DOI: https://doi.org/10.21203/rs.2.11444/v1
As is known, papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy[1]. Taken collectively, these studies[2-4] show that the most common metastases and local recurrences of PTC nodal disease were in the central neck compartment. In particular, it would cause problems for surgeons to reoperate on patients who have regional recurrence in the surrounding tissue of entrance point to recurrent laryngeal nerve (RLN); this reoperation can become complicated[5]. In clinics, there were two metastatic lesions in the central compartment and the two patients suffered a second operation, which both resulted in the overlooked lymph nodes of entrance point to recurrent laryngeal nerve (LN-epRLN). The purpose of this study was to call our attention of LN-epRLN metastasis in PTC patients.
In the current study, a total of 878 consecutive PTC patients were received initial thyroidectomy at Shanghai Ruijin Hospital between April 2016 and March 2017. A prophylactic or therapeutic central lymph node dissection (CLND) was routinely performed in PTC patients. Exclusion criteria: underwent previous thyroid surgery, pathological types of thyroid carcinomas other than PTC, with lateral neck lymph node matastases and gross extrathyroidal extension invading the surrounding tissue of entrance point to RLN. According to the guidance of the 2010 Tumour Node Metastasis (TNM) staging system of American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC)[6], we identified all the sample as T1-3N0-1aM0 PTC. Informed consent has been obtained from all participants, and the study was approved by the medical ethics review committee in Shanghai Ruijin Hospital.
All operations in our study were performed by the same group of surgeon（JQ Y.）. Central lymph nodes included the Delphian, pretracheal, and paratracheal lymph nodes (LNs). We defined that LN-epRLN was the lymph adipose tissue located within the distance from the outer edge of the lymph node to RLN entrance point less than 5 mm. Dissection of central LNs was performed as follows. Dissection of the lymph nodes around thyroid was completed at the same time as thyroidectomy. After thyroidectomy, the full length of RLN in the neck was revealed, and paratracheal lymph nodes were removed, including LN-epRLN. Carbon nanoparticles were injected into the lobe during the operation to help identify LNs (Fig.1).
All specimens of thyroid lesions were confirmed to be PTCs by postoperative pathological examination. The pre-operative and postoperative clinicopathological features were recorded and included the following variables: age, gender, TgAb and TPOAb levels, primary tumor size and location, LN-epRLN laterality, thyroid nodules in primary lobe, and lymph node metastasis based on the final pathology report. 73 cases all had completed follow-up data (follow-up period from 12 to 24 months). The present study included the postoperative US examination and procedure-related complications.
Statistical Analysis
To identify differences between groups for specific variables, SPSS version 16 software (SPSS Inc, Chicago, IL) was used for statistical analysis. Univariate analysis was performed using Chi-square test. A P-value of <0.05 was considered to represent statistical significance.
LN-epRLN was found in 73 of all the 878 patients and the metastasis rate was 3.76% (33/878). In the present study, we found that there were inconstant nodes, 1 to 4 (1 in average), and that the positive rate was 46.84% (37/79). There was no significant difference in gender (P =0.114) and age (P =0.118) between the two groups (Table 1).
Other central nodal metastasis was more common in the positive LN-epRLN group (93.9 vs. 42.5 %, P <0.001). In univariate analysis, a tumor located in the upper third and tumor multifocality showed a P <0.05 (Table 2). However, no significant relation was found between LN-epRLN metastasis and LN-epRLN laterality (P =0.424), tumor size (P =0.288), or serum TgAb and TPOAb levels (P =0.704).
No patient had permanent RLN injury or permanent hypoparathyroidism in this study, and no patient had a second operation during the follow-up period. Seven (0.8%) patients had transient hoarseness (4-6 weeks), which were checked under fiberlaryngoscopy at one month and 6 months after surgery. Six (0.7%) patients had postoperative transient hypoparathyroidism (5-14 days).
Previous literatures[2-4] have shown that lymph node involvement is relevant to local recurrence, in fact. This is controversial according to the current American Thyroid Association (ATA) guidelines for a routine prophylactic or therapeutic CLND in patients with PTC[7-8].
The anatomic boundaries of a CLND include the carotid arteries from the hyoid bone superiorly to the innominate artery inferiorly. An appropriate range of CLND should both reduce the local recurrence rate and the incidence of post-operative complications. Paratracheal LNs are the most commonly involved central LNs. For PTC, a precise range of paratracheal LN dissection is still controversial. There have been none articles written on the significance of the LN-epRLN, as part of paratracheal LNs. In the current study[9-10], therefore, LN-epRLN did not fall under the normal subdivisions of the central compartment.
The LN-epRLN was defined as the lymph node located within the distance from outer edge of the lymph node to the RLN entrance point less than 5 mm (Fig.1). In our study, there were inconstant nodes, 1 to 4 (1 in average), in diameter between 6 mm and 10 mm. In the present study, LN-epRLN was found in 73 of 878 patients and the metastasis rate was 3.76% (33/878). Thinking only about involved thyroid lobes, the positive LN-epRLN rate was 46.84% (37/79), and the incidence of the right side was slightly higher than that on the left side. The univariate analysis showed that the factors affecting LN-epRLN involvement were the other central cervical lymph node metastasis, the upper third tumor location and tumor multifocality.
The LN-epRLN receives afferent lymphatic drainage from the thyroid gland[11]. Considering the anatomical location of the LN-epRLN, it may be expected that tumors located in the upper third will spread to the LN-epRLN more frequently than other.
In our study, the rate of other central neck node metastasis in the presence of LN-epRLN metastasis was 93.9%. Supporting our results, the positive LN-epRLN was highly predictive of other central nodal metastasis. However, this tendency merits further investigation. On the other hand, the exploration and removal of LN-epRLN should be included in CLND for clinically node positive PTC.
Usually, most patients with PTC obtain a 10-year survival rate of 80–90%, but the regional recurrence rate after surgery is 5-20%[12]. Therefore, it’s important to improve the thoroughness of CLND. In our study, two PTC patients suffered second operation as a consequence of the presence of metastatic LN-epRLN, which may mistake for a parathyroid gland or give consideration to recurrent laryngeal nerve injury, and be reserved during the primary operation. After the second operation, the two patients both had transient hoarseness. Our results mirror the data from literature: Reoperative CLND has been shown to have rates of RLN injury 21% transiently and postoperative hypocalcemia with a large range of 0-24%[13-20]. PTC patients with clinically involved lymph nodes in the central compartment should be managed with a LN-epRLN dissection procedure as the time of CLND, taking into consideration RLN and parathyroid glands which are closely related to the nodal basins.
Our prospective study was limited by small samples, which means our results may not be as powerful as a randomized clinical trial with a large population. Moreover, patients with lateral neck lymph node matastases were excluded due to inclusion criteria. These patients may have experienced worse outcomes than patients enrolled in our study. However, to our knowledge, this is the first article in English to progress our understanding of LN-epRLN metastases in PTC patients.
In summary, we pioneered the confirmation of the significant involvement of LN-epRLN in metastasis. In PTC patients, especially in suspicious presence of central cervical lymph node metastasis, attention should be given to excising the nodal tissue in the surrounding tissue of entrance point to RLN.
PTC: papillary thyroid carcinoma
RLN: recurrent laryngeal nerve
LN-epRLN: lymph nodes of entrance point to recurrent laryngeal nerve
CLND: central lymph node dissection
TNM: Tumour Node Metastasis
AJCC/UICC: American Joint Committee on Cancer/International Union Against Cancer
LN: lymph node
ATA: American Thyroid Association
Ethics approval and consent to participate: Informed consent has been obtained from all participants and clearly state this in your manuscript.
Consent for publication: Not applicable.
Availability of data and material: Not applicable.
Competing interests: None.
Funding: None.
Authors' contributions: TL recorded the data and drafted the manuscript. ZL participated in the design of the study and performed the statistical analysis. JY conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
Acknowledgements: Address all correspondence and requests for reprints to: Jiqi Yan, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin er Road, Shanghai 200025, China. E-mail: [email protected]
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Table 1 Analysis on the involved patients of risk factors for LN-epRLN metastasis |
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|
|
LN-epRLN (+) |
LN-epRLN (-) |
P-value |
|
Total (patients) |
33 |
40 |
||
|
Age(years) |
34.20±10.34 |
40.00±10.25 |
0.118 |
|
|
Gender |
Male |
9(27.3%) |
5(12.5%) |
0.114 |
|
Female |
24(72.7%) |
35(87.5%) |
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|
TgAb and TPOAb levels |
Elevated |
18(54.5%) |
20(50.0%) |
0.704 |
|
Normal |
15(45.5%) |
20(50.0%) |
||
|
Other Lymph node metastases |
（+） |
31(93.9%) |
17(42.5%) |
0.000 |
|
（-） |
2(6.1%) |
23(57.5%) |
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Table 2 Analysis on the involved thyroid lobes of risk factors for LN-epRLN metastasis |
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|
|
LN-epRLN(+) |
LN-epRLN(-) |
P-value |
|
Total (involved thyroid lobes)* |
37 |
42 |
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|
Laterality |
Left |
16(43.2%) |
22(52.4%) |
0.424 |
|
Right |
21(56.8%) |
20(47.6%) |
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|
Multifocality |
（+） |
25(67.6%) |
14(33.3%) |
0.033 |
|
（-） |
12(32.4%) |
28(66.7%) |
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|
Tumor Size |
<10 mm |
9(24.3%) |
17(40.5%) |
0.288 |
|
10-20 mm |
15(40.5%) |
15(35.7%) |
||
|
>20 mm |
13(35.1%) |
10(23.8%) |
||
|
Tumor Location |
upper 1/3 |
25(67.6%) |
15(35.7%) |
0.044 |
|
lower 2/3 |
12(32.4%) |
27(64.3%) |
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* LN-epRLN was found in 73 of the 878 patients. Because of 6 cases involved in both thyroid lobes, there was 79 cases in total.