ORIGINAL ARTICLE
Carbon nanoparticle–guided central lymph node dissection in clinically node-negative patients with papillary thyroid carcinoma Youzhi Zhu, MM,# Xiangjin Chen, MM,* Huihao Zhang, MM, Ling Chen, MM, Shujun Zhou, MM, Kunlin Wu, MM, Zongcai Wang, MM, Lingjun Kong, MM, Hezhu Zhuang, MM Department of Thyroid and Breast Surgery, The First Affiliated Hospital of FuJian Medical University, FuZhou, FuJian Province, People’s Republic of China.
Accepted 27 March 2015 Published online 15 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24060
ABSTRACT: Background. Distinguishing the involved lymph nodes from other tissues during surgery is critical for lymph node dissection. The purpose of this study was to assess the feasibility by using carbon nanoparticles as guidance for lymph node dissection in patients with papillary thyroid carcinoma (PTC). Methods. Eighty-one patients were injected with carbon nanoparticles (carbon nanoparticle group), whereas the other 81 patients were not (control group). Routine pathological examination was performed. Results. The lymph node dissection and metastatic lymph node dissection rates of the carbon nanoparticle group were significantly higher than that of the control group. In the carbon nanoparticle group, the number of mistakenly dissected parathyroid gland, the case number of postoper-
ative hypocalcemia, the case number of postoperative hypoparathyroidism, and the recovery time from hypocalcemia were 4, 6, 8, and 2.33 6 0.58 weeks, respectively, significantly less than 14, 17, 20, 3, and 3.8 6 0.92 weeks in the control group (p < .05). Conclusion. Carbon nanoparticles can be applied to more accurately guide the dissection of lymph nodes during thyroidectomy in C 2015 Wiley Periodicals, Inc. Head Neck 38: 840– patients with PTC. V 845, 2016
INTRODUCTION
or esophageal injury. In patients who underwent the modified lateral neck node dissection, Kupferman et al2 have reported shoulder weakness in 27% and chyle leak in 4.5% of patients, whereas others report phrenic paralysis, Horner syndrome, cervical plexus neuropathic pain syndromes, and other complications in up to 1% of cases.3 In order to minimize the complications while ensuring the radical effects of thyroidectomy, the surgery should be performed by experienced surgeons who are familiar with the anatomic characteristics and have superb surgical skills. In addition, appropriate external aids often bring a remarkable effect. Using carbon nanoparticles is a novel type of lymphatic tracer, which has been applied in the surgery of thyroid cancer in a few studies.4,5 The purpose of this study was to further evaluate the clinical value of carbon nanoparticles by focusing on its guidance effect on lymph node dissection during thyroidectomy and CLND in clinically node-negative patients with PTC.
It is well known that lymph node metastases are common in patients with papillary thyroid carcinoma (PTC). According to the Kouvaraki et al1 study, regional lymph node metastases usually present when PTC is diagnosed, whereas distant metastases appear in the late stage. Surgical resection is the most effective treatment for PTC, and the complete removal of the primary tumor and the metastatic regional lymph nodes is a prerequisite for other adjuvant therapies. Therefore, prophylactic central lymph node dissection tends to have a better prognosis in patients with PTC. However, expansion of the scope of operation will inevitably bring about corresponding complications because of mistaken resection of tissues and organs other than lymph nodes. For example, the potential complications of central lymph node dissection (CLND) include hypoparathyroidism, recurrent laryngeal nerve paralysis, permanent recurrent laryngeal nerve injury, and tracheal
KEY WORDS: papillary thyroid carcinoma, carbon nanoparticles, lymph node dissection, clinically node-negative patients, retrospective analysis
MATERIALS AND METHODS #
Imaging agent for lymphatic vessels
*Corresponding author: X. Chen, Department of Thyroid and Breast Surgery, The First Affiliated Hospital of FuJian Medical University, No. 20, Chazhong Road, ChaTing Street, FuZhou, FuJian Province, People’s Republic of China. E-mail: [email protected]
Carbon nanoparticles (Chongqing Levin U.S. Pharmaceutical, China, approval number: Zhunzi H20073246), a lymphatic tracer, has a pronounced tropism for lymphatic tissues. The standard carbon nanoparticle suspension (1 mL: 50 mg) contains nanoparticles with an average diameter of about 150 nm, which is greater than the
MM stands for Master of Medicine
Contract grant sponsor: This study was supported by the Health Department of FuJian Province Youth Research (2011-1-16) and key Clinical Specialty Discipline Construction Program of Fujian, People’s Republic of China.
840
HEAD & NECK—DOI 10.1002/HED
JUNE 2016
CARBON
NANOPARTICLE–GUIDED LYMPH NODE DISSECTION
nanoparticle injection, whereas the patients in the control group (n 5 81) did not. All the patients underwent total or subtotal thyroidectomy with prophylactic bilateral central compartment neck dissection, and part of the cohort received prophylactic lateral compartment neck dissection. Postsurgical radioiodine remnant ablation was applied according to the postoperative pathological findings. For patients in T3 classification and above, radioiodine remnant ablation was used; for patients with a tumor size >1 cm that was confined within the thyroid or accompanied with metastasis in cervical lymph node, the selective radioiodine remnant ablation was used.
Surgical procedure FIGURE 1. Intraoperative view of the clusters of lymph nodes black-stained by carbon nanoparticle injection, indicating the excellent lymph node tracing effect of carbon nanoparticles.
capillary endothelial cell gap (approximately 20–50 nm) and smaller than the lymphatic capillary endothelial cell gap (approximately 120–500 nm). This feature enables carbon nanoparticles to enter the lymphatic duct but not the blood circulation. The tumor localization was roughly determined by preoperative ultrasonography, and it could be further accurately determined by intraoperative palpation in the majority of patients. Intraoperative ultrasonography was not used. For tumors 1 cm localized within the gland that cannot be palpated, carbon nanoparticles were injected under the ipsilateral thyroid true capsule. For most palpable tumors, carbon nanoparticles were injected into the tissues around the tumor but not inside the tumor. After injection, the carbon nanoparticles may be engulfed by macrophages and subsequently transported into the lymph nodes. The accumulated carbon nanoparticles in the lymph nodes makes the lymph nodes black-stained and it thus achieves the purpose of tracing and in vivo staining of the draining lymph nodes in the tumor area (Figure 1). Using carbon nanoparticles also avoids the disadvantage of all tissue staining because it cannot enter the blood circulation. Carbon nanoparticles cause little toxic side effects in the human body because they can be excreted via the lungs and intestines after a few months.
Patients This retrospective study was approved by the institutional review board of our hospital and included 162 consecutive patients with PTC who underwent surgery from April 2010 to April 2011. No patient had a history of thyroid or neck surgery for nonthyroidal head and neck cancers and all patients provided an informed consent. The operations were performed by the same medical team in our hospital. All the patients were diagnosed with PTC by preoperative fine-needle aspiration cytology, and had no preoperative evidence of cervical lymph node metastasis at physical examination, ultrasound, or CT imaging. The patients were randomly divided into 2 groups. The randomization was done using computer-generated random number tables. The patients in the carbon nanoparticle group (n 5 81) received an intraoperative carbon
General anesthesia was applied for all patients. Patients were positioned supine with the neck slightly hyperextended and the shoulders padded. A curvilinear incision of a length about 6 cm was placed in a skin crease 2 cm above the sternal notch. After skin incision, subcutaneous fat and platysma were separated and the cervical anterior muscles were pulled to both sides. The thyroid capsule was carefully dissociated to completely expose the thyroid gland, without causing injury to the capsule. In the carbon nanoparticle group, 0.1 mL per spot of carbon nanoparticles was injected into tissues surrounding the tumor using a skin test syringe. One or 2 spots were injected for each tumor. To prevent the carbon nanoparticles from leakage, the needle should be inserted deeply into the tissues before injection. To avoid injection of blood vessels, the plunger was pulled back slightly before injection to ensure that there was no blood back flowing into the syringe. The suspension was slowly pushed into the tissues. Upon completion, the needle was removed and pressure was applied to the injection site. Within a few minutes, the lymphatic ducts and the lymph nodes became black-stained and the parathyroid was “negatively developed” (Figures 1 and 2). Total thyroidectomy or near total thyroidectomy was then performed according to the meticulous capsular dissection technique. Node clearance of the central cervical compartment was performed cranially to the hyoid bone, caudally to the supraclavicular notch, laterally to the carotid sheaths, and dorsally to the prevertebral fascia.6 Excised lymph nodes were individually labeled as stained or nonstained, whereas the paratracheal lymph nodes on the right side were specifically labeled according to their location at either the shallow surface or the deep surface of the laryngeal recurrent nerve. Patients in the control group underwent the standard thyroidectomy and the central lymph node dissection without carbon nanoparticle injection. All resected nodes were sent for pathological examination. All specimens were dissected by the same pathologist and diagnosed by 2 pathologists blindly and independently of this study.
Statistical analysis Patients and primary carcinoma characteristics were investigated and the numbers, frequency, and locations of the detected central lymph nodes were analyzed. Postoperative complications were also evaluated. The measurement data were described as mean 6 SD. All data were analyzed by SPSS 17.0 package (SPSS 17.0 for Windows; SPSS, Chicago, IL).The paired, 2-tailed t test was used HEAD & NECK—DOI 10.1002/HED
JUNE 2016
841
ZHU ET AL.
FIGURE 2. Intraoperative view of the “negatively developed” parathyroid in contrast to the black-stained lymph node or tissues. The arrow indicates the parathyroid.
for continuous variables, and the Pearson chi-square test was used for categorical variables. Any p < .05 was considered statistically significant.
sive aspects between the control group and the carbon nanoparticle group.
Guide effects of carbon nanoparticles on lymph node resections
RESULTS General information The clinical pathological characteristics of the enrolled patients are summarized in Table 1. The postoperative pathological examination confirmed PTC in all 162 patients. There were no significant differences in age, sex, size of primary tumors, tumor multifocal, and inva-
All patients underwent CLND, 92 cases (56.79%) had been demonstrated with lymph node metastasis by postoperative pathological examination, including 50 cases (61.73%) and 42 cases (51.85%) in the carbon nanoparticle group and the control group, respectively. Of the patients with metastasis, the mean number of metastatic
TABLE 1. The clinical pathological characteristics of patients with papillary thyroid cancer (n 5 162).
Clinic pathologic data
Age, mean 6 SD, y Sex, female:male Primary tumor Size, mean 6 SD, mm Bilateral Extrathyroidal extension (minimal) Pathological type Lymph node status preoperatively Lymph node status postoperatively Rate of metastatic lymph nodes, % Mean no. of dissected lymph nodes Mean no. of metastatic lymph nodes Mean no. of lymph nodes with diameter 2 mm No. of dissected parathyroid glands Cases of postoperative hypocalcemia (Ca
Carbon nanoparticle–guided central lymph node dissection in clinically node-negative patients with papillary thyroid carcinoma Youzhi Zhu, MM,# Xiangjin Chen, MM,* Huihao Zhang, MM, Ling Chen, MM, Shujun Zhou, MM, Kunlin Wu, MM, Zongcai Wang, MM, Lingjun Kong, MM, Hezhu Zhuang, MM Department of Thyroid and Breast Surgery, The First Affiliated Hospital of FuJian Medical University, FuZhou, FuJian Province, People’s Republic of China.
Accepted 27 March 2015 Published online 15 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24060
ABSTRACT: Background. Distinguishing the involved lymph nodes from other tissues during surgery is critical for lymph node dissection. The purpose of this study was to assess the feasibility by using carbon nanoparticles as guidance for lymph node dissection in patients with papillary thyroid carcinoma (PTC). Methods. Eighty-one patients were injected with carbon nanoparticles (carbon nanoparticle group), whereas the other 81 patients were not (control group). Routine pathological examination was performed. Results. The lymph node dissection and metastatic lymph node dissection rates of the carbon nanoparticle group were significantly higher than that of the control group. In the carbon nanoparticle group, the number of mistakenly dissected parathyroid gland, the case number of postoper-
ative hypocalcemia, the case number of postoperative hypoparathyroidism, and the recovery time from hypocalcemia were 4, 6, 8, and 2.33 6 0.58 weeks, respectively, significantly less than 14, 17, 20, 3, and 3.8 6 0.92 weeks in the control group (p < .05). Conclusion. Carbon nanoparticles can be applied to more accurately guide the dissection of lymph nodes during thyroidectomy in C 2015 Wiley Periodicals, Inc. Head Neck 38: 840– patients with PTC. V 845, 2016
INTRODUCTION
or esophageal injury. In patients who underwent the modified lateral neck node dissection, Kupferman et al2 have reported shoulder weakness in 27% and chyle leak in 4.5% of patients, whereas others report phrenic paralysis, Horner syndrome, cervical plexus neuropathic pain syndromes, and other complications in up to 1% of cases.3 In order to minimize the complications while ensuring the radical effects of thyroidectomy, the surgery should be performed by experienced surgeons who are familiar with the anatomic characteristics and have superb surgical skills. In addition, appropriate external aids often bring a remarkable effect. Using carbon nanoparticles is a novel type of lymphatic tracer, which has been applied in the surgery of thyroid cancer in a few studies.4,5 The purpose of this study was to further evaluate the clinical value of carbon nanoparticles by focusing on its guidance effect on lymph node dissection during thyroidectomy and CLND in clinically node-negative patients with PTC.
It is well known that lymph node metastases are common in patients with papillary thyroid carcinoma (PTC). According to the Kouvaraki et al1 study, regional lymph node metastases usually present when PTC is diagnosed, whereas distant metastases appear in the late stage. Surgical resection is the most effective treatment for PTC, and the complete removal of the primary tumor and the metastatic regional lymph nodes is a prerequisite for other adjuvant therapies. Therefore, prophylactic central lymph node dissection tends to have a better prognosis in patients with PTC. However, expansion of the scope of operation will inevitably bring about corresponding complications because of mistaken resection of tissues and organs other than lymph nodes. For example, the potential complications of central lymph node dissection (CLND) include hypoparathyroidism, recurrent laryngeal nerve paralysis, permanent recurrent laryngeal nerve injury, and tracheal
KEY WORDS: papillary thyroid carcinoma, carbon nanoparticles, lymph node dissection, clinically node-negative patients, retrospective analysis
MATERIALS AND METHODS #
Imaging agent for lymphatic vessels
*Corresponding author: X. Chen, Department of Thyroid and Breast Surgery, The First Affiliated Hospital of FuJian Medical University, No. 20, Chazhong Road, ChaTing Street, FuZhou, FuJian Province, People’s Republic of China. E-mail: [email protected]
Carbon nanoparticles (Chongqing Levin U.S. Pharmaceutical, China, approval number: Zhunzi H20073246), a lymphatic tracer, has a pronounced tropism for lymphatic tissues. The standard carbon nanoparticle suspension (1 mL: 50 mg) contains nanoparticles with an average diameter of about 150 nm, which is greater than the
MM stands for Master of Medicine
Contract grant sponsor: This study was supported by the Health Department of FuJian Province Youth Research (2011-1-16) and key Clinical Specialty Discipline Construction Program of Fujian, People’s Republic of China.
840
HEAD & NECK—DOI 10.1002/HED
JUNE 2016
CARBON
NANOPARTICLE–GUIDED LYMPH NODE DISSECTION
nanoparticle injection, whereas the patients in the control group (n 5 81) did not. All the patients underwent total or subtotal thyroidectomy with prophylactic bilateral central compartment neck dissection, and part of the cohort received prophylactic lateral compartment neck dissection. Postsurgical radioiodine remnant ablation was applied according to the postoperative pathological findings. For patients in T3 classification and above, radioiodine remnant ablation was used; for patients with a tumor size >1 cm that was confined within the thyroid or accompanied with metastasis in cervical lymph node, the selective radioiodine remnant ablation was used.
Surgical procedure FIGURE 1. Intraoperative view of the clusters of lymph nodes black-stained by carbon nanoparticle injection, indicating the excellent lymph node tracing effect of carbon nanoparticles.
capillary endothelial cell gap (approximately 20–50 nm) and smaller than the lymphatic capillary endothelial cell gap (approximately 120–500 nm). This feature enables carbon nanoparticles to enter the lymphatic duct but not the blood circulation. The tumor localization was roughly determined by preoperative ultrasonography, and it could be further accurately determined by intraoperative palpation in the majority of patients. Intraoperative ultrasonography was not used. For tumors 1 cm localized within the gland that cannot be palpated, carbon nanoparticles were injected under the ipsilateral thyroid true capsule. For most palpable tumors, carbon nanoparticles were injected into the tissues around the tumor but not inside the tumor. After injection, the carbon nanoparticles may be engulfed by macrophages and subsequently transported into the lymph nodes. The accumulated carbon nanoparticles in the lymph nodes makes the lymph nodes black-stained and it thus achieves the purpose of tracing and in vivo staining of the draining lymph nodes in the tumor area (Figure 1). Using carbon nanoparticles also avoids the disadvantage of all tissue staining because it cannot enter the blood circulation. Carbon nanoparticles cause little toxic side effects in the human body because they can be excreted via the lungs and intestines after a few months.
Patients This retrospective study was approved by the institutional review board of our hospital and included 162 consecutive patients with PTC who underwent surgery from April 2010 to April 2011. No patient had a history of thyroid or neck surgery for nonthyroidal head and neck cancers and all patients provided an informed consent. The operations were performed by the same medical team in our hospital. All the patients were diagnosed with PTC by preoperative fine-needle aspiration cytology, and had no preoperative evidence of cervical lymph node metastasis at physical examination, ultrasound, or CT imaging. The patients were randomly divided into 2 groups. The randomization was done using computer-generated random number tables. The patients in the carbon nanoparticle group (n 5 81) received an intraoperative carbon
General anesthesia was applied for all patients. Patients were positioned supine with the neck slightly hyperextended and the shoulders padded. A curvilinear incision of a length about 6 cm was placed in a skin crease 2 cm above the sternal notch. After skin incision, subcutaneous fat and platysma were separated and the cervical anterior muscles were pulled to both sides. The thyroid capsule was carefully dissociated to completely expose the thyroid gland, without causing injury to the capsule. In the carbon nanoparticle group, 0.1 mL per spot of carbon nanoparticles was injected into tissues surrounding the tumor using a skin test syringe. One or 2 spots were injected for each tumor. To prevent the carbon nanoparticles from leakage, the needle should be inserted deeply into the tissues before injection. To avoid injection of blood vessels, the plunger was pulled back slightly before injection to ensure that there was no blood back flowing into the syringe. The suspension was slowly pushed into the tissues. Upon completion, the needle was removed and pressure was applied to the injection site. Within a few minutes, the lymphatic ducts and the lymph nodes became black-stained and the parathyroid was “negatively developed” (Figures 1 and 2). Total thyroidectomy or near total thyroidectomy was then performed according to the meticulous capsular dissection technique. Node clearance of the central cervical compartment was performed cranially to the hyoid bone, caudally to the supraclavicular notch, laterally to the carotid sheaths, and dorsally to the prevertebral fascia.6 Excised lymph nodes were individually labeled as stained or nonstained, whereas the paratracheal lymph nodes on the right side were specifically labeled according to their location at either the shallow surface or the deep surface of the laryngeal recurrent nerve. Patients in the control group underwent the standard thyroidectomy and the central lymph node dissection without carbon nanoparticle injection. All resected nodes were sent for pathological examination. All specimens were dissected by the same pathologist and diagnosed by 2 pathologists blindly and independently of this study.
Statistical analysis Patients and primary carcinoma characteristics were investigated and the numbers, frequency, and locations of the detected central lymph nodes were analyzed. Postoperative complications were also evaluated. The measurement data were described as mean 6 SD. All data were analyzed by SPSS 17.0 package (SPSS 17.0 for Windows; SPSS, Chicago, IL).The paired, 2-tailed t test was used HEAD & NECK—DOI 10.1002/HED
JUNE 2016
841
ZHU ET AL.
FIGURE 2. Intraoperative view of the “negatively developed” parathyroid in contrast to the black-stained lymph node or tissues. The arrow indicates the parathyroid.
for continuous variables, and the Pearson chi-square test was used for categorical variables. Any p < .05 was considered statistically significant.
sive aspects between the control group and the carbon nanoparticle group.
Guide effects of carbon nanoparticles on lymph node resections
RESULTS General information The clinical pathological characteristics of the enrolled patients are summarized in Table 1. The postoperative pathological examination confirmed PTC in all 162 patients. There were no significant differences in age, sex, size of primary tumors, tumor multifocal, and inva-
All patients underwent CLND, 92 cases (56.79%) had been demonstrated with lymph node metastasis by postoperative pathological examination, including 50 cases (61.73%) and 42 cases (51.85%) in the carbon nanoparticle group and the control group, respectively. Of the patients with metastasis, the mean number of metastatic
TABLE 1. The clinical pathological characteristics of patients with papillary thyroid cancer (n 5 162).
Clinic pathologic data
Age, mean 6 SD, y Sex, female:male Primary tumor Size, mean 6 SD, mm Bilateral Extrathyroidal extension (minimal) Pathological type Lymph node status preoperatively Lymph node status postoperatively Rate of metastatic lymph nodes, % Mean no. of dissected lymph nodes Mean no. of metastatic lymph nodes Mean no. of lymph nodes with diameter 2 mm No. of dissected parathyroid glands Cases of postoperative hypocalcemia (Ca
