Performance of current ultrasound-based malignancy risk stratification systems for thyroid nodules in patients with follicular neoplasms

Both follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC) originate from follicular cells [1]. FTC is the second most common thyroid malignancy accounting for 10–15% of all malignant thyroid tumors. FTC shows a high propensity for hematogenous spread and 15% to 27% of these patients develop distant metastasis [2, 3]. Compared with papillary thyroid carcinoma (PTC), which is the most common subtype of thyroid cancer (approximately 80%), patients with FTC have a twofold higher risk of lung metastasis and tenfold higher risk of bone metastasis resulting in worse survival outcomes [2, 4, 5]. However, preoperative differentiation of FTC from its benign counterpart (FTA) is an inherently challenging aspect of management of thyroid nodules.

Ultrasound is the first-line imaging tool to evaluate the risk of malignancy and for formulating the optimal management strategy, including determining the indication for fine-needle aspiration (FNA), and informing treatment decision-making (surgical resection, monitoring, or no follow-up) [6]. Use of a single parameter for ultrasound evaluation may lead to inter-observer variability resulting in suboptimal sensitivity and specificity [7]. To standardize the evaluation of malignant thyroid nodules, various clinical societies have recently developed ultrasound-based malignancy risk stratification systems [8‐13]. Based on the different versions of the Thyroid Imaging Reporting and Data System (TIRADS), several “pattern-based” systems and “score-based” systems have been established. The former are represented by 2015 ATA (American Thyroid Association), AACE/ACE/AME (American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinology), K-TIRADS (Korean Society of Thyroid Radiology), and EU-TIRADS (European Thyroid Association). The latter include ACR-TIRADS (American College of Radiology) and C-TIRADS (2020 Chinese Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules). All these systems have shown reliable performance for the diagnosis and for selecting candidates for FNA [14‐17].

As mentioned above, there are considerable differences in the incidence rates of various thyroid cancer subtypes [2]. In previous studies that evaluated these systems, the vast majority of malignant specimens were PTCs (88.9 to 99.6%) [18], which may have introduced an element of bias. Ultrasonographic features of FTC and PTC are considerably different [3]. The established malignant features, including hypoechogenicity, irregular margins, microcalcifications, and nonparallel orientation, are more common in PTC than in FTC.

Currently, few studies have focused on the value of ultrasound-based malignancy risk stratification systems in patients with follicular neoplasms [19‐21]. The performance of these systems in distinguishing FTC from FTA and in correctly determining the indications for biopsy is uncertain. Thus, we hypothesized that the relevant conclusions reported in the past could not be simply extrapolated to follicular tumors.

In this study, we aimed to investigate the performance of the currently used systems in the context of follicular neoplasms. For this purpose, we compared the ability of the current systems in distinguishing FTC from FTA. Additionally, we assessed whether these systems can help identify the nodules that require a biopsy and can reduce the rate of unnecessary biopsies.

This retrospective study was approved by the Institutional Review Board, and the requirement for informed consent to review images and medical records was waived.

A total of 329 patients (329 nodules) were included in this study. These included 216 (65.7%) women and 113 (34.3%) men; the mean age of patients was 43.5 ± 14.3 years (range, 3–82).

Our study showed that the stratification systems did not help distinguish FTA from FTC. In addition, while the systems showed acceptable performance for correctly determining the indication for biopsy in FTC, the performance with respect to reducing unnecessary biopsy was unsatisfactory.

In this study, on using high or intermediate suspicious stratification as the positive cutoff for FTC, the AUCs of all six systems (0.511 to 0.611) were less than 0.700. A Korean study that focused on the performance of K-TIRADS in classifying follicular neoplasms found the low efficiency of K-TIRADS using the same cutoff (AUC = 0.575, p = 0.439) [19]. However, Liu et al reported acceptable performances of 2015 ATA (AUC = 0.744, p < 0.001) and ACR-TIRADS (AUC = 0.744, p < 0.001) for distinguishing follicular neoplasms [20]. In our study, AUCs of K-TIRADS, EU-TIRADS, ACR-TIRADS, and C-TIRADS were disappointing (AUC = 0.573–0.611, p < 0.05). It may be difficult to improve clinical management of nodules based on these systems. The poor performance is attributable to the fact that follicular neoplasms present with substantially overlapping ultrasound features, and FTCs rarely present with features favoring malignancy as described in the current systems, such as nonparallel, markedly hypoechoic, irregular margin, and microcalcifications [3, 22, 23]. A recent meta-analysis identified sonographic features for differentiating between FTA and FTC and found that tumor protrusion, presence of calcifications (irrespective of type), irregular margins, marked hypoechogenicity, and irregular shape were associated with high risk of FTC [24]. Our group found similar high-risk features, such as presence of calcifications (10.7% vs 20.84%, p < 0.001) and irregular shape (1.1% vs 14.9%, p < 0.001). Therefore, future systems may need to reassess the significance of these features in distinguishing follicular neoplasms.

In addition, our study found that “pattern-based” systems (2015 ATA, AACE/ACE/AME, K-TIRADS, and EU-TIRADS) had more limitations in the classification of follicular neoplasms than previously reported in the literature [19‐21], in contrast to the “score-based” systems (ACR-TIRADS and C-TIRADS). Given the limitations of pattern-based systems in the classification of follicular neoplasms, these systems should incorporate findings, such as undetermined composition, irregular shape, iso/hyperechoic with microcalcification and ill-defined margin (Table 4), or switch to “score-based” systems in the future.

In our cohort, the missed biopsy rates for all FTCs ranged from 9.0 to 22.4% and for FTCs ≤ 4 cm ranged from 16.2 to 35.1%, which is concordant with the study by Castellana et al [21] in which 0 to 31% of FTCs were missed. Therefore, we believe that all six systems assessed in this study are effective tools to select FTC for FNA in clinical practice. In fact, previous studies have shown that follicular neoplasms are large [22‐27]. The mean maximum diameter of FTC (3.9 ± 2.1 cm) in our study was higher than any threshold proposed for ultrasound-based malignancy risk stratification systems. The highest maximum diameter was up to 12.1 cm, which is the main reason for the high performance in selecting FTC for FNA. Besides, the size of FTC at the time of management is important. FTCs larger than 2 cm have a higher risk of distant metastasis and are associated with worse prognosis [28]. In our study, a satisfactory performance (0 to 20.0%) was also seen for FTCs sized 2 to 4 cm. Apart from unclassifiable nodules, missed FTCs were classified as category 2 and 3 by ACR-TIRADS, and as category 3 by C-TIRADS. There were 4 FTC lesions that were missed by both systems, including a solid isoechoic nodule and three mixed (predominantly solid) isoechoic nodules, which are generally considered indicative of benignity. Therefore, meticulous care should be exercised while managing non-high risk nodules as well.

However, correctly determining the indication for biopsy is only a step towards further diagnostic workup, since the definitive distinction between follicular neoplasms is only based on postoperative histopathology [3]. The risk of malignancy associated with a FNA reading of Bethesda IV (follicular neoplasm or suspicious for a follicular neoplasm) is 10–40% and that with Bethesda III (atypia of undetermined significance or follicular lesion of undetermined significance) is 6–18% [29]. The possibility of FTC in lesions with the above suspicious malignant cytological findings is uncertain. In previous studies, 10.8% follicular neoplasm (FN) and 1.2% follicular lesion of undetermined significance (FLUS) were eventually found to be FTCs [30, 31]. As an extreme example, 1379 thyroid nodules with FNA findings consistent with FN were not diagnosed as FTC after surgery [32]. Other studies have shown that the efficacy of TIRADS depends on the incidence of PTC in the study population [33] and that suspicious ultrasound features may not be useful in predicting malignancy of FLUS [34]. Therefore, due discretion is required due to the limitations of cytology in the diagnosis of FTC.

In previous studies involving papillary carcinoma as the primary malignant tumor, unnecessary biopsy rates with ultrasound-based malignancy risk stratification systems were generally lower than 50% [14‐17]. However, our study found higher unnecessary biopsy rates in patients with follicular neoplasm. In our study, FNA was considered indicated for 65.3% to 93.1% of all FTAs and for 62.2% to 89.7% of FTAs sized ≤ 4 cm. We believe that this result is mainly due to the large size of follicular neoplasms [22‐27]. Furthermore, our study showed that the unnecessary biopsy rates with use of “pattern-based” systems were higher than those with use of “score-based” systems irrespective of the lesion size because of the different criteria for determining the indications for biopsy. According to “pattern-based” systems, FNA is not indicated only when nodules with special patterns exceed the above size threshold [8‐11], such as entirely spongiform and pure cyst nodules (3.3% and 0% of FTAs, respectively). In “score-based” systems [12, 13], FNA is not indicated for nodules that are classified as category 1 and 2 by ACR-TIRADS or as category 2 and 3 by C-TIRADS, irrespective of the size. In our study, a certain proportion of FTAs was categorized in the “no biopsy” group by the ACR-TIRADS and C-TIRADS (23.6% and 26.4% of FTAs, respectively).

Currently, there is an impetus on reducing unnecessary biopsy of thyroid nodules, because of the low rate of malignancy and the generally good prognosis of the most common thyroid malignancy (PTC) [8]. Nevertheless, FTC exhibits a more aggressive biological behavior than PTC. Although the precise diagnosis of follicular neoplasms requires postoperative histopathology, preoperative biopsy and further molecular testing may provide supplementary information aiding the differential diagnosis of follicular neoplasms [35]. Thus, deliberately avoiding biopsy and further testing for follicular neoplasms require careful consideration. Recently, some studies have demonstrated the value of molecular testing for follicular neoplasms. For example, a study using next-generation sequencing reported that the presence of FLT3 and TP53 with no RET mutations was consistent with FTC and the absence of FLT3 and TP53 with the presence of RET mutations was consistent with FTA [36]. Another study investigating DNA methylation haplotype block markers identified 70 DNA methylation markers that were significantly different between the FTC and FTA samples [37].

There are several limitations of our study. First, this was a single-center retrospective study. Only patients with a confirmed postoperative diagnosis of thyroid follicular neoplasm were included. Patients who did not undergo surgery were missed, which may have introduced an element of selection bias. Additionally, 126 nodules (27.7%, 126 of 455) were excluded which may also have resulted in selection bias. Finally, only non-dynamic images were available for recording the ultrasound features which may have affected the accuracy of data.

In conclusion, the currently used malignancy risk stratification systems for thyroid nodules showed poor ability in distinguishing FTA from FTC. The performance of these systems in selecting nodules for biopsy was acceptable, but the performance with respect to reducing unnecessary biopsy was unsatisfactory. Our findings indicate the need to develop a specific stratification system and recommendations for follicular neoplasms.