According to the global IARC tumor registration report on five continents, the incidence of thyroid cancer increased sharply from 1973 to 2002, and the incidence rate in women was three times higher than in men (1). According to statistics from the China Cancer Center, the age-standardized incidence rate of thyroid cancer in China was 168.08/100000 in 2012, with the age-standardized incidence rate in women being 169.4/100000 (2). The incidence rate of thyroid cancer in China is increasing at an annual rate of 5.92%, which is 4% higher than the global incidence rate. Moreover, the incidence in big cities is higher than that in rural areas. Overall, the incidence rate in females is higher than that in males (3–5). Due to the development of urbanization and improvement of economic conditions, women have higher esthetic requirements. To avoid neck scars, endoscopic thyroid surgery is increasingly carried out to improve the cosmetic effect (6, 7). Protecting the parathyroid gland versus the thoroughness of lymph node dissection in the central region during endoscopic thyroid cancer surgery has remained controversial. When the parathyroid gland is injured, parathyroid hormone levels may decrease, which may cause the patient to experience various symptoms, including perioral numbness and convulsions. Incomplete dissection of lymph nodes in the central region is an important reason for local recurrence after the operation. Indeed, a recent retrospective analysis of 399 patients showed that thorough lymph node dissection in the central region can significantly increase the disease-free survival (DFS) after thyroid cancer surgery, especially with respect to occult lymph node metastasis, which is an important factor affecting prognosis (8). Moreover, intraoperative use of indocyanine green and carbon nanoparticle suspensions as tracers can protect the parathyroid gland and increase the thoroughness of lymph node dissection in the central region (9). Our department uses a carbon nanoparticle suspension to trace lymph nodes during surgery in an effort to improve the thoroughness of lymph node dissection in the central area, protect parathyroid function, and reduce postoperative complications and local recurrence. As a new type of lymphatic tracer, carbon nanoparticles (CNs) have an active movement mechanism. CNs are phagocytosed by macrophages and then enter the lymphatic capillaries and accumulate in lymph nodes, such that the thyroid gland and lymph nodes in the drainage area quickly become blackened according to the order of thyroid lymphatic drainage (10, 11). As there are no communicating lymphatic vessels between the thyroid tissue and the parathyroid gland, the thyroid tissue and surrounding lymph nodes become stained black after CNs are injected into the thyroid tissue, whereas the parathyroid gland remains unstained. This is called the “negative parathyroid imaging effect” and is used to protect the parathyroid gland (12). In this study, we sought to assess the application value of refined extracapsular anatomy combined with a CNs suspension for protecting parathyroid function and lymph node dissection in the central region during endoscopic surgery for thyroid cancer.

Currently, the majority of young patients have accepted endoscopic thyroid surgery because of its advantages, such as minimal invasiveness and scarless. This approach has the advantages of enlarging the surgical area and high resolution of the surgical field of view. There were only 4 males but 104 females in our study, and average age was 30.98 ± 6.38 years old. May be young women have high requirements for beauty, and there is an advantage of scarlessness in endoscopic radical thyroidectomy.

Whether it can effectively protect the parathyroid gland and completely remove the lymph nodes in the central region has been the focus of controversy. In general, endoscopic lymph node dissection is difficult without navigation for tracking the lymph nodes. Therefore, searching for effective materials for lymph node navigation and tracking is a hot research topic. As a new lymphatic tracer, CNs have the advantages of rapid staining, long duration and clear lymphatic tracing, and they have been applied in both open thyroid cancer surgery and endoscopic thyroid cancer surgery. CNs have an active movement mechanism, whereby they are engulfed by macrophages and then enter the lymphatic capillaries, accumulating in the lymph nodes. Thus, the thyroid gland and lymph nodes in the drainage area quickly become blackened according to the order of thyroid lymphatic drainage (10, 11). CNs can help surgeons to distinguish between lymph nodes and fat particles. Some studies have shown that the small lymph nodes (diameter<5 mm) in the central area and the relatively hidden lymph nodes are difficult to identify during the cleaning process and are easily ignored. With CN staining and the magnifying effect of endoscopy, the operator can easily find and remove the small lymph nodes in this area, significantly promoting the thoroughness of lymph node cleaning (16, 17). The number of harvested LNs was 5.54 ± 3.84 in our study. Compared with a retrospective cohort study, 114 PTC patients undergoing bilateral axillo-breast approach robotic thyroidectomy (BABART) were enrolled and divided into CNs group (n=64) and control group (n=50). The mean number of retrieved central lymph node was significantly higher in the CNs group than in the control group (9.48 ± 4.88 vs. 5.40 ± 2.67, P<0.001) (18). The other prospective randomized study, three hundred two consecutive early-stage thyroid cancer patients eligible for endoscopic thyroidectomy via bilateral areola approach (ETBAA) were recruited and divided into two group: a carbon nanoparticles group (n=152) and a control group (n=150). The total number of dissected lymph nodes was 1059 in the carbon nanoparticles group and 872 in the control group (P=0.00) (19). The applying of carbon nanoparticle can help to detect lymph nodes and increase the number of lymph nodes visualized and preserved.

In addition, the tracing effect of CNs has a guiding role for pathologists to take lymph nodes after surgery, reducing the impact of human factors on the number of lymph nodes ( Figures 4A, B ) (20). In preventive lymph node dissection in the central region, CNs can be used as a tracer to make the parathyroid gland easy to identify, avoiding the risk of injury to the recurrent laryngeal nerve and parathyroid gland ( Figures 5A, B ) (21). In fact, parathyroid gland injury can lead to a decrease in parathyroid hormone, and patients will have symptoms such as perioral numbness and hypocalcemia convulsions. If permanent hypoparathyroidism occurs, long-term oral or intravenous calcium supplementation is needed, which affects quality of life (22, 23). When CNs are injected into the thyroid tissue, the surrounding lymph nodes stain black, though the parathyroid gland does not. When the thyroid gland is removed, fine envelope dissection is used to protect the nonblack-stained tissue as much as possible, reducing the risk of parathyroid damage during lymph node dissection of thyroid cancer (24). As there are no lymphatic vessels communicating between the thyroid tissue and the parathyroid gland, the thyroid tissue and surrounding lymph nodes are stained black after CNs are injected into the thyroid tissue, whereas the parathyroid gland remains unstained. This “negative parathyroid imaging effect” achieves localization, recognition and protection of the parathyroid gland and reduces the incidence of postoperative hypothyroidism (12). However, it has been reported that through the whole areola approach in endoscopic thyroid cancer surgery, the use of CNs cannot significantly enhance protection of the parathyroid glands, especially the lower parathyroid gland, and cannot significantly benefit protection of the parathyroid glands or lymph node dissection (25, 26). In our study, 2.77% (3/108) patients suffered transient postoperative hoarseness and 4.62% (5/108) patients appeared transient hypoparathyroidism. According to a meta-analysis, the median incidence of transient and permanent hypoparathyroidism was 27% (19%-38%) and 1% (0-3%) respectively (27). Another study based on the SEER-Medicare linked database shows that 11% of the cases need calcium and vitamin D supplementation for hypoparathyroidism (28). Furthermore, the immune response caused by residual CNs in the thyroid bed may increase tissue inflammation and edema, thus reducing the venous flow of the parathyroid gland, which has a negative impact on parathyroid gland function (29).

There are also some limitations of our study. Firstly, all the 108 patients received endoscopic thyroid cancer surgery and the CNs was used during operation. And we don’t get the data of patients without using CNs. However, there are many similar research in the literature, and our data ware basically consistent with others. Secondly, many postoperative symptoms were collected, but little objective indicator, like serum PTH and Ca²⁺ level, was tested. Mainly because that we didn’t test PTH or Ca²⁺ level after surgery routinely in our center, unless bilateral thyroidectomy was performed or patients with overt symptom. And we are preparing to conduct a prospective study in the near future.

In summary, the application of refined extracapsular anatomy combined with a CN suspension tracing technology has a definite effect in endoscopic thyroid cancer surgery, improving the thoroughness of preventing lymph node dissection in the central region, enhancing recognition of the parathyroid gland, and avoiding parathyroid injury or accidental resection as well as other complications, thus effectively preserving parathyroid function.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of the (Yijishan Hospital) First Affiliated Hospital of Wannan Medical College. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. The study protocol was approved by the Ethics Committee of the (Yijishan Hospital) First Affiliated Hospital of Wannan Medical College. Informed consent was obtained from all individual participants included in the study.

The article was mainly written by ZW and RS. ZW, HB, YX, and ZB, these authors contributed equally to the study, ZW, HB, YX, EL, XS and ZB helped with data analysis and paper editing. YW, ZW, ZY, and CY did an operation study. The whole study was instructed by BC, YW and RS. All authors contributed to the article and approved the submitted version.