Preoperative anti-thyroid antibodies predict malignancy risk in cytologically indeterminate thyroid nodules: a prospective multicenter study

Introduction

Background

Thyroid nodules (TNs) are the most common endocrine tumors, with an incidence of 20–76% diagnosed by neck ultrasound (US). They are typically evaluated by US with or without a fine needle aspiration biopsy (FNAB). TNs must be assessed to rule out thyroid cancer (TC), which occurs in 5–10% of cases (1-3). A total of 15–30% of all TN FNABs are characterized as “indeterminate”, and they are defined as cytologically indeterminate thyroid nodules (CITNs) [also called atypia/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm (FN), or suspicious for FN] (4,5). Of these, only 25% are diagnosed as TC in the final pathology (6).

Rationale and knowledge gap

The evaluation, assessment, and management of CITNs present considerable challenges for clinicians because a final diagnosis can only be achieved via surgical excision and histological examination (6). Depending on the clinical and radiological features of CITNs, active surveillance, molecular markers, repeat FNAB, or diagnostic lobectomy have been proposed as potential management strategies (7). However, these options are all suboptimal (5). Notably, repeat FNAB can identify CITNs that may benefit from molecular testing, thereby reducing the incidence of diagnostic surgery for histologically benign TNs (8). Moreover, repeat FNAB facilitates the reclassification of two-thirds of CITNs into a more definitive category (9). Molecular testing is therefore an effective tool for guiding the management of CITNs and combined with FNAB, is advantageous in the diagnostic assessment of CITNs. Per American Thyroid Association recommendations, molecular testing may influence the management of CITNs and the extent of thyroidectomy, especially concerning the decision between surgical intervention or observation (2). However, the lack of availability across laboratories and exorbitant expense of molecular testing limit its application. Diagnostic lobectomy may serve as a compromise to facilitate diagnosis; however, these are either superfluous when the lesion is confirmed as benign, or insufficient, necessitating a completion thyroidectomy, if the tumor is identified as malignant (5). Consequently, personalized approaches are recommended (9).

Differentiated thyroid carcinoma (DTC) represents >90% of all TC and comprises papillary and follicular TCs. Thyroglobulin (Tg) is recognized as a sensitive biomarker for residual or recurrent DTC after total thyroidectomy. However, Tg levels may be influenced by the presence of thyroglobulin antibodies (TgAbs), which can decrease or increase Tg levels, leading to inaccurate results (10). Therefore, Tg testing should consistently incorporate the assessment of TgAb levels. From a clinical perspective, thyroid peroxidase antibodies (TPOAbs) are superior to TgAbs for predicting thyroid dysfunction. Nonetheless, recent investigations have indicated a minor but persistent prognostic function of preoperative TgAbs for DTC (10). Vasileiadis et al. demonstrated an association between TgAbs and papillary thyroid cancer (PTC) in CITNs (3). Thus, TgAb positivity may affect the clinical evaluation and decision to perform total thyroidectomy (6). In 2020, a retrospective study showed that thyroid stimulating hormone (TSH) and anti-thyroid antibodies were associated with increased TC risk in patients with CITNs. Furthermore, TgAb and TSH may be indicators of a more aggressive biology, with both prognostic and diagnostic applications (5). However, few studies have investigated the impact of anti-thyroid antibodies (TgAb and TPOAb) in TC prediction in patients with CITNs (3,5,6,11,12).

Objective

We aimed to investigate the prognostic utility of anti-thyroid antibodies TgAb and TPOAb for predicting TC in patients with CITNs. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-441/rc).

Methods

Study design

This prospective multicenter analysis included all FNAB cases diagnosed as AUS or FN at the King Salman Armed Forces Hospital Northwestern Region and the Armed Forces Hospital Southern Region in Saudi Arabia between August 2023 and August 2024.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of King Salman Armed Forces Hospital Northwestern Region, Saudi Arabia (No. KSAFH-REC-2022-470) and informed consent was obtained from all individual participants. The Armed Forces Hospital Southern Region was also informed and agreed to the study.

Patients

Figure 1 presents the study flow chart. Patients whose age was ≥14 years and who underwent surgical intervention for primary TNs with an available preoperative thyroid antibody (TgAb and TPOAb) test and a final histological diagnosis were included. Patients were evaluated in a surgical clinic, and neck US was requested for all patients. Whenever FNAB was indicated and the cytological results showed AUS (Bethesda III) or FN (Bethesda IV), preoperative TSH, TgAb, and TPOAb levels were requested. Other variables collected included demographic data, nodule size, and aggressiveness features of malignant nodules (multifocality, lymph node metastasis, extrathyroidal extension, and lymphovascular invasion). The exclusion criteria included previous thyroid surgery, previous radiation exposure, and a history of neck cancer.

Figure 1 Flow chart of the study. AUS, atypia of undetermined significance; CITN, cytologically indeterminate thyroid nodule; FN, follicular neoplasm, FNAB, fine needle aspiration biopsy.

Study protocol and outcome measurements

Per standard procedures, all FNABs were US-guided. The slides were evaluated by expert cytopathologists using the 2023 Bethesda classification for cytological interpretation (13). Importantly, the cytopathologists were blinded to antibodies and TSH results. Molecular testing was not available in either hospital. The diagnosis of benign vs. malignant nodules was based on WHO criteria, and diagnosis of Hashimoto’s thyroiditis (HT) was established through histological examinations.

TSH levels were categorized using two methods: (I) three groups based on the normal range: <0.5, 0.5–5, and >5 mIU/L; and (II) two groups based on a cutoff of 1 mIU/L: <1 and ≥1 mIU/L, as this threshold was previously described as that above which the risk of malignancy increases (5).

Serum TSH and anti-thyroid antibody levels were measured using chemiluminescence-based immunoassays and an ATELLICA analyzer (Siemens Healthineers, Erlangen, Germany). Both hospitals define the normal range for TSH as 0.5–5 mIU/L, and the normal range for TgAb is <4.5 IU/mL. To unify the units for TPOAb, we used the following formula: U/mL = IU/mL × CF, where CF represents a conversion factor equal to 0.025. Ultimately, the normal range for TPOAb was defined as <5.6 IU/mL. TgAb, TPOAb, and TSH levels were examined separately and synergistically in relation to the risk of malignancy.

Statistical analysis

Excel (Microsoft, Redmond, WA, USA) was used for data collection, and data analysis was conducted using SPSS software (version 26; IBM, Armonk, NY, USA). Descriptive statistics were used to summarize demographic, clinical, and histopathological characteristics. All correlations were analyzed using cross-tabulation to assess statistical significance using the Pearson chi-square test or the exact probability test for low-frequency distributions. A P value <0.05 was considered statistically significant. Multivariate logistic regression analyses were performed to assess the adjusted odds ratios (AORs) of various predictors of TC. Anti-thyroid antibodies and TSH levels were combined to examine important interactions in predicting TC.

Results

A total of 76 patients were included in this study. Table 1 presents the demographic, clinical, and histopathological characteristics of the participants. Most patients (58/76, 76.3%) were younger than 55 years, with a mean age of 45.9±14.3 years. Most of the study cohort was female (70/76), representing 92.1% of the participants. Most TNs were found on the right side (39/76, 51.3%), followed by the left (31/76, 40.8%) and the isthmus (6/76, 7.9%). A total of 43/76 (56.6%) and 33/76 (43.4%) patients had a cytological diagnosis of AUS and FN, respectively. Surgical treatment was predominantly total thyroidectomy, performed in 56/76 (73.7%) cases, with the remaining patients undergoing hemithyroidectomy [right, 9/76 (11.8%); left, 11/76 (14.5%)]. In terms of pathology, benign nodules were more common, reported in 56/76 (73.7%) patients, whereas 20/76 (26.3%) had malignant lesions. Of the patients with malignant nodules, lymph node metastasis was observed in 6/20 (30.0%), extrathyroidal extension in 3/20 (15.0%), multifocality in 12/20 (60.0%), and lymphovascular invasion in 10/20 (50.0%). The mean tumor size measured using US was 2.8±1.5 cm, with 41/76 (53.9%) patients having tumors ≥2 cm. In addition, 47.4% (36/76) of patients had HT.

With respect to nodule subtypes, the most frequently reported benign tumors were nodular/multinodular goiter/adenomatoid nodule/colloid nodules (31/56, 55.4%), HT (10/56, 17.9%), follicular adenoma (9/56, 16.1%), Graves’ disease (1/56, 1.8%), and noninvasive follicular thyroid neoplasms with papillary-like features (5/56, 8.9%). In contrast, all malignant tumors (20/76, 26.3%) were diagnosed as PTC.

A comparison of the clinical and pathological features of patients with normal and elevated TgAb titer is shown in Table 2. Of the total study cohort, 36/76 patients (47.4%) had elevated preoperative TgAb levels. The age distribution was relatively balanced, and age and sex were comparable between the two groups.

Regarding tumor size, the proportions of patients with tumors <2 cm and those with tumors ≥2 cm were comparable between the groups (P=0.51). Additionally, pathology results did not have a significant association with TgAb levels (P=0.80). A significant difference was noted in the prevalence of HT; of the patients with this condition, 25/36 (69.4%) had high TgAb levels and 11/36 (30.6%) had normal TgAb levels (P=0.001). No significant differences were predicted between the two groups in terms of features of aggressiveness in malignant nodules. In addition, 10/16 (62.5%) patients with TSH levels <0.5 mIU/L had normal TgAb levels, whereas 4/5 (80.0%) patients with TSH levels >5 mIU/L had high TgAb levels (P=0.25). However, when categorizing TSH levels below or above 1 mIU/L, a higher percentage of patients with TSH levels <1 mIU/L had normal TgAb levels (62.1% vs. 37.9% for patients with high TgAb levels; P=0.05).

Table 3 presents the comparison of the clinical and pathological characteristics of patients with normal and high preoperative TPOAb levels. Only 21/76 (27.6%) cases had high preoperative levels of TPOAb. The age distribution showed no significant differences between the two groups (P=0.23). TPOAb levels were not significantly associated with tumor size (P=0.73) or pathology results (P=0.76). However, a significant difference was observed regarding the presence of HT; 19/36 (52.8%) patients with HT had normal TPOAb levels, whereas 17/36 (47.2%) had high TPOAb levels (P=0.001). No significant differences were noted in terms of lymph node metastasis (P=0.09), extrathyroidal extension (P=0.72), multifocality (P>0.99), or lymphovascular invasion (P=0.61). Similarly, no significant associations were noted between preoperative TSH levels and TPOAb status, with P values of 0.08 for TSH <0.5 mIU/L and 0.59 for TSH <1 mIU/L. However, a significant association was observed between preoperative TgAb and TPOAb levels (P=0.001).

A multivariate analysis was performed to identify independent predictors of TC (Table 4). Age >55 years, male sex, and tumor size ≥2 cm were not significantly associated with the occurrence of TC. In contrast, a Bethesda IV cytological diagnosis was a significant predictor, where patients with Bethesda IV nodules were approximately 4.7 times more likely to receive a malignant diagnosis than those with Bethesda III nodules [AOR =4.70, 95% confidence interval (CI): 1.26–17.58, P=0.02]. Likewise, HT showed a significant association with TC, and patients with HT had an approximately 3.25 times higher likelihood of a malignant diagnosis than those without HT (AOR =3.25, 95% CI: 1.01–12.62, P=0.05). A TSH level >1 mIU/L was also a significant predictor, with a 3.38 times higher likelihood of a TC diagnosis in patients with TSH levels >1 mIU/L (AOR =3.38, 95% CI: 1.00–13.28, P=0.05). However, high TgAb and TPOAb levels were not significantly associated with TC occurrence.

Figure 2 shows the correlations between various combinations of thyroid markers and the likelihood of a TC diagnosis in patients with CITNs. The combination of elevated levels of TSH and both anti-thyroid antibodies had the highest odds ratio (3.10; 95% CI: 1.14–5.47), which indicated a significant association with the occurrence of TC (P=0.003). Additionally, having elevated levels of one anti-thyroid antibody alongside high TSH levels yielded an odds ratio of 2.25 (95% CI: 1.02–6.44), which also demonstrated a significant correlation with TC diagnosis (P=0.04). In contrast, the combinations of normal anti-thyroid antibodies with high TSH levels and low TSH levels with elevated levels of either both or only one anti-thyroid antibody did not show significant correlations.

Figure 2 The forest plot of the relationship between different combinations of thyroid markers and the occurrence of thyroid cancer in patients with indeterminate thyroid nodules. The anti-thyroid antibodies examined were those against thyroid peroxidase and thyroglobulin. Blue lines indicate 95% confidence intervals. OR, odds ratio; TSH, thyroid stimulating hormone.

Discussion

Key findings

Neck US and US-guided FNABs are employed to evaluate TNs. Fortunately, 60–70% of all FNABs yield benign results; however, only 5–10% exhibit malignant cytology. Consequently, 10–25% of FNABs are categorized as CITNs (6). This classification comprises heterogeneous characteristics, and the assessment of these nodules remains controversial. Lobectomy is a sufficient surgical procedure for most patients with CITNs. However, the extent of thyroidectomy may be changed considering the molecular status and clinical, radiological, and cytological findings (2). In contrast, some investigators contend that total thyroidectomy is a suitable intervention for CITNs as it allows for the identification of extrathyroidal extension, histologic variants, and multifocality (6). However, only 25% of CITNs receive a final pathological diagnosis of TC, and the ambiguity in their management frequently results in unnecessary thyroid surgeries (9). Thus, the current study aimed to identify a straightforward method to predict malignancy in patients with CITNs.

Our data demonstrated that a combination of elevated anti-thyroid antibodies and TSH levels was a predictor of TC in CITNs. Our findings revealed that the risk of malignancy in CITNs was 26.3%, aligning with existing literature (13). In particular, the multivariate analysis showed that a cytological diagnosis of Bethesda IV was associated with an increased cancer risk (13).

Strengths and limitations

Our study has several strengths. First, it was the second study to investigate the synergistic effect of anti-thyroid antibodies and TSH in increasing malignancy risk in CITNs. Second, it was a prospective study with a multicenter design. Third, the definitive diagnosis of malignant or benign disease was confirmed via histological evaluation rather than cytological analysis. Nonetheless, our study has certain limitations, including a limited sample size, which may constrain the statistical power of subgroup analysis. Second, we exclusively included surgical cases, rendering our findings unrepresentative of the entire population with CITNs, which indicates selection bias and limits generalizability. Third, molecular testing was not available in our facilities. Lastly, radiological features, a component that may serve as an ancillary tool in cancer stratification, were not included in the analysis.

Comparison with similar research

TgAb incidence is approximately 1.5 times greater in individuals with DTC than in those with benign TNs (10). Moreover, thyroid autoimmunity and elevated TSH are independent risk factors for TC (14). Kim et al. demonstrated that the presence of TgAb is an independent predictor of TC in conjunction with TSH levels, regardless of autoimmune thyroiditis status (12). Furthermore, Vasileiadis et al. reported a correlation between TgAb levels and PTC in patients with CITNs (3). A retrospective study found a substantial correlation between PTC and the presence of TgAb in individuals with CITNs, with the multivariate analysis indicating that TgAb is an independent risk factor for PTC (6). Our results showed that pathological findings were not significantly associated with elevated TgAb or TPOAb levels. However, elevated levels of these antibodies combined with high TSH levels had a significant correlation with TC risk, which aligns with the findings of Adhami et al. (5).

TSH is a thyrocyte growth factor. Various reports have shown a relationship between high TSH levels and TC development, as well as an advanced stage of DTC, even if these levels are within the normal range (5,14-20). Furthermore, elevated preoperative TSH levels have been shown to correlate with advanced stages of PTC, extrathyroidal extension, and cervical nodal metastases (21). In another study, TSH levels were markedly elevated in patients with PTC compared with those with benign nodules (6). A recent meta-analysis indicated that TSH measurement in individuals with TNs exhibits great sensitivity and specificity for diagnosing DTC, demonstrating significant therapeutic applicability (22). Similarly, our data showed that high TSH levels combined with elevated levels of one or both anti-thyroid antibodies correlated with an increased risk of developing TC. In addition, our multivariate analysis revealed that a TSH level >1 mIU/L was associated with a higher risk of malignancy in CITNs.

Explanations of findings

Anti-thyroid antibodies are typically associated with autoimmune thyroid diseases; TgAb and TPOAb are found in HT, whereas TSH receptor antibodies are predictors of Graves’ disease (10). Consistent with this, our results showed a significant association between the presence of HT and elevated levels of TgAb and TPOAb. Furthermore, TgAb and TPOAb are immunoglobulin G antibodies that commonly co-occur (3), which aligns with our findings demonstrating that most patients with high TPOAb levels also had high TgAb levels. The cross-reactivity between Tg and TPO has been suggested as a cause of thyroid autoimmunity (3). Inflammation is crucial for the development and progression of cancer, and chronic inflammation can enhance the tumorigenic microenvironment (5). As a result, TgAb has been implicated in the association between autoimmune thyroiditis and TC, although the mechanism is unknown (10).

Implications and actions needed

The potential association between HT and PTC has long been disputed, and whether HT constitutes an accidental observation or an element of the host tumor response is unclear (6). The immune response in patients with PTC has been proposed to be directed against tumor antigens that are also present in normal thyroid tissues, resulting in specific thyroid autoimmunity. Nonetheless, there is no conclusive evidence demonstrating how the coexistence of thyroid autoimmunity influences TC features and prognosis (23). Additionally, some studies have demonstrated that HT is correlated with a heightened risk of PTC development due to the tumorigenic effects of thyroiditis (5,24). Karatzas et al. found that patients with HT and CITNs exhibited a significantly increased incidence of PTC in the final histopathological diagnosis compared with those without HT (6), which is in accordance with our results. Moreover, the dissemination of PTC to compartment VI lymph nodes was shown to be four times more likely in patients with HT than in those without (3). Similarly, TgAb positivity increases the likelihood of lymph node metastasis in patients with PTC (3,5); however, this is not consistent with our findings, which showed no significant association between elevated TgAb levels and the risk of features of aggressiveness.

Conversely, malignancy has been shown to have no correlation with autoimmunity in individuals with CITNs (25). Boi et al. found no association between malignancy and thyroid autoimmunity in individuals with CITNs, despite the greater prevalence of malignancy in the population with anti-thyroid antibody positivity (26). Another study confirmed these findings (27). Therefore, further investigations are recommended to resolve these conflicting results.

Conclusions

A combination of elevated levels of anti-thyroid antibodies and TSH was a predictor of TC in CITNs; emphasizing that both measurements may function as realistic surrogate risk stratifiers for malignancy in CITNs when advanced molecular testing is not accessible. These findings make a substantial contribution to the current discourse surrounding CITNs and may help guide endocrine surgeons when managing patients with these nodules. However, future large-sample studies are needed to validate our findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-441/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-441/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-441/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-441/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 and its subsequent amendments. The study was approved by the Ethics Committee of King Salman Armed Forces Hospital Northwestern Region, Saudi Arabia (No. KSAFH-REC-2022-470) and informed consent was obtained from all individual participants. The Armed Forces Hospital Southern Region was also informed and agreed to the study.

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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