Application of Nanocarbon in Breast Approach Endoscopic Thyroidectomy Thyroid Cancer Surgery

Abstract

Objective:

This study aimed to investigate the application of nanocarbon in surgical endoscopy in patients with thyroid cancer for the clinical tracing of level VI sentinel lymph nodes (SLNs) and for parathyroid gland protection.

Materials and Methods:

Ninety-three patients with papillary thyroid carcinoma (PTC) who underwent an endoscopic thyroid cancer operation were included. We randomly divided these patients into a control group (n = 42) and a nanocarbon group (n = 51). For the nanocarbon group, after thyroid exposure, nanocarbon was injected into the thyroid gland, and the SLNs were resected and subjected to frozen sectioning and routine pathological examination. In addition, the postoperative calcium and parathyroid hormone (PTH) levels of both groups were analyzed to compare the features of the nanocarbon application.

Results:

The number of central lymph (level VI) nodes dissected and the number of metastatic lymph nodes identified were analyzed in both groups. The number of dissected lymph nodes from both unilateral and bilateral thyroid surgeries was significantly larger in the nanocarbon group than in the control group. At the same time, the number of identified metastasis lymph nodes dissected were higher in the nanocarbon group than in the control group. We assessed the postoperative calcium and PTH level to evaluate the parathyroid function. Our results show that the nanocarbon group had a better protective effect on parathyroid function than the control group.

Conclusions:

As a lymph node trace agent, nanocarbon could better evaluate and permit a more clear lymph dissection for patients with PTC. Nanocarbon contributes to a decrease in the incidence rate of parathyroid damage, which has great clinical value.

Introduction

Endoscopic thyroid surgery was first reported by Gagner in 1996,¹ and endoscopic thyroidectomy developed rapidly in the subsequent 20 years. To avoid an ineradicable anterior neck scar in patients with papillary thyroid carcinoma (PTC), endoscopy and the video-assisted approach were implemented to improve the cosmetic result that accompanies satisfactory oncological resection.^2–4 To date, several approaches including transoral endoscopy,⁵ axillary approach endoscopy,⁶ and robotic thyroidectomy⁷ have been used based on the patients' needs and expectations. In our department, breast approach endoscopic thyroid cancer surgery has been performed since 2014 for both benign and malignant tumor treatment.

Radical lymph node resection is still the best method for thyroid cancer treatment as PTC is not sensitive to radiotherapy or chemotherapy. Due to limited operative space, regional lymph dissection of level VI nodes and inferior parathyroid protection usually act as the main challenges in thyroid cancer surgery. Insufficient intraoperative lymph node dissection usually results in retained residual lymph tissue or postoperative relapse.

Nanocarbon was first invented as a trace agent for imaging applications to trace lymph nodes and vessels. Since then, nanocarbon reagents have been used for sentinel lymph node (SLN) biopsies in treatment of various malignant tumors, including melanoma, breast cancer, penile cancer, and colon cancer. Their benefits include providing a more clear lymph node dissection region for the surgeon to choose.⁸ In the recent years, additional benefits of nanocarbon reagents include the more recent application in open thyroid cancer lymph node tracing and imaging⁹ and in parathyroid protection.¹⁰ In this study, we investigate the potential of a nanocarbon application to help lymph node dissection and parathyroid protection during our breast approach endoscopic thyroid cancer surgery.

Materials and Methods

Patients

From June 2014 to June 2019, 93 consecutive consenting patients with PTC who underwent total thyroidectomy or unilateral thyroidectomy accompanied by central compartment neck dissection at the Thyroid Surgery Department of the Lin Hai Hospital of Traditional Chinese Medicine were prospectively enrolled. All data for this study were collected from a prospective database approved by the Ethical Committee of the Second Affiliated Hospital, Zhejiang University College of Medicine. All included patients received ultrasonography or enhanced cervical computed tomography scans along with a primary tumor invasion assessment. The inclusion criteria were as follows: (1) a primary tumor size of <2.5 cm, (2) differentiated thyroid carcinoma without lateral cervical lymph node metastasis, (3) the largest level VI metastatic lymph node diameter <2.0 cm, and (4) high cosmetic demands. The exclusion criteria were as follows: (1) surgical history on the neck; (2) suspected metastatic lymph nodes measuring >2 cm in the level VI region; (3) metastatic lymph nodes fused with the surrounding tissue; (4) surrounding tissue invasion, especially in the trachea, esophagus, and/or in the recurrent laryngeal nerve (RLN); (5) cervical lymph node metastasis; and (6) no cosmetic demands.

Surgical procedures

All patients were administered general anesthesia agents. The operation procedures were as follows: the head of each patient was pulled back to expose the neck, and the suprasternal notch was identified as the bony landmark. Briefly, epinephrine inflation solution was injected into the subcutaneous layer of the anterior chest. At the nipple level, a 12-mm incision was made for access with a 10-mm trocar through the incision. CO₂ gas at a pressure of 6–8 mmHg was introduced and maintained for establishing the surgical work space. Another two 5-mm trocars were applied at incisions through the mammary areolas for auxiliary use. The surgical flap area was established to the thyroid cartilage at the upper side and to the lateral sides of the sternocleidomastoid (SCM) edge.

In the nanocarbon group, after the thyroid gland was exposed, nanocarbon suspension was injected into the thyroid gland from the top, middle, and lower points with a 1-mL syringe. In general, a total of 0.2 mL of nanocarbon suspension was enough. Back-drawing was performed to ensure the proper location of the needle to avoid mistakenly injecting directly into a blood vessel (Fig. 1), and the needle was drawn along the edge of the SCM to avoid residual nanocarbon contaminant in the skin. The thyroid gland was gently pressed for 5 minutes until the gland developed the staining after completing the injection (Fig. 2). After 10–15 minutes, the lymph vessel and lymph node staining developed (Fig. 3), but the parathyroid glands and the RLN were not injured (Fig. 4). After exploring the affected side of the thyroid gland, removing the lesioned lobes, and conducting intraoperative frozen section evaluation, the tissue was identified as thyroid cancer. If the preoperative biopsy confirmed that the condition was thyroid cancer, the nanocarbon suspension was directly injected, and then, total thyroidectomy and central lymph node dissection of the affected side were performed. In the control group, the thyroid gland of the affected side was directly explored and the lobes with lesions were removed. After the results of the intraoperative frozen section evaluation of thyroid cancer, the operation methods were the same as for those of the nanocarbon group. In both groups, the surgical site was precise, and the anatomical position was detailed; moreover, the parathyroid glands were protected, and the operation was completed by the same group of surgeons. The scope of the lymph node dissection was as follows: the upper pole of the thyroid gland to the lower bound of the suprasternal fossa area. The external bound extended to the inner edge of the common carotid artery, the inner bound to the median line of the neck, and the base boundary to the esophagus and prevertebral fascia. The RLNs were exposed and protected after careful examination (Fig. 5). We divided the right central region into VIa and VIb subregions, with the RLN as the boundary. The VIa subregion lymph nodes included the cricothyroid membrane and the pretracheal and perithyroid lymph nodes. The VIb region is located posterior to the RLN and attached to esophageal surface. After the lobectomy removal, if the parathyroid gland was found during dissection, the parathyroid gland was preserved along with the blood supply if possible. Then, we isolated the border along the boundary of the trachea to the intercross between the inferior thyroid artery and the RLN to remove the VIa region. Next, we reversed downward from the carotid vascular sheath that separates the lateral boundary of the RLN to the innominate artery surface for the VIb region dissection in right-sided thyroid cancer therapy. For a parathyroid with poor blood supply that is hard to reserve in situ, the gland was autografted into the contralateral side of the SCM.

FIG. 1.

Nanocarbon suspension. The syringe needle was inflected ∼1.2 cm from the tip to better estimate the depth of the injection.

FIG. 2.

The thyroid gland was stained with the black developing 5 minutes after the injection.

FIG. 3.

A lymph node and related vessel, with the staining developing after the injection.

FIG. 4.

RLN and parathyroid gland exposed. RLN, recurrent laryngeal nerve.

FIG. 5.

RLN and parathyroid gland remain uninjured after the thyroidectomy. RLN, recurrent laryngeal nerve.

Postoperative PTH and calcium monitoring

Patients who receive endoscopic surgery in our center routinely receive parathyroid hormone (PTH) and calcium testing preoperatively. The normal level of serum PTH is 15–66 pg/mL, and a level <15 pg/mL indicates hypoparathyroidism. The normal level of serum calcium is 2.03–2.53 mmol/L, and a level <2.03 mmol/L indicates hypocalcemia. The first postoperative day, we take blood samples to test PTH and serum calcium again to evaluate the parathyroid function postoperatively. In addition, the clinical manifestations of hypoparathyroidism were observed and recorded when they existed.

Statistical analysis

IBM SPSS Statistics software (version 20.0; IBM Corp., Armonk, NY) was used for analysis of the postoperative PTH and serum calcium levels and the pathological findings of the parathyroid glands between the two groups. Measurement data are expressed as sample mean ± standard deviation ( $\bar{x} \pm s$ ). A t-test was used for intergroup comparisons, and a chi-squared test was used for the qualitative comparisons of count data. Differences with a P < .05 were considered statistically significant.

Results

Clinicopathologic characteristics

The clinicopathologic characteristics are summarized in Table 1. The nanocarbon group included 51 patients (8 males and 43 females), with a mean age of 31.8 ± 7.3 years.

Table 1.

Clinical Characteristics

Characteristic	Nanocarbon group (n = 51)	Control group (n = 42)	P
Age (years)	31.8 ± 7.3	30.2 ± 9.2	.750
Male/female	8/43	5/37	.600
Operation time (minutes)	137.2 ± 27.6	142.3 ± 29.5	.734
Postoperative hospital stay (days)	5.24. ± 1.65	5.63 ± 1.94	.118
Average tumor size (cm)	0.87. ± 0.31	0.83 ± 0.39	.634
Unilateral thyroidectomy	20	16	.912
Bilateral thyroidectomy	31	26

The control group included 42 patients (5 males and 37 females), with a mean age of 30.2 ± 9.2 years. The basic characteristics for the two groups were similar in sex ratio (P = .600) and age (P = .750). The mean operating time was 137.2 ± 27.6 minutes in the nanocarbon group and 142.3 ± 29.5 minutes in the control group (P = .734). The average tumor size in the nanocarbon group and the control group was 0.87 ± 0.31 cm versus 0.83 ± 0.39 cm, respectively (P = .634), and the duration of the postoperative hospital stay was similar (5.24 ± 1.65 versus 5.63 ± 1.94 days) between the two groups (P = .118). Also, the unilateral and bilateral thyroidectomy ratio was similar between the nanocarbon and control groups.

Central lymph node dissection characteristics

Suspicion of complete metastasis in a lymph node dissection is the main malignant tumor therapy strategy. Here, we calculated the total and positive dissected lymph nodes in the level VI lymph region (Table 2). The nanocarbon group had a higher number of dissected lymph nodes in the level VI region (10.24 ± 3.48 versus 8.20 ± 2.45; P < .01) and had more metastatic lymph nodes (2.68 ± 0.76 versus 2.34 ± 0.53; P = .035) compared with the control group in the patients undergoing unilateral thyroid cancer therapy. We also calculated the number of level VI lymph nodes in the patients who underwent bilateral thyroidectomy (Table 3). As we found with unilateral thyroidectomy, for the patients who underwent bilateral thyroidectomy, the nanocarbon group had a higher number of level VI dissected lymph nodes (14.61 ± 5.88 versus 12.50 ± 4.35; P < .01) and had more metastatic lymph nodes (3.13 ± 1.04 versus 2.83 ± 0.73; P = .042) compared with the control group.

Table 2.

VI Region Lymph Node Dissection, Unilateral Thyroid Surgery

	Nanocarbon group	Control group	P
VI	10.24 ± 3.48	8.20 ± 2.45	<.01
Metastasis lymph node	2.68 ± 0.76	2.34 ± 0.53	.035

Table 3.

VI Region Lymph Node Dissection, Bilateral Thyroid Surgery

	Nanocarbon group	Control group	P
VI	14.61 ± 5.88	12.50 ± 4.35	<.01
Metastasis lymph node	3.13 ± 1.04	2.83 ± 0.73	.042

Parathyroid function and serum calcium

The preoperative and postoperative PTH data were collected for every patient who underwent bilateral thyroidectomy (Table 4). The preoperative PTH (45.28 ± 14.12 versus 43.27 ± 17.78; P = .913) and serum calcium (2.38 ± 0.38 versus 2.34 ± 0.27; P = .076) were similar between the two groups. After the nanocarbon application, the postoperative PTH (26.63 ± 12.98 versus 22.85 ± 17.59; P = .023) was higher in the nanocarbon surgery group, and the serum calcium level was not significantly different between the two groups (2.12 ± 0.16 versus 2.08 ± 0.14; P = .064).

Table 4.

Preoperative and Postoperative Parathyroid Function After Bilateral Thyroidectomy

	Nanocarbon group (n = 31)	Control group (n = 26)	P
Preoperative PTH	45.28 ± 14.12	43.27 ± 17.78	.913
Postoperative PTH	26.63 ± 12.98	22.85 ± 17.59	.023
Preoperative calcium	2.38 ± 0.38	2.34 ± 0.27	.076
Postoperative calcium	2.12 ± 0.16	2.08 ± 0.14	.064

PTH, parathyroid hormone.

Discussion

In general, 60%–80% of thyroid cancers are diagnosed as PTC, making this the most common pathological type. Lymph node metastasis acts as the main method of PTC cancer transfer. It has been reported that lymphatic metastasis occurs in 27% to 90% of patients with thyroid cancer.¹¹

Lymph node metastasis increases the postoperative recurrence rate in patients with PTC. As part of progression through SLNs for the thyroid gland, most patients are found to have central region (level VI) lymph node metastasis since their initial diagnosis. Based on this progression, clear dissection of the regional lymph nodes can obviously reduce the postoperative recurrence risk after thyroid surgery. In addition, level VI lymph node transfer was reported in ∼20% of patients with PTC.^12,13 Usually, lateral cervical metastasis lymph node transfer occurs from the level VI region, which reveals that level VI region lymph node metastasis incidence may be higher than was expected. As a result, we aim to make suspected metastatic lymph node dissection as clear as possible in the level VI region for patients undergoing endoscopic thyroid surgery.

The common procedures for thyroid cancer surgery usually result in an 8- to 10-cm scar after conventional surgery. This result often causes concern for young and especially unmarried female patients and people in special occupations. Compared with open surgery, “scarless” (in the neck) endoscopic thyroidectomy only requires three small incisions in the anterior chest and bilaterally at the areolas. These wounds were very well hidden in daily life, which meets the demand of private surgical history protection.¹⁴ In another aspect, endoscopic thyroidectomy usually increases the difficulty of level VI regional dissection due to the “chopsticks effect.” Due to blockage by the sternal manubrium and the clavicles, the visual field and management space are usually restricted during breast approach endoscopic surgery. The restricted blind area is especially severe during the process of central level VI dissection, possibly resulting in an incomplete dissection during surgery with a less experienced surgeon. In a report of endoscopic thyroid surgery, only an extremely experienced surgeon was sufficiently able to complete the central lymph node dissection for patients with thyroid cancer.¹⁵ This increases the possibility of retained residual lymph tissue accompanied by an increased incidence of recurrence.

Correct evaluation of the cervical lymph nodes in patients who are clinically node negative (CN0) seems to be the key factor in reducing the complication and recurrence rates through a clear evaluation of suspected metastatic lymph nodes. SLN biopsy to help identify the specific regional tumor lymph node metastasis has been applied in breast cancer and melanoma along with lymph node staining.¹⁶ In an SLN study of patients with PTC, which included 96 patients, 46.88% of patients were identified as having lymph node metastasis with 40.63% identified as level VI lymph node metastasis and 6.25% were identified as lateral cervical lymph node metastasis with pathological identification.⁹

Therefore, there is a great need for SLN biopsy development for patients with PTC. In our experience, the application of nanocarbon provided for accurate and convenient SLN detection around the thyroid. Nanocarbon diffusion methods are recommended for application in PTC SLN biopsy to evaluate lymph node metastasis without the occurrence of any other complications, which suggest the necessary safety and reliability for use in patients. In our study of endoscopy in patients, larger numbers of level VI region lymph node dissections were identified in patients who received nanocarbon therapy, resulting in a more radical lymph node dissection. More importantly, we calculated the number of metastatic nodes from those dissected. After nanocarbon use, more metastatic lymph nodes were identified, resulting in a lower likelihood of retained residual metastatic lymph node tissue after the nanocarbon use. We speculate that concealed lymph nodes located in the level VI region area may not be recognized and dissected without the nanocarbon use.

Accurate identification of the parathyroid glands and protection of the blood supply during surgery can reduce the incidence of postoperative hypoparathyroidism. However, the position of the thyroid glands, especially the inferior parathyroid gland, has great variability, and the number of individual glands varies significantly. Additionally, the size and appearance of the parathyroid glands differ and are difficult to distinguish visually.^17–19 For a parathyroid gland removed from patients, only autotransplantation of the parathyroid gland is available to retain the function of the gland. If the parathyroid gland is suspected to have been mistakenly cut during the operation, samples should be collected for intraoperative frozen sectioning and evaluation, and the remaining tissues should be transplanted into SCM once the sections are proved to be parathyroid tissues. However, Kihara et al.²⁰ showed that autotransplantation of parathyroid glands did not completely restore their normal function. To date, there is no effective method to stain and identify the position of the parathyroid glands.

In our study, we found that serum calcium and serum PTH decreased in both the nanocarbon and control groups 24 hours postoperatively. A transient decrease of parathyroid function occurred in 5 of 31 patients in the nanocarbon group and 8 of 26 patients in the control group at 24 hours postoperatively in patients who underwent bilateral thyroid surgery. By 3 months postoperatively, no patients exhibited persistent hypocalcemia after parathyroid gland compensation. This suggests that transient parathyroid gland damage was significantly reduced with the nanocarbon application. In addition, we found that the PTH function recovered to normal over a shorter period in the nanocarbon group than in the control group. We speculate that this may be due to the effect of better recognition and protection of the parathyroid blood supply with the nanocarbon application.

Injection of the nanocarbon infusion into the thyroid gland is more difficult in total endoscopic surgery than in open thyroid surgery. Here, we conclude with some of the most common problems, which may be encountered during the operation. We recommend a special needle with at least a 7- to 8-cm syringe for the percutaneous injection using a 20-gauge spinal needle for the skin puncture. The thyroid gland injection procedure was created to strategically avoid vessel injury, particularly the common carotid artery. Nanocarbon injury may stain the skin and subcutaneous fascia with obstinate black. As part of the injection procedure, the needle was drawn along the edge of the SCM to avoid residual nanocarbon contaminant in the skin while passing and exiting the skin layer, as this friction of the needle along the edge of the SCM is recommended to scrub the residue nanocarbon off of the needle tip. There is also a high risk of injecting nanocarbon directly into the tumor due to a sense of rigidity and limited awareness of the precise location. Preoperative evaluation of the tumor location may provide a benefit in avoiding the inadvertent injection into the tumor.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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