Primary Imaging Test and Appropriate Biopsy Methods for Thyroid Nodules: Guidelines by Korean Society of Radiology and National Evidence-Based Healthcare Collaborating Agency

The Korean Society of Radiology and the National Evidence-based Healthcare Collaborating Agency developed guidelines for primary imaging tests and appropriate biopsy methods for thyroid nodules. These guidelines were developed using an adaptation process by collaboration between the development committee and the working group. The development committee, composed of research methodology experts, established the overall plan and provided support about methodological strategies. The working group, composed of radiologist experts in thyroid imaging, wrote the proposals. The guidelines recommend neck ultrasound (US) as a first-line imaging modality for the diagnosis of thyroid nodules in patients with suspected nodules, and US-guided fine-needle aspiration as a primary method for histologic examination of thyroid nodules.

# Introduction
are found in 48% of the general population via palpation, in 1967% of patients via ultrasound (US), and in 50% of autopsy specimens [bib_ref] The spectrum of thyroid disease in a community: the Whickham survey, Tunbridge [/bib_ref] [bib_ref] A 64-year-old woman with a thyroid nodule, Mandel [/bib_ref] [bib_ref] Gross and microscopic findings in clinically normal thyroid glands, Mortensen [/bib_ref] [bib_ref] Very high prevalence of thyroid nodules detected by high frequency (13 MHz)..., Guth [/bib_ref] [bib_ref] Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging, Tan [/bib_ref]. Malignancies occur in 515% of thyroid nodules [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref] [bib_ref] Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation with pathological findings, Kim [/bib_ref] , and the incidence of thyroid cancer continues to increase worldwide due to various factors including genetic and environmental factors, development of medical devices, and the widespread implementation of healthcare programs. In Korea, thyroid cancer was the most common cancer in adults in 2013, being the most prevalent cancer in females and sixth most prevalent in males.
Various imaging techniques and procedures have been developed for the differential diagnosis of thyroid nodules.

## Quality appraisal of the guidelines
The selected guidelines underwent a quality appraisal process using the Korean Appraisal of Guidelines for Research and Evaluation II tool developed by the guideline development committee. Guidelines with a score of less than 50 in the "Rigour of Development" domain were not recommended by the development committee. An exception was the "ultrasonography and the ultrasoundbased management of thyroid nodules: consensus statement and recommendations" [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref] , which was selected despite its low score because it was established by domestic thyroidimaging experts. After this process, five guidelines each were selected for Key Questions 1 and 2 (Tables 1, 2).

## Grading the level of evidence and drafting the recommendation document
The working group members reviewed evidence literatures that supported the recommendations of the selected guidelines. Grading the level of evidence of each literatures was performed according to the evidence level criteria of the K-CIG [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref]. After discussion and comparison of recommendations and their evidence literatures of selected guidelines, draft recommendations were prepared by the working group.

## Agreement of the recommendation grades
The draft written by working group was reviewed and discussed by the development committee. Then, together, both groups came to a consensus on the recommendations core needle biopsy (CNB) allow confirmation of nodules [bib_ref] Korean Society of Thyroid Radiology (KSThR) and Korean Society of Radiology. Core..., Na [/bib_ref] [bib_ref] Korean Society of Thyroid Radiology (KSThR) and Korean Society of Radiology. Ultrasonography..., Shin [/bib_ref]. The need for standardized evidence-based clinical guidelines for the management of thyroid nodules has been proposed, and the Korean Society of Radiology (KSR) and the National Evidence-based Healthcare Collaborating Agency (NECA) organized a development committee and working group to develop such guidelines [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref].

## Development of korean clinical imaging guidelines for thyroid nodules

## Committee composition
The guideline development process involved collaboration between NECA and KSR. NECA is a national agency that provides evidence-based information about medical devices, medicines, and health technology obtained through objective and reliable analyses. The development committee included medical imaging experts, research methodology specialists, and clinical guideline specialists who support the overall planning and research methodology. They published a methodology for the guideline adaptation process in imaging diagnosis [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref]. The working group included expert members of the Korean Society of Thyroid Radiology (KSThR). KSThR is an organization composed of thyroid radiologists in Korea that is primarily involved in the diagnosis and nonsurgical treatment of thyroid nodules. KSThR has published several sets of guidelines for thyroid imaging [bib_ref] Korean Society of Thyroid Radiology (KSThR) and Korean Society of Radiology. Ultrasonography..., Shin [/bib_ref] [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref] , biopsy [bib_ref] Korean Society of Thyroid Radiology (KSThR) and Korean Society of Radiology. Core..., Na [/bib_ref] , and radiofrequency ablation [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Radiofrequency ablation..., Na [/bib_ref]. The working group participated in the guideline development process and wrote recommendations [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref].

## Adaptation process of the guideline
The guideline development process employed an adaptation methodology for Korean clinical imaging guidelines (K-CIG) established by the development committee [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref].

## Defining key questions
The Key Questions selected by the working group were reviewed by the development committee and a consensus group composed of clinical experts. Two final Key Questions were identified: 1) What is the primary imaging test for diagnosis in patients with suspected thyroid nodules?
2) What is the appropriate biopsy method for thyroid nodules?
grade and the evidence level, according to the criteria of the K-CIG [bib_ref] Methodology for developing evidence-based clinical imaging guidelines: joint recommendations by Korean Society..., Choi [/bib_ref].

## Finalizing the recommendation document
The Delphi method was used for formal consensus. The consensus group was composed of clinical imaging experts, clinical imaging guidelines-related academic societies (endusers), and research methodology experts. The agreement level for each recommendation, the grade of each recommendation, and the evidence level were rated from strongly disagree (level 1) to strongly agree (level 9). After two rounds of assessment, a consensus was reached. The

## External review and approval of clinical guidelines
Final recommendations were reviewed by clinical experts of a related medical society, the Korean Thyroid Association, and appropriate modifications were made.

## Recommendations

## Key question 1) what is the primary imaging test for diagnosis in patients with suspected thyroid nodules?
[Recommendation 1] We recommend neck US for the diagnosis of thyroid nodules detected by imaging other than US or in patients with suspected thyroid nodules.
(recommendation grade A, evidence level II)

## Evidence summary
After reviewing the guidelines for diagnosis and treatment of thyroid nodules, final five guidelines were selected [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref] [bib_ref] Associazione Medici Endocrinologi, and EuropeanThyroid Association medical guidelines for clinical practice for..., Gharib [/bib_ref] [bib_ref] American Thyroid Association management guidelines for adult patients with thyroid nodules and..., Haugen [/bib_ref] [bib_ref] British Thyroid Association. Guidelines for the management of thyroid cancer, Perros [/bib_ref]. In all five guidelines, neck US is recommended for diagnosis when a thyroid nodule is suspected. US is a highly sensitive diagnostic method for thyroid nodules and can be used to diagnose nodules and determine the need for FNA tests.
According to US and the US-based management of thyroid nodules: consensus statement and recommendations, high-resolution neck US is the most sensitive method for detecting thyroid nodules, and a neck US examination is recommended for diagnosis of suspected thyroid nodules [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref]. US is used to determine the size and morphologic features of the nodule, diagnose nodal involvement, and determine the need and possibility of US-guided FNA.
According to the American Thyroid Association (ATA) Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer, US of the thyroid [bib_ref] American Thyroid Association management guidelines for adult patients with thyroid nodules and..., Haugen [/bib_ref]. It is recommended to confirm via neck US whether the lesion causing the symptom is related to the thyroid nodule; analyze the location, size, and morphological characteristics of the nodule; and ascertain whether neck lymph node metastasis has occurred [bib_ref] Society of Radiologists in Ultrasound. Management of thyroid nodules detected at US:..., Frates [/bib_ref] [bib_ref] Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of..., Smith-Bindman [/bib_ref] [bib_ref] The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review..., Brito [/bib_ref]. The British Thyroid Association (BTA) Guidelines for the Management of Thyroid Cancer define neck US as a sensitive technique for the diagnosis of thyroid nodules and recommend neck US for differential diagnosis of papillary thyroid cancer [bib_ref] British Thyroid Association. Guidelines for the management of thyroid cancer, Perros [/bib_ref]. US is useful for determining the USguided FNA test according to the morphologic findings of the nodule and for increasing the diagnosis rate [bib_ref] Comparison of palpation-guided fineneedle aspiration biopsy to ultrasound-guided fine-needle aspiration biopsy in..., Cesur [/bib_ref] [bib_ref] Implementation of evidence-based guidelines for thyroid nodule biopsy: a model for establishment..., Hambly [/bib_ref].
According to the American Association of Clinical Endocrinologists (AACE), Associazione Medici Endocrinologi (AME), and European Thyroid Association (ETA) Medical Guidelines for clinical practice for the diagnosis and management of thyroid nodules, neck US is the most useful test for the detection and diagnosis of thyroid nodule, and for the determining changes in the thyroid parenchyma [bib_ref] Associazione Medici Endocrinologi, and EuropeanThyroid Association medical guidelines for clinical practice for..., Gharib [/bib_ref]. These guidelines recommend US if a nodule needs to be touched or if there is suspicion of thyroidopathy (25), as well as to confirm thyroid pathology in the presence of palpable neck lymph nodes, because cervical lymph node metastasis due to asymptomatic thyroid cancer cannot be excluded.
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for thyroid carcinoma (ver. 2) recommend neck US as a primary diagnostic test in patients with suspected thyroid nodules (19). US-guided FNA or US follow-up should be performed based on the comprehensive result of US finding of the initial scans, together with clinical findings, thyroid-stimulating hormone levels, and thyroglobulin levels.

## Considerations for recommendations harms and benefits
Ultrasound is a very sensitive method for the detection and diagnosis of thyroid nodules. There is no risk of radiation exposure, and it is also possible to evaluate changes in the thyroid parenchyma and to examine lymph node status. US can also be used to determine the need for US-guided FNA, and improves the accuracy of diagnosis [bib_ref] Comparison of palpation-guided fineneedle aspiration biopsy to ultrasound-guided fine-needle aspiration biopsy in..., Cesur [/bib_ref] [bib_ref] Implementation of evidence-based guidelines for thyroid nodule biopsy: a model for establishment..., Hambly [/bib_ref].
However, thyroid nodules are very common and often asymptomatic. No US features that are specific to malignant thyroid nodules have been identified [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref]. Furthermore, several US findings are evident in both benign and malignant thyroid nodules [bib_ref] Society of Radiologists in Ultrasound. Management of thyroid nodules detected at US:..., Frates [/bib_ref] [bib_ref] Implementation of evidence-based guidelines for thyroid nodule biopsy: a model for establishment..., Hambly [/bib_ref] [bib_ref] Differentiation between benign and malignant solid thyroid nodules using an US classification..., Lee [/bib_ref]. This may lead to unnecessary FNA of benign nodules, which may lead to increased medical expenditures and unnecessary complications. However, the cost-effective aspect of the increase in medical expenditures may vary depending on whether or not medical insurance is applied. Finally, the US diagnosis of nodules can cause unnecessary worry and anxiety in patient.

## Acceptability and applicability
Neck US was chosen as the primary imaging method for patients with suspected or diagnosed thyroid nodule in five medical guidelines. As a result of the evaluation of domestic acceptability and applicability of these five guidelines, it was concluded that the applicability of neck US to the detection and diagnosis of thyroid nodules was reasonable.

## Radiation dose
Neck US: 0

## Key question 2) what is the appropriate biopsy method for thyroid nodules?
[Recommendation 2] Ultrasound-guided FNA is recommended for histologic examination of thyroid nodules.
(recommendation A, evidence level II)

## Evidence summary
The five final guidelines were selected for appropriate testing methods for histologic diagnosis of thyroid nodules [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref] [bib_ref] Associazione Medici Endocrinologi, and EuropeanThyroid Association medical guidelines for clinical practice for..., Gharib [/bib_ref] [bib_ref] American Thyroid Association management guidelines for adult patients with thyroid nodules and..., Haugen [/bib_ref] [bib_ref] British Thyroid Association. Guidelines for the management of thyroid cancer, Perros [/bib_ref]. All five guidelines recommend FNA for histologic examination of thyroid nodules. Moreover, according to several comparisons between palpation-guided FNA and US-guided FNA [bib_ref] Comparison of palpation-guided fineneedle aspiration biopsy to ultrasound-guided fine-needle aspiration biopsy in..., Cesur [/bib_ref] [bib_ref] Comparison of palpation-versus ultrasoundguided fine-needle aspiration biopsies in the evaluation of thyroid..., Can [/bib_ref] [bib_ref] Fine-needle aspiration biopsy of the thyroid: comparison between thyroid palpation and ultrasonography, Deandrea [/bib_ref] [bib_ref] Ultrasound-guided fine-needle aspiration biopsy of thyroid masses, Carmeci [/bib_ref] , the latter is better in terms of non-diagnostic results, specimen errors, and falsenegative results.
The BTA Guidelines for the management of thyroid cancer published in 2014 state that FNA is a valuable, costeffective preoperative test and that US-guided FNA improves the accuracy of diagnosis and reduces the probability of obtaining an inappropriate sample [bib_ref] British Thyroid Association. Guidelines for the management of thyroid cancer, Perros [/bib_ref]. In a prospective study of 215 patients, the non-diagnostic result rate (21.4%) of the US-guided FNA was significantly lower than that of Korean J Radiol 19(4), Jul/Aug 2018 kjronline.org We recommend performing FNA for nodule of any size that has suspicious malignant findings if FNA is feasible and nodule is larger than 5 mm in size. For nodule smaller than 5 mm, selective FNA can be done according to patient's risk factors and experience of radiologists. If nodule has indeterminate findings on US and it is larger than 1 cm in diameter, then performing FNA is recommended due to fact that possibility of malignancy cannot be excluded. If nodule has indeterminate findings and it is 1 cm or less in size, then FNA biopsy is not necessary and followup US would suffice. If benign appearing nodule is larger than 1 cm, then we recommend performing follow-up US in two years and thereafter at 3-5 year intervals. If benign appearing nodule (i.e., spongiform nodule) is larger than 2 cm, then selective FNA biopsy can be done. Neither FNA nor follow up US is necessary for spongiform nodule and benign appearing nodule 1 cm or less in diameter. [bib_ref] American Thyroid Association management guidelines for adult patients with thyroid nodules and..., Haugen [/bib_ref]. In a retrospective study, US-guided FNA had a significantly low non-diagnostic rate (3.5%) and false-negative rate (1%), compared to palpation-guided FNA (8.7% and 2.3%, respectively) [bib_ref] Diagnostic accuracy of conventional versus sonographyguided fine-needle aspiration biopsy of thyroid nodules, Danese [/bib_ref]. Particularly in cases of cystic, untouchable, or deep-located nodules, US-guided FNA is recommended because of the high probability of non-diagnostic result and sample errors. However, if the nodules are palpable and have a solid component, both US-guided FNA and palpation-guided FNA can be used. The diagnostic sensitivity, specificity, and accuracy of US-guided FNA were 97.1%, 100%, and 75.9%, respectively [bib_ref] Ultrasound-guided fine-needle aspiration biopsy of thyroid masses, Carmeci [/bib_ref] [bib_ref] Diagnostic accuracy of conventional versus sonographyguided fine-needle aspiration biopsy of thyroid nodules, Danese [/bib_ref].
The ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations (13) recommend performing US-guided FNA for histological diagnosis but do not cite any specific evidence.
The AACE/AME/ETA Medical Guidelines for clinical practice for the diagnosis and management of thyroid nodules published in 2010 recommend that the diagnosis of thyroid nodules should be based on the results of US and FNA, and that FNA should be done under US guidance to increase reliability and reduce the non-diagnostic result rate [bib_ref] Associazione Medici Endocrinologi, and EuropeanThyroid Association medical guidelines for clinical practice for..., Gharib [/bib_ref]. US-guided FNA is strongly recommended when nodules are not palpable or are multinodular, when patients are obese, and/or when cervical muscles are highly developed [bib_ref] Comparison of palpation-versus ultrasoundguided fine-needle aspiration biopsies in the evaluation of thyroid..., Can [/bib_ref] [bib_ref] Fine-needle aspiration biopsy of the thyroid: comparison between thyroid palpation and ultrasonography, Deandrea [/bib_ref] [bib_ref] Diagnostic accuracy of conventional versus sonographyguided fine-needle aspiration biopsy of thyroid nodules, Danese [/bib_ref] [bib_ref] Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic..., Yang [/bib_ref] [bib_ref] Thyroid nodules: clinical importance, assessment, and treatment, Gharib [/bib_ref] [bib_ref] Fine-needle aspiration cytology of the thyroid: ten years experience in a community..., Wu [/bib_ref]. In one prospective study of 386 patients, US-guided FNA showed significantly lower non-diagnostic rate (12.5%) than that of palpation-guided FNA (27.2%) [bib_ref] Comparison of palpation-versus ultrasoundguided fine-needle aspiration biopsies in the evaluation of thyroid..., Can [/bib_ref].
The NCCN Clinical Practice Guidelines for thyroid carcinoma (ver. 2) recommend that FNA should be performed for histologic diagnosis if the US findings meet the indication (19), particularly when unsuitable specimens or non-diagnostic results are obtained from previous FNAs conducted on solid nodules. However, they cite no specific evidence.

## Considerations for recommendations

## Harms and benefits
Ultrasound-guided FNA of thyroid nodules is a relatively easy and safe procedure, and is more accurate and less complicated than palpation-guided FNA [bib_ref] Comparison of palpation-guided fineneedle aspiration biopsy to ultrasound-guided fine-needle aspiration biopsy in..., Cesur [/bib_ref] [bib_ref] Comparison of palpation-versus ultrasoundguided fine-needle aspiration biopsies in the evaluation of thyroid..., Can [/bib_ref] [bib_ref] Fine-needle aspiration biopsy of the thyroid: comparison between thyroid palpation and ultrasonography, Deandrea [/bib_ref] [bib_ref] Ultrasound-guided fine-needle aspiration biopsy of thyroid masses, Carmeci [/bib_ref]. Therefore, it can be performed by any doctor who specializes in thyroid.
However, the rate of non-diagnostic results depends on various factors such as technical proficiency of the practitioner, processing errors, and internal factors of the nodule itself. Therefore, efforts should be made to minimize non-diagnostic results [bib_ref] Korean Society of Thyroid Radiology (KSThR); Korean Society of Radiology. Ultrasonography and..., Moon [/bib_ref]. Recent reports have indicated that US-guided CNB may be an alternative to FNA in the case of nodules with non-diagnostic results in previous US-guided FNA [bib_ref] Current status of core needle biopsy of the thyroid, Baek [/bib_ref] [bib_ref] The role of core-needle biopsy for thyroid nodules with initially nondiagnostic fine-needle..., Suh [/bib_ref]. The reported complication rate of US-guided FNA were 0-8.6%, and most complications were hematoma around the thyroid gland, edema of the thyroid gland, and temporary changes in the voice. Severe complications requiring hospitalization were rare. Practitioners should be familiar with the appropriate preparation, prevention, and treatment methods to avoid complications in patients with a bleeding tendency. Unnecessary US-guided FNA for benign nodules can increase patient anxiety, and lead to unnecessary medical expenditures.

## Acceptability and applicability
Ultrasound-guided FNA was recommended as an appropriate histologic examination of thyroid nodules in all five medical guidelines. It was concluded that the domestic acceptability and applicability of the five guidelines were acceptable.

## Radiation dose
Neck US: 0

## Summary
These are the first evidence-based clinical imaging guidelines for thyroid imaging in Korea, and was developed using an adaptation process. The guidelines recommend that neck US as the first-line imaging modality for diagnosing thyroid nodules detected by imaging modalities other than US or in patients with suspected thyroid nodules, and US-guided FNA for primary histologic examination of thyroid nodules. We expect that these recommendations will be helpful in the clinical practice in the management of thyroid nodules.
[fig] Figure 1, Figure 2: Flow diagram of guideline selection (Key Question 1).Remaining studies after excluding duplicates (n = 100)Records excluded by abstract screening (n = 92)Guidelines excluded by full text review (n = 3) 1) Patients are not related to Key Question (n = 1) 2) Imaging tests are not related to Key Question (n = 1) 3) Not reported appropriate outcomes (n = 0) 4) Publication type is not clinical practice guideline (Flow diagram of guideline selection (Key Question 2). [/fig]
[table] Table 1: Recommendation Matrix of Existing Guidelines (Key Question 1)84US is extremely sensitive examination for thyroid nodules. It can be specific for diagnosis of thyroid carcinoma (particularly papillary carcinoma), and aids decision making about which nodules to perform FNA i. All patients being investigated for possible thyroid cancer should undergo US of neck in secondary care by appropriate, competent practitioner [/table]
[table] Table 2: Recommendation Matrix of Existing Guidelines (Key Question 2) [/table]