Defining inappropriate thyroid biopsy? – proposed definition based on clinical evidence and stakeholder engagement

Abstract

Purpose.

Identify factors that can be used to assess the appropriateness of a thyroid biopsy and propose a pathway to define inappropriate thyroid biopsies in practice.

Methods.

We identified factors utilized in clinical guidelines and existing literature to determine the clinical indications for a thyroid biopsy. Subsequently, we assembled a multidisciplinary panel of experts, including patients, clinicians, researchers and quality experts, to integrate these factors and develop a pathway for assessing the appropriateness of thyroid biopsies.

Results.

Through literature review and stakeholder engagement, we identified multiple factors to determine if a thyroid biopsy is necessary: ultrasound risk assessment, presence of symptoms and/or clinical suspicion of high-risk thyroid cancer, life expectancy, comorbidity burden, surgical risk, personal risk factors for thyroid cancer, thyroid function levels, local resources and medical expertise and patient values and preferences. We proposed a multiple-tier classification for the appropriateness of thyroid biopsy that begins with ultrasound findings (e.g., size, thyroid cancer risk) and encompasses the evaluation of additional patient-specific factors.

Conclusion.

Assessment of the appropriateness of a thyroid biopsy is possible. Although, thyroid nodule ultrasound risk assessment is a pivotal factor for this assessment, additional factors should be considered (e.g., life expectancy, personal risk factors for thyroid cancer, patient preferences). Yet, additional efforts are needed to operationalize the objective implementation of these factors in clinical practice.

Introduction

The rate of thyroid biopsy in the U.S. doubled between 2006 and 2011, a 16% annual growth.¹ Fine needle thyroid aspiration biopsy (thyroid biopsy) is a pivotal step in the diagnostic cascade that leads to thyroid cancer diagnosis, and an inappropriate selection of patients for thyroid biopsy precedes and contributes to the increased rates of thyroid cancer diagnosis, most of which represent low risk thyroid cancer.^2,3 To intervene in the diagnostic cascade of thyroid nodules that leads to overdiagnosis and associated harms, we need to understand not only the number of biopsies that are performed but which biopsies are unlikely to derive patient benefit.^5–7 Different criteria have been used to classify thyroid biopsies as appropriate or not and expand from biopsy results (e.g., benign cytological results) to contextualized recommendations according to patient factors (e.g., life expectancy).^2,8 Identification of important factors that guide the decision for a thyroid biopsy and engagement of stakeholders can help us identify situations in which a thyroid biopsy is clearly appropriate or inappropriate; the first step to develop upstream interventions that could mitigate the harms of thyroid cancer overdiagnosis.^7,9

Methods

The goal of this study was to develop a pathway to assess the appropriateness of a thyroid biopsy. To achieve this goal, we followed a two-step iterative process that included 1) a focused literature review, including clinical guidelines to identify factors used to define the appropriateness of a thyroid biopsy, and 2) input from a multidisciplinary team of key stakeholders on the identified factors to co-develop a pathway for the assessment of thyroid biopsy appropriateness.

1. Focused literature review. A comprehensive search of several databases from 2000 to Feb 2nd, 2023, English language, was conducted. The search strategy is available in the Appendix1. Additionally, we searched for available clinical practice guidelines for patients with thyroid nodules.

2. Stakeholder engagement. We recruited a multidisciplinary expert panel of 11 members, including primary care and endocrinology physicians, surgeons, radiologists, quality improvement experts, research methodologists, and patients. Non-patient panelists were identified through research networks, publications, and freely available information from professional societies. Patients were identified from the University of Florida Endocrinology Clinic. The University of Florida IRB approved this study, and participants completed informed consent and received compensation for study participation.

Panel members participated in three one hour remote sessions led by the research team (NSO). We used a modified Delphi approach for stakeholder engagement, including item identification, independent item ranking and case prompt discussions.¹⁰ During the first session, the research team presented short topic introductions, including clinical background on thyroid cancer and presented an initial definition of, and items related to, inappropriate thyroid biopsy based on clinical guidelines and literature review. Between the first and second meeting, panelists responded to an online survey to refine the items included in the initial definition of inappropriate thyroid biopsy (e.g., thyroid nodule ultrasound features, life expectancy, patient preferences) and decided which items to keep, eliminate or add. During the second meeting, the definition of inappropriate thyroid biopsy was updated based on the initial feedback and further refined based on the panel’s input. During the last session, the research team presented 5 cases and asked panelists to classify as a recommendation for thyroid biopsy as appropriate or inappropriate following the proposed definition. Panelist completed a final survey to provide approval or concerns on the final definition of inappropriate thyroid biopsy.

Results

Based on the literature review, we identified the following factors as part of definitions of thyroid biopsy appropriateness: 1) thyroid biopsy result (e.g., benign cytological result considered unnecessary), 2) ultrasound risk assessment (e.g., risk for thyroid cancer, nodule size), 3) presence of symptoms, 4) life expectancy, 5) comorbidity burden, 6) personal risk factors for thyroid cancer, 7) thyroid function levels, 8) local resources and expertise and 9) patient values and preferences.^{2,4,6,8,11–16}

After presenting these factors to the stakeholder group we reached several significant conclusions. Firstly, the panel identified specific scenarios in which the proposed definition would not be applicable. These unique circumstances encompassed cases involving a previous thyroid biopsy, toxic adenoma, or pregnancy. Secondly, even though a benign thyroid cytological result might suggest that a biopsy was unnecessary, the current definition primarily centers on the decision to perform the biopsy itself. Moreover, it was emphasized that comorbidity burden should serve as a contextual factor in assessing the necessity of a thyroid biopsy. This typically involves considering the deferral of a biopsy in cases of high comorbidity burden. However, it’s equally important to recognize situations where the presence of comorbidities can support the clinical need for a thyroid biopsy, such as in cases of solid organ transplantation, where biopsy might be required as part of eligibility criteria, or concomitant primary hyperparathyroidism.

During the ranking exercise, no additional criteria were added, and thyroid nodule ultrasound findings were considered the most important criteria, followed by risk factors for thyroid cancer, symptoms from the thyroid nodule, high surgical risk/life expectancy/comorbidities, and patient preference. The panel agreed on removing local resources or access to care, as this will be homogenous within their practices and considered a more important criterion for those practicing in referral hospitals. When operationalizing these criteria, the panel agreed on the use of guidelines to assess ultrasound factors, and clinical evaluation for the presence of risk factors for thyroid cancer or symptoms. Moreover, symptoms, also include those that might suggest high risk thyroid cancer (e.g., rapid growth or factors that raise clinical concern for anaplastic/medullary thyroid cancer). Although surgical risk, life expectancy, and comorbidities were considered important by clinical guidelines and panelists, there was a lack of clinical evidence related to particular cut-offs or tools to support the objective integration of these factors in practice.^3,15,17 Based on indirect data, the panel considered a cut-off < 5 years of life expectancy as conservative for the definition of possible inappropriate thyroid biopsies or the presence of end-stage liver, cardiac, renal disease, or active chemotherapy treatment.

The final operationalized pathway for assessing thyroid biopsy appropriateness is found in Figure 1. It starts with the classification of thyroid biopsy appropriateness based on thyroid nodule ultrasound findings. In cases in which a biopsy is considered likely appropriate based on ultrasound findings, cases in which life expectancy was < 5 years, the surgical risk or comorbidity index was high (e.g., active chemotherapy, end stage cardiac, renal or liver disease), these biopsies were considered possible inappropriate. In cases in which the biopsy is considered likely inappropriate according to ultrasound findings, the presence of risk factors for thyroid cancer, comorbidities (e.g., primary hyperparathyroidism, eligibility for organ transplant), patient preferences, high risk features/symptoms can suggest these biopsies are likely appropriate. Finally, if the thyroid biopsy is likely inappropriate according to ultrasound findings and performed in patients with life expectancy < 5 years and, high surgical risk/comorbidity index these can be considered extremely inappropriate. The proposed definition was used successfully to categorize five cases during the last panel meeting, and the panel recommended no final further changes. (Appendix)

Figure 1.

Pathway for assessing thyroid biopsy appropriateness

Discussion

Thyroid biopsies are a common and safe procedure in clinical practice.^1,2 Yet, thyroid biopsies are an important component of the diagnostic cascade of patients with thyroid nodules, leading to overdiagnosing thyroid cancer and associated harms.⁶ The first step to mitigate harm from inappropriate use of thyroid biopsy is to measure and understand the magnitude of the problem, in this case, how many thyroid biopsies are performed that are unlikely to derive clinical benefit and only exposes patient to harm.^7,9 We reviewed clinical evidence and practice guidelines to identify variables considered important when deciding if a thyroid biopsy is appropriate and engaged a multidisciplinary panel of experts to conceptualize and propose a pathway to assess the appropriateness of thyroid biopsy. As expected, the main driver of this assessment relates to thyroid nodule ultrasound assessment. Yet, other factors such as the presence of nodule symptoms, concerns for high risk thyroid cancer, risk factors for thyroid cancer, patient preferences, life expectancy and comorbidities need to be considered to understand if a thyroid biopsy is necessary.^7,18

A strength of this study is the evidence based approach to identifying the most important criteria according to the clinical literature and the engagement of a multidisciplinary team of stakeholders that can provide additional and complementary insight. Yet, our expert panel was based on members of academic institutions in the U.S. and further studies can build on our proposed definition by incorporating the insight from a larger and more diverse group of stakeholders. Moreover, although we were able to identify factors that are important for decision making, there was paucity of data when deciding particular threshold for some of these variables, different weight of these variables in decision making or tools that could support the use of these variables in practice. For example, limited life expectancy, high surgical risk, or comorbidity burden is likely to be associated with more harm than benefit in the case of underlying low-risk thyroid cancer, but how to define “limited” or “high” is unclear.

The definition of thyroid biopsy appropriateness that goes beyond the findings of thyroid nodule risk stratification can support patient centered care for patients with thyroid nodules and help mitigate harms from unnecessary procedures.^6,7,9,18 Our results suggest, this classification might be more challenging in patients with thyroid nodules when assessed at the point of care (e.g. to guide management) as well as after the event (e.g., health service research) as although it is anchored in ultrasound findings a series of additional contextual factors need to be evaluated. Yet, our proposed pathway and tiers could help us identify those with likely inappropriate and extremely inappropriate thyroid biopsies and serve as a first step to help understand the magnitude and downstream consequence of inappropriate thyroid biopsies in practice.

Table 1.

Clinical guidelines for the management of patients with thyroid nodules. Recommendations for thyroid biopsy according to ultrasound features (and other clinical factors.

Society, Year	Biopsy of Thyroid Nodule <1 cm	Clinical Factors Affecting Decision	Other Biopsy Recommendations
American Thyroid Association, 2015	Not recommended for any risk category	Surgical risk Life expectancy Age Patient preference	High suspicion: biopsy ≥1 cm Intermediate suspicion: biopsy ≥1 cm Low suspicion: biopsy ≥1.5 cm Very low suspicion: consider biopsy ≥2 cm Benign: no biopsy
American College of Radiology, 2017	Not recommended for any risk category	Referring physician’s preference Patient’s risk factors for thyroid cancer Anxiety Comorbidities Life expectancy	TR1: no biopsy TR2: no biopsy TR3: biopsy ≥2.5 cm TR4: biopsy ≥1.5 cm TR5: biopsy ≥1 cm
American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE) and Associazione Medici Endocrinologi (AME), 2016	FNA is recommended for the following high-risk nodules 0.5 to 1 cm: Subcapsular or paratracheal lesions Suspicious lymph nodes or extrathyroid spread Positive personal or family history of thyroid cancer History of head and neck irradiation Coexistent suspicious clinical findings (e.g., dysphonia)	Clinical setting Operator expertise	Class 1 Low risk: >2 cm and increasing in size or associated with a high-risk history and before thyroid surgery or minimally invasive ablation therapy. Class 2 Intermediate risk: >2 cm Class 3 High risk: >1 cm
European Thyroid Association, 2017	High risk nodules <1 cm can be given the option of biopsy	Surgical risk Life expectancy Patient preference	EU-TIRADS 1, normal, No biopsy EU-TIRADS 2, benign, No biopsy, unless compressive symptoms EU-TIRADS 3, low risk, >2 cm EU -TIRADS 4, intermediate risk, >1.5 cm EU-TIRADS 5, high risk, >1 cm
Korean Thyroid Association, 2016	Selective strategy for 0.5–1 cm nodules, biopsy should be performed for patients with risk factors requiring immediate surgery, who have poor prognostic factors (extra-thyroidal extension and nodal or distant metastasis, subcapsular nodules with possible tumor invasion of the trachea or the recurrent laryngeal nerve, or evidence of tumor progression (≥3 mm) upon serial examination)	Clinical risk factors for thyroid cancer Age Life expectancy Surgical risk	1 No nodule: no biopsy 2 Benign: ≥2 cm 3 Low suspicion: ≥1.5 cm 4 Intermediate suspicion: ≥1 cm 5 High suspicion: ≥1 cm
Latin American Thyroid Society, 2009	Nodules <1 cm should be evaluated by fine-needle aspiration biopsy only in patients with history of familial thyroid cancer, multiple endocrine neoplasia 2, cervical irradiation during childhood, or suspicious ultrasound findings (growth, extracapsular invasion, lymph nodes)	Clinical variables that affect thyroid cancer risk	All solid and solitary nodules ≥ 1 cm should be evaluated with biopsy
National Netherlands, 2015	Not recommended	Risk factors for thyroid cancer Mechanism of detection	Biopsy only of palpable (i.e., usually >1 cm) thyroid nodules and nondecreased TSH value

Abbreviations: FNA, fine needle aspiration biopsy; TR1–5, American College of Radiologists Thyroid Imaging Reporting and Data System categories; EU-TIRADS 1–5, European Thyroid Imaging Reporting and Data System categories.