Current controversies in the management of patients with indeterminate thyroid nodules

Thyroid nodules (TNs), which are clinically palpable in approximately 5% of adults, are a common surgical condition.¹ Neck ultrasound (US), a simple and useful tool in the assessment of TNs, is by far more sensitive than clinical palpation in detecting TNs with a prevalence of 20-76%. Although the majority of TNs are benign and asymptomatic, the risk of malignant transformation ranges between 5 and 15%.² The risk of malignancy (ROM) in a solitary TN ranges from 2.7% to 33%; however, from 1.4% to 10% in a multinodular goiter. Barroeta et al³ reported that the ROM is equal in one or 2 TNs >1 cm and decreases with ≥3 TNs.

Fine-needle aspiration cytology (FNAC) is a valuable diagnostic modality to evaluate TNs. It is characterized by high accuracy rates in detecting most benign and malignant conditions, such as papillary thyroid cancer (PTC) and anaplastic thyroid cancer. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), which is commonly used, has a 97% sensitivity, a 50.7% specificity, a 3% false-negative rate, and a 0.5% false-positive rate.⁴ However, 25% of all FNAC diagnoses are in a gray zone of uncertain cytology; they are referred to as “cytologically indeterminate TNs” (CITNs). In these categories, no or little colloid is detected, and it is difficult to distinguish malignant tumors (follicular variant of PTC and follicular carcinoma) from benign lesions (nodular adenomatous goiter and follicular adenoma).⁵

Cytologically indeterminate TNs comprise the categories Bethesda III, which is called atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS), and Bethesda IV, which is called follicular neoplasm (FN) or suspicious for a follicular neoplasm (SFN). Both Bethesda categories are known for their ambiguity and heterogeneity and the ROM is 5–15% in Bethesda III and 15-30% in Bethesda IV.^2,6 However, according to an updated TBSRTC version, the respective ROMs are 6-18% and 10–40% if noninvasive follicular thyroid neoplasm with papillary-like nuclear features is not considered a malignancy. When it is included in the malignancy risk assessment, the ROM increases to 10–30% in AUS/FLUS and 25-40% in FN/SFN nodules.7 Notably, the actual ROMs in surgically excised AUS/FLUS nodules range from 6% to 48% and in FN/SFN resected nodules from 14% to 34%.⁸

Although 70-80% of CITNs have benign histology after surgery, they remain a clinically challenging group, and an accurate estimation of their ROM is critical.4,5 In addition, being heterogeneous categories, their management remains difficult as to whether a conservative approach with long-term observation or surgical intervention should be chosen.9 According to TBSRTC, the recommended strategy for Bethesda III TNs is a repeat FNAC, molecular testing, or diagnostic lobectomy, whereas in Bethesda IV TNs, the usual management is molecular testing or diagnostic lobectomy.⁷

Cytologically indeterminate TNs have been studied from a variety of perspectives, including clinical, radiological, cytological, biochemical, and molecular markers. In recent years, a personalized approach has been recommended for patients with CITNs.¹⁰ The overarching aim is to make a diagnosis in order to treat malignant TNs while avoiding unnecessary invasive surgical procedures in asymptomatic benign TNs.¹¹ Table 1 summarizes different studies of CITNs in Saudi Arabia. Moreover, this is the first review from the Gulf region regarding the management of these specific nodules.

Clinical features

In general, a clinical assessment is the first step in TN evaluation. Compressive symptoms, rapidly growing nodules, male gender, a family history of thyroid cancer, age of presentation <20 years or >70 years, and previous radiation exposure, particularly during childhood, are all potential risk factors for malignancy. Thyroid nodules greater than 4 cm in size, fixed and hard nodules, the presence of cervical lymphadenopathy and distant metastases, and vocal fold immobility are signs suggestive of malignancy.¹⁸

It has been reported that male gender increases ROM in patients with CITNs, particularly when Hürthle cells are present.⁵ This is confirmed by pooled data from a meta-analysis suggesting that male patients have a higher ROM than female patients.⁵ Similarly, a retrospective study of 115 cases of AUS/FLUS found a significant correlation between gender and ROM, with men (64.3%) having a higher ROM than women (41.4%).13 In contrast, some authors found no statistically significant relationship between ROM and gender in patients with CITNs.^19-21 Interestingly, Sorrenti et al²² found that classical and follicular variants were more common in male patients, whereas more aggressive subtypes of PTC (tall cell, sclerosing, oncocytic) were more prevalent in female patients.

The effect of age as a risk factor for malignancy in CITNs is still a matter of controversy. Notably, some reports found that patients with ages more than 40 or 50 years had a higher ROM. Likewise, some studies have reported that the ROM increases at the extremes of age.5 Based on univariate logistic regression analyses, Ho et al²³ concluded that AUS/FLUS patients with younger ages along with some US findings had a higher probability of undergoing surgery. However, other studies found no significant correlation between ROM and age.^{2,13,19-21,24} Furthermore, it has been reported that older patients with TNs had a higher ROM.²⁵

Repeat FNAC

When repeating FNAC in patients with CITNs, 76.0% had the same cytological diagnosis (Bethesda III or IV), whereas 7.4% of CITNs were reclassified as benign.²⁶ Furthermore, repeat US-guided FNAC revised the diagnosis to malignancy and suspicious for malignancy in 20% of patients who eventually underwent the proper procedure of total thyroidectomy (TT).²⁶ Another report showed that repeating FNAC in AUS/FLUS TNs results in a more definitive diagnosis in 56–68% of cases, whereas 15.6-48.6% of patients will have the same cytological AUS/FLUS diagnosis.21 Based on a retrospective cohort study, it has been concluded that repeating FNAC in AUS/FLUS TNs is crucial and aids in discriminating benign from malignant TNs.13 This was also supported by the results of Chen et al²⁷ and Broome et al.²⁸ Furthermore, repeating FNAC in AUS/FLUS nodules >3 months after the initial diagnosis resulted in a higher diagnostic resolution (29).

A recent meta-analysis found that repeating FNAC helped reclassify two-thirds of the AUS/FLUS nodules into a more definitive category. Notably, 50% of the nodules were reclassified as benign with a negative predictive value of >96%. The authors of that study recommend repeat FNACs in the setting of AUS/FLUS TNs, especially in countries in which molecular testing is not available.³⁰

Ultrasound features

Different medical societies have developed various US guidelines to reduce unnecessary FNACs and to better estimate cancer risk, but no single sonographic characteristic can appropriately discriminate benign from malignant TNs.^8,31-37

Generally, TNs with hypoechogenicity, solid components, irregular margins, microcalcifications, taller than wider shapes, rim calcifications with small extrusive soft tissue components, and extrathyroidal extension all increase ROM by 70–90%.8 Eisa et al³⁸ found that nuclear atypia along, with certain US features, is valuable in determining AUS patients with a higher ROM. Similarly, Barbosa et al¹¹ suggested that the 2015 American Thyroid Association (ATA) and American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) guidelines may help in the management of patients with CITNs.

A recent study comparing the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) with the ACR TI-RADS guidelines in the assessment of cancer risk of CITNs showed that both guidelines had comparable diagnostic performances for assessing the ROM of CITNs. Furthermore, the K-TIRADS aided in the assessment of the ROM of CITNs, particularly in PTC-prevalent areas.³⁹ A retrospective study of 110 AUS/FLUS cases concluded that US features and ACR TI-RADS scoring were ineffective in distinguishing benign from malignant lesions.¹⁷ Other reports confirmed these findings,^2,21,40 Kotecka-Blicharz et al4 demonstrated that US features were insufficient for determining the ROM of CITNs, and patients with CITNs were overtreated based on current diagnostic tools available in Poland.

A retrospective observational study showed that the pattern of malignancy in CITNs was well-differentiated, with low-risk follicular behavior and a favorable outcome regardless of nodule size. The authors of that study concluded that the extent of thyroidectomy (depending on tumor size and in the absence of other potential risk factors) contributes to overtreatment in the majority of patients.⁴¹

According to a recent cohort study of 652 CITNs, the vast majority (>90%) of cases were benign or low-risk malignant tumors. Therefore, the authors recommended lobectomy as an initial sufficient procedure independent of tumor size if other indications for total thyroidectomy were absent.⁴² In contrast, in a meta-analysis of 3,494 patients with CITNs, the ROM was higher in nodules with a diameter of >4 cm.⁵

Of note, a negative 18F-fluorodeoxyglucose positron emission tomography/computed tomography result helps in determining a benign histopathology and can, thereby, aid in avoiding unnecessary surgery due to its high negative predictive rate.⁴³

Surgery

The extent of thyroidectomy (TT versus hemithyroidectomy [HT]) is determined by the presence of other factors such as clinical (history of radiation exposure), radiological (such as size >4 cm), and cytological features, as well as the molecular status. These factors should be considered in conjunction with other indicators such as the presence of comorbidities, hyperthyroidism, contralateral nodules, and ultimately the patient’s preference.⁴¹

Some researchers argue that TT is required in the setting of CITNs because this allows the histopathologist to evaluate the whole gland and determine extrathyroidal extension, histologic variants of the tumor, and multifocality.^44-46 Other authors advocate that TT should be considered for patients with CITNs with worrisome features on US, size >3-4 cm, progressive growth of nodules, and in the presence of clinical risk factors.²⁵

In contrast, HT is sufficient for lesions ≤1 cm in size.^44-46 According to the 2015 ATA guidelines, lobectomy alone is sufficient in most patients.8Similarly, Almquist and Muth recommend HT without lymph node dissection as the procedure of choice in patients with CITNs.⁴⁷ In contrast, Jooya et al²⁶ argue that HT is not the ideal procedure in patients with CITNs because it is either insufficient in the setting of malignant nodules or unnecessary in the setting of benign lesions. Schneider et al⁴⁸ found that 30% of patients with CITNs had an insufficient initial thyroidectomy (under- or overtreatment). The study by Kotecka Blicharz et al⁴ concluded that the vast majority of patients were overtreated by using TT instead of lobectomy resulting in postoperative complications such as hypoparathyroidism, recurrent laryngeal nerve palsy, and hypothyroidism.

Some authors proposed “watchful waiting” as a strategic management option in certain patients with AUS/FLUS in the event of low epidemiological and radiological risk or according to the patients’ preferences. It can also be considered in older FN/SFN patients with coexisting comorbidities and increased surgical risk.⁴⁷

Molecular testing

Molecular testing is an effective tool for guiding CITN management.⁹ Based on the ATA recommendations, molecular findings may influence the extent of thyroidectomy and the management of CITNs, especially whether surgical treatment or follow-up should be considered.⁴ A study by Duick et al⁴⁹ demonstrated a significant reduction in diagnostic surgeries of CITNs after the implementation of the Afirma® Gene Expression Classifier test. Furthermore, molecular testing during FNAC may be valuable in the diagnostic workup of CITNs.4 Unfortunately, the unavailability of these markers prevents their use in most centers. Furthermore, molecular testing increases both complexity and cost of management.²⁴

Cytological subtypes

Several studies have concluded that the presence of nuclear atypia raises the ROM in both Bethesda III and IV categories.^38,50,51 Eisa et al³⁸ concluded that both ATA high-risk US findings and nuclear atypia are valuable in determining AUS patients with an increased ROM. Yoo et al⁵¹ utilized different US risk stratification systems in their study (ATA, K-TIRADS, ACR TI-RADS, and European TIRADS). They also concluded that the categorization of AUS/FLUS nodules using such guidelines is helpful for determining the best treatment, particularly when combined with findings of the cytological subtype.

Furthermore, the ROM of AUS/FLUS nodules with cytologic atypia is higher than that of AUS/FLUS nodules with architectural atypia, and surgery can be considered in such lesions with low or indeterminate suspicious features. However, the ROM of AUS/FLUS nodules with architectural atypia is low (12.5%), whereas the risk was found to be 50% in the high suspicion category.⁵¹ Therefore, cytological subclassification in CITNs is a valuable adjunct tool in risk stratification for both diagnostic and therapeutic purposes.⁵⁰

Biochemical markers

Several studies have been carried out to examine the roles of anti-thyroid antibodies and thyroid-stimulating hormone (TSH) in all cytological categories of TNs.^52-57 However, very few studies addressed the effects of these markers in CITNs.^44,55,58

Adhami et al58 found that anti-thyroid antibodies (thyroglobulin antibodies and thyroid peroxidase antibodies) and TSH levels were linked to higher ROM in patients with CITNs. Thyroglobulin antibodies and TSH may also be indicators of aggressive tumor biology. Thus, they can be utilized for diagnosis and prognosis. Another study found that preoperative thyroglobulin antibodies could be used to detect PTC in CITNs, potentially improving diagnostic accuracy. This suggests that thyroglobulin antibodies positivity may influence the clinical evaluation and subsequent patient selection for TT.⁴⁴ A recent retrospective study of 342 patients with AUS/FLUS found that a higher preoperative TSH level could be a valuable tool in predicting thyroid malignancy.¹⁰ Certain US features with TSH levels >4.5 mIU/L were associated with a higher ROM; however, this did not reach statistical significance.²⁴ This is supported by additional reports.^59,60 Low TSH levels, on the other hand, cause less thyroid epithelial cell differentiation and increase the risk of malignant cell transformation in 3 variants.⁶¹ Another study showed a significantly lower PTC rate in patients with TSH levels <0.4 mU/L compared to patients with TSH levels >3.4 mU/L.⁶²

In conclusion, the clinical management of CITNs remains controversial and challenging. Therefore, in recent years, personalized approaches have been recommended. Suspicious clinical, radiological, and cytological features, as well as biochemical data and molecular analysis, should be considered and weighted to stratify cancer risk and aid in the management of patients with CITNs. Furthermore, large collaborative multicenter prospective studies are needed to overcome these challenges.