Oncological characteristics predict permanent hypoparathyroidism following total thyroidectomy for papillary thyroid carcinoma: a study from China

Introduction

Thyroid cancer is one of the most common endocrine malignancies, with its incidence rising steadily over the past few decades. Among the different types of thyroid cancer, papillary thyroid carcinoma (PTC) is the most prevalent, accounting for approximately 90% of all cases (1). Surgery is the preferred treatment for PTC. Depending on the extent of the disease, surgical options range from unilateral thyroidectomy to total or near-total thyroidectomy. Total thyroidectomy is particularly recommended in cases where there is evidence of bilateral disease, larger tumors, local invasion, or evidence of metastasis.

One of the most significant complications associated with total thyroidectomy is hypoparathyroidism, which occurs due to inadvertent damage to or removal of the parathyroid glands (PGs), or disruption of their blood supply during surgery (2-4). The PGs play a crucial role in regulating calcium homeostasis, and their dysfunction can lead to hypocalcemia. Hypocalcemia can manifest with a spectrum of symptoms ranging from mild, such as tingling and numbness, to severe, such as tetany and life-threatening cardiac arrhythmias. Hypoparathyroidism, especially permanent hypoparathyroidism, has significant clinical implications and can substantially affect the patient’s quality of life (5-8).

While several studies have explored risk factors for hypoparathyroidism in general thyroidectomy populations, few have focused specifically on the oncological characteristics predictive of permanent hypoparathyroidism in PTC patients. This study aims to fill this gap by analyzing a cohort of Chinese patients undergoing total thyroidectomy for PTC, with a focus on identifying oncological predictors of permanent hypoparathyroidism. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-21/rc).

Methods

A retrospective cohort study was conducted at a tertiary medical center in China from January 2017 to January 2021, reviewing all patients who underwent total thyroidectomy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The University of Hong Kong-Shenzhen Hospital (No. 2023102) and individual consent for this retrospective analysis was waived. Patients who were postoperatively diagnosed with PTC were included. All procedures were carried out by a single dedicated thyroid surgical team, with each lead surgeon having an annual thyroid surgery volume exceeding 200 cases. The indications for total thyroidectomy for PTC at our center followed the 2015 American Thyroid Association (ATA) guidelines (9), and included the presence of any of the following: tumors larger than 4 cm, gross extrathyroidal extension (ETE) (clinical T4 stage), clinically positive lymph nodes (cN1), distant metastases (clinical M1), contralateral thyroid involvement, or coexisting Graves’ disease. Prophylactic or therapeutic central neck dissection (CND) was routinely performed during surgery. Lateral neck dissection was performed in patients with clinically confirmed or suspected lateral neck lymph node metastasis (cN1b). Patients with postoperative pathology confirming benign disease or other types of thyroid cancer, or those with incomplete clinical data, were excluded.

Data were collected from medical records, including preoperative, intraoperative, and postoperative information. Key variables analyzed included demographic data (such as age and gender), surgical details (extent of lymph node dissection, duration of surgery, and use of carbon nanoparticles), and postoperative pathology variables [maximum tumor diameter, multifocality, ETE, presence of PGs in pathological specimens, and the number of total and involved central lymph nodes (CLNs)]. Postoperative outcomes focused on the incidence of permanent hypoparathyroidism, postoperative calcium and parathyroid hormone (PTH) levels, and other complications. Hypoparathyroidism was defined as a low intact PTH level below the lower limit of the laboratory standard (PTH <12 pg/mL) accompanied by hypocalcemia. Permanent hypoparathyroidism is defined as hypoparathyroidism that persists for more than 6 months after surgery (10).

Serum PTH levels were routinely measured at 6 hours postoperatively, on postoperative day 1, and on postoperative day 2 during hospitalization. The follow-up protocol after surgery included visits at 1 week, 1 month, 3 months, 6 months, and 1 year. All enrolled patients, including those who received radioactive iodine (RAI) therapy, were followed within our unit for at least 6 months. During each visit, assessments included thyroid function tests, serum thyroglobulin, thyroglobulin antibody levels, serum calcium, and PTH levels. After 6 months, follow-up evaluations were expanded to include neck ultrasound examinations. Postoperative RAI therapy was routinely administered for high-risk patients according to the ATA guidelines. For intermediate-risk patients, RAI was recommended but ultimately individualized based on clinical factors and patient preference.

In our center, all patients routinely received calcium supplementation at a dose of 600 mg twice daily immediately after surgery. Once postoperative PTH and serum calcium results were available, supplementation was adjusted accordingly. For patients with normal postoperative PTH levels but who developed hypocalcemia, calcium supplementation was increased to 1,200 mg twice daily. For patients with PTH levels between 6–12 pg/mL (the lower limit of normal), calcitriol (active vitamin D) was added at a dose of 0.5 µg once daily. For patients with PTH levels below 6 pg/mL accompanied by hypocalcemia, calcitriol was administered at a dose of 0.5 µg twice daily. The indication for attempting discontinuation of calcium and/or calcitriol supplementation was the normalization of both serum PTH and calcium levels. If, after discontinuation, follow-up testing revealed a decline in serum calcium levels, the patient was considered to have persistent hypoparathyroidism and supplementation was resumed.

Statistical analysis

Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) and compared using the Student’s t-test or the Mann-Whitney U test as appropriate, based on the normality of distribution. Categorical variables were presented as counts and percentages, and compared using the chi-square test or Fisher’s exact test when expected cell counts were less than 5. Univariate analysis was conducted to identify potential risk factors for permanent hypoparathyroidism, and variables with a P value <0.1 were subsequently included in a multivariate logistic regression model to identify independent predictors. A two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics

During the study period, a total of 421 patients underwent total thyroidectomy. Of these, 24 patients were excluded due to missing follow-up data, and 30 patients were excluded due to postoperative pathology confirming other thyroid conditions (16 with benign disease, 4 with follicular carcinoma, 8 with medullary carcinoma, and 2 with anaplastic carcinoma). Ultimately, 367 patients were included in the final analysis. The characteristics of these patients are detailed in Table 1.

The cohort had a mean age of 39.5±11.2 years, with 126 males (34.33%). All surgeries were performed by a single surgical team, with an average duration of 136.6±48.2 minutes. Carbon nanoparticles were used in 202 surgeries (55.04%), and bilateral CND was performed in 123 cases (33.51%).

Among all study participants, the mean maximum tumor diameter was 18.3±12.0 mm, with 238 cases (64.85%) exhibiting multifocality. ETE was present in 198 cases (53.95%), while 32 patients (8.71%) exhibited microscopic ETE, and 166 patients (45.23%) had gross ETE. CLN metastasis was observed in 309 patients (84.20%), with a mean total CLN yield of 10.4±6.8 and an involved lymph node yield of 4.8±5.0. Postoperative RAI ablation was administered to 231 patients (62.94%), and distant metastasis was identified in 9 patients (2.45%). Parathyroid tissue was identified in the pathological specimens of 142 patients (38.69%). On the first postoperative day, 165 patients (44.96%) experienced hypoparathyroidism, while permanent hypoparathyroidism occurred in 27 patients (7.36%). Among the 27 patients, 12 had PTH levels less than 6 pg/mL, 9 had PTH levels between 6 and 12 pg/mL, and 6 had PTH levels greater than 12 pg/mL. Other complications included vocal cord paralysis in 27 patients (7.36%) and postoperative bleeding in 2 patients (0.54%). Wound infection and lymphatic leakage were each reported in 3 patients (0.82%).

The results of the univariate and multivariate analyses for risk factors of permanent hypoparathyroidism are presented in Tables 2,3. In the univariate analysis, significant associations were found with ETE, presence of PGs in pathological specimens, maximum tumor diameter, number of involved CLN and distant metastasis. However, multivariate analysis confirmed that gross ETE [odds ratio (OR) =3.584, 95% confidence interval (CI): 1.266–10.147; P=0.02], the presence of PG tissue in the pathological specimen (OR =3.809, 95% CI: 1.504–9.648, P=0.005), and number of involved CLN (OR =1.147, 95% CI: 1.000–1.315; P=0.049), remained significant predictors.

Discussion

Hypoparathyroidism remains a significant complication following total thyroidectomy. Patients with permanent hypoparathyroidism after total thyroidectomy have an increased risk of long-term morbidity (8). Although many studies have explored the risk factors of hypoparathyroidism in general thyroidectomy populations (10-16), this study specifically examines these risk factors within the context of PTC. Our study identified four independent risk factors: three tumor-related factors, including gross ETE, more involved CLNs, and accidental parathyroidectomy during surgery.

Microscopic and gross ETE were significantly associated with decreased overall survival and increased risks of lymph node and distant metastases (17,18). In a retrospective analysis of 177,497 patients with classic papillary thyroid cancer using the 2016 National Cancer Database, Bortz et al. demonstrated that even minimal ETE has important prognostic implications, despite its exclusion from the current American Joint Committee on Cancer (AJCC) staging system (19). For gross ETE, the critical aspect with regard to recurrence and outcomes is whether all of the tumor was removed. In this study, gross ETE was a strong predictor of permanent hypoparathyroidism, with an odds ratio of 3.584 in the multivariate analysis. Gross ETE, present in 53.95% of the patients, signifies a more advanced tumor that invades surrounding tissues, potentially including the PGs. Gross ETE often necessitates more extensive resection, which can compromise both the preservation and vascular integrity of the PGs. As parathyroid function is critically dependent on intact vascular supply, even minor disruptions can result in hypoparathyroidism, especially if parathyroid autotransplantation is not feasible or successful. Therefore, concerns over ETE should be raised when considering the initial surgical procedure.

CND is a common procedure in thyroid cancer surgery, particularly when lymph node involvement is suspected or confirmed. In this study, all patients underwent at least unilateral CND. The anatomical proximity of the PGs to the central compartment lymph nodes increases the risk of gland injury and the subsequent development of hypoparathyroidism (20,21). Superior PGs are relatively easier to identify and preserve in situ; in contrast, inferior glands are more difficult to preserve due to their variable anatomical location during CND. Although many studies have suggested that bilateral CND is significantly associated with hypoparathyroidism (22,23), our findings did not demonstrate a higher risk of PG injury in patients undergoing bilateral versus unilateral CND.

Nevertheless, the persistence of CLN yield as an independent predictor of permanent hypoparathyroidism in multivariate analysis suggests that the disease burden in the central neck compartment plays a critical role in this complication. A higher number of positive or resected lymph nodes may reflect not only more aggressive tumor biology, but also necessitate wider dissection and greater manipulation of the PGs and surrounding tissues, thereby increasing the likelihood of devascularization or inadvertent resection.

Incidental parathyroidectomy was a high-risk factor for permanent hypoparathyroidism. In 38.69% of cases, parathyroid tissue (including whole glands or microscopic fragments) was found in the pathological specimens, indicating that inadvertent removal of PGs during surgery is not uncommon. This highlights the difficulty of accurately identifying and preserving the PGs during thyroid surgery. Gschwandtner et al. report that even an experienced surgeon is not always able to find all four PGs during thyroidectomy and occasionally identifies none. Rather than focusing on identifying a minimum number of PGs, it is more important not to miss them in risky positions (24). Despite it not being necessary to visualize all four PGs (24,25), Thomusch et al. demonstrated that identifying and preserving at least two PGs is essential to avoid permanent hypoparathyroidism (26). The use of contrast agents or photosensitizers [such as indocyanine green, amino levulinic acid hydrochloride (5-ALA), and methylene blue] during surgery can assist in the identification of the PGs. Nano-carbon imaging technology is widely used in China to enhance the identification of the PGs while also visualizing the CLNs to achieve more thorough lymph node dissection (27,28). However, in our previous research, despite a lower rate of inadvertent parathyroid removal in the nano-carbon group, the incidence of hypoparathyroidism was not reduced, suggesting that extensive lymph node dissection under nano-carbon tracing may negatively impact the blood supply to the PGs (29). Similarly, in this study, the use of nano-carbon did not reduce the probability of permanent hypoparathyroidism. Recently, the successful detection of label-free parathyroid autofluorescence using near-infrared fluorescence spectroscopy has been reported (30-33). Other strategies such as the use of meticulous surgical technique (34,35), loupe magnification (36), and consideration of parathyroid autotransplantation are crucial in reducing the risk of hypoparathyroidism.

There are several limitations in this study that should be acknowledged. First, as a retrospective cohort study conducted in a single center, the findings may be subject to selection bias and may not be generalizable to other settings or populations. The single-center design also limits the diversity of surgical techniques and practices, which could influence the observed outcomes. Second, the reliance on medical records for data collection may introduce inaccuracies or result in incomplete data, particularly regarding intraoperative details and long-term postoperative follow-up. Third, although all surgeries were performed by high-volume, experienced surgeons, the study did not distinguish between different lead surgeons. Variations in individual surgical technique and decision-making could influence parathyroid preservation outcomes and act as a confounding factor in the development of hypoparathyroidism. Fourth, the study did not analyze the role or impact of parathyroid auto-transplantation. In clinical practice, auto-transplantation is often employed when parathyroid viability is compromised, and it may significantly influence the preservation of long-term parathyroid function. The lack of data on this variable may limit the interpretation of some results. Fifth, permanent hypoparathyroidism in this study was defined as lasting more than six months postoperatively, which is a commonly used time point. However, it is possible that a small number of patients could recover parathyroid function beyond this six-month threshold. In summary, future multicenter, prospective studies with standardized surgical protocols, detailed documentation of intraoperative findings—including surgeon identity and parathyroid autotransplantation—and larger sample sizes are necessary to validate these findings and further clarify the risk factors for hypoparathyroidism following total thyroidectomy for PTC.

Conclusions

In conclusion, this retrospective study identifies three significant oncological predictors of permanent hypoparathyroidism in patients undergoing total thyroidectomy for PTC: gross ETE, a greater number of involved CLNs, and the presence of parathyroid tissue in surgical specimens. These findings underscore the critical importance of meticulous surgical technique and comprehensive intraoperative strategies to preserve PG integrity and vascularization, particularly in patients with aggressive disease characteristics. Our results highlight that tumor invasiveness and nodal burden not only guide oncological management but also directly impact postoperative functional outcomes such as calcium homeostasis. Special attention should be paid to surgical planning and intraoperative decision-making in high-risk patients. Future prospective multicenter studies with standardized surgical protocols and long-term follow-up are warranted to confirm these findings and explore additional strategies for preventing permanent hypoparathyroidism while maintaining oncological safety.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-21/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-21/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-21/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-2025-21/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 The University of Hong Kong-Shenzhen Hospital (No. 2023102) and individual consent for this retrospective analysis was waived.

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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