Role of clinicopathologic and sonographic characteristics for the management of patients with cytological diagnosis of thyroid follicular neoplasm

Introduction

Thyroid nodules are a very common clinical condition all around the world (1) and low-risk thyroid nodules can be safely monitored with minimal diagnostic intervention (2). Ultrasound-guided fine-needle aspiration biopsy (FNAB) is recognized as the gold standard for the evaluation of thyroid nodules and used to guide treatment planning (3); however, the diagnosis of “follicular neoplasm” (FN) is one of the indeterminate diagnoses and has always been difficult for pathologists and clinicians (4,5). Because of the limitations of needle biopsy and even intraoperative frozen section, this category has a wide differential diagnosis ranging from hyperplastic/adenomatoid nodules to follicular adenomas (FAs) and follicular-patterned carcinomas (6). The definite characterization of a FN remains a postoperative histopathological diagnosis, hampering targeted preoperative surgical planning or intraoperative adaptation of the surgical strategy.

Diagnosis of a suspicious follicular lesion in the thyroid gland still poses a challenge to the thyroid surgeon nowadays. How to accurately identify malignant tumors, determine the appropriate scope of surgery, and reduce unnecessary thyroidectomy in patients with the FNAB Bethesda IV category has become the goal of generations of doctors (7). With the advantages of quick, non-invasive, cheap, and reproducible, ultrasound is nowadays a routine examination (8). Therefore, it is of considerable significance to find accessible criteria that would allow distinguishing risk of FN in case of inconclusive biopsy results (9).

Even global guidelines and numerous studies have focused on this surgical dilemma. In 2022, the 5th edition of the World Health Organization (WHO) classification of endocrine tumors was released (10), by which follicular-derived thyroid neoplasms have been sharply classified according to prognostic risk categories into “Benign tumors”, “Low-risk neoplasms” and “Malignant neoplasms”. Then, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) incorporates those changes and adapts new terminologies (11,12). The introduction of histopathological tumor grading is likely to improve the risk stratification of patients, and the practical effects and clinical implications should be discussed further. Up to now, there are still no articles discussing the influencing factors and expected consequences in real-world practice for pathologists and clinicians. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-337/rc).

Methods

We performed this retrospective cohort study based on the database of thyroid surgery at Peking Union Medical College Hospital (PUMCH). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of Peking Union Medical College Hospital (No. JS-2670) and informed consent was taken from all the patients.

Patients

A total of 286 consecutive patients with the diagnosis of “follicular neoplasm” and undergoing surgery between January 2015 and December 2023 at Peking Union Medical College Hospital were pooled initially.

The inclusion criteria were as follows: (I) older than 18 years old; (II) diagnosed with thyroid FN confirmed by needle biopsy in the database; (III) with detailed and extractable medical data and laboratory results.

The exclusion criteria were as follows: (I) previously treated with ultrasound-guided thermal ablation; (II) without routine examination before surgery; (III) performed initial surgery in other institutions.

We also found that eight patients were accidentally diagnosed with papillary thyroid microcarcinoma. However, since the nodule found in the postoperative pathological examination may not be the same as the one biopsied, these patients were also excluded from the risk analysis and are described separately.

Finally, 192 patients were included and analyzed in this study (Figure 1).

Figure 1 Flow chart of this study.

Data collection

Following clinicopathological characteristics of patients were routinely collected from a database of thyroid surgery, including age, gender, symptom, body mass index (BMI), tumor location, tumor size, tumor volume, symptom, interval to surgery, hematological indices (including thyroid function tests and antibody tests), gene mutation, nodule components, sonographic feature (including taller than wide, irregular shape, irregular margins, heterogenous echostructure, hypoechogenicity, calcifications, vascularization and ), color Doppler flow imaging (CDFI) pattern, operation, capsular invasion, the total number of lymph nodes removed, positive lymph nodes removed, contralateral nodule, repeat FNAB, pathology and so on. Routine ultrasound examination and blood test were performed within 7 days before surgery.

All oncologic resections were performed by senior surgeons specialized to reach the rigorous standard at our institution and were diagnosed by experienced pathologists. When multiple tumors are different in risk classification, the tumor is recorded according to the most advanced one.

Statistical analysis

Categorical variables were compared using Pearson’s Chi-squared test or Fisher’s exact test, according to whether at least one of the expected values is below five. Mann-Whitney U-test was utilized to analyze continuous variables, which are presented as medians and interquartile ranges (IQRs) at least, with additional mean ± standard deviation (SD) in some conditions. Ordinal logistic regression analysis, including all variables from univariate analysis that were associated with malignancy, was performed to test factors’ independence. Odds ratio (OR) and 95% confidence intervals (CIs) were also calculated.

We used SPSS 26.0 (IBM Corp, Armonk, NY, USA) and R software version 4.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). Statistical significance would be considered when P<0.05.

Tumor classification

The last released 5th edition of the WHO classification of endocrine tumors divided follicular-derived thyroid neoplasms into three main classifications. Follicular nodular disease, FA, FA with papillary architecture, and oncocytic adenoma were defined as benign tumors. Low-risk neoplasms include noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), hyalinizing trabecular tumors, well-differentiated tumors of uncertain malignant potential (WDT-UMP) and follicular tumour of uncertain malignant potential (FT-UMP). Other thyroid neoplasms, such as invasive encapsulated follicular variant papillary thyroid carcinoma (IEFV-PTC), papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), oncocytic thyroid carcinoma (OTC), differentiated high-grade thyroid carcinoma (DHGTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), were subdivided into malignant neoplasms.

Results

Demographic and clinical characteristics

Of 286 consecutive patients, 192 patients who met the criteria were finally included. Among these patients, 87, 19, and 86 were divided into benign, low-risk, and malignant groups, respectively. The relationships between demographic and clinical characteristics and tumor classification were shown (Table 1).

The mean age at diagnosis was 43.56±13.06 years old, moreover, 38 male and 154 female cases were included. The location of the tumor did not show a significant difference among the three groups. More than half of the tumor is located in the right lobe (59.38%), with 62.07% in benign tumors, 42.11% in low-risk neoplasms, and 60.47% in malignant neoplasms, respectively. There was no statistically significant difference in the proportion of patients with clinical symptoms (including neck swelling and airway compression) among the three groups. The same trend was observed in BMI scores. Interestingly, we found that malignant tumors may be associated with smaller tumor diameter (1.38±1.17 cm compared with 2.44±1.42 cm of benign and 2.54±1.21 cm of low-risk). In contrast, benign tumors were associated with longer observation time before surgery (38.47±42.46 months compared with 20.73±30.45 months of malignant and 19.89±29.38 months of low-risk).

Ultrasonographic characteristics and blood parameters

Thyroid function tests included thyroid stimulating hormone (TSH, also known as thyrotropin), tri-iodothyronine (T3), thyroxine (T4), free T4 (FT4), and free T3 (FT3). Thyroid antibody tests including thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibody (TG-Ab) were also performed. In addition, the thyroglobulin (Tg) of some patients was also measured and recorded. However, no statistically significant differences were observed in these thyroid-related blood parameters collected preoperatively (Table 2).

A small number of our patients underwent preoperative gene mutation testing, but unfortunately, no correlation between gene mutation status and tumor properties was found, 0.314 for B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation, and 0.232 for NRAS proto-oncogene, GTPase (NRAS) mutation.

In terms of ultrasound characteristics, the three groups show great differences in some aspects. Compared with the benign and low-risk groups, the nodules in the malignant tumor group were more likely to be solid (91.86%), and the difference was statistically significant (P<0.001). In addition, some ultrasound features, such as taller than wide (P<0.001), irregular shape (P<0.001), irregular margins (P<0.001), hypoechogenicity (P<0.001), and calcifications (P<0.001), also showed a significant increase in the proportion of malignant tumors. No significant differences were seen in the presence or absence of vascularization, but interestingly, the different risk tumors seemed to have different distribution patterns in terms of blood flow patterns (including peripheral, intranodal and both patterns).

Surgery-related and pathological characteristics

Among all 192 patients, 39 (20.31%) received hemithyroidectomy (HT), 63 (32.81%) received HT with lymph node dissection (LD), 21 (10.94%) received total thyroidectomy (TT), and 69 (35.94%) received TT with LD, respectively (Table 3). Patients with benign tumors were more likely to undergo HT (58.62% in total), while patients with malignant tumors were more likely to undergo lymphadenectomy (96.51% in total).

In the postoperative pathological result, capsular invasion (P<0.001) and the number of positive lymph nodes (P<0.001) were consistent with the grouping. No capsular invasion and positive lymph nodes were observed in the benign tumor group. In contrast, in the malignant tumor group, the capsular invasion was observed in 59.30% of cases, and 1.34±2.93 positive lymph nodes could be detected among 9.23±8.55 lymph nodes.

In addition, we also analyzed the nodules in the contralateral lobes of FNs (Table S1). Among all included patients, 80 (41.67%) had no nodules on the contralateral side, 29 (15.10%) patients performed HT, and the contralateral nodule could not be identified. Among patients whose contralateral nodules were resected, the benign tumor group had the highest proportion of contralateral nodules that were also benign (28.74%). At the same time, the proportion of contralateral nodules with malignant tumors was also the highest in the malignant tumor group (24.42%). The difference is statistically significant (P<0.001).

Among all patients, 66 patients underwent repeat FNAB, and the results varied widely, but Bethesda IV remained the predominant grade. In the final pathological results, thyroid follicular nodular disease is the most common result of benign FNs, followed by FA and oncocytic adenoma. The low-risk group mainly consists of WDT-UMP, FT-UMP and NIFTP. In the malignant tumor group, PTC (including classic, follicular, and oncocytic subtypes) accounts for the majority, followed by follicular thyroid carcinoma, and a small amount of DHGTC and PDTC. However, it should be noted that 8 patients had micropapillary carcinomas that were unexpectedly discovered during surgery and were not even the nodules of preoperative concern.

In addition, we also specifically listed the clinical pathology, surgical and ultrasound-related characteristics of patients who were unexpectedly found to have papillary thyroid microcarcinoma (Table S2) or were diagnosed with follicular thyroid carcinoma (Table S3) after postoperative pathology, hoping to provide perspectives for the diagnosis and treatment of these patients in the future.

Finally, to more intuitively reflect the problems in disease management and surgical methods caused by patients with FNs in the clinical diagnosis and treatment process, we also performed an alluvial diagram based on each patient’s repeat FNAB results, postoperative pathology, and surgery received (Figure 2).

Figure 2 Alluvial diagram of each patient. Visually demonstrates the correlation between repeat FNAB results, surgical procedures and final pathology in patients diagnosed with follicular tumors at our center. HT, hemithyroidectomy; LD, lymph node dissection; TT, total thyroidectomy; FNAB, fine-needle aspiration biopsy; NA, not available.

Ordinal logistic regression analysis

Further analysis was carried out using ordinal logistic regression to appraise the relative risks of malignancy (Table 4). Ordinal logistic regression analysis found that sonographic characteristics such as taller than wide (OR =3.219, 95% CI: 1.121–9.240, P=0.03), irregular margins (OR =4.118, 95% CI: 1.636–10.366, P=0.003), hypoechogenicity (OR =2.134, 95% CI: 1.012–4.498, P=0.046) and calcifications (OR =2.144, 95% CI: 1.109–4.146, P=0.02) were independent risk factors for malignancy. Tumor size (OR =0.904, 95% CI: 0.686–1.191, P=0.47), irregular shape (OR =0.936, 95% CI: 0.373–2.349, P=0.89) and solid components (OR =1.623, 95% CI: 0.716–3.682, P=0.25) of thyroid nodules were found to be significant risk factors for malignancy in univariate analysis were not to be significant and independent risk factors on multivariate analysis.

Discussion

Nearly two-thirds of the adult population are found to have thyroid nodules. The ultimate goal of diagnostic assessment of thyroid nodules is to accurately identify malignancy while avoiding overtreatment. Male patients, patients with a family history of thyroid cancer, and patients with a history of radiation to the head and neck are thought to be at increased risk for upfront malignancy (13). Current international guidelines, as well as numerous published studies, focus on the oncological management challenges of patients with a cytological diagnosis of follicular thyroid neoplasm (14,15). Despite various previous studies, distinguishing between benign and malignant forms of FNs remains difficult on cytological testing (16). Therefore, it is recommended to diagnose and treat FNs through surgery, but this is undoubtedly contrary to the concept of reducing excessive medical treatment and advocating personalized precision medicine (17,18). Many studies have been conducted to provide evidence-based guidelines for the management of FN, but most of them are based on postoperative pathology to identify risk factors of different malignant degrees (19). Today, as FNAB becomes increasingly popular, its guiding significance for clinical diagnosis and treatment is gradually decreasing. So, we conducted this study to help doctors make better preoperative decisions and patients make better management strategies. We found that it is difficult to accurately classify and guide patients diagnosed with follicular tumors based on routine blood indicators, baseline characteristics, and repeated needle biopsies. However, some patients with high-risk ultrasound manifestations have a higher risk of malignancy and should be treated more cautiously than other patients, and surgical intervention may be performed if necessary.

According to previous studies, about 5% of FNAB thyroid nodules turn out to be FNs, also known as Bethesda category IV or Thy3f, and the malignancy risk is estimated at 25–40% (20-23). In our study, the malignant proportion was approximately 44.79% (86/192), which was slightly higher in ours than in other centers. The main reason is that for such patients, conservative observation is usually chosen, and those who undergo surgery are usually those with malignant ultrasound findings or a strong willingness to undergo surgery. At the same time, since our medical center receives a large number of referrals from other hospitals (the FNAB results of most patients are made by other hospitals), the consistency of pathological examinations is also affected to some extent. In our study, 87.2% (75/86) of malignant nodules were PTC, but this is also consistent with the changes in the Bethesda reporting system (24) in recent years. Many recent studies have also shown similar trends (25,26).

In our cohort, there were no statistically significant differences in age, gender, and tumor location among different risk groups. Regarding tumor size, a recent meta-analysis found that no cutoff value can be recommended as a decision-making parameter for diagnostic surgery in Bethesda IV thyroid nodules (27). At our medical center, malignant tumors appear to have smaller tumor diameters. Kamran et al. said that when the tumor is malignant, the proportion of papillary carcinoma decreases, while follicular carcinoma increases as nodules enlarge (28), which may explain our research results. A pooled analysis of 500,000 men and women by the Asian Cohort Consortium (29) found that higher BMI is associated with an elevated risk of thyroid cancer in both men and women, while no statistically significant differences were found in our cohort.

Our study shows that chief complaint does not affect tumor grouping, and even the long-term regular follow-up period is longer in the benign tumor group, which may provide support for active surveillance. Kim et al. conducted a single-center randomized controlled trial on non-surgical treatment of patients with Bethesda III/IV thyroid nodules remained stable over 3 years of follow-up (30). Similarly, Gaunt et al. found that after a median follow-up of 27 months, patients who received conservative management had no obvious disease progression on ultrasonography. They state that conservative treatment of thyroid nodules in Bethesda IV is safe in the short term and may be indicated in selected cases after appropriate discussion of the risks and benefits of surgery (31). In our study, many patients chose to undergo surgical treatment after conservative observation for more than three years, but there was a lack of data on patients who were still under active surveillance, which needs further study.

In the published literature, some researchers have found that serum Tg levels (32) and TSH levels (33) can assist in the diagnosis and treatment of Bethesda IV nodules, and TSH non-suppressive thyroid hormone therapy (NSTHT) can significantly reduce the incidence of malignant tumors in such patients (34). However, in our study, blood parameters based on thyroid function and thyroid antibodies did not show significant differences, which was consistent with findings of Ding et al. (35).

In recent years, molecular testing has gradually become an important tool to assist in the differentiation of benign and malignant tumors (36,37). De Napoli et al. found that mutational markers (BRAF and NRAS) can be combined with ultrasound features to enhance diagnostic accuracy (38). However, the detection rate of recorded gene mutations in our institution is low and it is difficult to reflect sufficient statistical differences.

According to several meta-analyses, there are certain ultrasound features associated with increased risk of malignancy of both PTC and FTC and could potentially be used to stratify the risk of malignancy in Bethesda IV categories (39,40). In recent years, many studies have revealed the ultrasonic characteristics of malignant risk in Bethesda IV nodules (41,42), and many studies have tried to stratify the risk of malignancy of cytologically indeterminate thyroid nodules under American Thyroid Association (ATA) sonographic patterns (43). In addition, ultrasound evaluation systems from different countries (44) and elasticity scores were also used for evaluation (45). In our study, solid components, taller than wide, irregular shape, irregular margins, hypoechogenicity, and calcifications all showed statistical differences. Subsequently, ordinal logistic regression analysis demonstrated that taller than wide (OR =3.219), irregular margins (OR =4.118), hypoechogenicity (OR =2.134) and calcifications (OR =2.144) were independent risk factors for malignancy. This reminds us that in clinical practice, we should be particularly careful when dealing with Bethesda IV nodules that are malignant on ultrasound. However, it should be noted that the malignant tumors we included have a high proportion of PTC, and further research is still needed to distinguish FTC. At the same time, we found some patients who were accidentally diagnosed with thyroid micropapillary carcinoma in our study. These tiny nodules usually do not require additional treatment and may not be discovered for life if they are not surgically removed. However, some of these patients already have local lymph node metastasis, and the nodules have some high-risk characteristics, which also suggests that more sensitive tests may be needed in the future to monitor these time bombs lurking around FN.

For Bethesda IV nodules, there has been controversy over the best surgical method for a long time, and there are even different surgical tendencies between the East and the West (46-50). Our study found that even in the malignant tumor group, cervical lymph node metastasis was not found in most patients, so diagnostic lobectomy alone may be sufficient, and prophylactic LD may not have a significant benefit. However, this still requires further well-designed randomized controlled studies to demonstrate. In the contralateral gland lobe, how to choose the surgical method is still a tangled problem. We found that the proportion of malignant nodules on the contralateral side was higher in the malignant tumor group, which may have certain clinical guiding significance. The reason is not yet clear and needs further study. Another concern has been the scope of surgery for patients with postoperative pathological diagnosis of follicular thyroid cancer. In our cohort, there were 9 patients with the above situation, 3 of whom underwent secondary surgery because only lobectomy was performed at the first surgery. These patients usually have some high-risk factors for ultrasound imaging, and we also list them separately for reference.

For Bethesda class III nodules, repeat FNAB is usually recommended (51). However, patients with Bethesda IV categories nodules sometimes refuse surgery and require conservative observation and repeat FNAB 6 months later (52,53). Previous studies have not emphasized the benefit of repeated biopsies, and it is difficult to develop management strategies based on the results of multiple biopsies, which is similar to our results.

In the real world, follicular thyroid carcinoma is the second most prevalent form of differentiated thyroid carcinoma, following PTC, lacking evidence behind guideline recommendations (54). Since FNs are predominantly postoperative histological diagnosis according to capsular, vascular, and adjacent tissue invasion, FNAB as well as supplemental molecular analysis cannot unambiguously distinguish between FTC and benign tumors, the malignant potential of FNs often assessed by clinical risk factors preoperatively (55). In addition, many studies have been conducted to explore the identification of FTC. An example is the application of follicular cell pattern analysis in the interpretation of thyroid lesions (56). Circulating tumor cells (CTCs) may contain information on primary tumors and preoperatively distinguish thyroid FAs from follicular carcinomas (57,58). Some microRNA-based classifiers have also been performed with high sensitivity and specificity (59,60). With the development of multi-omics technology, epigenetics, and metabolomics are also continuously developed and applied in this field (61,62). In recent years, with the rapid advancement of artificial intelligence technology, more and more researchers have made outstanding contributions to relying on ultrasound images (63,64). Some studies try to distinguish benign from malignant through special physical properties, such as dielectric properties (65). These studies distinguished malignant tumors from different perspectives. However, we should also note that these studies usually use postoperative histological specimens, or only differentiate between FA and follicular carcinoma, which is still far from clinical trials in the real world. We are very much looking forward to prospective studies for promotion, verification, and application.

At the same time, it cannot be ignored that as important as diagnosis is the prognosis of patients with FNs. Ito et al. followed up with patients with FNs of uncertain malignant potential (66). Luo re-examined and followed up with patients who were initially pathologically confirmed to be benign follicular nodules of the thyroid and found distant metastases in some cases and the underestimated malignancy (67). We should also make the same efforts to guide the treatment of FNs from the perspective of prognosis.

There are many highlights of our research. First, we gave a detailed and comprehensive description of the entire diagnosis and treatment process of patients with FNs to facilitate subsequent research. At the same time, our cohort is also one of the largest in the relevant field. What is more, we are also the first to make a preliminary attempt to target the three risk categories of FNs, namely “Benign tumors”, “Low-risk neoplasms” and “Malignant neoplasms”, after the WHO and TBSRTC updated the pathological classification. It may be more in line with the actual clinical diagnosis and treatment.

There are several limitations in this study. First, we excluded patients who had been treated at other institutions, and a large proportion of FNAB diagnoses were made by other hospitals, which may introduce bias. Second, the proportion of genetic mutation testing in our cohort was low and lacked sufficient statistical power. Last, as a retrospective study, some intraoperative and postoperative information may not be assiduously observed and detailedly recorded. We would carry out multi-center trials for comparison in the future.

Conclusions

In summary, our study found that due to practical limitations, it is still difficult to accurately preoperatively classify and guide treatment for patients diagnosed with FNs based on conventional blood indicators, baseline characteristics, and repeated needle biopsies. Patients with ultrasound findings of taller than wide, irregular margins, hypoechogenicity, and calcifications might be at high risk of malignancy and should be treated with caution compared to other patients, with surgical intervention if necessary. Of course, with the rapid development of multi-dimensional evaluation methods, we have reason to believe that we will gradually find fast, economical, efficient, and accurate auxiliary means, to assist us in stratifying and developing treatments for patients with Bethesda category IV nodules.

Acknowledgments

Funding: The study was supported by the National Natural Science Foundation of China (grant No. 82172727), Nature Science Foundation of Beijing (grant No. 7202164), CAMS Innovation Fund for Medical Sciences (CIFMS) (grant No. 2021-I2M-1-002), and National High-Level Hospital Clinical Research Funding (grant Nos. 2022-PUMCH-D-001 and 2022-PUMCH-B-004).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-337/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-337/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-337/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-337/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of Peking Union Medical College Hospital (No. JS-2670) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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