Abstract

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association’s guidelines for the management 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 and level 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 regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum 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 independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

THYROID NODULES ARE a common clinical problem. Epidemiologic studies have shown the prevalence of palpable thyroid nodules to be approximately 5% in women and 1% in men living in iodine-sufficient parts of the world (1,2). In contrast, high-resolution ultrasound (US) can detect thyroid nodules in 19–67% of randomly selected individuals with higher frequencies in women and the elderly (3). The clinical importance of thyroid nodules rests with the need to exclude thyroid cancer which occurs in 5–15% depending on age, sex, radiation exposure history, family history, and other factors (4,5). Differentiated thyroid cancer (DTC), which includes papillary and follicular cancer, comprises the vast majority (90%) of all thyroid cancers (6). In the United States, approximately 37,200 new cases of thyroid cancer will be diagnosed in 2009 (7). The yearly incidence has increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a 2.4-fold increase (p < 0.001 for trend) and this trend appears to be continuing (8). Almost the entire change has been attributed to an increase in the incidence of papillary thyroid cancer (PTC), which increased 2.9-fold between 1988 and 2002. Moreover, 49% of the rising incidence consisted of cancers measuring 1 cm or smaller and 87% consisted of cancers measuring 2 cm or smaller (8). This tumor shift may be due to the increasing use of neck ultrasonography and early diagnosis and treatment (9), trends that are changing the initial treatment and follow-up for many patients with thyroid cancer.

In 1996, the American Thyroid Association (ATA) published treatment guidelines for patients with thyroid nodules and DTC (10). Over the last decade, there have been many advances in the diagnosis and therapy of both thyroid nodules and DTC. Controversy exists in many areas, including the most cost-effective approach in the diagnostic evaluation of a thyroid nodule, the extent of surgery for small thyroid cancers, the use of radioactive iodine to ablate remnant tissue following thyroidectomy, the appropriate use of thyroxine suppression therapy, and the role of human recombinant thyrotropin (rhTSH). In recognition of the changes that have taken place in the overall management of these clinically important problems, the ATA appointed a task force to re-examine the current strategies that are used to diagnose and treat thyroid nodules and DTC, and to develop clinical guidelines using principles of evidence-based medicine. Members of the taskforce included experts in thyroid nodule and thyroid cancer management with representation from the fields of endocrinology, surgery, and nuclear medicine. The medical opinions expressed here are those of the authors; none were dictated by the ATA. The final document was approved by the ATA Board of Directors and endorsed (in alphabetical order) by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology, British Association of Head and Neck Oncologists (BAHNO), The Endocrine Society, European Association for Cranio-Maxillo-Facial Surgery (EACMFS), European Association of Nuclear Medicine (EANM), European Society of Endocrine Surgeons (ESES), European Society for Paediatric Endocrinology (ESPE), International Association of Endocrine Surgeons (IAES), and Latin American Thyroid Society (LATS).

Other groups have previously developed guidelines, including the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons (11), the British Thyroid Association and The Royal College of Physicians (12), and the National Comprehensive Cancer Network (13) that have provided somewhat conflicting recommendations due to the lack of high quality evidence from randomized controlled trials. The European Thyroid Association has published consensus guidelines for the management of DTC (14). The European Association of Nuclear Medicine has also recently published consensus guidelines for radioiodine (RAI) therapy of DTC (15).

The ATA guidelines taskforce used a strategy similar to that employed by the National Institutes of Health for its Consensus Development Conferences (http://consensus.nih.gov/aboutcdp.htm), and developed a series of clinically relevant questions pertaining to thyroid nodule and thyroid cancer diagnosis and treatment. These questions were as follows:

Questions regarding thyroid nodules

  • What is the appropriate evaluation of clinically or incidentally discovered thyroid nodule(s)?
    • What laboratory tests and imaging modalities are indicated?
    • What is the role of fine-needle aspiration (FNA)?
  • What is the best method of long-term follow up of patients with thyroid nodules?
  • What is the role of medical therapy of patients with benign thyroid nodules?
  • How should thyroid nodules in children and pregnant women be managed?

Questions regarding the initial management of DTC

  • What is the role of preoperative staging with diagnostic imaging and laboratory tests?
  • What is the appropriate operation for indeterminate thyroid nodules and DTC?
  • What is the role of postoperative staging systems and which should be used?
  • What is the role of postoperative RAI remnant ablation?
  • What is the role of thyrotropin (TSH) suppression therapy?
  • Is there a role for adjunctive external beam irradiation or chemotherapy?

—Questions regarding the long term management of DTC

  • What are the appropriate features of long-term management?
  • What is the role of serum thyroglobulin (Tg) assays?
  • What is the role of US and other imaging techniques during follow-up?
  • What is the role of TSH suppression in long-term follow-up?
  • What is the most appropriate management of patients with metastatic disease?
  • How should Tg-positive, scan-negative patients be managed?
  • What is the role of external radiation therapy?
  • What is the role of chemotherapy?

What are directions for future research?

The initial ATA guidelines were published in 2006 (16). Because of the rapid growth of the literature on this topic, plans for revising the guidelines within 24–36 months of publication were made at the inception of the project. Relevant articles on thyroid cancer were identified using the same search criteria employed for the original guidelines (16). Individual task force members submitted suggestions for clarification of prior recommendations, as well as new information derived from studies published since 2004. Relevant literature continued to be reviewed through December 2008. To begin the revision process, a half-day meeting was held on June 2, 2007. The Task Force was broadened to include European experts and a head and neck surgeon. Three subsequent half-day meetings were held on October 5, 2007; July 13, 2008; and October 5, 2008, to review these suggestions and for additional comments to be considered. The meeting in July 2008 also included a meeting with six additional surgeons in an effort to produce guidelines related to central neck dissection that would be as authoritative as possible. The organization of management guideline recommendations is shown in Table 1. It was agreed to continue to categorize the published data and strength of recommendations using a modified schema proposed by the U.S. Preventive Services Task Force (17) (Table 2).

Table 1. Organization of Management Guideline Recommendations, Tables, and Figures for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

 

Page

Location keya

Sections and subsections

Itemb

1171

[A1]

THYROID NODULE GUIDELINES

T1

1171

[A2]

Evaluation of Newly Discovered Thyroid Nodules

F1

1171

[A3]

Laboratory tests

 

1171

[A4]

Serum TSH

R1–R2

1171

[A5]

Serum thyroglobulin (Tg)

R3

1171

[A6]

Serum calcitonin

R4

1173

[A7]

Role of fine-needle aspiration (FNA)

 

1173

[A8]

Ultrasound (US) with FNA

R5, T3

1174

[A9]

Cytopathological interpretation of FNA samples

 

1174

[A10]

Nondiagnostic cytology

R6

1174

[A11]

Cytology suggesting papillary thyroid cancer (PTC)

R7

1174

[A12]

Indeterminate cytology

R8–R10

1175

[A13]

Benign cytology

R11

1175

[A14]

Multinodular goiter (MNG)/multiple thyroid nodules

R12–R13

1175

[A15]

Long-Term Follow-Up of Thyroid Nodules

R14–R15

1176

[A16]

Medical therapy for benign thyroid nodules

R16–R17

1176

[A17]

Thyroid nodules in children

R18

1176

[A18]

Thyroid nodules in pregnant women

R19–R20

1176

[B1]

DIFFERENTIATED THYROID CANCER (DTC):
INITIAL MANAGEMENT GUIDELINES

 

1176

[B2]

Goals of Initial Therapy of DTC

 

1177

[B3]

Preoperative staging of DTC

 

1177

[B4]

Neck imaging

R21–R22

1177

[B5]

Serum Tg

R23

1177

[B6]

Thyroid surgery

 

1178

[B7]

Surgery for nondiagnostic biopsy

R24–R25

1178

[B8]

Surgery for biopsy diagnostic of malignancy

R26

1179

[B9]

Lymph node dissection

R27–R28, F2

1180

[B10]

Completion thyroidectomy

R29–R30

1180

[B11]

Postoperative staging systems

 

1180

[B12]

Role of postoperative staging

 

1180

[B13]

AJCC/UICC TNM staging

R31, T4

1181

[B14]

Role of postoperative remnant ablation

R32, T5

1183

[B15]

Preparation for radioiodine (RAI) remnant ablation

R33, F3

1183

[B16]

rhTSH preparation

R34

1183

[B17]

RAI scanning before RAI ablation

R35

1185

[B18]

Radiation doses for RAI ablation

R36–R37

1185

[B19]

Low-iodine diet for RAI ablation

R38

1185

[B20]

Post RAI ablation whole-body RAI scan

R39

1185

[B21]

Post Initial Therapy of DTC

 

1185

[B22]

Role of TSH suppression therapy

 

1185

[B23]

Degree of initial TSH suppression required

R40

1186

[B24]

Adjunctive measures

 

1186

[B25]

External beam irradiation

R41

1186

[B26]

Chemotherapy

R42

1186

[C1]

DTC: LONG-TERM MANAGEMENT

 

1186

[C2]

Appropriate Features of Long-Term Management

 

1186

[C3]

Appropriate method of follow-up after surgery

F4

1186

[C4]

Criteria for absence of persistent tumor

 

1186

[C5]

Role of serum Tg assays

R43–R45

1189

[C6]

Whole body RAI scans, US, and other imaging

 

1189

[C7]

Diagnostic whole-body RAI scans

R46–R47

1189

[C8]

Cervical ultrasound

R48a–c

1189

[C9]

FDG-PET Scanning

R48d

1189

[C10]

Role of thyroxine suppression of TSH

R49

1190

[C11]

Management of Metastatic Disease

 

1190

[C12]

Surgery for locoregional metastases

R50

1190

[C13]

Surgery for aerodigestive invasion

R51

1191

[C14]

RAI for local or distant metastatic disease

 

1191

[C15]

Methods for administering RAI

R52–R54

1191

[C16]

The use of lithium in RAI therapy

R55

1191

[C17]

Metastasis to various organs

 

1192

[C18]

Pulmonary metastasis

R56–R58

1192

[C19]

Non–RAI-avid pulmonary disease

R59

1193

[C20]

Bone metastases

R60–R64

1193

[C21]

Brain metastases

R65–R67

1194

[C22]

Management of Complications of RAI Therapy

R68–R70

1194

[C23]

Secondary malignancies and leukemia from RAI

R71

1194

[C24]

Other risks to bone marrow from RAI

R72

1194

[C25]

Effects of RAI on gonads and in nursing women

R73–R74

1195

[C26]

Management of Tg Positive, RAI Scan–Negative Patients

R75–R77, F5

1197

[C27]

Patients with a negative post-treatment whole-body scan

R78–R79

1197

[C28]

External beam radiation for metastatic disease

R80

1197

[D1]

DIRECTIONS FOR FUTURE RESEARCH

 

1197

[D2]

Novel Therapies and Clinical Trials

 

1197

[D3]

Inhibitors of oncogenic signaling pathways

 

1197

[D4]

Modulators of growth or apoptosis

 

1197

[D5]

Angiogenesis inhibitors

 

1197

[D6]

Immunomodulators

 

1197

[D7]

Gene therapy

 

1198

[D8]

Better Understanding of the Long-Term Risks of RAI

 

1198

[D9]

Clinical Significance of Persistent Low-Level Tg

 

1198

[D10]

The Problem of Tg Antibodies

 

1198

[D11]

Small Cervical Lymph Node Metastases

 

1198

[D12]

Improved Risk Stratification

 

 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 2. STRENGTH OF PANELISTS’ RECOMMENDATIONS BASED ON AVAILABLE EVIDENCE

Rating

Definition

A

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 in representative populations that directly assess effects on health outcomes.

B

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 strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes.

C

Recommends. The recommendation is based on expert opinion.

D

Recommends against. The recommendation is based on expert opinion.

E

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.

F

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.

I

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 intervention improves important health outcomes, the evidence is of poor quality, or the evidence is conflicting. As a result, the balance of benefits and harms cannot be determined.

Adapted from the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality (17).