Comparable long-term survival outcomes after lobectomy versus total thyroidectomy treatment of minimal extrathyroidal extension differentiated thyroid cancer patients

Introduction

Thyroid cancer (TC) is the most common endocrine malignancy, representing over 821,000 cases worldwide in 2022, and is the seventh most common cancer overall and the fifth in women (1). Papillary TC (PTC) and follicular TC (FTC) are categorized as differentiated TC (DTC), which originates from thyroid follicular cells and accounts for over 95% of all TC patients (2). Patients with DTC typically have an excellent prognosis, with 10-year survival rates exceeding 90–95% (3). Following the 2025 American Thyroid Association (ATA) guidelines, lobectomy is recommended for the treatment of cT1N0M0 DTC patients and is a choice for the treatment of cT2N0M0 DTC patients (4). Total thyroidectomy is recommended for the treatment of cT3–4N0M0 DTC patients (4). According to the 8th American Joint Committee on Cancer (AJCC) staging system and 2025 ATA guidelines, minimal extrathyroidal extension (MEE: microscopic or histological) is eliminated from the definition of T3 disease (3,4). MEE does not influence either the T category or the overall stage (3,4). Therefore, DTC patients (tumor size ≤4 cm) with MEE, which was used to be classified as T3 disease according to the 7th AJCC staging system (5), now are classified as T1/T2 disease according to the largest tumor size. As a result, lobectomy, not total thyroidectomy, will be the choice for the treatment of TC patients with MEE (tumor size ≤4 cm) at present. The association between MEE and its risk of TC recurrence remains controversy (6-9). MEE might gently increase the risk of recurrence in DTC patients and has no impact on disease-related mortality (10). However, there are few studies are exploring the survival outcomes for DTC patients with MEE who received lobectomy or total thyroidectomy treatment. In this study, we conducted a retrospective cohort analysis to examine the long‑term survival outcomes after lobectomy versus total thyroidectomy treatment of DTC patients with MEE using nationwide cancer registry data. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-507/rc).

Methods

Study population

The research data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program (www.seer.cancer.gov) Database: Incidence-SEER Research Data, 17 Registries, November 2023 submission, which covers approximately 28% of the US population (11). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. We extracted DTC patients with MEE from the SEER database by using the third revision of the International Classification of Diseases for Oncology (ICD-O-3) code C73.9, which corresponds to the thyroid gland, to select the primary tumor sites (8050/3, 8260/3, 8330/3, 8335/3, 8340/3 and 8341/3). Year of diagnosis, age at diagnosis, sex, and race were selected as demographic characteristics. Tumor size, tumor extension, and lymph node status were selected as tumor characteristics. The included process for first primary DTC patients with MEE is shown in Appendix 1.

Outcomes assessment

The primary outcome of this study was cancer-specific survival (CSS). CSS refers to the time interval from TC diagnosis to death from the disease. In the competing risk model, deaths are classified into two categories: those related to TC and those unrelated, with the latter treated as competing risks. Patients who remained alive were censored at their last follow-up date. DTC patients undergoing lobectomy usually could not receive radioactive iodine therapy (RAI). Therefore, we explored the influence of RAI effect as a sensitive analysis in this study.

Statistical analysis

The chi-squared (χ²) test was used to evaluate differences in patient demographics and tumor characteristics between DTC patients received lobectomy or total thyroidectomy. The CSS probabilities were calculated using the Kaplan-Meier method and analyzed with the log-rank test. Cumulative incidence curves of cancer-specific death were calculated using the Nelson-Aalen method and assessed with Gray’s test. To address potential confounding factors, we used multivariate Cox proportional hazards regression to calculate the adjusted hazard ratio (HR) and Fine and Gray’s competing risk regression to determine the subdistribution hazard ratio (SHR) (12). All statistical analyses were performed using R 4.0.2 software, with a two-tailed P value <0.05 indicating statistical significance.

Results

Patient demographics and tumor characteristics

A total of 1,889 DTC patients with MEE were included in the study (Appendix 1). Table 1 shows the characteristics of the DTC patients with MEE, including demographics and tumor characteristics. Patients had a median age of 50 years [interquartile range (IQR), 38–60 years]. The majority of patients were female (82.5%) and white (77.0%). Most tumors were pT1b tumors (42.9%) and pN0 (64.5%). Of these, 113 patients (6.0%) received lobectomy and 1,776 patients (94.0%) received total thyroidectomy. pT1a stage, pN0 were seen more frequently in the lobectomy group (Table 1). The median follow-up time for the entire cohort was 119 (IQR, 92–156) months (129 months lobectomy versus 118 months total thyroidectomy).

Survival outcomes

The CSS probabilities calculated by the Kaplan-Meier method are shown in Figure 1A. The 10-year CSS rate was 98.8% (95% CI: 98.2–99.3%) for all DTC patients with MEE, 99.1% (95% CI: 97.4–100%) for the lobectomy group, and 98.8% (95% CI: 98.2–99.4%) for the total thyroidectomy group. DTC patients with MEE who underwent lobectomy experienced a similar CSS rate compared with those who underwent total thyroidectomy (P=0.99, Figure 1A). Excluding deaths unrelated to TC, the 10-year cumulative incidence of cancer-related death was 1.2% overall, with a 10-year cumulative incidence of cancer-related death of 0.9 % for the lobectomy group and 1.2% for the total thyroidectomy group. As shown in Figure 1B, DTC patients with MEE who underwent lobectomy experienced a similar cancer-related death compared with those who underwent total thyroidectomy (P=0.99).

Figure 1 Comparison of cancer-specific survival (A) and cumulative incidence of cancer-specific death (B) for differentiated thyroid cancer patients with minimal extrathyroidal extension who underwent lobectomy or total thyroidectomy.

To adjust potential confounding factors, we performed the multivariate Cox regression model. As shown in Figure 2, DTC patients with MEE who underwent lobectomy experienced a similar hazard of death compared with those who underwent total thyroidectomy (adjusted HR, 1.99; 95% CI: 0.45–8.80; P=0.36). Age of diagnosis, pT stage, and pN stage were independent factors of CSS (all P<0.05, Figure 2). Considering death unrelated to TC, we used a multivariate Gray’s competing risk regression model. As shown in Figure 3, DTC patients with MEE who underwent lobectomy experienced a similar hazard of death compared with those who underwent total thyroidectomy (adjusted SHR, 1.99; 95% CI: 0.44–8.89; P=0.37).

Figure 2 Forest plot showing results of the multivariate Cox regression model performed for differentiated thyroid cancer patients with minimal extrathyroidal extension. CI, confidence interval; HR, hazard ratio; pN, pathologic node; pT, pathologic tumor.

Figure 3 Forest plot showing results of the multivariate competing risk regression model performed for differentiated thyroid cancer patients with minimal extrathyroidal extension. CI, confidence interval; pN, pathologic node; pT, pathologic tumor; SHR, subdistribution hazard ratio.

We also evaluated the survival difference between the lobectomy group and the total thyroidectomy group by pT stage. The lobectomy group has a comparable CSS outcome compared with the total thyroidectomy group in the pT1 patients (10-year CSS: 98.8% vs. 99.5%, P=0.50, Figure 4A). Taking death not related to TC into consideration, the lobectomy group also experienced a compared cumulative incidence of cancer-related death compared with the total thyroidectomy group in the pT1 patients (10-year cumulative incidence of cancer-related death: 1.2% vs. 0.5%, P=0.43, Figure 4B) Similarly, the lobectomy group has a compared CSS outcome (10-year CSS: 100% vs. 97.6%, P=0.95, Figure 5A) and a compared cumulative incidence of cancer-related death (10-year cumulative incidence of cancer-related death: 0% vs. 2.3%, P=0.96, Figure 5B) compared with the total thyroidectomy group in pT2 patients. These results did not change using the multivariate Cox regression model and the competing risk model both in the pT1 and pT2 stage group after taking the confound factors into consideration (Table 2).

Figure 4 Comparison of cancer-specific survival (A) and cumulative incidence of cancer-specific death (B) for pT1 differentiated thyroid cancer patients with minimal extrathyroidal extension who underwent lobectomy or total thyroidectomy. pT, pathologic tumor.

Figure 5 Comparison of cancer-specific survival (A) and cumulative incidence of cancer-specific death (B) for pT2 differentiated thyroid cancer patients with minimal extrathyroidal extension who underwent lobectomy or total thyroidectomy. pT, pathologic tumor.

Considering that DTC patients who underwent lobectomy typically could not receive RAI, we further evaluate the impact of RAI on survival in the present study. A total of 1,243 patients with total thyroidectomy have received RAI in the present study. DTC patients with MEE who received lobectomy experienced a similar CSS outcome compared to those who received total thyroidectomy whether without or with RAI (reference: without RAI: adjusted HR: 3.58; 95% CI: 0.64–19.89; P=0.15; reference: with RAI: adjusted HR: 1.62; 95% CI: 0.36–7.34; P=0.53). These results did not change after considering death not related to TC (both P>0.05, Table 3).

Discussion

The presence of MEE does not constitute T3 disease. TC (tumor size ≤4 cm) with MEE is now be categorized as T1/T2 disease according to the largest tumor size (3,4). As a result, lobectomy will be the choice for the treatment of DTC patients with MEE (tumor size ≤4 cm) following the 2025 ATA guidelines (4).

After the 2015 ATA guidelines, several studies have explored the survival difference between lobectomy and total thyroidectomy for cT1–2N0M0. Half of the studies showed no difference in recurrence or survival rates between lobectomy and total thyroidectomy (13-15). The other half of the studies showed that the recurrence rates of DTC patients who underwent total thyroidectomy were significantly lower than those of DTC patients who underwent lobectomy (16-18). Most cases of recurrence after lobectomy only occur in the other thyroid lobe, which can be successfully saved through total thyroidectomy (16,17). We also evaluated the survival difference between DTC patients (pT1/pT2N0–1aM0) with or without MEE in additional analysis, similar to the 8th AJCC staging system, we found that MEE was not a prognosis factor in pT1 patients (adjusted HR, 1.12; 95% CI: 0.51–2.44; P=0.78) and pT2 DTC patients (adjusted HR, 0.75; 95% CI: 0.38–1.53; P=0.44). Also, more aggressive surgery choices did not enhance the excellent survival outcomes of DTC with MEE in the present study. We found that DTC patients with MEE also have an excellent prognosis whether they underwent lobectomy or total thyroidectomy. The 10-year CSS was 99.1% for DTC patients with MEE who received lobectomy, and 98.8% for those who received total thyroidectomy. We also did subgroup analysis according to the pT stage, similar results were found both in pT1 and pT2 patients. However, total thyroidectomy would enhance the surgical complications during the treatment of DTC compared with the lobectomy (19-21). Compared with hemithyroidectomy, total thyroidectomy had a higher risk of temporary and permanent hypocalcemia (22,23). Similarly, total thyroidectomy had a higher risk of temporary and permanent damage to the recurrent laryngeal nerve (RLN) or vocal fold paralysis (22,24). Indeed, surgery performed by low-volume surgeons was associated with a higher risk of postoperative complications compared to surgery performed by high-volume surgeons (25). It should be noted that total thyroidectomy performed by high-volume surgeons still had a higher risk of surgical complications compared with lobectomy performed by low-volume surgeons (26). Most DTC patients with MEE in the present study have received total thyroidectomy as their first surgical choice. However, we believed that lobectomy will be increasingly used in the treatment of DTC with MEE, considering the comparable excellent survival outcomes and significantly lower surgical complications.

Compared with total thyroidectomy, DTC patients who underwent lobectomy typically could not receive RAI. In low-risk DTC patients, a follow-up strategy that did not use RAI was non-inferior to a RAI ablation strategy in terms of the occurrence of functional, structural, and biological events (27,28). Also, several studies reported that DTC patients with low risk did not benefit from RAI in terms of overall survival or disease-free survival (29-31). In comparison, DTC patients with high risk will benefit from postoperative RAI (32). MEE does not affect risk stratification for a single DTC and is not an indication for RAI. We further evaluated the impact of RAI on survival in the present study. DTC patients with MEE who received lobectomy experienced a similar CSS outcome compared to those who received total thyroidectomy whether without or with RAI. We also evaluated the prognosis value of radiation treatment in the DTC patients with MEE who received total thyroidectomy. In the post hoc analysis, DTC patients with MEE who received total thyroidectomy experienced a similar CSS outcome compared with those who did not receive RAI (adjusted HR: 1.17; 95% CI: 0.44–3.16; P=0.743).

Several limitations should be noted in the present study. First, there were no data about the recurrence of tumor. Even though we had a median follow-up time of 10 years, we were unable to use CSS to mirror the recurrence due to the excellent survival outcomes of DTC. Most cases of recurrence in the other lobe after lobectomy can be effectively treated through total thyroidectomy. We expected that the SEER database would collect the data related to tumor recurrence. Secondly, only 113 (6%) patients who underwent lobectomy as the first choice were included in this study, which might introduce potential selection bias and limit the statistical ability. Patients with a low lobectomy rate: (I) according to the 7th AJCC staging system, DTC patients (tumor size ≤4 cm) with MEE will be classified as pT3 stage, and total thyroidectomy will be the optional choice for these patients; (II) the total thyroidectomy will be performed more frequently for those patients with suspected capsule invasion; (III) MEE was a risk factor for lymph node metastasis. According to ATA guidelines, patients with cN1 will be recommended for total thyroidectomy. Therefore, patients with MEE are more likely to have lymph node metastasis and are more inclined to undergo total thyroidectomy. We believed that lobectomy will be increasingly used in the treatment of DTC with MEE, considering the comparable excellent survival outcomes and significantly lower surgical complications. Lastly, patients with a greater suspicion of lymph node metastasis (cN+), who should have received total thyroidectomy as the first choice following the ATA guidelines, could not be excluded in the present study. However, we excluded all pN+ patients in the total thyroidectomy group for a consecutive conservation, the result that patients who received lobectomy experienced a similar hazard risk of death compared with those who received total thyroidectomy did not change.

Conclusions

pT1/pT2 DTC patients with MEE who underwent lobectomy or total thyroidectomy have excellent comparable survival outcomes, supporting the increased use of lobectomy in treating these patients following the AJCC staging system changes. Further large-scale randomized controlled clinical trials considering subtypes of DTC: PTC vs. FTC, informed care consent, patient shared decision making and personalized care are warranted (33).

Acknowledgments

We would like to thank the SEER database for the collection of clinical data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-507/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-507/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-aw-507/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.

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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