The incidence of papillary thyroid carcinoma (PTC) continues to increase (1, 2). PTC is the most common type of thyroid malignancy and is characterized by a well-differentiated, slow-growing and high rate of lymph node metastasis. Surgical resection is the best treatment when visible nodules are present (3–5). Thyroid with isthmus subtotal resection or total resection is determined by the thyroid disease of patients. Total thyroidectomy (TT) can effectively avoid the occurrence of residual metastases in the gland, especially for differentiated thyroid cancer. However, this operation also has several shortcomings. Once the patient relapses, a second surgery is needed. The metastasis rate of central lymph nodes is high in patients with stage C node-negative (N0) PTC. Therefore, some scholars have proposed that the treatment of this disease can be combined with central lymph node dissection to reduce the risk of postoperative metastasis and recurrence and to avoid long-term secondary surgical dissection of central lymph nodes (6). To date, PCND have be considered in patients with PTC with clinically uninvolved central neck lymph nodes who have advanced primary tumors (T3 or T4) (5), there has been debate on whether to conduct prophylactic central lymph node neck dissection (PCND) for clinically node-negative (cN0) patients (7–11). Reasons to omit PCND are listed as follows: (1) no survival benefit, (2) increasing the risk of recurrence and postoperative complications, and (3) associated with longer hospitalization times and additional costs (12). Thus, a meta-analysis was conducted to provide strong evidence for clinical practice by assessing the effectiveness and safety of TT with PCND in cN0 PTC patients.

A total of 3916 publications were obtained from PubMed and 10 from hand searches. After 40 inappropriate articles were excluded, 15 studies (7, 9–12, 14–23) were eligible and incorporated into our study ( Figure 1 ). The basic characteristics of the included studies are shown in Table 1 . The clinical outcomes of the included studies are shown in Table 2 . There were 11 retrospective studies and 4 RCTs. All the included studies demonstrated a relatively high quality, and the results are shown in Supplementary Table 1 and Figure 2 . No publication bias was found, and the results of Begg’s and Egger’s tests are shown in Supplementary Figure 1 .

In the present meta-analysis, the efficacy of TT with PCND in cN0 PTC patients was shown to be relatively satisfactory. PCND reduced the risk of local recurrence. Several factors might explain our findings. First, thyroid cancer metastasizes through the lymphatic pathway, and the central lymph node is the first stop of thyroid lymphatic reflux. Second, lymph node metastases are often difficult to detect before surgery (24, 25). The completeness of surgical resection is an important determinant of prognosis in patients with PTC (26). PCND improves the accuracy of staging, removes undetected involved lymph nodes, and reduces recurrence in patients with cN0 PTC. Thus, PCND could avoid the metastatic spread of cancer cells and prevent future recurrence (22). However, some studies are inconsistent with our conclusions. Kim, Conzo et al. (9, 16) proposed that PCND did not help regional recurrence and suggested radioactive iodine therapy to control the disease. Conzo et al. (9) showed that reoperations occurred less frequently when an experienced endocrine surgeon performed the procedure. This is in contrast to the findings of Moo et al (20), who found a trend toward lower recurrence in TT with PCND, which could be due to increased control over local metastases or increased doses of radioiodine therapy (RAI) ablation in patients with recognized lymph node metastases. Yazıcı et al. (12) also recommended PCND in cN0 PTC patients, and they found that patients who received TT with PCND had less laryngeal nerve injury recurrence, reoperation and need for RAI therapy than patients who received TT alone.

Regarding safety, while the incidence of permanent hypocalcemia and transient hypoparathyroidism in the TT with PCND group was higher than that in the TT group, other complications were similar between the two groups. Transient hypoparathyroidism is the most common complication after TT. The results of our study showed that the incidence of postoperative transient hypoparathyroidism increased in the TT with PCND group compared with the TT alone group. It is speculated that the structure of the parathyroid glands is tiny and is easily injured or accidentally cut during surgery. Therefore, we recommend that experienced endocrine surgeons perform surgical operations as much as possible, use techniques to accurately locate the parathyroid glands during surgery, and use advanced stripping medical equipment to decrease the risk of accidental debridement and removal of the parathyroid glands.

Moreover, our study showed no significant difference in permanent hypoparathyroidism between the TT alone and TT with PCND groups. However, this result is still controversial. We found that in the study by Moo et al., the number of patients with transient hypoparathyroidism in the TT with PCND group was more than that in the TT alone group at the beginning (20). Some researchers (10, 12, 17, 18) also reached similar conclusions as Moo et al. (20); all of them found that PCND was a risk factor for transient hypothyroidism, while the rate of permanent hypoparathyroidism was very low, and there were no significant differences from patients who received TT alone. In contrast, Dobrinja et al. (19) reported that the incidence of permanent hypothyroidism in the TT with PCND group was significantly higher than that in the TT group, but we found that in this study, the follow-up time of the TT with PCND group was only 37 months, while that of the TT alone group was 76 months. We speculated that this might be because some patients with symptom elimination were not included in the statistics, which caused an increased incidence of permanent hypothyroidism.

Transient hypocalcemia is also a common complication of TT due to the decreases in parathyroidism function (27, 28). Our pooled results showed that no increased risk of postoperative transient hypocalcemia was found in the TT with PCND group compared with the TT alone group. However, our result was inconsistent with some studies. Roh et al. (17) found that the incidence of transient hypocalcemia was higher in the TT with PCND group than in the TT alone group, which was attributed to the fact that expanding lymph node dissection in the process of TT with PCND increases the risk of parathyroid blood vessel resection. In So et al.’s study, the incidence of tumor multifocality was higher in the TT with PCND group than in the TT alone group (15). Overall, the cause of hypocalcemia is related to the scope, mode and frequency of surgery, lymph node dissection, and malignant degree of histopathological examination (29).

Permanent hypocalcemia is defined as the requirement for calcium active vitamin D and/or calcium supplementation within half a year after thyroidectomy, and permanent hypocalcemia requires lifelong treatment (29). Herein, the pooled results of our study showed that the TT with PCND group had a higher risk of permanent hypocalcemia than the TT alone group. We speculated that permanent hypocalcemia may be caused by severe intraoperative parathyroid damage or poor response to treatment of transient hypocalcemia. Moreover, PCND might be a risk factor for permanent hypocalcemia in children (30). Therefore, effective identification and prudent preservation of parathyroid glands and autotransplantation of at least one gland may be a wise move to prevent permanent hypoparathyroidism (31). Careful protection of the vascular supply and parathyroid drainage system during lymph node dissection may reduce the incidence of hypocalcemia (17). Intriguingly, one meta-analysis suggested that the application of intraoperative near-infrared autofluorescence imaging (NIRAF) in thyroidectomy does not increase the risk of hypocalcemia (32). Weng et al. (32) stated that intraoperative NIRAF was used to assist parathyroid imaging and help the surgeon visually localize parathyroid tissue during surgery. It can accurately detect parathyroid glands in almost real time, which could reduce the cost and save time for parathyroid frozen section biopsy. Taken together, the identification and preservation of parathyroid glands should be performed in PTC patients receiving TT with PCND, and using NIRAF to assist in locating thyroid tissue during surgery should be recommended to reduce thyroid blood vessel damage or miscut during lymph node dissection (32). In the case of accidental injury during surgery, parathyroid autotransplantation should be considered.

Additionally, in our meta-analysis, TT with PCND did not increase the incidence of vocal cord paralysis. However, Roh et al. (17) demonstrated an increased risk of transient vocal cord paralysis in TT with PCND, which could be explained by increased recurrent laryngeal nerve injury caused by dissection of the lymph nodes. The same conclusion was found by Hyun et al. (11) They found that the technique of the operator might have contributed to this phenomenon. In contrast, Jin et al. (16) found that the incidence of transient vocal cord paralysis in the PCND with TT group was lower than that in the TT alone group, but permanent vocal cord paralysis did not occur between the two groups. Therefore, we suggest that a skilled surgeon should be selected for PCND.

In the present study, the incidence of recurrent laryngeal nerves was similar among these two groups. It is possible that PCND has the significance of sentinel lymph node biopsy without causing additional damage and could avoid injury to the recurrent laryngeal nerve during neck dissection (33). However, Dobrinja et al. (19) reported that TT with PCND increased the risk of transient recurrent laryngeal nerve injury, whereas permanent recurrent laryngeal nerve injury did not reach statistical significance. This is because PCND means a larger surgical scope and operation time, which increases the chance of recurrent laryngeal nerve injury, but these injuries can be recovered in a period of time after surgery and do not cause permanent recurrent laryngeal nerve injury. Further studies focusing on the mechanisms of the restoration of laryngeal nerve function are still needed.

Another advantage of TT with PCND seems to be the reduction in postoperative triglyceride levels (34). In Korkmaz MH’s study, median postoperative triglyceride levels were higher in the TT alone group (23), which sometimes led to unnecessary testing, increased use of radioiodine therapy, and reoperations (2).

Thyroid surgery is a delicate operation involving a very narrow area. Surgeons not only need to be skilled but also need systematic microsurgical techniques to avoid complications and the risk of reoperation. Anerea et al. (35) noted that microsurgical techniques and magnifying glass magnification enabled us to record the doctor’s enlarged field of view and optimize all anatomical and technical details. These records are an aid to surgical teaching, a training tool for inexperienced surgeons, and a method for self-analysis of surgical techniques (35). Some studies reached similar conclusions that thyroidectomy by an experienced surgeon using microsurgical techniques under an optical magnifying glass significantly reduced the incidence of permanent hypoparathyroidism (36, 37).

It is worth noting that several studies have shown that ipsilateral PCND (Ipsi-PCND) plus frozen section examination (FSE) can be considered an effective alternative to bilateral PCND. Marco and his colleagues noted that FSE was highly accurate in the lymph node status of patients classified as cN0 before and during surgery, and FSE of ipsilateral lymph nodes could be used as a reliable method to evaluate the lymph node status of cN0 patients and determine the scope of central neck dissection during surgery (38–40). In their study, the Ipsi-PCND group had a lower tendency for transient hypocalcemia and a lower complication rate than the TT group. In clinical single-focal cN0 PTC, conventional Ipsi-PCND plus ipsilateral lymph node FSE may be an effective alternative to bilateral PCND, but the risk of contralateral metastasis can be ignored. More clinical trials are needed to confirm the safety and efficacy of Ipsi-PCND.

Several limitations cannot be ignored. First, high-quality RCTs were not included. Second, due to the limitation of sample sizes in different studies, we did not perform subgroup analysis of unilateral and bilateral PCND to determine its impact on complications and local recurrence. Third, we cannot avoid the influence of surgeons in different countries and institutions. Last, the inconsistent criteria for TT with PCND in patients with cN0 PTC in included studies is a weakness of our study.

From our meta-analysis, we found that TT with PCND in cN0 PTC patients increases the incidence of permanent hypocalcemia and transient hypoparathyroidism while reducing the rate of local recurrence, with no significant difference in other complications compared to TT alone. Thus, we recommend TT with PCND in cN0 PTC patients. Moreover, intraoperative NIRAF is beneficial in reducing the incidence of hypocalcemia. Conventional PCND combined with NIRAF may be a safe and reliable operation and could provide accurate staging for patients with PTC for adjuvant treatment. We recommend that patients go to a more specialized medical center for safe treatment. However, these studies still have some limitations, and more RCTs and prospective studies with long-term follow-up are needed to further confirm the results.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

YW and XH originated and designed the study. YW, YX, YP, KL conducted the literature search, data extraction, data analysis and interpretation and drafting of the manuscript. SY and KL conducted the data interpretation and methodology. YW and WZ conducted critical revision of article and final approval. All authors contributed to the article and approved the submitted version.