Emotional burden of TI-RADS 4 thyroid nodules: clinical and psychosocial correlation

Abstract

Background

Thyroid nodules classified as the Thyroid Imaging Reporting and Data System 4 (TI-RADS 4) present an intermediate risk of malignancy, often necessitating further diagnostic evaluation. While clinical and imaging factors are routinely assessed, the psychological impact of these findings is underexplored. This study investigates the prevalence and correlation of anxiety and depression in patients with TI-RADS 4 nodules.

Methods

In this retrospective cross-sectional study, 65 patients with TI-RADS 4 thyroid nodules evaluated between 2021 and 2024 were included. Demographic, clinical, and biochemical data were collected, including body mass index (BMI), carcinoembryonic antigen (CEA) and thyroid-stimulating hormone (TSH) levels. Psychological symptoms were assessed using the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS). Correlation analyses were performed to examine associations between psychological scores and clinical variables.

Results

The mean age of participants was 45.8 years, with 58.5% being female. Most patients (54/65, 83.1%) had normal thyroid function, and only 10 (15.4%) had undergone prior surgery. A minority had undergone fine-needle aspiration biopsy. Anxiety and depression scores showed a positive correlation (Pearson r=0.80, P<0.001). Weak or negligible correlations are observed between psychological scores and clinical markers such as TSH, BMI, and CEA.

Conclusions

In this cohort of patients with TI-RADS 4 thyroid nodules, symptoms of anxiety and depression are common, but showed only weak associations with clinical and imaging characteristics. These symptoms appear to be weakly related to clinical and imaging characteristics, underscoring the importance of routine psychological screening and support in this population.

Highlight box.

Key findings

• In patients with Thyroid Imaging Reporting and Data System (TI-RADS) 4 thyroid nodules, symptoms of anxiety and depression are common and strongly correlated (Pearson r=0.80, P<0.001).

• Psychological distress scores showed only weak or negligible correlations with clinical variables (thyroid-stimulating hormone, body mass index, carcinoembryonic antigen) and imaging characteristics (nodule size, TI-RADS subclass, calcification).

What is known and what is new?

• Patients with thyroid nodules often experience psychological distress due to cancer-related concerns.

• This study adds evidence specific to TI-RADS 4 nodules, showing that psychological symptoms are common but largely independent of objective clinical, biochemical, and sonographic features, suggesting diagnostic uncertainty as a primary driver.

What is the implication, and what should change now?

• The emotional burden of TI-RADS 4 nodules is substantial and not reflected by routine clinical markers.

• Clinical management should routinely incorporate validated psychological screening (e.g., Zung Self-Rating Anxiety Scale and Depression Scale) and offer psychosocial support to improve patient well-being and adherence to follow-up care.

Introduction

Thyroid nodules are a common clinical finding, with an increasing prevalence driven by advances in high-resolution ultrasonography (1,2). Among the various classification systems developed to assess malignancy risk, the Thyroid Imaging Reporting and Data System (TI-RADS) offers a standardized approach to stratifying nodules based on sonographic features (3,4). Nodules categorized as TI-RADS 4 carry an intermediate risk of malignancy and often prompt further diagnostic workup, including fine-needle aspiration (FNA) (5). While the primary focus of clinical management typically centers on oncologic risk and endocrinologic function, the psychological impact of an uncertain or potentially serious diagnosis has received comparatively less attention.

Emerging research highlights a significant psychosocial burden among patients undergoing evaluation for thyroid nodules. Anxiety and depression can arise from the fear of malignancy, the ambiguity of imaging findings, and the anticipation of invasive procedures or surgery (6,7). These emotional responses are not only distressing in themselves but may also influence patients’ adherence to medical recommendations and their overall quality of life (8-10). However, few studies have systematically explored the prevalence and correlation of psychological symptoms in patients with TI-RADS 4 nodules—a population facing particular diagnostic uncertainty and potential risk (11).

This exploratory study aimed to describe the prevalence of anxiety and depression symptoms in patients with TI-RADS 4 thyroid nodules and to examine their bivariate associations with demographic, biochemical, and imaging features. By better understanding the psychological profile of this patient group, our goal is to inform more holistic clinical care strategies that address not only physical but also emotional well-being. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-524/rc).

Methods

Study design and population

This retrospective cross-sectional study was conducted to investigate the clinical, demographic, and psychosocial characteristics of patients with TI-RADS 4 thyroid nodules and their associations with anxiety and depression symptoms. The study included patients who underwent evaluation at Tianjin Cancer Hospital Health Management Center between 2021 and 2024. Inclusion criteria were: (I) adults aged 18 years or older; (II) diagnosis of TI-RADS 4 thyroid nodules based on ultrasonographic assessment; and (III) availability of complete clinical, laboratory, and psychological assessment data. Patients with prior psychiatric diagnoses or incomplete records were excluded.

Data collection

Clinical and demographic data were extracted retrospectively from electronic medical records and included age, sex, marital status, education level, occupation, body mass index (BMI), and thyroid function indicators. Information on thyroid nodule characteristics such as TI-RADS subclassification (4a, 4b, etc.), nodule size, and presence of calcification was collected from imaging reports. Laboratory values included carcinoembryonic antigen (CEA) and thyroid-stimulating hormone (TSH). Prior procedures, such as FNA biopsy and thyroid surgery, were also noted.

Psychological assessment

Psychological distress was assessed using standardized self-report instruments administered during routine clinical visits. Anxiety was measured using the Zung Self-Rating Anxiety Scale (SAS), and depression was assessed with the Zung Self-Rating Depression Scale (SDS). Both instruments are validated for use in medical populations and provide quantitative scores that indicate symptom severity. In this sample, the SAS and SDS demonstrated high internal consistency (Cronbach’s α=0.876) and a strong correlation (Pearson r=0.797, P<0.001). Only patients with complete SAS and SDS data were included in the analyses.

Statistical analysis

Descriptive statistics were used to summarize demographic and clinical characteristics, expressed as mean and standard deviation (SD) or median with interquartile range (IQR) for continuous variables, and frequencies with percentages for categorical variables. Due to the low prevalence of clinically elevated depressive symptoms in the sample (n=1 exceeding standard SDS cutoff), no dichotomous analyses of depression status were performed.

Both Pearson and Spearman correlation analyses were performed to evaluate the relationships between psychological scores (SAS and SDS) and clinical variables, including BMI, TSH, CEA, and thyroid nodule characteristics. Pearson correlation was used to assess the strength and direction of linear relationships assuming normality, while Spearman correlation was employed as a non-parametric alternative to assess monotonic relationships and to provide robustness against potential violations of normality or the presence of outliers. Heatmaps and scatter plots were used to visually depict correlation patterns.

All analyses were performed using GraphPad Prism 10.0, and a P value <0.05 was considered statistically significant.

Ethical considerations

This study was approved by the ethics committee of Tianjin Cancer Hospital Health Management Center (Date. 2024.3; No. EK20240148). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given the retrospective design, patient consent was waived, and data were anonymized prior to analysis.

Results

Participant characteristics

A total of 65 patients with TI-RADS 4 thyroid nodules are included in this cross-sectional study, with data collected between 2021 and 2024. The mean age of participants was 45.8 years (SD =7.3 years), and the median age was 47.0 years (IQR: 40.0–51.0 years). The cohort was predominantly female (58.5%). Most participants are married and held a college-level education or higher. Occupations are diverse, with a notable proportion working in finance, enterprise, and technical professions. Regarding thyroid nodule characteristics, the majority of nodules are classified as TI-RADS 4a or 4b. The presence of calcification varied among participants. The average BMI was 25.0 (SD =4.0) kg/m², indicating that a significant proportion of patients are overweight. Biochemical markers showed a mean CEA level of 1.70 (SD =1.34) ng/mL and a mean thyroid-stimulating hormone (TSH) level of 2.17 (SD =1.85) µIU/mL. Most patients had normal thyroid function, although a small number exhibited hyperthyroidism or hypothyroidism. Only a minority of patients had undergone FNA biopsy or thyroid surgery prior to or during the study period. A full summary of baseline demographic and clinical characteristics is presented in Table 1.

Table 1. Participant characteristics.

Characteristics	Data
Age (years)	45.77±7.30
BMI (kg/m2)	25.03±4.00
CEA (ng/mL)	1.70±1.34
TSH (μIU/mL)	2.17±1.85
Sex
Female	38 (58.5)
Male	27 (41.5)
Marital status
Married	63 (96.9)
Unmarried	2 (3.1)

Data are presented as mean ± standard deviation or n (%). BMI, body mass index; CEA, carcinoembryonic antigen; TSH, thyroid-stimulating hormone.

Correlation analysis

Correlation between anxiety and depression score

A strong and statistically significant positive correlation was observed between anxiety (SAS scores) and depression (SDS scores) among participants. The Pearson correlation coefficient was r=0.80 (P<0.001), indicating a high linear association. The Spearman correlation coefficient was even higher at ρ=0.83 (P<0.001), confirming a strong monotonic relationship (Figure 1). These findings suggest that individuals with elevated anxiety symptoms also tend to report higher levels of depressive symptoms. This supports the known comorbidity between anxiety and depression in medical populations.

Figure 1.

Scatter plot showing the correlation between anxiety and depression scores. This scatter plot illustrates the relationship between anxiety (SAS scores) and depression (SDS scores) among patients with TI-RADS 4 thyroid nodules. Each point represents an individual participant. A red linear regression line is overlaid to demonstrate the positive association. Pearson correlation analysis revealed a strong, statistically significant correlation (r=0.80, P<0.001). SAS, Zung Self-Rating Anxiety Scale; SDS, Zung Self-Rating Depression Scale; TI-RADS, Thyroid Imaging Reporting and Data System.

Correlation between psychological and clinical variables

We examined the correlations between psychological scores and selected thyroid and clinical biomarkers, including TSH, BMI, and CEA (Figure 2). Pearson correlation analysis revealed weak negative relationships between anxiety scores (SAS) and both TSH (r=–0.09) and BMI (r=–0.22), while the correlation with CEA was negligible (r=–0.06). Similarly, depression scores (SDS) showed a weak negative correlation with TSH (r=–0.13) and BMI (r=–0.19), and a very weak positive correlation with CEA (r=0.03). These findings suggest no meaningful linear association between psychological distress and the selected thyroid or metabolic indicators in this sample.

Figure 2.

Heatmap of correlations between psychological scores and clinical variables. This heatmap illustrates the Pearson correlation coefficients between anxiety (SAS) and depression (SDS) scores and selected clinical indicators, including TSH, BMI, and CEA. Color intensity reflects the strength and direction of the correlations, with values ranging from –1 (perfect negative correlation) to +1 (perfect positive correlation). BMI, body mass index; CEA, carcinoembryonic antigen; SAS, Zung Self-Rating Anxiety Scale; SDS, Zung Self-Rating Depression Scale; TSH, thyroid-stimulating hormone.

Correlation between psychological scores and nodule characteristics

We analyzed the correlation between psychological scores and thyroid nodule characteristics, including nodule size, TI-RADS classification, and the presence of calcification (Figure 3). Anxiety scores (SAS) showed a weak negative correlation with nodule size (r=–0.11), a negligible positive correlation with TI-RADS level (r=0.02), and a slight positive correlation with calcification (r=0.06). Depression scores (SDS) are weakly and positively correlated with both nodule size (r=0.06) and TI-RADS level (r=0.11), and showed a similarly weak correlation with calcification (r=0.12). These results suggest that the imaging and structural characteristics of thyroid nodules have minimal linear association with psychological distress in this patient population.

Figure 3.

Heatmap of correlations between psychological scores and thyroid nodule characteristics. This heatmap presents the Pearson correlation coefficients between anxiety (SAS) and depression (SDS) scores and nodule characteristics, including nodule size, TI-RADS classification (scored numerically), and the presence of calcification. Warmer colors indicate stronger positive correlations, while cooler colors indicate negative correlations. All observed associations are weak, suggesting minimal linear relationships between the structural features of thyroid nodules and psychological distress in this cohort. SAS, Zung Self-Rating Anxiety Scale; SDS, Zung Self-Rating Depression Scale; TI-RADS, Thyroid Imaging Reporting and Data System.

Discussion

This study highlights the significant psychological burden experienced by patients with TI-RADS 4 thyroid nodules. Despite their intermediate malignancy risk, the psychological ramifications of this diagnostic category—particularly the associated anxiety and depression—are often underappreciated in routine clinical workflows. Our findings reveal high comorbidity between anxiety and depression scores, with a positive correlation (r=0.80), reinforcing existing evidence that these emotional responses are tightly intertwined in patients facing potential oncological threats.

Prior research corroborates the psychological vulnerability of this population. For instance, Li et al. found that patients undergoing thyroid nodule screening and evaluation often experience significant emotional distress, particularly during the diagnostic ambiguity of intermediate TI-RADS categories (6). This aligns with our observation that most clinical and imaging variables—including TSH, BMI, and calcification—are only weakly associated with psychological outcomes, suggesting that the emotional burden is largely driven by uncertainty itself rather than by objective risk markers.

Importantly, even patients under non-invasive management experience psychological repercussions. A longitudinal study found that individuals under active surveillance for suspicious nodules continued to report elevated anxiety and impaired quality of life over time (10), emphasizing that the mere knowledge of harboring a potentially malignant lesion is sufficient to cause persistent emotional distress.

Moreover, although biomarkers such as CEA and TSH have been considered in some diagnostic models for thyroid nodules, their role in predicting emotional outcomes appears limited. This is consistent with findings that emotional distress in patients with TI-RADS 4 nodules was not consistently linked to biochemical profiles (11).

Given these insights, integrating routine psychological screening into the clinical management of thyroid nodules—particularly TI-RADS 4—may be warranted. Tools such as the Zung scales used in our study are accessible and validated for medical populations, offering practical value in identifying patients in need of early intervention. Psychological support, mindfulness-based stress reduction, and patient-centered communication strategies have shown promise in alleviating procedural anxiety during FNA biopsy (7) and should be explored further in this subgroup.

Additionally, there are several limitations in this study. First, the sample size was relatively small, and the prevalence of depression was extremely low (only one SDS-positive case), which substantially limited the statistical power to detect meaningful associations, particularly in subgroup analyses such as occupational categories. Second, the retrospective, single-center design may reduce the generalizability of the results to other settings or populations. Third, although validated self-report instruments are used, the SAS and SDS rely on subjective symptom reporting and may be influenced by recall bias or social desirability effects; structured clinical interviews are not conducted to confirm diagnoses. Finally, the cross-sectional nature of the study precludes any causal inferences regarding the relationship between psychological distress and clinical or imaging variables. Future research with larger, multi-center cohorts and longitudinal follow-up is warranted to better understand the psychological burden in patients with TI-RADS 4 thyroid nodules. Moreover, the very low prevalence of elevated depressive symptoms (n=1) limited our ability to examine correlation of depression specifically, though analyses of continuous symptom scores mitigated this to some extent.

Conclusions

In this cohort of patients with TI-RADS 4 thyroid nodules, symptoms of anxiety and depression were common and exhibited a strong positive correlation. However, psychological distress scores demonstrated only weak or negligible associations with clinical variables (thyroid-stimulating hormone, body mass index, carcinoembryonic antigen), biochemical markers, and imaging characteristics (nodule size, TI-RADS subclassification, calcification). These findings indicate that emotional burden in this population is largely independent of objective clinical or sonographic features and is likely driven primarily by diagnostic uncertainty. Routine psychological screening using validated tools and integration of psychosocial support into clinical management are recommended to address this underrecognized aspect of care and improve overall patient well-being.

Supplementary

The article’s supplementary files as

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. This study was approved by the ethics committee of Tianjin Cancer Hospital Health Management Center (Date. 2024.3; No. EK20240148). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Given the retrospective design, patient consent was waived, and data were anonymized prior to analysis.

Data Sharing Statement

Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-524/dss

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DOI: 10.21037/gs-2025-aw-524