Abstract
Background: To evaluate the clinical effectiveness of lateral cervical region (LCR) lymphadenectomy as a preventative procedure for stage CN0 papillary thyroid cancer (PTC).Methods: From December 2019 to October 2021, 108 patients with CN0 stage PTC hospitalized to our general surgery department were recruited. After analysis, the clinical data of these patients were separated into two groups: 57 cases were in the Surgical + lymphatic dissection group and 51 instances were in the surgical group. Total thyroidectomy with central node dissection (TTCD) was carried out on the surgical group, whereas intraoperative ultrasound (IOUS) for prophylactic LCR lymph nodes dissection was carried out on the basis of TTCD in the Surgical + lymphatic dissection group. The postoperative complications, cervical lymph node metastases and recurrent reoperation were analyzed in both groups.Results: In the Surgical + lymphatic dissection group, the rate of lymph node metastasis (LNM) identified by IOUS in the LCR of PTC was 29.82% (17/57). In the central group with >2 lymph node metastases compared to the central group with < 2 lymph node metastases, the rate of LCR LNM was considerably greater (20% vs. 43%). Between the two groups, there was no statistically significant difference in the frequency of postoperative complications (P > 0.05). At the 1-year postoperative follow-up, the recurrence rate in the surgical group was 13.73%, whereas there was no recurrence in the Surgical + lymphatic dissection group.Conclusions: The recurrence/reoperation rate of PTC in individuals with stage CN0 can be decreased by IOUS guided prophylactic lymph node dissection in the LCR.
Introduction
The most prevalent thyroid cancer is a papillary thyroid carcinoma (PTC). Although the majority of PTC has a slow progression and a good prognosis, with a 10-year survival rate of more than 90% after surgical treatment, patients with PTC are prone to early lymph node metastasis (LNM), which can be as high as 20–90% in the neck [Citation1–3] and 30–50% in the lateral cervical region (LCR) lymph node occult metastasis [Citation4–6]. Thyroidectomy and thorough and rational lymph node dissection are recognized as the best options for the treatment of PTC [Citation7–8]. The current standard procedure for PTC is thyroidectomy with central group lymph node dissection [Citation9–10], but there is still a long-standing controversy at home and abroad about the need for prophylactic cervical lymph node dissection [Citation11, Citation12], especially for patients with negative lymph nodes on preoperative imaging, there is no unanimous opinion on whether prophylactic LCR lymph node dissection is needed, as well as the extent and timing of dissection.
Up to 90% of PTC patients may have lymph node metastases, and LCR metastasis affects the likelihood of PTC recurrence [Citation13, Citation14]. Radical or modified radical neck dissection has typically been the basis of treatment for individuals with lymph node metastases from PTC [Citation15]. The most sensitive approach for identifying nodal metastatic illness in PTC patients with nodes as small as 2 to 3 mm in diameter has reportedly been found to be high-resolution cervical ultrasound (US) [Citation16–19]. Preoperative ultrasound has been demonstrated to increase the likelihood that lymph node removal would be successful, but it has also been shown to miss up to 80% of tiny lymph node metastases that might later present as recurrence or persistent illness [Citation20, Citation21]. Additionally, the patient’s position and compliance may have an impact on the ability to detect nodal disease. Therefore, intraoperative prediction of LNM in the LCR and simultaneous elective lymph node dissection in the LCR can effectively avoid secondary surgery due to recurrence within a short period of time after surgery. Intraoperative ultrasonography (IOUS) can assist in the diagnosis and localization of lymph nodes in the LCR.
There is evidence to suggest that IOUS may offer a node mapping that is more precise and dependable, particularly for the challenging node levels and sublevels [Citation21]. Particularly in the difficult neck levels like IIb and V, IOUS showed enhanced sensitivity for the detection of LCR nodes in comparison to preoperative US scans: up to 25% of patients who underwent tests had nodes newly discovered by IOUS that were subsequently confirmed by pathology [Citation22]. This paper aimed to investigate the clinical efficacy and feasibility of IOUS for prophylactic lymph node dissection of the LCR in patients with stage CN0 PTC.
Methods
Patients’ selection
This paper investigated the clinical efficacy and feasibility of IOUS for prophylactic lymph node dissection of the LCR in patients with stage CN0 PTC. From December 2019 to October 2021, one hundred and eight patients with primary papillary thyroid cancer who admitted to the general surgery department of the Ruijin Luwan Branch of Shanghai Jiaotong University were recruited. These patients were recruited according to the inclusion criteria and exclusion criteria. These patients randomly assigned to the surgical group (51 cases) or the Surgical + lymphatic dissection group (57 cases) for the study by touching red and blue balls randomly. The patient who touched the red ball was assigned to the surgical group, and those who touched the blue ball was the Surgical + lymphatic dissection group. The study was conducted in compliance with Declaration of Helsinki, and approved by the ethics committee of our hospital (LWEC2019005). The written consent was achieved from each participant.
Inclusion criteria include 18 years < age <80 years, new patients with US suspected and FNA confirmed PTC, primary tumor ≤3 cm in size, no US suspected or FNA confirmed LNM in the LCR, no distant metastasis, and voluntary signature of the informed consent.
Exclusion criteria include refusion to join the study, non-primary resection, T3 and T4 stage PTC, US suspected or FNA confirmed lymph node LNM metastasis in the LCR, distant metastasis of the tumor, abnormal enlarged lymph nodes and central liquefaction necrosis found by preoperative ultrasound or CT, intraoperative frozen pathology suggestion of central lymph node metastasis, and a history of external radiation irradiation to the neck and family history of thyroid cancer.
Methods
Preoperative CN0 judgment criteria
According to the clinical evaluation criteria of cervical lymph nodes in the literature of Kowalski [Citation23], the following conditions were also met: (1) no enlarged lymph nodes were found clinically; (2) no abnormal enlarged lymph nodes were found by US or CT, showing lymphatic portals visible on lymph nodes without central liquefaction necrosis and peripheral enhancement, etc.
Preoperative auxiliary examinations
All patients underwent preoperative clinical physical examination, thyroid function test, neck US, neck CT imaging, and laryngoscopy. The general condition, age and sex of the patients were recorded.
Surgical methods
In both groups, lymph node dissection was performed on the affected side of the thyroid gland + isthmus + central group lymph node dissection, while in the Surgical + lymphatic dissection group, lymph node dissection was performed simultaneously in LCR II, III and IV under IOUS guidance. The surgical approach was as follows: a nanocarbon suspension was injected in the middle of the thyroid gland, 0.1 ml was injected when the volume of the unilateral gland lobe was less than 2.8 cm3, and 0.2 ml was injected when it was larger than 2.8 cm3, and the injection was slowly pushed in 2 points. Intraoperatively, thyroidectomy + isthmus resection + central group lymph node dissection was performed using a combination of electric knife and ultrasonic knife. The cleared lymph nodes were sent for cryopathological examination. All the procedures were performed by the same surgical team (with 8 years of experience).
Intraoperative ultrasound methods for the surgical + lymphatic dissection group
The color US diagnostic instrument from GE, USA, with a frequency of 5–10 HZ was used, and the cable connecting the probe was covered with a disposable sterile plastic lens cover outside in the operation, and the test was performed on the operating table by the same radiologist (with 10 years of experience) with the following steps: the patient’s head was turned to the opposite side, and the radiologist holding the probe swept the lymph nodes in the four, three, and two regions of the neck in order from the bottom to the top, and 0.9% saline was used as acoustic coupling agent during the scan. During the scan, lymph nodes with disorders in aspect ratio, poorly defined borders, with fine calcifications, and with localized cystic changes were observed [Citation24], and suspicious lymph nodes were localized according to the position of the US probe. Subsequently, lymph node dissection was performed in the prophylactic cervical levels II, III and IV according to the location and extent of the lymph nodes found by US scan. Postoperative US exploration was performed again to avoid residual lymph nodes. Lateral cervical lymph node dissection specimens were sent for pathological examination, and drainage tubes were placed in each of the affected tracheoesophageal groove and lateral cervical lymph node dissection wound.
Postoperative treatment and postoperative follow-up
Patients in both groups were treated with postoperative TSH suppression - levothyroxine tablets (eugenol), regular rechecking of serum thyroid function and adjustment of medication dose to keep T3 and T4 within the normal range, with TSH as close as possible to 0.1 mmol/L in low-risk patients and maintaining TSH < 0.1 mmol/L in medium- and high-risk patients.
Observation indexes
Incidence of postoperative complications
The incidence of postoperative complications such as bleeding, Injury to the recurrent laryngeal nerve, hypoparathyroidism, lymphatic leakage, and postoperative infection were compared between the two groups.
Parathyroid function and serum calcium level
Parathyroid hormone and serum calcium were tested in both groups before and 1 day after surgery, and the test results were compared.
Postoperative follow-up
The follow-up included medical history, a specialist physical exam, a full panel of thyroid function tests, blood electrolyte and PTH tests, a neck US examination, the recurrence rate and number of patients who underwent a second surgery within a year of the first, as well as the number of patients who had LNM in levels II, III, IV, and VI. The follow-up term was one year, with a follow-up interval of three months.
The number of metastases and metastasis rate of the obtained post-clearing cervical lymph node counted by partition
The American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery’s standards [Citation25] were followed for the Neck Dissection Classification: lymph nodes in the submental triangle at Level IA; lymph nodes in the digastric muscle’s anterior and posterior belly and the body of the mandible at Level IB; and lymph nodes at Level IIA, where the anterior boundary is the stylohyoid muscle and the posterior boundary is a vertical plane determined by the spinal accessory nerve; the sternocleidomastoid muscle’s posterior border serves as the level IIB’s posterior boundary, while the spinal accessory nerve’s vertical plane serves as the level IIB’s anterior boundary; Level III, middle jugular group: lymph nodes situated around the internal jugular vein’s middle third; Level IV, lower jugular group: lymph nodes around the internal jugular vein’s bottom third; Level V, posterior jugular triangle lymph nodes, which are situated along the transverse cervical artery and the lower portion of the spinal accessory nerve; precricoid lymph node, perithyroidal lymph nodes, paratracheal lymph nodes, and lymph nodes along the recurrent laryngeal nerve are all included in the Level VI, anterior compartment group, which surrounds the central visceral tissues of the neck; The pretracheal, paratracheal, and esophageal groove lymph nodes are included in the Level VII, superior mediastinal group.
Statistical analysis
Using the SPSS 23.0 programme, statistical analysis was carried out. Using the chi-square test, the enumeration data were examined. Independent sample t test was used to evaluate the data reported as mean standard deviation (SD), and p-values under 0.05 were deemed statistically significant.
Results
No patients refused to participate in or withdrew from the study. All 108 patients had complete diagnosis and treatment records. In the surgical group, there were 20 males and 31 females; 34 cases were under 45 years old and 17 cases were 45 years old and above; the disease duration was 10 days-5 years, 45 cases had single primary lesions and 6 cases had multiple primary lesions. Primary lesions were present in 39 cases where the unilateral glandular lobe was affected, 12 cases where the bilateral glandular lobe was affected, 15 cases where the maximal diameter of the tumor was greater than 1 cm, and 5 cases where there was perineural invasion. In 2 cases, the top pole of the thyroid gland, 7 cases, the middle pole, and 17 cases, the lower pole, were the areas affected by the lesions. The lesions were simultaneously implicated in the middle and lower poles in 12 instances, the middle and higher poles in 8 cases, the upper and lower poles in 1 case, and the upper and middle poles in 4 cases. The Surgical + lymphatic dissection group included 20 males and 37 females; 26 cases were under 45 years old, 31 cases were 45 years and older; the disease duration ranged from 5 days to 10 years; 45 cases had single primary lesions, 12 cases had multiple primary lesions; 40 cases had primary lesions in the unilateral glandular lobe, and 17 cases had primary lesions in the bilateral glandular lobe. Tumors with a maximum diameter of 1 cm were found in 34 instances, whereas tumors with a maximum diameter of >1 cm was found in 23 cases. There were 7 cases of invasion of the tumor peritoneum. The lesions were located in the upper pole of the thyroid gland in 5 cases, in the middle pole in 11 cases, in the lower pole in 7 cases, in the middle and lower poles in 12 cases, in the middle and upper poles in 11 cases, in the upper and lower poles in 5 cases, and in the upper and middle poles in 6 cases ().
Table 1. Age and sex of 108 patients with papillary thyroid cancer (cases).
Comparison of complications in the two groups
In terms of complications, among the 57 patients in the Surgical + lymphatic dissection group, there was one case (1.75%) of postoperative bleeding, one case (1.75%) of lymphatic leakage, one case (1.75%) of infection, 11 cases (19.30%) of clinical hypocalcemia with numbness in the hands and feet, and 7 cases (17.07%) of hoarseness. In the surgical group, there were no cases of postoperative bleeding, lymphatic leakage, or infection, and 11 cases (21.57%) showed clinical hypocalcemia with numbness in the hands and feet, and 3 cases (5.88%) showed hoarseness. The symptoms of hypocalcemia in both groups resolved after intravenous or oral calcium administration, and the functional impairment of the recurrent laryngeal nerve recovered within 6 months after surgery in both groups. Moreover, there was no significant difference in the overall complication rate in the Surgical + lymphatic dissection group (36.84%) compared with the surgical group (27.45%), (P > 0.05, ).
Table 2. Comparison of postoperative complication rates between the two groups (n,(%)).
Comparison of parathyroid function and serum calcium levels in the two groups
In terms of parathyroid hormone and serum calcium tests, there was no considerable difference between the preoperative test values of the Surgical + lymphatic dissection group and the surgical group (P > 0.05). At 1 d postoperatively, the values of these indexes decreased significantly in both groups, and the serum calcium values in the Surgical + lymphatic dissection group were significantly lower than those in the surgical group, suggesting that prophylactic lymph node dissection in the LCR may block the blood supply to the parathyroid glands, resulting in insufficient secretion of parathyroid hormone after surgery and causing hypocalcemia (P < 0.05, ).
Table 3. Comparison of preoperative and 1 d postoperative parathyroid hormone and blood calcium levels in the two groups (mean ± SD).
Comparison of postoperative follow-up between the two groups
The 2 groups were followed up for 1 year after surgery, and the follow-up rate was 100%. There were no fatal cases in either group during the follow-up period. The recurrence rate 1 year after surgery in the surgical group was 13.73% (7/51), and the reoperation rate was 13.73% (7/51). In the Surgical + lymphatic dissection group, there were 0 cases of recurrence and reoperation at 1 year after surgery, and the difference was statistically substantial compared with the surgical group (P < 0.05, ).
Table 4. Recurrence of patients within 1 year after surgery in both groups (n,(%)).
Clinical risk factors of patients with lymph node metastasis in the LCR
From , it can be seen that the metastasis rate of lymph nodes in the LCR increased with the increase in the number of central group lymph node metastases, especially when the number of central group lymph node metastases was 2 and more, the metastasis rate of lymph nodes in the LCR of the same patient increased significantly P = 0.032).
Table 5. Relationship between lymph node metastasis in LCR and the number of lymph node metastasis in the central group.
Discussion
PTC is the most common type of pathology among thyroid malignancies, with low malignancy, long course time and good prognosis, but more prone to early LNM [Citation26]. At present, preoperative US is still the preferred method for the examination of cervical lymph nodes, but US is greatly influenced by human factors and is highly subjective, and the lymph nodes in the LCR are mostly located behind the internal jugular vein, and most of them are small in size, and the sensitivity of US to the LCR is only 27% as reported in the literature, so it is not always clear whether there is lymph node LNM metastasis by preoperative US. However, the incidence of occult LNM in the LCR is still 30–50%. The currently accepted surgical principle for CN0 patients is to perform only prophylactic central group lymph node dissection, and routine prophylactic lymph node dissection of the LCR is not necessary. However, once postoperative LNM in the LCR is detected, a therapeutic secondary surgery increases the difficulty of protecting the function of the parathyroid glands and the laryngeal recurrent nerve.
During thyroid surgery, removal or injury to the parathyroid glands can affect the blood supply to the parathyroid glands, leading to hypoparathyroidism and causing hypocalcemia [Citation27]. According to the study’s findings, both groups’ parathyroid and blood calcium levels reduced one day after surgery compared to the preoperative period, and the Surgical + lymphatic dissection group’s serum calcium test results were considerably lower than those of the surgical group, suggesting that prophylactic lymph node dissection of the LCR is a possible way to affect parathyroid function and lead to a decrease in serum calcium. However, all patients within this study recovered from postoperative hypocalcemia manifestations within six months after surgery and did not develop permanent hypoparathyroidism. Thyroid surgery is highly likely to damage the recurrent laryngeal nerve, and the greater the extent of the surgery, the higher the risk of injury [Citation28]. The results of this study showed that the incidence of hoarseness was significantly higher in the Surgical + lymphatic dissection group than in the surgical group, but all patients recovered from postoperative hoarseness within six months after surgery, and no permanent damage to the recurrent laryngeal nerve occurred.
LNM in patients with thyroid cancer occurs first in the central lymph nodes and then metastasizes to the lymph nodes in the LCR [Citation29]. In this study, we found that there was a close relationship between the number of metastases in the central group lymph nodes and the metastasis rate of lymph nodes in the LCR. As the number of central group lymph node metastases increased, the metastasis rate of lymph nodes in the LCR increased, especially when the number of central group lymph node metastases was two and more, the metastasis rate of lymph nodes in the LCR increased significantly. Therefore, it is very important to ensure the number of lymph nodes cleared in the central region intraoperatively. The number of lymph nodes in the central region can be increased by intraoperative injection of nanocarbon suspension, and the positive detection rate of lymph nodes in the central region can be increased by intraoperative analysis of pathological sections.
Although there are clinical methods to determine whether there is metastasis in the lymph nodes in the lateral cervical area, such as US, enhanced CT, and even PET-CT, the most commonly used and effective one is still preoperative US, which has the advantages of convenience, economy, and non-invasiveness. The ideal imaging examination approach for thyroid-related disorders is conventional ultrasonography [Citation30], which has a low detection rate for LNM in the central neck but a good diagnostic efficiency for metastatic lymph nodes in the LCR. A research found that, when used to diagnose metastatic lymph nodes in the lateral and central regions, IOUS had sensitivity, specificity, and accuracy of 89.04% vs. 82.98%, 93.83% vs. 80.00%, and 90.97% vs. 81.10%, respectively [Citation31]. For nodal compartments that the Pre-US had not expected, the IOUS indicated selective neck dissection (SND) in nine (27.2%) of the patients, of whom eight (24.2%) later revealed to have positive nodes at pathology [Citation22]. The IOUS can increase the completeness of lateral neck dissections, especially at levels II, IV, and V, by locating additional nodes that eye inspection or palpation missed [Citation21]. In this study, no abnormalities of lymph nodes in the LCR were detected by preoperative US, but the detection rate of lymph nodes in the LCR was increased by IOUS in the Surgical + lymphatic dissection group, and LNM in the LCR was detected in 29.82% of patients (17/57). IOUS -assisted lymph node dissection in the LCR can display the tiny lymph nodes in the LCR in real time, accurately locate the lymph nodes, and improve the accuracy of lymph node dissection, which is simple, safe and effective. At the same time, it is also possible to check whether there are any remaining lymph nodes at any time, so that the lymph node dissection can be more complete.
The IOUS images in this study are two-dimensional and require some experience to determine the three-dimensional orientation of the lesion. There is no standard IOUS image for reference, which limits the use of IOUS in thyroid surgery to a certain extent. In addition, a larger sample size is needed to further confirm this finding.
Conclusion
Intraoperative ultrasonography is practical, simple, not time or space constrained, may be used frequently, and has the benefit of precise localization, which has great clinical relevance and can result in improved surgical outcomes for patients. In patients with stage CN0 and intraoperative detection of 2 lymph node metastases in the central region, combined with IOUS for prophylactic lymph node dissection in the LCR, the local recurrence rate can be reduced and the prognosis improved, which is both safe and feasible.
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Additional information
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