Systematic review of clinical practice guidelines in the diagnosis and management of thyroid nodules and cancer

We selected CPGs that provided recommendations on the diagnosis and management of thyroid nodules or cancer. For inclusion in our study, the guidelines were required to (1) have published in English, and (2) examine all subgroups of the population to ensure that the CPGs catered for the needs of those with comorbidities in various settings. When more than one set of guidelines was produced by the same professional body, only the most recently issued was considered. We excluded guidelines that (1) focused exclusively on thyroid disease among special groups (for example, anaplastic thyroid cancer, pregnant women or children); (2) focused entirely on a unique technique, such as the procedure guideline for radioiodine therapy; (3) concentrated on a non-nodular disease, such as thyroid dysfunction; (4) contained recommendations for other diseases, such as neuroendocrine tumors or head and neck cancer; or (5) reported non-original recommendations (referring to other sets of guidelines).

Two reviewers (K-WT and T-WH) searched for relevant studies using keyword searches of the following electronic databases: MEDLINE, EMBASE, CINAHL, the National Guideline Clearinghouse, the National Institute for Health and Clinical Excellence, the Scottish Intercollegiate Guidelines Network (SIGN), and the Guidelines International Network (G-I-N) International Guideline Library. The following terms and Boolean operators were used in MeSH and free-text searches: thyroid, cancer OR carcinoma OR neoplasm, nodule OR mass OR tumor, and guidelines OR recommendations. The ‘related articles’ facility in PubMed was used to broaden the search. The last search was performed in June 2013.

Two reviewers (K-WT and T-WH) independently extracted the details of the guidelines pertaining to the CPG characteristics (for example, country or region, year of dissemination, development team, and funding organization), the goals of the guidelines, the target population and audience, the recommendations related to the diagnosis of thyroid nodules, the recommendations related to the management of thyroid nodules and cancer, and the evaluation of options for postoperative follow-up. The individually recorded decisions of two reviewers were compared, and any disagreement was resolved based on the evaluation of a third reviewer (J-HL).

We constructed a table to compare the recommendations from the selected guidelines. The table was divided into the following sections and items, based on the types of clinical practices that focus on thyroid nodules and cancer: (1) diagnosis: an indication of FNA, the role of routine serum calcitonin, and an indication of a thyroid scan; (2) treatment: an indication of total thyroidectomy for DTC, and the role of cervical lymph node dissection in node-negative patients; and (3) postoperative care: an indication of I¹³¹ ablation, and a target level of thyroid-stimulating hormone (TSH) suppression therapy.

Four investigators (K-WT, T-WH, J-HL and M-YW) independently appraised all the selected guidelines by using the AGREE-II instrument [10]. AGREE-II consists of 23 key items organized into 6 domains: (1) ‘scope and purpose’thinsp;, (2) ‘stakeholder involvement’thinsp;, (3) ‘rigor of development’thinsp;, (4) ‘clarity and presentation’thinsp;, (5) ‘applicability’thinsp;, and (6) ‘editorial independence’. Each domain captured a separate dimension of the guideline quality with a seven-point scale (from 7 (strongly agree) down to 1 (strongly disagree)). For each reviewer, AGREE-II scores were calculated as a percentage by using the sum of the seven-point scale and the maximum possible score (range 0% to 100%). Item scores were discussed by the four reviewers, and large scoring discrepancies (defined as ≤3 points difference in the score assigned by the appraisers to the same item) were resolved by consensus. We considered satisfactory any guideline that scored at least 50% in all six domains, as defined by AGREE-II. Upon completing the 23 items, each reviewer provided an overall assessment of the guideline. We compared the mean values of each of the six domain scores and the overall scores obtained by the four reviewers to evaluate the possible risk of bias and the recommendation for future use for each CPG appraised.

The flowchart in Figure 1 shows the process by which we screened and selected the guidelines. Our initial search yielded 1,203 citations, of which 1,051 were deemed ineligible by screening their titles and abstracts, and 62 were excluded due to irrelevant topic. This left 90 eligible studies. Of these, 79 reports were excluded from our final analysis for the following reasons: 17 were non-English guidelines, 2 were concentrated on non-thyroid cancer, 36 were the procedure guidelines, 12 guidelines were not the most recent version, 2 being duplicate publication, and 11 were the comment of original guidelines. The remaining ten eligible guidelines were included in our analysis [14‐23].

Table 1 presents a summary of the characteristics of the selected guidelines. The ten guidelines were published between 2000 and 2013. Of the ten guidelines, four were new [19, 20, 22, 23], and the rest were updates. Of the selected guidelines, 3 were developed in multiple countries: the Latin American Thyroid Society (LATS) used the guidelines from 13 Latin American countries [20], the European Society for Medical Oncology (ESMO) was approved in Europe [17], and American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association (AACE/AME/ETA) was contributed by the USA and Europe [14]. The remaining CPGs were conducted in the USA [15, 21], the UK [16, 22], Germany [18], The Netherlands [19], and Spain [23]. Nine guidelines were produced by independent professional scientific organizations, and the remaining guideline was developed with the endorsement of a regional independent body [22]. Five CPGs were funded by independently professional organizations [14‐16, 19, 21], and the remainder did not disclose a funding source.

With the exception of the ESMO and Spanish Society of Medical Oncology (SEOM) CPGs [17, 23], all the selected guidelines stated the methods used in the literature search, the quality of the evidence, and the strengths of the recommendations reported. Table 2 presents the domain scores (%) for the ten CPGs that were assessed using the AGREE-II instrument. Three of the selected guidelines performed satisfactorily, achieving a score of greater than 50% in all six AGREE-II domains [16, 19, 21]. The guidelines generally received the lowest scores for domain 5, ‘applicability’, among all six AGREE-II domains (≤38.5% for five CPGs). Guidelines scored highest in domain 1 (≥61.1% for eight CPGs). The British Thyroid Association (BTA) and Dutch Endocrine Society/Dutch Society of Nuclear Medicine (IKNL) guidelines scored the highest on domain 1 (87.5% and 87.5%) and domain 2 (76.4% and 75%) [16, 19]. Moreover, the IKNL guideline scored the highest for domain 3 (88.5%) [19]. The National Comprehensive Cancer Network (NCCN) guideline scored the highest for domain 4 (81.9%) and domain 6 (85.4%) [21]. Domain 5 scored consistently low across the CPGs.

Table 3 details the mean scores for the 23 items and the overall mean scores for each domain from the 10 guidelines evaluated as assessed with AGREE-II, by averaging the scores from each of the 4 investigators. The overall quality of the CPGs ranged from 3.00 ± 0.00 to 6.25 ± 0.50 of a possible 7 on the AGREE-II tool. In general, the lowest mean scores were for item 5 (range 1.75 ± 0.50 to 4.25 ± 1.71) and item 21 (range 2.0 ± 0.0 to 4.0 ± 0.82), which indicated that the included guidelines seldom provided the views or preferences of the target population or the monitoring or auditing criteria of the key recommendations.

Recommendations for the diagnosis and management of thyroid nodules and cancer extracted from these guidelines are shown in Table 4. Regarding the diagnostic procedures, all guidelines advocated thyroid sonography. In addition, a measurement of TSH and free thyroxine levels should be performed in all patients. A routine measurement of serum thyroidglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended. However, although all the guidelines supported FNA as the procedure of choice in the evaluation of solid thyroid nodules, the CPGs define various nodular sizes as indications for FNA. The German Association of Endocrine Surgeons (GAES), IKNL, and Northern Cancer Network (NCN) guidelines recommend that FNA should be performed in all nodules [18, 19, 22], two CPGs recommend that the indication of FNA must be performed in nodules >0.5 cm in diameter [15, 16], and the other three CPGs suggest that FNA cytology is needed when the thyroid nodule is bigger than 1 cm in the absence of clinical suspicion [14, 17, 23]. In the 2013 version of the NCCN guidelines, the threshold for FNA is a solid thyroid nodule >1.5 cm, if no suspicious sonographic features are present [21]. For laboratory evaluation, four CPGs recommend routine serum calcitonin, particularly before surgery for nodular thyroid disease [17‐19, 23]. Four guidelines suggest a serum calcitonin assay as an optional test [14, 20‐22], but the American Thyroid Association (ATA) guidelines cannot recommend or discourage the routine measurement of serum calcitonin, because of insufficient evidence [15]. For radionuclide scanning, three guidelines mentioned thyroid scintigraphy in a single thyroid nodule with a low TSH level [14, 15, 21], and the GAES CPGs recommend thyroid scintigraphy before the planning and execution of an operation [18].

Concerning thyroid surgery for DTC, patients with node-negative cancer 1 cm in diameter or more should be treated with total or near-total thyroidectomy, except where contraindications prevent this surgery [15‐19, 22]. However, the NCCN and SEOM CPGs recommend total or subtotal thyroidectomy in tumors >4 cm in diameter [21, 23]. In contrast, the LATS guidelines recommend total thyroidectomy for DTC, regardless of tumor size [20]. An additional surgical consideration is cervical lymph node dissection for patients with DTC. Three CPGs recommend that prophylactic central-compartment neck dissection may be performed in patients who present with a DTC with clinically uninvolved central-neck lymph nodes, especially for advanced primary tumors (nodule >4 cm) [15, 16, 20].

Recommendations for the postoperative care of DTC are varied. First, radioiodine ablation is recommended for all high-risk patients, as determined from the presence of metastases, incomplete excision, gross extrathyroidal extension of the tumor regardless of tumor size, or a primary tumor >4 cm, even in the absence of other higher-risk factors [15]. However, the NCN guidelines mention that routine postoperative I¹³¹ ablation of thyroid remnants has been shown to reduce local recurrence and improve patient survival when they have tumors more than 1 cm in diameter [22]. Moreover, the NCCN guidelines recommend that I¹³¹ ablation be performed in patients with thyroglobulin >1 ng/ml [21]. Second, all CPGs emphasized the need for TSH suppression therapy following DTC surgery. However, the target levels of the TSH varied across the guidelines. Initial TSH suppression to below 0.1 mU/L is recommended for high-risk patients [15‐17, 19‐21, 23], whereas NCN guidelines suggest the maintenance of the TSH at 0.01 to 0.1 mU/L [22]. Moreover, CPG recommendations were inconsistent regarding the maintenance of the TSH in low-risk patients.