum Tg levels in metastatic cervical lymph nodes in the anterior compart- whom imaging has failed to reveal a potential tumor source.
ments, cross-sectional imaging with either neck CT or MRI If the posttherapy scan is negative, no further RAI therapy should be considered to evaluate the retropharyngeal lymph should be administered. Recommendation rating: C nodes that cannot be imaged by sonography. If imaging isnegative for disease that is potentially curable by surgery, orthe serum Tg appears out of proportion to the identified RECOMMENDATION 76 surgically resectable disease, then whole-body 18FDG-PET If persistent nonresectable disease is localized after an imaging may be obtained if the stimulated serum Tg is empiric dose of RAI, and there is objective evidence of COOPER ET AL.
ALGORITHM for MANAGEMENT of DTC
TWELVE or more MONTHS after REMNANT ABLATION
Empiric 131I Therapy Under Consideration: Evaluate History of Prior Therapy, Response to Therapy, Confounding Factors, and Current Staging of Patient as Assessed by Physical Examination, Laboratory Tests, and Imaging Studiesa False Elevation in Serum Declining Serum Tg or Tg or Evidence of Tg <1 with Declining Heterophile Antibody Interference Present b Do Not Treat with
Continue 131I if Beneficiald 18FDG-PET/CT if Not Done Grade 3 Blood/Bone Marrow Compromisec 5–8 Day Post Rx WBS Result 131I Therapy with 100 to 150 mCi Bulky Tumor Present when TSH >30 or after rhTSH e Consider Surgery/EBRT/Clinical Trials
Patient Unable to Raise Preparation with Consider 131I Therapy TSH or Tolerate THW with 100 to 150 mCi History of CT Contrast in Past 3–4 Months or of Other Iodine Contamination Considerations for empiric treatment with radioiodine.
aEmpiric 131I therapy should be done with meticulous patient preparation, including low-iodine diet and, if iodine con- tamination is a possibility, urinary iodine measurements. If the RxWBS is negative or subsequent follow-up studies show notherapeutic benefit, further empiric 131I should not be administered.
bTg that rises with TSH stimulation and falls with TSH suppression is unlikely to result from heterophile antibodies.
cNational Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0, (http:==ctep.cancer.gov).
dDosimetry could be considered to allow administration of maximum radioiodine activity if the tumor is life-threatening.
eA dose of 200 mCi could exceed the maximum tolerable dose in older individuals (see Recommendation 52b).
REVISED ATA THYROID CANCER GUIDELINES significant tumor reduction, then RAI therapy should be [D1] WHAT ARE DIRECTIONS FOR FUTURE RESEARCH? repeated until the tumor has been eradicated or the tumorno longer responds to treatment. The risk of repeated [D2] Novel therapies and clinical trials therapeutic doses of RAI must be balanced against uncer- While surgery and the judicious use of RAI, as described in tain long-term benefits. Recommendation rating: C these guidelines, is sufficient treatment for the majority ofpatients with DTC, a minority of these patients experience RECOMMENDATION 77 progressive, life-threatening growth and metastatic spread of In the absence of structurally evident disease, stimulated the disease. The recent explosion of knowledge regarding the serum Tg <10 ng=mL with thyroid hormone withdrawal or molecular and cellular pathogenesis of cancer has led to the <5 ng=mL with rhTSH can be followed with continued LT4 development of a range of targeted therapies, now undergoing therapy alone, reserving additional therapies for those clinical evaluation. Efficacy has already been demonstrated for patients with rising serum Tg levels over time or other several agents in phase II studies, including axitinib, motesanib, evidence of structural disease progression. Recommenda- sorafenib, pazopanib, and thalidomide, whereas many others are in ongoing trials. Randomized phase III trials to demon-strate improved survival, improved progression free survival, [C27] What is the management of patients with a negative or superiority of one therapy over another have not been per- formed, however, and none of these drugs have been specifi-cally approved for treatment of metastatic thyroid carcinoma.
RECOMMENDATION 78 These therapies can be grouped into a number of categories.
(a) If an empiric dose (100–200 mCi) of RAI fails to localize the persistent disease, 18FDG-PET=CT scanning should [D3] Inhibitors of oncogenic signaling pathways.
be considered, especially in patients with unstimulated kinase inhibitors of interest in thyroid carcinoma usually target serum Tg levels >10–20 ng=mL or in those with ag- transmembrane tyrosine kinase receptors that initiate signal- gressive histologies, in order to localize metastatic le- ing through the MAP kinase pathway. This signaling pathway sions that may require treatment or continued close is activated in the majority of PTCs. Inhibitors of RET, RAS, observation (425,426). Recommendation rating: B RAF, and MEK kinases target various members of the samesignaling pathway. Several of these agents are in development Stimulation with endogenous TSH following thyroxine with several clinical trials completed or underway. Specific withdrawal or rhTSH (316) and CT fusion (427) may mini- oncogene targeting for follicular thyroid cancer and Hu¨rthle cell mally enhance the sensitivity and specificity of 18FDG-PET cancer awaits better understanding of the pathways involved in initiation of these tumor types, although responses in pa-tients with these subtypes have been reported in clinical trials.
(b) Tg-positive, RxWBS-negative patients with disease that is incurable with surgery and is structurally evi- [D4] Modulators of growth or apoptosis.
dent or visualized on 18FDG-PET=CT scan can be of growth and apoptotic pathways are targeted by PPARg managed with thyroid hormone suppression therapy, activators, including COX2 inhibitors; rexinoids, which acti- external beam radiotherapy, chemotherapy, radio- vate RXR; bortezomib, which inactivates the cancer pro- frequency ablation, chemo-embolization, or monitor- teasome; and derivatives of geldanomycin, which target the ing without additional therapy if stable. Clinical trials hsp-90 protein. Clinical trials in thyroid cancer of each of these should also be considered. Recommendation rating: C agents are available.
RECOMMENDATION 79 [D5] Angiogenesis inhibitors.
Targeting of vascular en- Tg-positive, RxWBS-negative patients with no structural dothelial growth factor (VEGF) receptors and other members evidence of disease can be followed with serial structural of the signaling cascades responsible for neoangiogenesis may imaging studies and serial Tg measurements, with both limit the growth of cancers by restricting their blood supply.
performed more frequently if the Tg level is rising. When Many of the kinase inhibitors that have been studied to date and how often to repeat 18FDG-PET=CT imaging in this are very potent inhibitors of the tyrosine kinase of the VEGF setting is less certain. Recommendation rating: C receptors. Trials of several of these agents are currently un-derway in all subtypes of thyroid cancer.
[C28] What is the role of external beam radiotherapy Stimulation of the immune re- in treatment of metastatic disease? sponse to cancer may be achieved by augmenting the activityof antigen-presenting dendritic cells. This approach has RECOMMENDATION 80 shown possible benefits in phase I clinical trials, but has not External beam radiation should be used in the management yet been studied in thyroid cancer. The apparent immuno- of unresectable gross residual or recurrent cervical disease, genicity of thyroid cells makes this an attractive approach for painful bone metastases, or metastatic lesions in critical future clinical trials.
locations likely to result in fracture, neurological, or com-pressive symptoms that are not amenable to surgery (e.g., [D7] Gene therapy.
Preclinical studies have demon- vertebral metastases, CNS metastases, selected mediastinal strated some efficacy in thyroid cancer cell lines. Approaches or subcarinal lymph nodes, pelvic metastases) (277). Re- include introducing toxic genes under the control of thyroid- commendation rating: B specific promoters, or restoration of the p53 tumor suppressor COOPER ET AL.
gene in anaplastic thyroid cancer cell lines. Problems with usually interferes with serum Tg measurement and recovery gene delivery limit the clinical utility of these approaches, assays do not appear to accurately predict this interference which have not yet reached clinical trials in thyroid cancer.
(305,428). Decreasing antibody levels are correlated with Each of these targeted approaches holds promise for our ‘‘disease-free'' status while increasing levels suggest persistent future ability to treat patients with life-threatening disease disease (306,429). However, there are clear exceptions to this unresponsive to traditional therapy. In the meantime, for ‘‘rule.'' These patients are therefore a challenge to manage or appropriate patients, entry into one of the available clinical study because one often can not be certain of their disease trials may be an attractive option.
status. This problem limits definitive investigation which, inturn, hampers development of evidence-based guidelines [D8] Better understanding of the long-term risks of RAI such as these to assist clinicians. Measurement of Tg mRNA inthe blood may be a sensitive marker for persistent thyroid With the more widespread use of RAI in the management cells even in the presence of anti-Tg antibodies (430–432), but of thyroid cancer, and the normal life expectancy of most RNA extraction is not well standardized and some studies patients with the disease, it is imperative that we have a better question the specificity of this marker (433,434). Future understanding of the long-term risks associated with its use.
studies optimizing the measurement of Tg mRNA and per- Research that focuses on how to minimize the impact of RAI haps other thyroid-related substances in blood from DTC on the salivary glands in order to prevent sialadenitis and patients with anti-Tg antibodies are needed to better monitor xerostomia would provide a significant benefit to patients. A this challenging subgroup of DTC patients. This goal would better understanding of the long-term effects of RAI on re- also be enhanced by development of Tg assays that have productive issues in men and women is also an important limited interference by anti-Tg antibodies and by methods to topic. Finally, while the risk of second malignancies appears clear anti-Tg antibodies prior to Tg measurement.
small following the usual activities of RAI used for remnantablation, we need better understanding of the long-term risksfor salivary gland tumors, bladder tumors, and colon cancers [D11] Small cervical lymph node metastases when repeated doses of RAI are needed in young patients The rates of cervical lymph node metastases generally range who are potentially long-term survivors of thyroid cancer.
from about 20% to 50% in most large series of DTC, with higherrates in children or when micrometastases are considered. The [D9] Clinical significance of persistent low location and number of lymph node metastases is often diffi- levels of serum Tg cult to identify before, during, or after surgery, especially mi- After initial surgery and RAI therapy some patients will crometastases. Although postoperative 131I given to ablate the have persistently detectable stimulated serum Tg when eval- thyroid remnant undoubtedly destroys some micrometastases, uated 9–12 months later. Most of these patients have stimu- the most common site of recurrence is in cervical lymph nodes, lated Tg levels in the range of 1–10 ng=mL, levels typically which comprise the majority of all recurrences. Future research associated with a small volume of tissue. Some of these patients must consider the dilemma of minimizing iatrogenic patient demonstrate a subsequent spontaneous fall in Tg over time, harm versus preventing cancer morbidity and (perhaps) mor- others remain stable, while still others demonstrate rising Tg tality. Perhaps techniques will be developed to safely remove levels. The optimal management of these patients is unknown.
or destroy small cervical nodal metastases, which in some cases How often should they undergo neck US or stimulated serum would otherwise progress to overt, clinically significant me- Tg testing? Will sensitive Tg assays combined with neck US tastases. Conversely, the clinical significance of very small replace stimulation testing? Which (if any) of these patients (<0.5 cm) nodal metastases needs to be clarified by long-term should undergo chest CT, PET, or empiric RAI therapy? Can follow-up studies. Development of a cost-effective method to we improve our abilities to predict and monitor which patients determine which metastases can be safely followed without are likely to be harmed by their disease as opposed to those intervention would be of great benefit.
who will live unaffected by theirs? Does metastatic disease insmall local lymph nodes have the potential to metastasize to [D12] Improved risk stratification distant sites during observation while on TSH suppressiontherapy? The current impetus to test and treat all of these pa- Current risk stratification schemes rely almost exclusively tients is based on the argument that early diagnosis may lead to on clinical, pathological, and radiological data obtained dur- early treatment of residual disease when treatment is more ing the initial evaluation and therapy of the patient. However, likely to be effective, as opposed to less effective treatment none of the commonly used risk stratification schemes ade- when the tumor is more bulky, more extensive, or has spread to quately incorporate the prognostic implications of the very inoperable locations. However, there is no current proof that detailed pathological descriptions that are provided (e.g., aggressive treatment of minimal residual disease improves various histological subtypes of thyroid cancer, frequent mi- patient outcome. This is brought into focus by the fact that only toses, areas of tumor necrosis, minor degrees of extrathyroidal about 5% of all PTC patients die of their disease, yet 15–20% of extension, or capsular invasion) or the molecular character- low-risk PTC patients are likely to have persistent disease istics of the primary tumor. Furthermore, current staging based on persistent measurable Tg with stimulation testing.
systems are static representations of the patient at the time ofpresentation and are not easily modifiable over time as newdata become available during follow-up. Therefore, a risk [D10] The problem of Tg antibodies stratification system that incorporates all the important in- Anti-Tg antibodies are a common clinical problem in formation available at presentation and also evolves over time patients with DTC (305). The presence of these antibodies as new data become available would be useful in providing REVISED ATA THYROID CANCER GUIDELINES ongoing risk assessments that would optimize management spectrum of thyroid disease in a community: the Whick- throughout the life of the patient.
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2. Vander JB, Gaston EA, Dawber TR 1968 The significance of nontoxic thyroid nodules. Ann Intern Med 69:537–540.
3. Tan GH, Gharib H 1997 Thyroid incidentalomas: manage- The taskforce wishes to thank Ms. Bobbi Smith, Executive ment approaches to nonpalpable nodules discovered inci- Director, American Thyroid Association, and Ms. Sheri dentally on thyroid imaging. Ann Intern Med 126:226–231.
Slaughter, Assistant to the Taskforce, for their constant help 4. Hegedus L 2004 Clinical practice. The thyroid nodule. N and support. We also wish to thank Sally Carty, M.D., Quan- Engl J Med 351:1764–1771.
Yang Duh, M.D., Gregory Randolph, M.D., David Steward, 5. Mandel SJ 2004 A 64-year-old woman with a thyroid nod- M.D., David Terris, M.D., Ralph Tufano, M.D., and Robert ule. JAMA 292:2632–2642.
Udelsman, M.D., for their help in developing recommenda- 6. Sherman SI 2003 Thyroid carcinoma. Lancet 361:501–511.
tions related to central neck dissection.
7. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ 2009 Cancer statistics, 2009. CA Cancer J Clin. Published online before print May 27, 2009.
It is our goal in formulating these guidelines, and the ATA's 8. Davies L, Welch HG 2006 Increasing incidence of thyroid goal in providing support for the development of these cancer in the United States, 1973–2002. JAMA 295:2164– guidelines, that they assist in the clinical care of patients, and share what we believe is current, rational, and optimal med- 9. Leenhardt L, Bernier MO, Boin-Pineau MH, Conte DB, Marechaud R, Niccoli-Sire P, Nocaudie M, Orgiazzi J, ical practice. In some circumstances, it may be apparent that Schlumberger M, We´meau JL, Che´rie-Challine L, De Va- the level of care recommended may be best provided in lim- thaire F 2004 Advances in diagnostic practices affect thyroid ited centers with specific expertise. Finally, it is not the intent cancer incidence in France. Eur J Endocrinol 150:133–139.
of these guidelines to replace individual decision making, the 10. Singer PA, Cooper DS, Daniels GH, Ladenson PW, wishes of the patient or family, or clinical judgment.
Greenspan FS, Levy EG, Braverman LE, Clark OH,McDougall IR, Ain KV, Dorfman SG 1996 Treatment Disclosure Statement guidelines for patients with thyroid nodules and well-dif- These guidelines were funded by the American Thyroid ferentiated thyroid cancer. American Thyroid Association.
Association without support from any commercial sources.
Arch Intern Med 156:2165–2172.
GMD is a consultant for MedTronic ENT. BRH has received 11. American Association of Clinical Endocrinologists 2001 honoraria from Genzyme and grant=research support from AACE=AAES medical=surgical guidelines for clinical Veracyte. RTK has received grant=research support from practice: management of thyroid carcinoma. Endocr Pract Genzyme, Bayer-Onyx, Eisai, and Veracyte; is a consultant for Genzyme, Bayer-Onyx, Abbott, and Veracyte; and is on the 12. British Thyroid Association and Royal College of Physi- cians. 2007 Guidelines for the management of thyroid Speakers Bureau for Genzyme and Abbott. He has received no cancer, 2nd Edition. www.british-thyroid-association.org.
honoraria for commercial speaking since November 2006 and 13. National Comprehensive Cancer Network. 2009 Thyroid all commercial consulting since that time has been approved by the ATA Board of Directors, the ATA Ethics Committee, and PDF=thyroid.pdf. Accessed January 28, 2009.
has been without financial compensation. SLL has received 14. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, grant=research support from Bayer and is a consultant for Wiersinga W 2006 European consensus for the manage- Abbott, Onyx, and Bayer. SJM has received grant=research ment of patients with differentiated thyroid carcinoma of support from Veracyte and has been a CME speaker for Gen- the follicular epithelium. Eur J Endocrinol 154:787–803.
zyme. ELM is on the Speakers Bureau for Genzyme. FP has 15. Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, received grant=research support from Amgen, Exelixis, and Oyen WJ, Tennvall J, Bombardieri E 2008 Guidelines for AstraZeneca and is a consultant and on the Speakers Bureau radioiodine therapy of differentiated thyroid cancer. Eur J for Genzyme. MS has received grant=research support from Nucl Med Mol Imaging 35:1941–1959.
Genzyme, Amgen, AstraZeneca, Bayer, Exelixis, and Eisai; is a 16. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, consultant for Genzyme, AstraZeneca, Bayer, and Exelixis; and Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM is on the Speakers Bureau for Genzyme, AstraZeneca, and 2006 The American Thyroid Association Guidelines Task- Exelixis. SIS has received grant=research support from Gen- force. Management guidelines for patients with thyroid nod- zyme, Amgen, AstraZeneca, and Eisai; is a consultant for ules and differentiated thyroid cancer. Thyroid 16:109–142.
AstraZeneca, Eisai, Exelixis, Plexxikon, Oxigene, Semalore, 17. U.S. Preventive Services Task Force Ratings: Strength of Celgene, and Eli Lily; is on the Speakers Bureau for Genzyme; Recommendations and Quality of Evidence. Guide to and has received honoraria from Abbott. DLS has received Clinical Preventive Services, Third Edition: Periodic Up- grant=research support from Veracyte, Wyeth, Astra-Zeneca, dates, 2000–2003. Agency for Healthcare Research andQuality, Rockville, MD.
and Gyrus. RMT is a consultant for Genzyme, Abbott, and Eli 18. Marqusee E, Benson CB, Frates MC, Doubilet PM, Larsen Lily, and has received honoraria from Genzyme and Abbott.
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Mild or comedonal acne consists of comedones material within, are open to the surface, and have a acne lesions during this time. With female menopause, (blackheads and whiteheads) only and is • Higher androgen levels cause the overproduction of black color due to melanin pigment in the cells that estrogen and progesterone levels decrease as the non-inflammatory. Inflammatory acne consists of both