Impact of Lymph Node Metastases with Recurrent Laryngeal Nerve Invasion on Patients with Papillary Thyroid Carcinoma

Abstract

Background:

Although rare, invasion by papillary thyroid carcinoma (PTC) of the upper aerodigestive tract significantly affects patients' prognosis and quality of life. Within the central compartment, the recurrent laryngeal nerve (RLN) is most frequently invaded by lymph node metastases (LNM). However, such an invasion has not been described in the literature, although reports on RLN invasion by primary tumors have been published. The present study aimed to characterize LNM with RLN invasion in patients with PTC.

Methods:

The participants of this retrospective investigation were selected from 629 PTC patients who received initial surgical treatment at our institution between January 1981 and December 2012. They included 38 (6%) patients with 40 cases of RLN invasion by LNM (LNM invasion group) and 112 (17.8%) patients with 117 cases of RLN invasion by the primary tumor (primary invasion group).

Results:

In the LNM invasion group, 70% of the RLN invasion cases occurred on the right side, whereas those in the primary invasion group were almost equally distributed. RLN invasion caused vocal cord paralysis, affecting 13 nerves (32.5%) in the LNM invasion group and 68 nerves (58%) in the primary invasion group. Significant differences in laterality and preoperative vocal cord paralysis were observed between the two groups. In the LNM invasion group, the longest diameter of metastatic lymph nodes (mean±standard deviation) of patients with RLN paralysis was 21±8 mm, whereas it was significantly different at 14±7 mm in those without RLN paralysis.

Conclusions:

Our results indicate that most patients with RLN invasion by LNM did not experience preoperative vocal cord paralysis. LNM invasion of the RLN (70%) more often occurred on the right side as expected given the complexity and three-dimensional anatomy of the RLN in the right paratracheal region compared to the left. RLN invasion by LNM should be considered if preoperative paratracheal nodal disease, especially when bulky, is noted in the right paratracheal region.

Introduction

Although papillary thyroid carcinoma (PTC) generally has an excellent prognosis, PTC invasion of the upper aerodigestive tract, although rare, often causes significant morbidity. Excision of the tumor usually affects adjacent organs, resulting in substantial functional loss involving phonation, swallowing, and breathing. Even when invasion occurs only in the recurrent laryngeal nerve (RLN), ipsilateral vocal cord paralysis can cause hoarseness and aspiration, whereas bilateral vocal cord paralysis causes dyspnea. Therefore, PTC invasion of the upper aerodigestive tract has an adverse effect on both patient prognosis and quality of life.

Cervical lymph node metastases (LNM) are detected at the time of diagnosis in 20–90% of patients with PTC. Although the presence of cervical LNM reportedly is of little prognostic significance for the survival of PTC, it has been suggested to represent an independent risk factor for diminished survival of PTC patients over 45 years of age (1). The impact of cervical LNM and optimal surgical management of the neck in PTC patients is controversial. LNM most frequently occurs in the central compartment of the upper aerodigestive tract. Although therapeutic central compartment neck dissection is necessary for patients with clinical lymph node involvement, the effectiveness of prophylactic central neck dissection remains unclear (2 –5).

In addition, RLN invasion by the primary tumor has been described in the literature, but, to the best of our knowledge, no studies of such an invasion by LNM have been reported, and the characteristics of LNM in the central compartment remain poorly understood. The present study therefore aimed to characterize LNM with RLN invasion in PTC patients.

Materials and Methods

Medical records of patients with PTC who initially received surgical treatment at Kyoto Medical Center and Kusatsu General Hospital between January 1981 and December 2012 were retrospectively reviewed. Those with RLN invasion by either LNM (LNM invasion group) or the primary tumor (primary invasion group) were selected. Data on patient characteristics, tumor differentiation, T stage, LNM location, preoperative vocal cord paralysis rate, RLN invasion laterality, and surgical methods of RLN invasion for the two groups were collected and compared. Information was also compiled on the laterality of RLN invasion and the size of metastatic lymph nodes in the LNM invasion group. Such information was then compared between cases with and without RLN paralysis.

Our therapeutic strategy for invasive PTC was complete resection and functional reconstruction. With the intention of avoiding excessive resection and achieving better postoperative function, we adopted a conservative but thorough surgical approach for invasive PTC. Curative resection was performed using an operating microscope if necessary. Multiple margin samples were sent for frozen section analysis to confirm negativity during surgery. If the result was positive, additional resection was performed until negativity was achieved. Similarly, we also adopted a conservative but thorough surgical strategy for RLN invasion. We tried to preserve the RLN in partial invasion cases and to reconstruct the RLN if gross invasion was present, if possible.

RLN invasion was defined as an intraoperative finding or cryosection analysis indicating gross invasion of the RLN by LNM or primary tumors.

Resection was defined as resection without reconstruction of the RLN in cases of gross invasion. Partial layer resection (6) was defined when the nerve was preserved via careful dissection using a No. 11 surgical blade under an operating microscope in partial invasion cases. Reconstruction was defined when the RLN was resected in a gross invasion case, followed by immediate reconstruction of the RLN using one of the three methods: primary RLN anastomosis, ansa cervicalis-to-RLN anastomosis, or RLN to RLN or ansa cervicalis-to-RLN with neural implantation. RLN reconstruction was intended for vocal improvement in patients with nerve resection but unrestored vocal cord movement.

The institutional review boards of our hospitals approved the present study. The chi-square test and Mann–Whitney U-test were used for all statistical analyses of the results. Differences were considered significant for p-values of <0.05. Commercially available software (Ekuseru-Toukei 2012; SSRI Co., Ltd., Tokyo, Japan) was used to perform all statistical analyses.

Results

Of 629 PTC patients treated at Kyoto Medical Center and Kusatsu General Hospital between January 1981 and December 2012, 38 (6%) with 40 RLN invasion events (LNM invasion group) and 112 (17.8%) with 117 RLN invasion cases were enrolled. The adjacent organs of 12 patients (32%) in the LNM invasion group had been invaded by the primary tumor (T4), and 12 patients (11%) in the primary invasion group did not have lymph node metastases (N0). However, no significant differences in age, sex, tumor differentiation, and locations of LNM were observed between the two groups (Table 1).

Table 1.

Baseline Patient Characteristics

	LNM invasion (n=38)	Primary invasion (n=112)
Age (years)	55±14	59±19	p=0.15
Sex
Male	14	26	p=0.10
Female	24	86
Differentiation
Well	34	99	p=0.86
Poor	4	13
T stage
T1	13 (34%)
T2	5 (13%)
T3	8 (21%)
T4	12 (32%)	112
LNM
N0		12 (11%)	p=0.08
Central	5 (13%)	10 (9%)
Ipsilateral	16 (42%)	56 (50%)
Bilateral	17 (45%)	34 (30%)

LNM invasion, the invasion from lymph node metastases group; Primary invasion, the invasion from primary tumors group; LNM, lymph node metastases; N0, no lymph node metastasis; Central, LNM in the central compartment; Ipsilateral, LNM in the affected central and lateral neck; Bilateral, LNM in the bilateral neck.

Thirty-five nerves (87.5%) invaded by LNM and 92 (78.6%) by the primary tumor could be preserved by partial layer resection or reconstructed (Table 2). Of 94 nerves receiving immediate RLN reconstruction, primary RLN anastomosis was performed for 25 nerves (LNM invasion group: 8; primary invasion group: 17), ansa cervicalis-to-RLN anastomosis for 35 nerves (LNM invasion group: 8; primary invasion group: 27), and RLN to RLN or ansa cervicalis-to-RLN with neural implantation for 34 nerves (LNM invasion group: 8; primary invasion group: 26; Table 3).

Table 2.

Surgical Methods of RLN Invasion for Each Group

	Resection	Partial layer resection	Reconstruction
LNM invasion (n=40)	5 (12.5%)	11 (27.5%)	24 (60%)
Primary invasion (n=117)	25 (21.4%)	22 (18.8%)	70 (59.8%)

RLN, recurrent laryngeal nerve.

Table 3.

Surgical Management of RLN Reconstruction

	RLN–RLN	Ansa–RLN	Implantation
LNM invasion (n=24)	8	8	8
Primary invasion (n=70)	17	27	26

RLN–RLN, primary RLN anastomosis; Ansa–RLN, ansa cervicalis-to-RLN anastomosis; Implantation, RLN to RLN or ansa cervicalis-to-RLN with neural implantation.

Of 33 nerves receiving RLN partial layer resection, 15 (45%) were preserved or had recovery from temporal vocal cord paralysis, whereas RLN paralysis was observed in 18 (55%; Table 4).

Table 4.

Postoperative Vocal Cord Function Received Partial RLN Excision

	Vocal cord movement (+)	Vocal cord movement (−)
LNM invasion (n=11)	7	4
Primary invasion (n=22)	8	14

Bilateral RLN invasion affected 10 patients: two infiltrated by bilateral LNM, five by primary tumors, and three by both LNM and primary tumors. Six patients underwent immediate RLN reconstruction; two had bilateral RLN resection, whereas partial layer resection and RLN reconstruction were performed in two. Only the two patients with partial layer resection experienced recovery from temporal vocal cord paralysis and had their stoma closed, while the other eight suffered bilateral RLN paralysis. Only one patient with closed stoma received vocal cord lateral fixation (7).

Of 75 nerves (LNM invasion group: 27; primary invasion: 48) without preoperative vocal cord paralysis, 29 (38.7%) had partial layer resection, whereas the remaining 46 (61.3%) underwent RLN resection or immediate RLN reconstruction (Table 5).

Table 5.

Surgical Management of RLN Invasion With or Without Preoperative Vocal Cord Paralysis

	Resection or reconstruction	Partial layer resection
With paralysis (n=81)	77	4
Without paralysis (n=75)	46	29

Comparison of the laterality of RLN invasion between the two groups showed that RLN invasion occurred more frequently on the right (70%, 28 nerves) than the left (30%, 12 nerves) in the LNM invasion group, whereas it was almost equally distributed in the primary invasion group. RLN invasion caused vocal cord paralysis, affecting 13 nerves (32.5%) in the LNM invasion group and 68 (58%) in the primary invasion group. Significant differences in laterality (p=0.0091) and preoperative conditions of patients with RLN paralysis (p=0.0044) were observed between the two groups (Table 6).

Table 6.

Comparison of RLN Invasion Laterality and Preoperative Condition of RLN Paralysis of Patients Between the LNM and Primary Invasion Groups

	LNM invasion (n=40)	Primary invasion (n=117)
Laterality^*
Right	28 (70%)	54 (46.2%)
Left	12 (30%)	63 (53.8%)
Condition^*
With paralysis	13 (32.5%)	68 (58.5%)^#
Without paralysis	27 (67.5%)	48 (41.5%)

Significant differences in laterality and preoperative conditions of patients with RLN paralysis were observed between the two groups ( ^*p<0.05).

#One intubated patient with RLN invaded primary thyroid carcinoma was transported, thus preoperative vocal cord condition was unknown.

In the LNM invasion group, the longest diameter of metastatic lymph nodes (mean±standard deviation) of patients with RLN paralysis was 21±8 mm and 14±7 mm for those without RLN paralysis. This difference was statistically significant (p=0.0325). Focus on the laterality of RLN invasion by LNM, LNM caused vocal cord paralysis, affecting 10 nerves (35%) in the right side and three (25%) in the left side. There was no significant difference in laterality of RLN invasion with or without vocal cord paralysis by LNM (p=0.768; Table 7). Moreover, the longest diameter of metastatic lymph node size in cases without RLN paralysis in the LNM invasion group was 14 mm for both the right and the left side. Therefore, no significant difference was observed in the size of metastatic lymph nodes in cases without RLN paralysis (p=0.957; Table 8).

Table 7.

Sizes of Metastatic Lymph Nodes With or Without RLN Paralysis and RLN Paralysis Laterality in the LNM Invasion Group

	RLN invasion	With paralysis	Without paralysis
Laterality
Right	28	10 (35.7%)	18 (63.4%)
Left	12	3 (25%)	9 (75%)
LN size^*		21±8 mm	14±7 mm

A significant size difference was observed between metastatic lymph nodes in cases with and without RLN paralysis ( ^*p<0.05). However, no significant difference was observed for RLN paralysis laterality in the LNM invasion group.

LN, lymph node.

Table 8.

Differences in Metastatic Lymph Node Sizes for Cases Without RLN Paralysis in the LNM Invasion Group

	Without paralysis	LN size without paralysis
Right	18	14±8 mm
Left	9	14±7 mm

Discussion

Our findings indicate that many patients with RLN invasion via LNM do not suffer from preoperative vocal cord paralysis. LNM invasion of the RLN (70%) more often occurred on the right side as expected given the complexity and three-dimensional anatomy of the RLN in the right paratracheal region compared to the left. RLN invasion by LNM should be considered if preoperative paratracheal nodal disease, especially when bulky, is noted in the right paratracheal region.

PTC invasion in the upper aerodigestive tract is a significantly unfavorable prognostic factor and causes symptoms of dysphagia and airway insufficiency (8 –14). Although RLN invasion reportedly has no significant independent effect on survival, ipsilateral vocal cord paralysis causes hoarseness and dysphagia, whereas bilateral vocal cord paralysis leads to dyspnea, resulting in considerable deterioration of the patients' quality of life (15 –17). Since there are reported studies on RLN invasion by the primary tumor but not by LNM in the literature (18), we conducted this investigation to compare the two situations.

The optimal strategy for surgical management of RLN invasion remains controversial, mainly because removal of the RLN does not increase overall survival rate. In addition, most RLNs that are functional prior to surgical treatment can be expected to remain so post-surgery. Previous reports have suggested that functional RLNs should be preserved even when RLN involvement is discovered during surgery (19 –21). In cases of RLN resection due to thyroid malignancy, the successful use of various re-innervation techniques has been reported, including ansa cervicalis-to-RLN anastomosis, primary RLN anastomosis, ansa-to-RLN with cricothyroid muscle-nerve-muscle pedicle, ansa-to-thyroarytenoid neural implantation, and ansa-to-thyroarytenoid neuromuscular pedicle for initial surgery, or phonosurgical techniques such as type I thyroplasty and arytenoid adduction for subsequent procedures (22 –26).

In this study, we adopted a conservative but thorough surgical strategy for RLN invasion, preserving the RLN in partial invasion cases and reconstructing it in cases of gross invasion if possible. Thirty-five (87.5%) nerves invaded by LNM and 92 (78.7%) by the primary tumor were treated with such strategies. All patients experienced improvement in voice quality within several months and did not require subsequent phonosurgery.

RLN invasion is easy to diagnose via endoscopic examination when hoarseness and vocal cord paralysis are present. However, as ultrasonography and computed tomography of the central neck compartment suffer from low sensitivity, a conclusive diagnosis in cases without paralysis is reportedly challenging (27 –31). In our study, the diagnostic accuracy of preoperative RLN invasion by LNM was also low, as 27 (67.5%) patients did not have vocal cord paralysis. Of the 29 (38.7%) nerves without preoperative vocal cord paralysis undergoing RLN partial layer resection, vocal cord movement was preserved or recovery from temporal vocal cord paralysis in only 15 (45%). However, Kihara et al. (6) reported that 83% of the 18 patients who underwent partial layer resection of the RLN had functioning vocal cords one year after surgery. The difference in these outcomes might be due to difference in the extent of dissection.

Recently, intraoperative nerve monitoring (IONM) data have proved to be useful for prognosticating postoperative RLN function. Additionally, intraoperative electrophysiological activity is thought to provide information on RLN viability and persistent function of RLN invaded by thyroid malignancy (32). Thus, IONM for RLN invasion might help improve vocal cord function.

Furthermore, our results indicate that RLN invasion by LNM occurs more frequently on the right than the left side of the central compartment. Such laterality may be due to the anatomical features of the RLN, which branches off the vagus at the vessel where the carotid originates, with the aortic arch on the left and the subclavicular artery on the right. The recurrent branches then pass anteriorly to the vessel, wrapping it from behind and underneath. The left RLN is longer and at a more superficial level than the right RLN in the central compartment. As it ascends in the neck, the RLN gives off branches, more abundantly on the left than on the right side, toward the esophagus, the trachea, and the superior pharyngeal constrictor muscle. Finally, the right RLN reportedly runs more superficially than the left in relation to the inferior thyroid artery (33,34). Such differences in the RLN depth and its sag owing to its relation with the inferior thyroid artery are considered contributing factors to the observed laterality. Additionally, the less sagging nature of the right RLN compared to the left might also expose the former to a higher risk of invasion.

Although the size of invading LNM on the right in cases without RLN paralysis is predicted to be smaller than that on the left, no significant differences in size was observed between the two sides in this study.

To the best of our knowledge, RLN invasion by LNM in the central compartment has not been discussed in the literature. Since our study included only a limited number of RLNs invaded by LNM (6%, 40 nerves), further investigations involving more patients will be necessary to clarify fully the clinical implications of RLN invasion by LNM, especially of its laterality.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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