Abstract
Background
The optimal surgical approach for patients with low-risk differentiated thyroid cancer (DTC) remains controversial. Current evidence comparing long-term outcomes between total thyroidectomy and hemithyroidectomy is limited by short follow-up and a lack of comprehensive patient-reported outcomes.
Objective
To compare the effectiveness of total thyroidectomy versus hemithyroidectomy in patients with low-risk DTC, evaluating oncologic outcomes, complications, thyroid function, quality of life, and healthcare costs.
Methods
We conducted a multicenter retrospective cohort study of 800 patients with low-risk DTC treated at three tertiary centers between 2014 and 2021, with follow-up through 2023. Propensity score matching (1:1) was performed using age, sex, tumor size, histology, and BRAF V600E status. Patients were analyzed according to the operation actually performed (as-treated analysis). Primary outcomes were overall survival and recurrence-free survival. Secondary outcomes included complications, thyroid function, quality of life (HADS, SCL-90), and healthcare costs. Analyses included Kaplan–Meier survival analysis with log-rank tests and Cox proportional-hazards regression, with Bonferroni correction for the two primary endpoints.
Results
After propensity score matching, 400 patients were included in each group (median follow-up 7.2 years, IQR 5.1–8.9). The 8-year overall survival rates were 97.2% (95% CI 95.6–98.8%) for total thyroidectomy versus 96.1% (95% CI 94.2–97.9%) for hemithyroidectomy (HR 0.79, 95% CI 0.44–1.42, p = 0.43). The 8-year recurrence-free survival rates were 96.8% versus 94.2% (HR 1.48, 95% CI 0.73–2.98, p = 0.28). Hemithyroidectomy was associated with a significantly lower rate of permanent hypoparathyroidism (2.0% vs 8.0%, p < 0.001, NNH = 17). Total thyroidectomy entailed a universal requirement for lifelong levothyroxine (100% vs 15% requiring replacement in the hemithyroidectomy group); among hemithyroidectomy patients not requiring replacement, subclinical hypothyroidism was common. At one year, fewer hemithyroidectomy patients reported clinically significant anxiety/depression (18% vs 25%, p = 0.018). Mean total 8-year healthcare costs were lower with hemithyroidectomy (¥28,247 vs ¥55,439, p < 0.001).
Conclusions
For appropriately selected patients with low-risk DTC, hemithyroidectomy provides oncologic outcomes comparable to total thyroidectomy while offering advantages in complications, thyroid-function preservation, quality of life, and healthcare costs. Treatment decisions should be individualized through shared decision-making. These findings support consideration of de-escalated surgery but require validation in prospective randomized trials.
Keywords: Differentiated thyroid cancer, Total thyroidectomy, Hemithyroidectomy, Propensity score matching, Comparative effectiveness research
Introduction
Differentiated thyroid cancer (DTC) represents over 90% of thyroid malignancies, with incidence rates increasing worldwide owing to enhanced diagnostic capabilities and screening [1]. The age-adjusted incidence of thyroid cancer has nearly tripled over the past four decades, from 4.9 to 14.3 per 100,000 [2]. A substantial proportion of these diagnoses are low-risk DTC, defined by the American Thyroid Association (ATA) as intrathyroidal tumors ≤ 4 cm without extrathyroidal extension, lymph-node metastasis, or aggressive histological features [3].
Surgical management of low-risk DTC evolved following the 2015 ATA guidelines, which recommended hemithyroidectomy as sufficient treatment for appropriately selected patients with 1–4 cm unifocal, intrathyroidal DTC [3]. This shift from the traditional preference for total thyroidectomy was based on evidence of comparable oncologic outcomes between the two approaches for low-risk disease [4–6].
Total thyroidectomy theoretically offers complete tumor removal and facilitates postoperative radioactive-iodine therapy and thyroglobulin monitoring [7], but it necessitates lifelong thyroid-hormone replacement and carries higher risks of permanent complications, including hypoparathyroidism and recurrent laryngeal nerve injury [8]. Hemithyroidectomy preserves thyroid function in many patients and reduces complication rates, although concerns remain regarding residual disease and surveillance limitations [9, 10].
Molecular diagnostics, particularly BRAF V600E analysis, have informed DTC risk stratification [11]. The BRAF V600E mutation, present in approximately 60% of papillary thyroid carcinomas, is associated with adverse clinicopathologic features and higher recurrence in some series (17.6% vs 9.6%) [12, 13]. However, its independent prognostic value is attenuated after adjustment for clinicopathologic factors, and current ATA guidelines do not recommend using BRAF status alone to determine the extent of surgery; coexisting alterations such as BRAF/TERT-promoter co-mutation carry greater prognostic weight [3, 13]. The clinical utility of BRAF for surgical decision-making therefore remains limited and should be interpreted within the broader risk profile rather than in isolation.
Despite numerous comparative studies, consensus on the optimal surgical approach remains elusive owing to methodological limitations, including short follow-up, small samples, heterogeneous populations, and inconsistent outcome measures [14–18]. Most studies have emphasized oncologic endpoints while neglecting patient-reported outcomes, quality of life, and economic considerations [19, 20]. Using propensity score matching to reduce selection bias, this multicenter retrospective cohort study comprehensively compares total thyroidectomy and hemithyroidectomy for low-risk DTC across oncologic outcomes, complications, thyroid function, quality of life, and healthcare costs over extended follow-up.
Materials and Methods
Study design and setting
This multicenter retrospective cohort study was conducted across three tertiary referral centers: the Fourth Affiliated Hospital of Xinjiang Medical University, the Fifth Affiliated Hospital of Xinjiang Medical University, and Shanghai Hospital of Traditional Chinese Medicine. These centers were selected for their comprehensive thyroid-cancer programs, standardized surgical protocols, and high-volume thyroid-surgery practices (> 200 procedures annually).
Participants and eligibility criteria
Inclusion criteria: (1) adults aged 18–75 years with pathologically confirmed low-risk DTC per the 2015 ATA guidelines (tumor diameter ≤ 4 cm; no extrathyroidal extension; no lymph-node metastasis [clinical or pathological]; no distant metastasis; no aggressive histological variants); (2) primary surgical treatment with total thyroidectomy or hemithyroidectomy; (3) complete clinical, pathological, and follow-up data; and (4) surgery performed between January 2014 and December 2021 (minimum 2-year follow-up).
Exclusion criteria: (1) previous thyroid surgery or neck irradiation; (2) concurrent malignancy; (3) previous radioactive-iodine or systemic therapy; (4) incomplete follow-up (> 2 missed key time points); (5) completion thyroidectomy after an initial hemithyroidectomy; and (6) high-risk histological variants (tall-cell, columnar-cell, hobnail). The potential bias introduced by criterion 5 is addressed in the Limitations.
Sample-size calculation
Based on pilot data and prior literature suggesting a potential 5% difference in 8-year recurrence-free survival (95% vs 90%), with 80% power, α = 0.05, and 10% loss to follow-up, the minimum required sample size was 350 patients per group. We targeted 400 per group to ensure adequate power for secondary analyses.
Surgical procedures and standardization
Procedures were performed by experienced thyroid surgeons stratified by experience (5–10 years vs > 10 years). Total thyroidectomy comprised complete bilateral thyroid removal, systematic parathyroid identification and preservation, recurrent laryngeal nerve monitoring and preservation, and central-compartment lymph-node sampling when indicated [21]. Hemithyroidectomy comprised ipsilateral lobe and isthmus removal with parathyroid and recurrent laryngeal nerve preservation and frozen-section analysis when indicated [22]. Quality-assurance measures included mandatory video documentation, standardized operative reports, and regular technique audits.
Propensity score matching
To reduce selection bias, propensity scores were estimated using multivariable logistic regression including age (continuous), sex, tumor size (continuous), histological type (papillary vs follicular), BRAF V600E status, surgeon experience level, and institution. Patients were matched 1:1 using nearest-neighbor matching with a caliper of 0.2 SD of the logit propensity score. Covariate balance was assessed using standardized mean differences (SMD), with values < 0.1 indicating adequate balance. We acknowledge that several clinically relevant confounders (multifocality, preoperative TSH, thyroid-autoantibody status/Hashimoto thyroiditis, comorbidity burden, year of surgery, and baseline quality of life) were not incorporated into the matching model; their potential residual confounding is discussed in the Limitations.
Outcome measures
Primary outcomes were overall survival (time from surgery to death from any cause) and recurrence-free survival (time to locoregional recurrence, distant metastasis, or death from any cause). Secondary outcomes were: complications — permanent hypoparathyroidism (hypocalcemia requiring calcium/active-vitamin-D supplementation beyond 12 months, with a documented attempt at withdrawal), recurrent laryngeal nerve injury (persistent voice change > 6 months), and postoperative bleeding; thyroid function (TSH, FT4, FT3; requirement for levothyroxine replacement); quality of life using the Hospital Anxiety and Depression Scale (HADS; 14 items; validated Chinese version, Cronbach’s α = 0.85) [23, 24] and the Symptom Checklist-90 (SCL-90; validated Chinese version) [25, 26]; healthcare costs (surgery, hospitalization, medications, follow-up); and lifestyle modifications by standardized questionnaire.
Follow-up protocol
Standardized follow-up was performed at 1, 3, 6, and 12 months and annually thereafter, including physical examination and neck ultrasonography, thyroid-function tests, serum thyroglobulin and anti-thyroglobulin antibodies (total thyroidectomy group), quality-of-life questionnaires (1, 3, 5 years), and healthcare-utilization tracking. All total thyroidectomy patients received levothyroxine replacement/suppression targeting a TSH of 0.5–2.0 mIU/L in accordance with ATA risk-adapted recommendations [27].
Statistical analysis
Analyses used SPSS 28.0 and R 4.3.0. The primary analysis was performed according to the operation actually performed (as-treated analysis); a per-protocol sensitivity analysis examined the influence of treatment crossover. Continuous variables are presented as mean ± SD or median (IQR) according to distribution (Shapiro–Wilk), and categorical variables as frequency (percentage). Between-group comparisons used independent t-tests or Mann–Whitney U tests, and χ2 or Fisher’s exact tests. Survival analyses used Kaplan–Meier estimation, log-rank tests, and Cox proportional-hazards regression; the proportional-hazards assumption was verified using Schoenfeld residuals and log–log plots. Multiple comparisons were adjusted using Bonferroni correction (α = 0.025 for the two primary endpoints). Sensitivity analyses included per-protocol analysis, competing-risk analysis, inverse probability weighting, and stratified analyses by tumor size, age, and institution. Missing data were handled with multiple imputation (m = 5) under a missing-at-random assumption.
Ethics and regulatory approval
This study was performed in accordance with the Declaration of Helsinki and approved by the institutional review boards of the three participating centers: the Ethics Committee of the Fourth Affiliated Hospital of Xinjiang Medical University (Protocol No. EX1682022; 15 January 2022); the Ethics Committee of the Fifth Affiliated Hospital of Xinjiang Medical University (Protocol No. EX1682022-A; 10 February 2022); and the Ethics Committee of Shanghai Hospital of Traditional Chinese Medicine (Protocol No. 2022-SH-01; 5 March 2022). The need for individual informed consent to participate was waived by each of these institutional review boards because of the retrospective design, the use of fully de-identified data, and the minimal risk to participants, in accordance with the Measures for Ethical Review of Life Science and Medical Research Involving Humans (China, 2023) and the Declaration of Helsinki.
Results
Patient selection and characteristics
The initial cohort included 1,247 patients with low-risk DTC. After applying inclusion and exclusion criteria, 856 patients remained eligible. Following propensity score matching, the final analytical cohort comprised 800 patients (400 per group). The selection process is shown in Fig. 1.
Fig. 1.
CONSORT flow diagram of patient selection and follow-up. The diagram shows application of inclusion and exclusion criteria, propensity score matching, and follow-up completion for both treatment groups
Baseline characteristics after matching are presented in Table 1. The median age was 42.8 years (IQR 36.2–49.5), with 70% female. All baseline variables included in the matching model achieved adequate balance (SMD < 0.1), confirming successful matching. Before matching, there was notable imbalance between groups (SMD = 0.42), which was effectively corrected after matching (SMD = 0.03).
Table 1.
Baseline characteristics after propensity score matching
| Characteristic | Total thyroidectomy (n = 400) | Hemithyroidectomy (n = 400) | SMD | P |
|---|---|---|---|---|
| Age, years (mean ± SD) | 42.5 ± 8.0 | 43.0 ± 8.5 | 0.061 | 0.43 |
| Female, n (%) | 280 (70.0) | 270 (67.5) | 0.055 | 0.38 |
| Tumor size, cm (median, IQR) | 2.0 (1.5–2.5) | 2.1 (1.6–2.6) | 0.088 | 0.31 |
| Papillary carcinoma, n (%) | 360 (90.0) | 350 (87.5) | 0.073 | 0.31 |
| BRAF V600E positive, n (%) | 200 (50.0) | 190 (47.5) | 0.050 | 0.48 |
| Surgeon experience > 10 y, n (%) | 240 (60.0) | 245 (61.3) | 0.026 | 0.70 |
SMD Standardized mean difference, IQR Interquartile range. All SMD values < 0.1 indicate adequate balance after matching. Confounders not included in the matching model (e.g., multifocality, preoperative TSH, autoantibody status, comorbidity, year of surgery, baseline quality of life) are addressed in the Limitations
Follow-up and loss to follow-up
The median follow-up was 7.2 years (IQR 5.1–8.9; range 2.0–9.8). Overall, 89 patients (11.1%) were lost to follow-up, with no significant difference between groups (10.8% vs 11.5%, p = 0.74). The median time to loss of follow-up was 5.8 years.
Primary outcomes
Overall survival
During the study period, 28 deaths occurred (14 in each group). The 8-year overall survival rates were 97.2% (95% CI 95.6–98.8%) for total thyroidectomy versus 96.1% (95% CI 94.2–97.9%) for hemithyroidectomy. The hazard ratio for death in the hemithyroidectomy group was 0.79 (95% CI 0.44–1.42, p = 0.43), indicating no significant difference (Fig. 2).
Fig. 2.
Kaplan–Meier curves for overall survival. Curves are comparable between groups over 8 years, with overlapping confidence intervals (HR 0.79, 95% CI 0.44–1.42, p = 0.43). The risk table shows patients at risk at each time point
Multivariable analysis. Cox regression for overall survival is shown in Fig. 3. Variables associated with overall survival included age ≥ 55 years (HR 2.31, 95% CI 1.47–3.62, p < 0.001), tumor size > 2.5 cm (HR 1.78, 95% CI 1.12–2.83, p = 0.015), and BRAF V600E positivity (HR 1.65, 95% CI 1.03–2.64, p = 0.038). Surgical approach was not an independent predictor (HR 0.89, 95% CI 0.52–1.53, p = 0.68). Because only 28 deaths occurred, this overall-survival model was statistically underpowered (events-per-variable < 10); these associations — in particular that of BRAF V600E with overall survival — should therefore be regarded as hypothesis-generating rather than confirmatory.
Fig. 3.
Forest plot of multivariable Cox regression for overall survival. Points denote hazard ratios with 95% confidence intervals; variables whose intervals cross HR = 1 are not statistically significant
Recurrence-free survival
Recurrence occurred in 36 patients (14 total thyroidectomy, 22 hemithyroidectomy). The 8-year recurrence-free survival rates were 96.8% (95% CI 95.0–98.6%) versus 94.2% (95% CI 91.8–96.6%). The hazard ratio for recurrence in the hemithyroidectomy group was 1.48 (95% CI 0.73–2.98, p = 0.28), not significant after Bonferroni correction (α = 0.025) (Fig. 4).
Fig. 4.
Kaplan–Meier curves for recurrence-free survival. A non-significant trend toward higher recurrence was seen with hemithyroidectomy (HR 1.48, 95% CI 0.73–2.98, p = 0.28). The risk table displays patients at risk throughout follow-up
The cumulative incidence of recurrence by time point is summarized in Table 2.
Table 2.
Cumulative incidence of recurrence by time point
| Time point | Total thyroidectomy | Hemithyroidectomy | HR (95% CI) | P |
|---|---|---|---|---|
| 2 years | 0.5% (2/400) | 1.0% (4/400) | 2.00 (0.37–10.84) | 0.41 |
| 5 years | 2.3% (9/400) | 4.0% (16/400) | 1.78 (0.78–4.06) | 0.17 |
| 8 years | 3.5% (14/400) | 5.5% (22/400) | 1.57 (0.79–3.12) | 0.20 |
HR Hazard ratio, CI Confidence interval. No significant differences were observed at any time point after adjustment for multiple comparisons
Subgroup analysis for recurrence-free survival (Fig. 5) demonstrated consistent treatment effects across major subgroups, with all confidence intervals crossing the reference line.
Fig. 5.
Subgroup analysis for recurrence-free survival. Hazard ratios with 95% confidence intervals across patient characteristics; the overall result (diamond) and subgroup results (circles) all cross the reference line, indicating no significant differences between approaches in any subgroup
Secondary outcomes
Complications
Postoperative complications are summarized in Table 3 and Fig. 6. Permanent hypoparathyroidism occurred in 32/400 (8.0%) total thyroidectomy versus 8/400 (2.0%) hemithyroidectomy patients (RR 4.00, 95% CI 1.87–8.56, p < 0.001; number needed to harm [NNH] 17, 95% CI 12–28). Under our relatively strict definition (calcium/active-vitamin-D dependence beyond 12 months with a documented withdrawal attempt), the 8.0% rate lies at the higher end of the published range; meta-analyses report 0–3% at high-volume centers and up to 9–14% in population-based registries [28, 29]. Among surgeons with > 10 years’ experience, the rate was substantially lower (3.5%; see below). Recurrent laryngeal nerve injury occurred in 20/400 (5.0%) versus 12/400 (3.0%) (RR 1.67, 95% CI 0.81–3.42, p = 0.16; not significant), and postoperative bleeding in 12/400 (3.0%) versus 10/400 (2.5%) (RR 1.20, 95% CI 0.52–2.76, p = 0.67; not significant).
Table 3.
Postoperative complications between groups
| Complication | Total thyroidectomy (n = 400) | Hemithyroidectomy (n = 400) | Risk difference (95% CI) | P | NNH |
|---|---|---|---|---|---|
| Permanent hypoparathyroidism, n (%) | 32 (8.0) | 8 (2.0) | 6.0% (3.1–8.9) | < 0.001 | 17 |
| Recurrent laryngeal nerve injury, n (%) | 20 (5.0) | 12 (3.0) | 2.0% (− 0.4–4.4) | 0.16 | – |
| Postoperative bleeding, n (%) | 12 (3.0) | 10 (2.5) | 0.5% (− 1.6–2.6) | 0.67 | – |
NNH Number needed to harm (calculated only for statistically significant differences). RR Risk ratio
Fig. 6.
Postoperative complication rates between groups. Error bars represent 95% confidence intervals; asterisks indicate statistical significance (*p < 0.05, **p < 0.001). The principal difference is in permanent hypoparathyroidism
Complication rates were inversely correlated with surgeon experience in both groups: surgeons with > 10 years’ experience had significantly lower permanent hypoparathyroidism (3.5% vs 8.2%, p = 0.007) and recurrent laryngeal nerve injury (2.1% vs 5.7%, p = 0.011) than those with 5–10 years’ experience.
Thyroid function
Thyroid-function outcomes are presented in Table 4 and Fig. 7. By design, all total thyroidectomy patients were rendered athyreotic and required lifelong levothyroxine (100%); with replacement targeting a TSH of 0.5–2.0 mIU/L, these patients were biochemically euthyroid throughout follow-up. In the hemithyroidectomy group, 60/400 (15.0%) developed overt hypothyroidism requiring levothyroxine by 12 months (median time to onset 8.5 months, IQR 3.2–14.7). Notably, the elevated group-mean TSH in the hemithyroidectomy group (Table 4) indicates that subclinical hypothyroidism (isolated TSH elevation without overt biochemical hypothyroidism) was frequent and is consistent with pooled meta-analytic estimates of post-hemithyroidectomy hypothyroidism of approximately 22–29%, which are higher in Asian populations [30]. Accordingly, the proportion of patients not requiring replacement should not be equated with fully normal thyroid status, and intermittent testing may have underestimated subclinical hypothyroidism (see Limitations).
Table 4.
Thyroid function over time
| Time point | Group | TSH (mIU/L) | FT4 (pmol/L) | FT3 (pmol/L) | Requiring levothyroxine, n (%) |
|---|---|---|---|---|---|
| Preoperative | Total thyroidectomy | 2.1 ± 0.8 | 14.2 ± 2.1 | 4.8 ± 0.7 | 0 (0) |
| Hemithyroidectomy | 2.0 ± 0.7 | 14.1 ± 2.0 | 4.7 ± 0.6 | 0 (0) | |
| 1 month | Total thyroidectomy | 3.2 ± 1.3 | 15.1 ± 1.9 | 4.3 ± 0.6 | 400 (100) |
| Hemithyroidectomy | 5.7 ± 2.1 | 12.4 ± 2.0 | 4.1 ± 0.7 | 40 (10.0) | |
| 6 months | Total thyroidectomy | 1.4 ± 0.7 | 16.2 ± 1.8 | 4.5 ± 0.6 | 400 (100) |
| Hemithyroidectomy | 7.2 ± 2.6 | 11.6 ± 1.8 | 4.0 ± 0.7 | 55 (13.8) | |
| 1 year | Total thyroidectomy | 1.2 ± 0.6 | 16.5 ± 1.7 | 4.6 ± 0.5 | 400 (100) |
| Hemithyroidectomy | 8.0 ± 2.9 | 11.2 ± 1.7 | 3.9 ± 0.6 | 60 (15.0) | |
| 8 years | Total thyroidectomy | 1.1 ± 0.5 | 16.4 ± 1.6 | 4.6 ± 0.5 | 400 (100) |
| Hemithyroidectomy | 8.1 ± 3.0 | 11.1 ± 1.6 | 3.9 ± 0.6 | 60 (15.0) |
Normal ranges: TSH 0.4–4.0 mIU/L, FT4 9.0–19.0 pmol/L, FT3 2.9–6.0 pmol/L. All total thyroidectomy patients received levothyroxine replacement/suppression targeting a TSH of 0.5–2.0 mIU/L; values shown reflect treated (euthyroid) status. “Requiring levothyroxine” denotes athyreotic status (total thyroidectomy) or overt hypothyroidism necessitating replacement (hemithyroidectomy)
Fig. 7.
Thyroid function over time. A serum TSH; total thyroidectomy patients are maintained within the normal range on levothyroxine, whereas the hemithyroidectomy remnant shows a mild rise in mean TSH reflecting frequent subclinical hypothyroidism. The normal range (0.4–4.0 mIU/L) is shaded. B proportion of patients requiring levothyroxine replacement
Predictors of replacement need in the hemithyroidectomy group. Multivariable logistic regression identified preoperative subclinical hypothyroidism (OR 3.24, 95% CI 1.78–5.91, p < 0.001) and resection of > 50% of thyroid-gland volume (OR 2.15, 95% CI 1.26–3.67, p = 0.005).
Quality of life and economic analysis
Quality-of-life outcomes are presented in Table 5 and Fig. 8. At 12 months, 100/400 (25%) total thyroidectomy versus 72/400 (18%) hemithyroidectomy patients had clinically significant anxiety/depression (HADS ≥ 8) (RR 1.39, 95% CI 1.06–1.82, p = 0.018). Because adequately replaced total thyroidectomy patients were biochemically euthyroid, the higher scores are unlikely to be explained by untreated hypothyroidism; nonetheless, residual confounding by the burden of lifelong hormone dependency and the absence of baseline quality-of-life matching cannot be excluded (see Limitations). Multivariable analysis identified age < 45 years (OR 1.86, 95% CI 1.23–2.81, p = 0.003), female sex (OR 1.53, 95% CI 1.02–2.29, p = 0.041), total thyroidectomy (OR 1.49, 95% CI 1.07–2.08, p = 0.018), and thyroid-hormone dependency (OR 2.13, 95% CI 1.42–3.19, p < 0.001) as predictors of anxiety/depression.
Table 5.
Quality-of-life assessment results
| Time | Scale | Measure | Total thyroidectomy | Hemithyroidectomy | P |
|---|---|---|---|---|---|
| Preop | HADS | Anxiety/depression ≥ 8, n (%) | 80 (20.0) | 75 (18.8) | 0.56 |
| 1 year | HADS | Anxiety/depression ≥ 8, n (%) | 100 (25.0) | 72 (18.0) | 0.018* |
| 1 year | SCL-90 | Interpersonal sensitivity (mean ± SD) | 1.8 ± 0.5 | 1.5 ± 0.4 | < 0.001* |
| 1 year | SCL-90 | Depression dimension (mean ± SD) | 1.7 ± 0.4 | 1.4 ± 0.3 | < 0.001* |
| 1 year | SCL-90 | Anxiety dimension (mean ± SD) | 1.6 ± 0.4 | 1.3 ± 0.3 | < 0.001* |
| 3 years | HADS | Anxiety/depression ≥ 8, n (%) | 80 (20.0) | 60 (15.0) | 0.11 |
| 5 years | HADS | Anxiety/depression ≥ 8, n (%) | 72 (18.0) | 52 (13.0) | 0.09 |
*Statistically significant (p < 0.05). HADS Hospital Anxiety and Depression Scale, SCL-90 Symptom Checklist-90
Fig. 8.
Quality of life and economic analysis. A anxiety/depression rates over time (significant difference at 1 year, p = 0.018). B healthcare-cost breakdown over 8 years
Healthcare costs are presented in Table 6. The 8-year cumulative cost was ¥55,439 ± 8,247 for total thyroidectomy versus ¥28,247 ± 6,432 for hemithyroidectomy (difference ¥27,192, 95% CI 25,634–28,750, p < 0.001), a 49% reduction with hemithyroidectomy, driven mainly by avoidance of lifelong hormone-replacement costs and reduced follow-up requirements.
Table 6.
Healthcare costs over 8-year follow-up
| Cost component | Total thyroidectomy (¥) | Hemithyroidectomy (¥) | Difference (95% CI) | P |
|---|---|---|---|---|
| Initial surgery | 25,012 ± 3,016 | 18,025 ± 2,531 | 6,987 (6,429–7,545) | < 0.001 |
| Annual follow-up | 3,019 ± 512 | 1,025 ± 316 | 1,994 (1,910–2,078) | < 0.001 |
| Hormone replacement (total) | 19,248 ± 2,384 | 0 ± 0 | 19,248 (18,970–19,526) | < 0.001 |
| Complication management | 1,160 ± 2,347 | 285 ± 1,142 | 875 (546–1,204) | < 0.001 |
| 8-year cumulative total | 55,439 ± 8,247 | 28,247 ± 6,432 | 27,192 (25,634–28,750) | < 0.001 |
All costs in Chinese Yuan (¥). Hormone-replacement costs include medication and monitoring over 8 years
Sensitivity analyses
Multiple sensitivity analyses confirmed the robustness of the primary findings (Table 7). A per-protocol analysis excluding 23 patients with protocol deviations was consistent (OS HR 0.81, 95% CI 0.44–1.49; RFS HR 1.52, 95% CI 0.74–3.11). Competing-risk analysis showed an 8-year cumulative incidence of thyroid-cancer-specific mortality of 1.5% versus 2.0% (Gray’s test p = 0.58), confirming no difference in disease-specific outcomes. Inverse probability weighting and complete-case analyses were also concordant.
Table 7.
Sensitivity analyses
| Analysis | OS HR (95% CI) | P | RFS HR (95% CI) | P |
|---|---|---|---|---|
| Primary analysis (PSM) | 0.79 (0.44–1.42) | 0.43 | 1.48 (0.73–2.98) | 0.28 |
| Per-protocol analysis | 0.81 (0.44–1.49) | 0.49 | 1.52 (0.74–3.11) | 0.25 |
| Inverse probability weighting | 0.77 (0.43–1.39) | 0.39 | 1.44 (0.72–2.87) | 0.30 |
| Complete-case analysis | 0.83 (0.45–1.53) | 0.55 | 1.41 (0.69–2.89) | 0.34 |
PSM Propensity score matching, HR Hazard ratio, CI Confidence interval, OS Overall survival, RFS Recurrence-free survival. All analyses were consistent with the primary findings
Discussion
In this multicenter, propensity-matched cohort of patients with low-risk DTC, hemithyroidectomy achieved oncologic outcomes comparable to total thyroidectomy while conferring advantages in complications, thyroid-function preservation, quality of life, and healthcare costs. We summarize these findings in context below.
Oncologic outcomes in context
The comparable 8-year overall survival (97.2% vs 96.1%) and recurrence-free survival (96.8% vs 94.2%) are consistent with large cohorts and meta-analyses showing that surgical extent does not significantly affect survival in low-risk thyroid cancer [4, 5, 16, 31–33]. Although hemithyroidectomy showed a numerically higher recurrence hazard (HR 1.48), this did not reach statistical or clinical significance, and competing-risk analysis confirmed no difference in disease-specific mortality [34]. Age ≥ 55 years and tumor size > 2.5 cm were associated with worse outcomes, consistent with established prognostic factors; the association of BRAF V600E with overall survival should be interpreted cautiously given the small number of events, and aligns with the view that BRAF status alone is insufficient to guide the extent of surgery [3, 12, 13].
Complications, thyroid function and patient-reported outcomes
Hemithyroidectomy reduced permanent hypoparathyroidism four-fold (2.0% vs 8.0%; NNH 17). Permanent hypoparathyroidism substantially impairs quality of life and entails lifelong calcium management [28, 35]. Our 8.0% rate is higher than the 0–3% reported at the most experienced centers and reflects our strict definition and routine central-compartment exploration; the markedly lower rate among the most experienced surgeons (3.5%) underscores the influence of surgical expertise and volume on outcomes [29, 36]. The difference in recurrent laryngeal nerve injury (5.0% vs 3.0%) was not significant. As expected, total thyroidectomy mandated lifelong levothyroxine in all patients, whereas 15% of hemithyroidectomy patients developed overt hypothyroidism requiring replacement; subclinical hypothyroidism was nonetheless common, consistent with the literature [30]. Hemithyroidectomy patients reported less anxiety/depression at one year, and hormone dependency was an independent predictor of psychological distress, although baseline quality of life was not matched and residual confounding cannot be excluded [37]. These patient-reported differences reinforce the value of incorporating quality of life into surgical decisions for a disease with excellent survival [31, 38].
Economic and molecular considerations
The 8-year cost difference of ¥27,192 (approximately US$4,200) mainly reflects hormone-replacement and monitoring expenses and is increasingly relevant in resource-limited settings [39, 40]. Beyond BRAF V600E, molecular markers including RAS mutations, RET/PTC rearrangements, and TERT-promoter co-mutations are increasingly integrated into risk stratification and may refine individualized decisions [11–13, 41]. Different approaches require tailored surveillance: total thyroidectomy permits thyroglobulin monitoring, whereas hemithyroidectomy relies primarily on neck ultrasonography [42]. These considerations support a shared decision-making framework rather than a single default operation [43].
Strengths and limitations
Strengths include a relatively large, propensity-matched sample, long-term follow-up, comprehensive outcomes including patient-reported measures, multiple concordant sensitivity analyses, and standardized surgical techniques. Several limitations warrant emphasis. First, the retrospective design carries inherent selection bias despite matching, and the propensity model omitted clinically relevant confounders — multifocality, preoperative TSH, thyroid-autoantibody status/Hashimoto thyroiditis, comorbidity burden, year of surgery, and baseline quality of life — so residual confounding may persist. Second, patients who underwent completion thyroidectomy after an initial hemithyroidectomy were excluded from the as-treated cohort; because such patients are typically those upstaged on final pathology, their exclusion may bias outcomes in favour of hemithyroidectomy. Third, thyroid-function testing at fixed intervals may have underestimated subclinical hypothyroidism in the hemithyroidectomy group. Fourth, quality-of-life and economic analyses used surrogate measures and a single national cost framework, limiting generalizability. Fifth, the overall-survival multivariable model was underpowered (28 events), so its estimates are hypothesis-generating. Finally, multiple imputation assumptions may not hold for all variables. Prospective, adequately powered randomized trials with standardized molecular risk stratification and longer follow-up are needed to confirm these findings.
Conclusions
For carefully selected patients with low-risk DTC, hemithyroidectomy provides oncologic outcomes comparable to total thyroidectomy while offering advantages in complications, thyroid-function preservation, quality of life, and healthcare costs. Treatment decisions should remain individualized, integrating tumor characteristics, patient preferences, surgical expertise, and institutional capability through shared decision-making. These findings support hemithyroidectomy as a reasonable first-line option for appropriate patients but require validation in prospective randomized trials before they can inform definitive recommendations.
Acknowledgements
Not applicable.
Clinical trial registration
Not applicable. This study is a retrospective observational cohort analysis and was not registered as a clinical trial.
Abbreviations
- DTC
Differentiated thyroid cancer
- TT
Total thyroidectomy
- HT
Hemithyroidectomy
- ATA
American Thyroid Association
- PSM
Propensity score matching
- OS
Overall survival
- RFS
Recurrence-free survival
- HR
Hazard ratio
- RR
Risk ratio
- OR
Odds ratio
- CI
Confidence interval
- SMD
Standardized mean difference
- NNH
Number needed to harm
- IQR
Interquartile range
- TSH
Thyroid-stimulating hormone
- FT4
Free thyroxine
- FT3
Free triiodothyronine
- HADS
Hospital Anxiety and Depression Scale
- SCL-90
Symptom Checklist-90
- IPW
Inverse probability weighting
- RAI
Radioactive iodine
Authors’ contributions
ZM: Conceptualization, methodology, formal analysis, writing—original draft. IEA: Supervision, methodology, writing—review & editing. VGVF: Data curation, investigation, writing—review & editing. WW: Data collection, validation, writing—review & editing. JG: Funding acquisition, resources, supervision, writing—review & editing. ZZ: Data analysis, visualization, writing—review & editing. All authors have read and approved the final manuscript.
Funding
This research was supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region, China (2022D01C175) and a hospital-level project of the Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University, China (ZYY202213). The funding bodies had no role in study design, data collection, analysis, interpretation, or manuscript preparation.
Data availability
In accordance with institutional policies and ethical guidelines, de-identified patient data used to support the conclusions of this study may be made available to qualified researchers upon reasonable request and in accordance with appropriate data sharing agreements. Data requests may be sent to: Corresponding Author: Dr. Ihab E. Ali Email: ihab.ali@taylors.edu.my Institution: Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, Selangor Darul Ehsan, 47,500 Malaysia Or Mr.Jinqiang Pan Email: 18,599,416,461@163.com Institution: Department of Thyroid Surgery, the Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830,011, China Requests will be reviewed by the institutional ethics committees and data sharing will be subject to approval and completion of data transfer agreements.
Declarations
Ethics approval and consent to participate
This study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review boards of the three participating centers: the Ethics Committee of the Fourth Affiliated Hospital of Xinjiang Medical University (Protocol No. EX1682022; 15 January 2022); the Ethics Committee of the Fifth Affiliated Hospital of Xinjiang Medical University (Protocol No. EX1682022-A; 10 February 2022); and the Ethics Committee of Shanghai Hospital of Traditional Chinese Medicine (Protocol No. 2022-SH-01; 5 March 2022). The need for individual informed consent to participate was waived by each of these institutional review boards because of the retrospective design, the use of fully de-identified data, and the minimal risk to participants, in accordance with the Measures for Ethical Review of Life Science and Medical Research Involving Humans (China, 2023) and the Declaration of Helsinki.
Consent for publication
Not applicable. This manuscript contains no individual person’s identifiable data (images, videos, or personal or clinical details) that would require consent for publication.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
In accordance with institutional policies and ethical guidelines, de-identified patient data used to support the conclusions of this study may be made available to qualified researchers upon reasonable request and in accordance with appropriate data sharing agreements. Data requests may be sent to: Corresponding Author: Dr. Ihab E. Ali Email: ihab.ali@taylors.edu.my Institution: Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, Selangor Darul Ehsan, 47,500 Malaysia Or Mr.Jinqiang Pan Email: 18,599,416,461@163.com Institution: Department of Thyroid Surgery, the Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830,011, China Requests will be reviewed by the institutional ethics committees and data sharing will be subject to approval and completion of data transfer agreements.