Thyroid Nodules and Biopsy

Abstract

The present chapter provides an in-depth review of the prevalence, diagnostic challenges, and management strategies for thyroid nodules, emphasizing the integration of various diagnostic modalities to enhance precision and guide therapeutic decisions. Thyroid nodules are frequently encountered in clinical settings, with a significant proportion detected incidentally. While most are benign, the potential for malignancy necessitates careful evaluation, primarily through ultrasound-guided fine-needle aspiration (FNA). However, FNA has limitations, including unsatisfactory and indeterminate results, which may lead to unnecessary interventions. The chapter discusses the evolution of diagnostic techniques, including the role of ultrasonography, molecular diagnostics, and core needle biopsy, alongside traditional FNA. It highlights recent clinical experiences and studies that address diagnostic ambiguities, aiming to optimize patient outcomes by reducing unnecessary surgeries and improving diagnostic accuracy. The impact of external factors, such as the COVID-19 pandemic on thyroid nodule diagnostics, is explored. Through a comprehensive analysis, the chapter seeks to provide clinicians with updated strategies and insights into managing thyroid nodules effectively in diverse clinical contexts.

1. Introduction

Thyroid nodules are commonly detected in clinical practice, with their prevalence reported to be over 60% in radiological examinations [1, 2, 3]. Although most thyroid nodules are benign, thyroid cancer remains the most prevalent endocrine malignancy, with a relatively low rate of malignancy [3, 4, 5]. Recent data indicate a rise in the incidence of thyroid cancer, making it the thirteenth most commonly diagnosed cancer globally and the sixth most common among women [6]. The primary diagnostic method for assessing thyroid nodules preoperatively is ultrasound-guided fine-needle aspiration (FNA) biopsy [7]. However, the limitations of FNA, including unsatisfactory results in up to 20% of cases, indeterminate findings in up to 30%, and significant rates of false positives and false negatives, complicate the diagnostic process [8, 9, 10]. High concordance rates among pathologists are typically seen in clearly benign or malignant cases, but variability arises in interpreting indeterminate cytology [11, 12, 13]. Moreover, there is no consensus among pathologists regarding the precise definition of indeterminate cytology, which may include atypia of undetermined significance and follicular lesion of uncertain significance, as well as follicular neoplasm or suspicious for a follicular neoplasm, or suspicious for malignancy [14]. Due to the diagnostic uncertainties, FNA may lead to unnecessary thyroidectomies in patients where the procedure could have been avoided [15].

In light of these challenges, there has been a growing emphasis on integrating ultrasonography, molecular diagnostics, and core needle biopsy with FNA to enhance diagnostic precision and guide appropriate therapeutic decisions. This chapter assesses FNA’s efficacy and explores the role of supplementary diagnostic biopsy techniques in the preoperative management of thyroid nodules. Through this comprehensive analysis, we shared our clinical experience and reviewed the current strategies employed to mitigate diagnostic ambiguities and optimize patient outcomes in the context of thyroid nodule management.

2. Thyroid nodules

2.1 Diagnosis

Globally, iodine deficiency is the primary cause of goiter and thyroid nodule formation [16]. The prevalence of this deficiency varies significantly based on dietary iodine intake, gender, and age [17]. In regions where iodine consumption is sufficient, the prevalence of thyroid nodules is relatively low [18]. Notably, women are four times more likely to develop thyroid nodules than men, with prevalence increasing in both genders after the age of 40 [19, 20]. Thyroid nodules are typically detected during routine physical examinations by healthcare providers or when patients seek medical advice due to noticeable swelling in the neck or through elective thyroid ultrasonography (USG) [21, 22]. Incidental findings of thyroid nodules can also occur during imaging studies that do not specifically target the thyroid [23, 24]. Palpation tends to identify nodules larger than 1 cm in diameter; palpation detects thyroid nodules in about 6% of women and 1.5% of men in iodine-sufficient regions. Conversely, imaging techniques have discovered thyroid nodules in up to 70% of otherwise healthy individuals [25, 26, 27].

Thyroid nodules are often multiple, although solitary nodules can occur [28]. In studies, approximately 50% of individuals with a palpably solitary nodule were found to have multiple nodules upon USG examination [29]. Most patients with thyroid nodules are euthyroid, showing normal thyroid function without other symptomatic manifestations, though signs of hyperthyroidism or hypothyroidism can occasionally be observed [30]. Recent nonsurgical data indicate that 4–6.5% of all thyroid nodules are malignant. Upon detecting a thyroid nodule, the initial diagnostic test should involve assessing thyroid status via a TSH measurement [31, 32]. Subsequently, all patients with a suspected nodule or nodules should undergo a thyroid USG to conduct a sonographic risk assessment [33, 34]. The primary objective must be to evaluate the risk of malignancy within these nodules [35].

2.2 Clinical evaluation

When assessing a thyroid nodule, clinicians should address three critical questions: What is the functional status of the nodule (is it hyperfunctioning)? What is the risk of malignancy? Are there any compressive symptoms or signs associated with the nodule? To effectively respond to these queries, a series of diagnostic procedures should be implemented. These include a detailed patient history and physical examination, thyroid-stimulating hormone (TSH) level measurement, ultrasound imaging, and FNA for nodules presenting a higher risk of malignancy [36]. Additionally, thyroid scintigraphy is advised only for nodules that suppress TSH and are more significant than 1.5 cm in diameter [32].

As previously outlined, the etiological causes of thyroid nodules are summarized in Table 1. This table serves as a reference for understanding thyroid nodules’ potential origins and nature, guiding the diagnostic and management strategies.

Benign nodular goiter	Medullary carcinoma
Simple or hemorrhagic cysts	Anaplastic carcinoma
Follicular adenoma	Primary thyroid lymphoma
Focal thyroiditis areas	Rare primary malignancies (sarcoma, i.e.)
Papillary carcinoma	Metastatic tumors
Follicular carcinoma	Poorly differentiated carcinoma
Hurtle cell carcinoma

Table 1.

Etiological causes of thyroid nodules.

2.2.1 History and physical examination

The initial step after detecting a thyroid nodule is a comprehensive patient history collection [37]. Nodules are often incidentally discovered and are predominantly asymptomatic [38]. Rarely, a nodule may bleed internally or undergo sudden enlargement, stretching the thyroid capsule and skin, leading to pain and sensitivity [19, 39]. Rapid and painful growth should raise concerns for aggressive conditions such as anaplastic thyroid cancer, Riedel’s thyroiditis, or primary thyroid lymphoma [40, 41]. The patient history should include age, gender, body mass index (BMI), presence of metabolic syndrome, personal or family history of thyroid disease or cancer, associated syndromes such as Familial medullary thyroid cancer, endocrine neoplasia, Cowden syndrome, Carney complex, Werner syndrome, Familial adenomatous polyposis, DICER1 syndrome, previous imaging and biopsies, history of acromegaly, exposure to head or neck radiation, the growth rate of the neck mass, anterior neck pain, symptoms of dysphonia, dysphagia or dyspnea, signs of hyperthyroidism or hypothyroidism, use of iodine-containing medications or supplements, tobacco use, and stress [42].

The presence of certain risk factors may increase the potential for malignancy in thyroid nodules, summarized in Table 2. The prevalence of nodules increases with age, making them less common in children; however, the likelihood of malignancy in pediatric cases is twice that of adults [43]. Thyroid cancer rates in nodular patients, when viewed by gender, are found to be twice as high in men (8%) compared to women (4%). Additionally, the incidence of thyroid cancer is more common in adults under 30 or over 60 years compared to those between the ages of 30 and 60 [44]. Those with a history of head and neck radiation therapy or who have undergone bone marrow or solid organ transplantation have an increased incidence of cancer [45, 46].

Risk factors
Children
Adults under 30 and over 60 years
Male gender
History of head and neck radiation
Family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, or papillary thyroid carcinoma
The rapid growth of the nodule
Hard and fixed nodule on palpation
Presence of cervical lymphadenopathy
Persistent dysphonia, dysphagia, or dyspnea

Table 2.

Risk factors increasing the potential for malignancy in thyroid nodules.

The physical examination of the thyroid is the simplest and most cost-effective method for detecting nodules, though its sensitivity is relatively low depending on the examiner’s experience and the size of the palpable nodule [47]. If the thyroid gland is palpable, its size, the presence and number of nodules, irregularities in nodule borders, and consistency should be assessed [48]. Generally, nodules larger than 1 cm and anteriorly in the thyroid are palpable. During the examination, the cervical and supraclavicular lymphadenopathy should be assessed [30]. Rigid, fixed, palpable thyroid nodules, cervical lymphadenopathy, or symptoms such as hoarseness indicate malignancy. Physical findings, such as mucosal neuromas and a Marfanoid habitus, should raise suspicion for MEN 2B [49].

The most common and suitable method for grading goiter during a thyroid examination is the Pan American Health Organization (PAHO) grading system. This expanded section offers a comprehensive overview of the clinical assessment necessary for the management of thyroid nodules, detailing both the history to be gathered and the physical examination protocols:

• Grade 0. No goiter was detected visually or through palpation

• Grade 1a. No visible goiter, but palpable

• Grade 1b. Goiter is visible when the neck is slightly extended and palpable

• Grade 2. Goiter visible when the neck is in a normal position

• Grade 3. Goiter is visible from a distance and easily palpable

2.2.2 Laboratory assessment

In all patients diagnosed with a thyroid nodule, serum thyroid-stimulating hormone (TSH) levels must be measured without exception [37]. If the TSH level is low, particularly if the nodule exceeds 1.5 cm, a radionuclide thyroid scan should be conducted to determine the functionality of the nodule [29]. In cases where the nodule is identified as “hot,” it can be assumed that the risk associated with these nodules is negligible; hence, FNAB is unnecessary [50]. In patients with high TSH levels, the thyroid nodule evaluation is similar to that in euthyroid patients, and assessments should be carried out accordingly [51]. Clinicians should consider the following algorithm when evaluating patients with thyroid nodules (Figure 1).

Figure 1.

Algorithm of thyroid nodule assessment.

Thyroglobulin (Tg) should not be used as a tumor marker in evaluating thyroid nodules [50]. However, its utility becomes apparent in cases where suspicious lymphadenopathy is detected through neck ultrasound in the presence of a nodule [52]. High thyroglobulin washout values in FNAB washout fluids from lymph nodes are beneficial for detecting lymph node metastases of differentiated thyroid cancers [53]. Furthermore, preoperative Tg measurement may be prudent in patients scheduled for thyroid cancer surgery. In managing thyroid nodules, measuring calcitonin (CT) can be helpful in suspicious biopsies, repeatedly insufficient biopsies, or when the cytological diagnosis is unknown before thyroid surgery [54]. If there is suspicion of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2, calcitonin measurement is imperative and should be repeated if initially found to be elevated [55, 56]. Elevated CT levels in the presence of symptoms such as diarrhea, lymph node metastasis, or flushing warrant further investigation [56]. Significantly high calcitonin levels are diagnostic of MTC, particularly when basal CT levels exceed 100 pg/ml, suggesting a high probability of MTC [57]. For CT levels between 10 and 100 pg/ml, a pentagastrin stimulation test is recommended after ruling out renal insufficiency and using proton pump inhibitors [58]. Due to the difficulty of obtaining pentagastrin, some centers utilize long/short calcium stimulation tests as alternatives [59, 60].

2.2.3 Thyroid USG

Diagnostic thyroid ultrasound should be performed in patients suspected of having a thyroid nodule, those diagnosed with nodular goiter, or those with radiological findings indicating incidental nodules (detected in CT, MRI, or 18FDG-PET). High-resolution ultrasound is a noninvasive, cost-effective, universally applicable and repeatable imaging tool that provides a high accuracy rate with quality equipment and experienced operation [61]. Currently, it is critically essential in diagnosing and monitoring thyroid nodules [62]. Thyroid ultrasound offers the ability to confirm whether a palpable anomaly is indeed a nodule and assess its size, location, benign or suspicious characteristics, composition, and the presence of cervical lymph nodes [63]. When evaluating a thyroid nodule via ultrasound, the recommended reporting system includes:

• Nodule size (reported in three dimensions in millimeters) and its localization within the thyroid gland must always be specified.

• Nodule composition (solid, cystic, or mixed, i.e., complex)

• Nodule echogenicity (hyperechoic, isoechoic, hypoechoic, markedly hypoechoic)

• Nodule margin (well-defined and regular, indistinct and irregular)

• Calcifications (no calcifications, microcalcifications, macrocalcifications, linear, eggshell calcifications)

• Halo (a discernible rim around the nodule, either absent, thick or thin, continuous, or interrupted)

• Doppler findings (vascularity of the nodule) (Avascular—Type 1; Noticeable peripheral with minimal intra-nodular increase—Type 2; Prominent intra-nodular with minimal peripheral increase—Type 3)

The primary reason for evaluating a nodule with ultrasound is to investigate features that might predict the malignancy risk. General ultrasound characteristics of benign and malignant nodules are specified in Table 3. Additionally, certain cancer types may present characteristic features that can guide diagnosis.

Malignant features	Benign features
Hypoechoicity	Hyper/Isoechoicity
Microcalcifications or interrupted rim calcifications	Continuous edge integrity with eggshell calcifications
Irregular margins	Spongy (spongiform) nodule
Absence of halo or incomplete halo	The presence of a halo or smooth border
Increased intra-nodular vascularity (Type 3)	Absence of vascularity (Type 1) or peripheral (Type 2) vascularity
Height greater than width (in transverse section)	Purely cystic nodule
Invasion into the anterior neck muscles	Decrease in nodule size over time, multiple coalescent nodules (merged nodules)
Presence of pathological cervical LAP	Reactive features in cervical LAP

Table 3.

Malignancy based on the USG characteristics of thyroid nodules.

For instance, papillary thyroid carcinoma (PTC) typically appears solid or predominantly solid and hypoechoic, often with infiltrative irregular margins and microcalcifications [64]. In contrast, follicular thyroid carcinoma (FTC) is generally isoechoic, rarely hyperechoic, features a thick and irregular halo, and lacks microcalcifications [65]. Certain sonographic appearances can be highly diagnostic for benign nodules. For example, a purely cystic nodule (less than 2% of all nodules) or a spongiform nodule—described as having more than half of its volume filled with multiple microcystic components—indicates a 99.7% likelihood of a benign thyroid nodule.

The American College of Radiology (ACR) recently published a guide for managing thyroid nodules based on USG findings [66]. This guide introduces the ACR Thyroid Imaging Reporting and Data System (ACR-TIRADS), a five-tiered classification system [67]. ACR-TIRADS serves as a structured framework to standardize the reporting of thyroid ultrasound studies [68]. This system facilitates clear communication among healthcare providers by categorizing nodules according to their likelihood of malignancy, thereby assisting clinicians in making decisions about the need for biopsy or ongoing surveillance. The classification system ranges from TIRADS 1, suggesting no nodules are present, to TIRADS 5, indicating a high suspicion of malignancy [69]. Each level corresponds to a set of specific ultrasound characteristics, such as echogenicity, presence of microcalcifications, and nodule borders, among others, which collectively contribute to an overall risk score [70]. This score then guides the recommended clinical actions, balancing the benefits of early detection of thyroid cancer against the risks of unnecessary procedures [71]. It stratifies the risk of cancer within a thyroid nodule based on its ultrasonographic characteristics and size and also outlines the management of thyroid nodules—whether through FNAB or USG monitoring—dependent on these USG features (Tables 4 and 5).

Composition	P	Echogenicity	P	Shape	P	Margin	P	Echogenic foci	P
Cystic or almost completely cystic	0	Anechoic	0	Wider-than-tall	0	Smooth	0	None of the large comet-tail artifacts	0
Spongiform	0	Hyperechoic or isoechoic	1	Taller-than-wide	3	Ill-defined	0	Macrocalcifications	1
Mixed cystic and solid	1	Hypoechoic	2	—		Lobulated or irregular	2	Peripheral (rim) calcifications	2
Solid or almost completely solid	2	Very hypoechoic	3	—		Extrathyroidal extension	3	Punctate echogenic foci	3

Table 4.

ACR (2017)—TIRADS classification scheme for thyroid nodules.

Abbreviations. P: points.

TIRADS category	Total points	Malignancy risk (%)
TR1	0	0.3
TR2	2	1.5
TR3	3	4.8
TR4	4–6	9.1
TR5	7+	35

Table 5.

Risk stratification based on total points.

Abbreviations. TIRADS: Thyroid Imaging Reporting and Data System.

While the EU-TIRADS, developed by the European Thyroid Association (ETA), is similar to the ACR-TIRADS, it is somewhat simpler [61, 68]. The EU-TIRADS system designates irregular shapes, margins, microcalcification, and marked hypoechoicity as high-risk criteria [61]. The recommendations are summarized in Table 6.

EU-TIRADS category	Sonographic pattern	Ultrasound characteristics
EU-TIRADS 1	Normal	No nodule
EU-TIRADS 2	Benign	Pure cystic or completely spongiform
EU-TIRADS 3	Low risk	Oval, well-defined isoechoic/hyperechoic, no high-risk features
EU-TIRADS 4	Intermediate risk	Oval, well-defined, hypoechoic, no high-risk features
EU-TIRADS 5	High risk	At least one of the following: non-oval shape, irregular margins, microcalcifications, marked hypoechogenicity (and solid)

Table 6.

EU-TIRADS classification.

2.2.4 Thyroid fine-needle aspiration biopsy

Thyroid fine-needle aspiration biopsy is the decision-making tool in patients with nodules, guided by ultrasonographic and clinical findings [72]. It is the gold standard for distinguishing between benign and malignant thyroid nodules [73]. Sampling for cytological or histological examination from thyroid nodules can be performed using several techniques, including thick or fine-needle aspiration, Tru-cut biopsy needle, or fine-needle capillary sampling [74]. It is mandatory to obtain signed informed consent after providing the patient with the necessary information before the procedure. The patient lies supine on a standard examination table with a pillow under the shoulders to increase neck extension. Patients are instructed not to swallow or speak during the procedure. The biopsy is usually performed with a 25-gauge needle (ranging from 23 to 27 gauge), with or without the use of local anesthesia (such as lidocaine cream or a jet injector). The skin over the nodule is cleansed with alcohol. The nodule is then identified under ultrasound guidance, and the needle is inserted parallel or at a slight angle to the skin, following visualization of the needle shaft on the ultrasound screen. The needle tip appears brightly on the ultrasound and is advanced and monitored as it enters the nodule. The needle is moved back and forth within the nodule 4–5 times, and if necessary, aspiration is performed using a 10 ml syringe. The aspirate from the nodule is then gently and swiftly spread onto microscope slides. Each nodule is accessed once or several times, depending on its size. Experienced physicians can achieve adequate sampling from solid nodules in 90–97% [75].

The risk of obtaining bloody cell aspirate increases in patients on anticoagulant or antiplatelet therapy due to the heightened risk of bleeding within the nodule [76]. Accordingly, the possibility of reporting the nodule as non-diagnostic increases as not enough cells will be found in the examination. There are views suggesting that in patients taking antiplatelet agents, the medication should ideally be discontinued 5–7 days before to be in a safe range, although there are also opinions that the procedure can be performed without stopping the medication. Some clinicians recommend performing biopsies on patients with an INR < 2 or within the normal range. After the procedure, applying pressure to the nodule for 5–10 minutes is recommended, and performing an ultrasound for bleeding control 15–30 minutes later. Discontinuing new-generation anticoagulants, such as rivaroxaban, apixaban, and dabigatran, is not recommended before the procedure [76, 77].

In the presence of multinodular goiter, rather than biopsy the dominant nodule, each nodule should be independently evaluated, and TFNAB should be performed on each nodule were indicated based on risk factors [37]. It is recommended that the TFNAB decision be based on the EU-TIRADS score. EU-TIRADS 3 nodules >20 mm (very low risk, malignancy risk 2–4%); EU-TIRADS 4 nodules >15 mm (low-medium risk, malignancy risk 6–17%); EU-TIRADS 5 nodules >10 mm (medium-high risk, malignancy risk 26–87%) should undergo TFNAB [36, 65]. The cytology of the thyroid nodule should be reported according to the diagnostic groups stated in the Bethesda system. Since its definition for reporting thyroid cytopathology in 2007, the Bethesda system has been applied extensively and yielded consistent results [78]. Practitioners must use a common language, which plays a significant role in standardizing follow-up and treatment. The Bethesda diagnostic categories, malignancy risk, and clinical approach are summarized in Table 7.

Diagnostic category	Risk	Clinical approach
I. Nondiagnostic or unsatisfactory	5–10%	Repeat FNA under ultrasound guidance
II. Benign	0–3%	Follow-up with clinical and ultrasound assessment
III. Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS)	10–30%	Repeat FNA, molecular testing, or lobectomy
IV. Follicular neoplasm or suspicion of follicular neoplasm	25–40%	Molecular testing, lobectomy
V. Suspicious for malignancy	50–75%	Near-total thyroidectomy or lobectomy
VI. Malignant	97–99%	Near-total thyroidectomy or lobectomy

Table 7.

Bethesda diagnostic categories, malignancy risk, and clinical approach.

3. Clinical experience on thyroid nodules

We have performed two comprehensive published studies of thyroid nodules and their evaluation and management. One of these studies was about low-risk thyroid neoplasms. This study titled “investigation of preoperative demographic, biochemical, sonographic and cytopathological findings in low-risk thyroid neoplasms” explored various preoperative factors in low-risk thyroid neoplasms (LRTNs) [79]. Our research included a retrospective analysis of 2453 cases, narrowing down to 99 cases diagnosed as LRTNs. These were further divided into four subgroups, providing a rich analysis dataset. Most LRTNs were identified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features, constituting 69.7% of the cases. The volume of the index nodule was significantly different among the subgroups, serving as a potential discriminative factor in sonographic evaluations. Well-differentiated carcinoma, which was not otherwise specified, had the smallest average volume, whereas follicular tumors of uncertain malignant potential displayed the largest. Despite variations in nodule volume and other sonographic features, prognostic scores suggested similar outcomes across the groups, underscoring the complexity of predicting disease progression based solely on initial sonographic assessments. These observations suggest that while certain sonographic features like volume can aid in subgroup differentiation, the prognostic outcomes remain uncertain across different types of LRTNs.

The second study, “examining the impact of several factors including COVID-19 on thyroid fine-needle aspiration biopsy,” focused on how the pandemic might have influenced the outcomes of thyroid fine-needle aspiration biopsies (TFNAB) [80]. This retrospective observational study involved 482 thyroid nodules and examined various factors, including COVID-19 history and vaccination status. The longitudinal diameter of thyroid nodules was significantly larger in nodules, yielding diagnostic results compared to nondiagnostic ones. This point suggests that smaller nodules are more challenging to diagnose accurately. No differences were observed concerning COVID-19 history or vaccination status. It indicates that, within the study’s timeframe, these factors did not markedly affect the diagnostic yield of TFNAB.

These studies underscore the intricate balance required in thyroid nodule management, highlighting the challenges and the advancements in diagnostic techniques. The findings from the low-risk thyroid neoplasms study emphasize the nuanced differences in sonographic evaluations and the need for careful interpretation of such imaging results to guide clinical decisions. Meanwhile, the research on the impact of COVID-19 on thyroid fine-needle aspiration biopsy offers a reassuring indication that the pandemic has not significantly compromised the diagnostic effectiveness of TFNAB despite concerns to the contrary. Both strands of research collectively advance our understanding of thyroid pathology and the effects of external factors on medical diagnostics. As we continue to integrate these insights into clinical practice, they will improve the precision of diagnostic processes and enrich our strategies for managing thyroid conditions in a world where medical and societal variables are constantly evolving. This knowledge is invaluable in refining our approaches and ensuring that patient care remains informed and adaptable.

4. Conclusion

In addressing the complexities of thyroid nodule management, this chapter has illuminated the strides made in refining diagnostic procedures and therapeutic approaches. Using FNA, supplemented by advanced USG and molecular diagnostics, has dramatically enhanced our capacity to discern between benign and malignant thyroid nodules, thereby steering clinical decision-making toward more targeted and conservative treatments even though the challenges posed by indeterminate cytology and the inherent limitations of FNA, innovations in diagnostic techniques such as integrating core needle biopsy and applying refined cytological classification systems such as the Bethesda system have facilitated a more precise characterization of thyroid nodules. Moreover, the development of imaging protocols, such as ACR and EU-TIRADS, has standardized the assessment and management of thyroid nodules, contributing to a more uniform approach across clinical settings.

Our clinical experience, supported by studies on the demographic, biochemical, and sonographic variables influencing the prognosis of low-risk thyroid neoplasms as well as the resilience of thyroid diagnostics in the face of global challenges, such as the COVID-19 pandemic, emphasizes the evolving landscape of thyroid nodule management. These insights highlight the critical importance of individualized patient care and the need for continuous refinement of diagnostic and therapeutic strategies. We must continue to harness these diagnostic advancements while focusing on patient outcomes. As the field of thyroidology progresses, integrating emerging technologies and interdisciplinary approaches will be essential in addressing the nuanced needs of patients with thyroid nodules, thereby enhancing both the efficacy and safety of thyroid nodule management. This holistic and adaptive approach will undoubtedly contribute to better clinical outcomes and optimize patient care in the dynamic context of modern medicine.

Conflict of interest

The author declared no conflict of interest.

Appendix A: diagnostic imaging and ultrasound characteristics

This appendix provides detailed information on diagnostic imaging techniques, particularly ultrasound characteristics crucial in assessing thyroid nodules. It includes a reference guide for ultrasound markers associated with benign and malignant thyroid nodules, as in Table 3 of the main text.

Appendix B: bethesda diagnostic categories

This appendix elaborates on the Bethesda system for reporting thyroid cytopathology. It provides a comprehensive breakdown of each diagnostic category, associated malignancy risk, and recommended clinical approaches as outlined in Table 7 of the main text.

Appendix C: ACR and EU-TIRADS classification systems

Comparison and detailed descriptions of the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System and the European Thyroid Association (EU-TIRADS). This appendix helps clinicians understand both systems’ specific criteria and risk stratification methodologies.

Nomenclature

Thyroid-stimulating hormone (TSH)	A hormone produced by the pituitary gland that regulates the production of hormones by the thyroid gland.
Fine-needle aspiration biopsy (FNA)	A diagnostic procedure for investigating lumps or masses. In this context, it is used to sample cells from thyroid nodules.
Sonographic risk assessment	Using ultrasound features to estimate the risk of a thyroid nodule being malignant.
Medullary thyroid carcinoma (MTC)	A type of thyroid cancer that originates from the parafollicular cells (C cells) that produce the hormone calcitonin.
Thyroglobulin (Tg)	A protein produced by the thyroid gland, used as a tumor marker for certain types of thyroid cancers.
Calcitonin (CT)	A hormone produced by the thyroid gland that helps regulate calcium levels in the blood.
Pentagastrin stimulation test	A diagnostic test used to measure calcitonin levels to screen for medullary thyroid carcinoma, particularly when basal levels are moderately elevated.
ACR-TIRADS	Thyroid Imaging Reporting and Data System developed by the American College of Radiology to standardize the reporting and diagnosis of thyroid nodules based on ultrasound characteristics.
EU-TIRADS	A similar system developed by the European Thyroid Association for the same purpose as ACR-TIRADS, using slightly different criteria.