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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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Title Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma
Sueyoshi Moritani, MD Center for Head and Neck Surgery, Kusatsu General Hospital 1660 Yabase Cho, Kusatsu, Shiga 5258585, Japan E-mail: [email protected]
Running title: LNM with RLN invasion in PTC
Key words: Recurrent laryngeal nerve invasion, lymph node metastases, primary tumor invasion, laterality, preoperative vocal cord paralysis
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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
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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 indicated 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, was 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
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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.
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 5 of 31
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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
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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 less than 0.05. Commercially available software (Ekuseru-Toukei 2012; SSRI Co., Ltd., Tokyo, Japan)
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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was used to perform all statistical analyses.
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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). 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). Of 33 nerves receiving RLN partial layer resection, 15 (45%) were preserved or had recovery from temporal vocal cord paralysis, whereas RLN paralysis was
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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observed in 18 (55%) (Table 4). Bilateral RLN invasion affected 10 patients, including 2 infiltrated by bilateral LNM, 5 by primary tumors, and 3 by both LNM and primary tumors. Six patients underwent immediate RLN reconstruction; 2 had bilateral RLN resection, whereas partial layer resection and RLN reconstruction were performed in 2. Only the two patients with partial layer resection experienced recovery from temporal vocal cord paralysis and had their stoma closed, while the other 8 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). 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 (Chi-square test, p = 0.0091) and preoperative
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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conditions of patients with RLN paralysis (Chi-square test, p = 0.0044) were observed between the two groups (Table 6). 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 (Mann-Whitney U-test, 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 3 (25%) in the left side. There was no significant difference in laterality of RLN invasion with or without vocal cord paralysis by LNM (Chi-square test, 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 14mm for both right and left side. Therefore, no significant difference was observed in the size of metastatic lymph nodes in cases without RLN paralysis (Mann- Whitney U-test, p = 0.957) (Table 8).
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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
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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
muscle-nerve-muscle
RLN
pedicle,
anastomosis,
ansa-to-RLN
ansa-to-thyroarytenoid
neural
with
cricothyroid
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
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conclusive diagnosis in cases without paralysis is reportedly challenging (27–31). In our study, the diagnostic accuracy of pre-operative 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 1 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 occurr 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
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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, towards 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 fully clarify the clinical implications of RLN invasion by LNM, especially of its laterality.
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Disclosure statement
No competing financial interests exist.
Address correspondence to: Sueyoshi Moritani, MD
Center for Head and Neck Surgery, Kusatsu General Hospital
1660 Yabase Cho, Kusatsu, Shiga 5258585, Japan
E-mail: [email protected]
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References 1. Zaydfudim V, Feurer ID, Griffin MR, Phay JE 2008 The impact of lymph node
involvement on survival in patients with papillary and follicular thyroid carcinoma. Surgery 144:1070-1077; discussion 1077-1078. 2. Sadowski BM, Snyder SK, Lairmore TC 2009 Routine bilateral central lymph node
clearance for papillary thyroid cancer. Surgery 146:696-703; discussion 703-695. 3. Carling T, Carty SE, Ciarleglio MM, Cooper DS, Doherty GM, Kim LT, Kloos RT,
Mazzaferri EL, Sr., Peduzzi PN, Roman SA, Sippel RS, Sosa JA, Stack BC, Jr., Steward DL, Tufano RP, Tuttle RM, Udelsman R, American Thyroid Association Surgical Affairs C 2012 American Thyroid Association design and feasibility of a prospective randomized controlled trial of prophylactic central lymph node dissection for papillary thyroid carcinoma. Thyroid 22:237-244. 4. Giordano D, Valcavi R, Thompson GB, Pedroni C, Renna L, Gradoni P, Barbieri V
2012 Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature. Thyroid 22:911-917. 5. Barczynski M, Konturek A, Stopa M, Nowak W 2013 Prophylactic central neck
dissection for papillary thyroid cancer. Br J Surg 100:410-418.
Page 18 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
18
6. Kihara M, Miyauchi A, Yabuta T, Higashiyama T, Fukushima M, Ito Y, Kobayashi K,
Miya A 2014 Outcome of vocal cord function after partial layer resection of the recurrent laryngeal nerve in patients with invasive papillary thyroid cancer. Surgery 155:184-189. 7. Ejnell H, Mansson I, Hallén O, Bake B, Stenborg R, Lindström J 1984 A simple
operation for bilateral vocal cord paralysis. Laryngoscope 94:954-958. 8. Hotomi M, Sugitani I, Toda K, Kawabata K, Fujimoto Y 2012 A novel definition of
extrathyroidal invasion for patients with papillary thyroid carcinoma for predicting prognosis. World J Surg 36:1231-1240. 9. McCaffrey JC 2006 Aerodigestive tract invasion by well-differentiated thyroid
carcinoma: diagnosis, management, prognosis, and biology. Laryngoscope 116:1-11. 10. Czaja JM, McCaffrey TV 1997 The surgical management of laryngotracheal invasion
by well-differentiated papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 123:484-490. 11. McCaffrey JC 2000 Evaluation and treatment of aerodigestive tract invasion by
well-differentiated thyroid carcinoma. Cancer Control 7:246-252. 12. Ark N, Zemo S, Nolen D, Holsinger FC, Weber RS 2008 Management of locally
invasive well-differentiated thyroid cancer. Surg Oncol Clin N Am 17:145-155, ix.
Page 19 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
19
13. Patel KN, Shaha AR 2005 Locally advanced thyroid cancer. Curr Opin Otolaryngol
Head Neck Surg 13:112-116. 14. Martins AS, Melo GM, Valerio JB, Langner E, Lage HT, Tincani AJ 2001 Treatment of
locally aggressive well-differentiated thyroid cancer. Int Surg 86:213-219. 15. McCaffrey TV, Bergstralh EJ, Hay ID 1994 Locally invasive papillary thyroid
carcinoma: 1940-1990. Head Neck 16:165-172. 16. Ito Y, Kihara M, Takamura Y, Kobayashi K, Miya A, Hirokawa M, Miyauchi A 2012
Prognosis and prognostic factors of papillary thyroid carcinoma in patients under 20 years. Endocr J 59:539-545. 17. Roh JL, Yoon YH, Park CI 2009 Recurrent laryngeal nerve paralysis in patients with
papillary thyroid carcinomas: evaluation and management of resulting vocal dysfunction. Am J Surg 197:459-465. 18. Machens A, Hinze R, Lautenschlager C, Thomusch O, Dralle H 2001 Thyroid
carcinoma invading the cervicovisceral axis: routes of invasion and clinical implications. Surgery 129:23-28. 19. Amini
K, Frank DK 2007 True vocal fold immobility in the setting of
well-differentiated thyroid carcinoma: unusual illustrative cases and recommendations for operative strategy. Ann Otol Rhinol Laryngol 116:324-328.
Page 20 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
20
20. Lang BH, Lo CY, Wong KP, Wan KY 2013 Should an involved but functioning
recurrent laryngeal nerve be shaved or resected in a locally advanced papillary thyroid carcinoma? Ann Surg Oncol 20:2951-2957. 21. Nishida T, Nakao K, Hamaji M, Kamiike W, Kurozumi K, Matsuda H 1997
Preservation of recurrent laryngeal nerve invaded by differentiated thyroid cancer. Ann Surg 226:85-91. 22. Aynehchi BB, McCoul ED, Sundaram K 2010 Systematic review of laryngeal
reinnervation techniques. Otolaryngol Head Neck Surg 143:749-759. 23. Miyauchi A, Inoue H, Tomoda C, Fukushima M, Kihara M, Higashiyama T, Takamura
Y, Ito Y, Kobayashi K, Miya A 2009 Improvement in phonation after reconstruction of the recurrent laryngeal nerve in patients with thyroid cancer invading the nerve. Surgery 146:1056-1062. 24. Sanuki T, Yumoto E, Minoda R, Kodama N 2010 The role of immediate recurrent
laryngeal nerve reconstruction for thyroid cancer surgery. J Oncol 2010:846235. 25. Isshiki N 2000 Progress in laryngeal framework surgery. Acta Otolaryngol
120:120-127. 26. Isshiki N, Tanabe M, Sawada M 1978 Arytenoid adduction for unilateral vocal cord
paralysis. Arch Otolaryngol 104:555-558.
Page 21 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
21
27. Moreno MA, Edeiken-Monroe BS, Siegel ER, Sherman SI, Clayman GL 2012 In
papillary thyroid cancer, preoperative central neck ultrasound detects only macroscopic surgical disease, but negative findings predict excellent long-term regional control and survival. Thyroid 22:347-355. 28. Mulla M, Schulte KM 2012 Central cervical lymph node metastases in papillary thyroid
cancer: a systematic review of imaging-guided and prophylactic removal of the central compartment. Clin Endocrinol (Oxf) 76:131-136. 29. Lee DW, Ji YB, Sung ES, Park JS, Lee YJ, Park DW, Tae K 2013 Roles of
ultrasonography and computed tomography in the surgical management of cervical lymph node metastases in papillary thyroid carcinoma. Eur J Surg Oncol 39:191-196. 30. Hwang HS, Orloff LA 2011 Efficacy of preoperative neck ultrasound in the detection of
cervical lymph node metastasis from thyroid cancer. Laryngoscope 121:487-491. 31. Choi YJ, Yun JS, Kook SH, Jung EC, Park YL 2010 Clinical and imaging assessment
of cervical lymph node metastasis in papillary thyroid carcinomas. World J Surg 34:1494-1499. 32. Kamani D, Randolph GW 2013 Electrophysiologic monitoring characteristics of the
recurrent laryngeal nerve preoperatively paralyzed or invaded with malignancy. Otolaryngol Head Neck Surg 149:682-688.
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33. Hirata K 1992 Relationship between the recurrent laryngeal nerve and the inferior
thyroid artery in Japanese. Kaibogaku Zasshi 67:634-641. 34. Makay O, Icoz G, Yilmaz M, Akyildiz M, Yetkin E 2008 The recurrent laryngeal nerve
and the inferior thyroid artery--anatomical variations during surgery. Langenbecks Arch Surg 393:681-685.
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Tables Table 1: Baseline patient characteristics
Age (years) Male
LNM invasion
Primary invasion
(n = 38)
(n = 112)
55 ±14
59 ±19
14
26
Sex
p = 0.15
p = 0.10 Female
24
86
Well
34
99
Differentiation
p = 0.86 Poor
4
13
T1
13 (34%)
T2
5 (13%)
T3
8 (21%)
T4
12 (32%)
T stage
N0 Central
112 12 (11%)
5 (13%)
10 (9%)
LNM
p = 0.08 Ipsilateral
16 (42%)
56 (50%)
Bilateral
17 (45%)
34 (30%)
Abbreviations: LNM invasion, the invasion from lymph node metastases group;
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Primary invasion, the invasion from primary tumors group; LMN, 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
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Table 2: Surgical methods of RLN invasion for each group
LNM invasion (n = 40)
Primary invasion (n = 117) 25 (21.4%) Resection Partial layer resection Reconstruction
5 (12.5%) 11 (27.5%) 24 (60%)
22 (18.8%) 70 (59.8%)
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve
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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
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve; RLN– RLN, primary RLN anastomosis; Ansa–RLN, ansa cervicalis-to-RLN anastomosis; Implantation, RLN to RLN or ansa cervicalis-to-RLN with neural implantation
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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
Abbreviations: LNM, Lymph node metastasis; RLN, recurrent laryngeal nerve
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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
Abbreviation: RLN, recurrent laryngeal nerve
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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)
Right
28 (70%)
54 (46.2%)
Left
12 (30%)
63 (53.8%)
With paralysis
13 (32.5%)
68 (58.5%)#
Laterality*
Condition* Without paralysis 27 (67.5%)
48 (41.5%)
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve 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.
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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
Right
28
10 (35.7%)
18 (63.4%)
Left
12
3 (25%)
9 (75%)
21 ±8 mm
14 ±7 mm
Laterality
LN size*
Abbreviations: LN, lymph node; RLN, recurrent laryngeal nerve 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.
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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
Abbreviations: LN, lymph node
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Title Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma
Sueyoshi Moritani, MD Center for Head and Neck Surgery, Kusatsu General Hospital 1660 Yabase Cho, Kusatsu, Shiga 5258585, Japan E-mail: [email protected]
Running title: LNM with RLN invasion in PTC
Key words: Recurrent laryngeal nerve invasion, lymph node metastases, primary tumor invasion, laterality, preoperative vocal cord paralysis
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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
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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 indicated 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, was 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
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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.
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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
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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 less than 0.05. Commercially available software (Ekuseru-Toukei 2012; SSRI Co., Ltd., Tokyo, Japan)
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was used to perform all statistical analyses.
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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). 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). Of 33 nerves receiving RLN partial layer resection, 15 (45%) were preserved or had recovery from temporal vocal cord paralysis, whereas RLN paralysis was
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observed in 18 (55%) (Table 4). Bilateral RLN invasion affected 10 patients, including 2 infiltrated by bilateral LNM, 5 by primary tumors, and 3 by both LNM and primary tumors. Six patients underwent immediate RLN reconstruction; 2 had bilateral RLN resection, whereas partial layer resection and RLN reconstruction were performed in 2. Only the two patients with partial layer resection experienced recovery from temporal vocal cord paralysis and had their stoma closed, while the other 8 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). 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 (Chi-square test, p = 0.0091) and preoperative
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conditions of patients with RLN paralysis (Chi-square test, p = 0.0044) were observed between the two groups (Table 6). 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 (Mann-Whitney U-test, 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 3 (25%) in the left side. There was no significant difference in laterality of RLN invasion with or without vocal cord paralysis by LNM (Chi-square test, 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 14mm for both right and left side. Therefore, no significant difference was observed in the size of metastatic lymph nodes in cases without RLN paralysis (Mann- Whitney U-test, p = 0.957) (Table 8).
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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
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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
muscle-nerve-muscle
RLN
pedicle,
anastomosis,
ansa-to-RLN
ansa-to-thyroarytenoid
neural
with
cricothyroid
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
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conclusive diagnosis in cases without paralysis is reportedly challenging (27–31). In our study, the diagnostic accuracy of pre-operative 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 1 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 occurr 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
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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, towards 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 fully clarify the clinical implications of RLN invasion by LNM, especially of its laterality.
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Disclosure statement
No competing financial interests exist.
Address correspondence to: Sueyoshi Moritani, MD
Center for Head and Neck Surgery, Kusatsu General Hospital
1660 Yabase Cho, Kusatsu, Shiga 5258585, Japan
E-mail: [email protected]
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References 1. Zaydfudim V, Feurer ID, Griffin MR, Phay JE 2008 The impact of lymph node
involvement on survival in patients with papillary and follicular thyroid carcinoma. Surgery 144:1070-1077; discussion 1077-1078. 2. Sadowski BM, Snyder SK, Lairmore TC 2009 Routine bilateral central lymph node
clearance for papillary thyroid cancer. Surgery 146:696-703; discussion 703-695. 3. Carling T, Carty SE, Ciarleglio MM, Cooper DS, Doherty GM, Kim LT, Kloos RT,
Mazzaferri EL, Sr., Peduzzi PN, Roman SA, Sippel RS, Sosa JA, Stack BC, Jr., Steward DL, Tufano RP, Tuttle RM, Udelsman R, American Thyroid Association Surgical Affairs C 2012 American Thyroid Association design and feasibility of a prospective randomized controlled trial of prophylactic central lymph node dissection for papillary thyroid carcinoma. Thyroid 22:237-244. 4. Giordano D, Valcavi R, Thompson GB, Pedroni C, Renna L, Gradoni P, Barbieri V
2012 Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature. Thyroid 22:911-917. 5. Barczynski M, Konturek A, Stopa M, Nowak W 2013 Prophylactic central neck
dissection for papillary thyroid cancer. Br J Surg 100:410-418.
Page 18 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
18
6. Kihara M, Miyauchi A, Yabuta T, Higashiyama T, Fukushima M, Ito Y, Kobayashi K,
Miya A 2014 Outcome of vocal cord function after partial layer resection of the recurrent laryngeal nerve in patients with invasive papillary thyroid cancer. Surgery 155:184-189. 7. Ejnell H, Mansson I, Hallén O, Bake B, Stenborg R, Lindström J 1984 A simple
operation for bilateral vocal cord paralysis. Laryngoscope 94:954-958. 8. Hotomi M, Sugitani I, Toda K, Kawabata K, Fujimoto Y 2012 A novel definition of
extrathyroidal invasion for patients with papillary thyroid carcinoma for predicting prognosis. World J Surg 36:1231-1240. 9. McCaffrey JC 2006 Aerodigestive tract invasion by well-differentiated thyroid
carcinoma: diagnosis, management, prognosis, and biology. Laryngoscope 116:1-11. 10. Czaja JM, McCaffrey TV 1997 The surgical management of laryngotracheal invasion
by well-differentiated papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 123:484-490. 11. McCaffrey JC 2000 Evaluation and treatment of aerodigestive tract invasion by
well-differentiated thyroid carcinoma. Cancer Control 7:246-252. 12. Ark N, Zemo S, Nolen D, Holsinger FC, Weber RS 2008 Management of locally
invasive well-differentiated thyroid cancer. Surg Oncol Clin N Am 17:145-155, ix.
Page 19 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
19
13. Patel KN, Shaha AR 2005 Locally advanced thyroid cancer. Curr Opin Otolaryngol
Head Neck Surg 13:112-116. 14. Martins AS, Melo GM, Valerio JB, Langner E, Lage HT, Tincani AJ 2001 Treatment of
locally aggressive well-differentiated thyroid cancer. Int Surg 86:213-219. 15. McCaffrey TV, Bergstralh EJ, Hay ID 1994 Locally invasive papillary thyroid
carcinoma: 1940-1990. Head Neck 16:165-172. 16. Ito Y, Kihara M, Takamura Y, Kobayashi K, Miya A, Hirokawa M, Miyauchi A 2012
Prognosis and prognostic factors of papillary thyroid carcinoma in patients under 20 years. Endocr J 59:539-545. 17. Roh JL, Yoon YH, Park CI 2009 Recurrent laryngeal nerve paralysis in patients with
papillary thyroid carcinomas: evaluation and management of resulting vocal dysfunction. Am J Surg 197:459-465. 18. Machens A, Hinze R, Lautenschlager C, Thomusch O, Dralle H 2001 Thyroid
carcinoma invading the cervicovisceral axis: routes of invasion and clinical implications. Surgery 129:23-28. 19. Amini
K, Frank DK 2007 True vocal fold immobility in the setting of
well-differentiated thyroid carcinoma: unusual illustrative cases and recommendations for operative strategy. Ann Otol Rhinol Laryngol 116:324-328.
Page 20 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
20
20. Lang BH, Lo CY, Wong KP, Wan KY 2013 Should an involved but functioning
recurrent laryngeal nerve be shaved or resected in a locally advanced papillary thyroid carcinoma? Ann Surg Oncol 20:2951-2957. 21. Nishida T, Nakao K, Hamaji M, Kamiike W, Kurozumi K, Matsuda H 1997
Preservation of recurrent laryngeal nerve invaded by differentiated thyroid cancer. Ann Surg 226:85-91. 22. Aynehchi BB, McCoul ED, Sundaram K 2010 Systematic review of laryngeal
reinnervation techniques. Otolaryngol Head Neck Surg 143:749-759. 23. Miyauchi A, Inoue H, Tomoda C, Fukushima M, Kihara M, Higashiyama T, Takamura
Y, Ito Y, Kobayashi K, Miya A 2009 Improvement in phonation after reconstruction of the recurrent laryngeal nerve in patients with thyroid cancer invading the nerve. Surgery 146:1056-1062. 24. Sanuki T, Yumoto E, Minoda R, Kodama N 2010 The role of immediate recurrent
laryngeal nerve reconstruction for thyroid cancer surgery. J Oncol 2010:846235. 25. Isshiki N 2000 Progress in laryngeal framework surgery. Acta Otolaryngol
120:120-127. 26. Isshiki N, Tanabe M, Sawada M 1978 Arytenoid adduction for unilateral vocal cord
paralysis. Arch Otolaryngol 104:555-558.
Page 21 of 31
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
21
27. Moreno MA, Edeiken-Monroe BS, Siegel ER, Sherman SI, Clayman GL 2012 In
papillary thyroid cancer, preoperative central neck ultrasound detects only macroscopic surgical disease, but negative findings predict excellent long-term regional control and survival. Thyroid 22:347-355. 28. Mulla M, Schulte KM 2012 Central cervical lymph node metastases in papillary thyroid
cancer: a systematic review of imaging-guided and prophylactic removal of the central compartment. Clin Endocrinol (Oxf) 76:131-136. 29. Lee DW, Ji YB, Sung ES, Park JS, Lee YJ, Park DW, Tae K 2013 Roles of
ultrasonography and computed tomography in the surgical management of cervical lymph node metastases in papillary thyroid carcinoma. Eur J Surg Oncol 39:191-196. 30. Hwang HS, Orloff LA 2011 Efficacy of preoperative neck ultrasound in the detection of
cervical lymph node metastasis from thyroid cancer. Laryngoscope 121:487-491. 31. Choi YJ, Yun JS, Kook SH, Jung EC, Park YL 2010 Clinical and imaging assessment
of cervical lymph node metastasis in papillary thyroid carcinomas. World J Surg 34:1494-1499. 32. Kamani D, Randolph GW 2013 Electrophysiologic monitoring characteristics of the
recurrent laryngeal nerve preoperatively paralyzed or invaded with malignancy. Otolaryngol Head Neck Surg 149:682-688.
Page 22 of 31
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33. Hirata K 1992 Relationship between the recurrent laryngeal nerve and the inferior
thyroid artery in Japanese. Kaibogaku Zasshi 67:634-641. 34. Makay O, Icoz G, Yilmaz M, Akyildiz M, Yetkin E 2008 The recurrent laryngeal nerve
and the inferior thyroid artery--anatomical variations during surgery. Langenbecks Arch Surg 393:681-685.
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Tables Table 1: Baseline patient characteristics
Age (years) Male
LNM invasion
Primary invasion
(n = 38)
(n = 112)
55 ±14
59 ±19
14
26
Sex
p = 0.15
p = 0.10 Female
24
86
Well
34
99
Differentiation
p = 0.86 Poor
4
13
T1
13 (34%)
T2
5 (13%)
T3
8 (21%)
T4
12 (32%)
T stage
N0 Central
112 12 (11%)
5 (13%)
10 (9%)
LNM
p = 0.08 Ipsilateral
16 (42%)
56 (50%)
Bilateral
17 (45%)
34 (30%)
Abbreviations: LNM invasion, the invasion from lymph node metastases group;
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Primary invasion, the invasion from primary tumors group; LMN, 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
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 25 of 31
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Table 2: Surgical methods of RLN invasion for each group
LNM invasion (n = 40)
Primary invasion (n = 117) 25 (21.4%) Resection Partial layer resection Reconstruction
5 (12.5%) 11 (27.5%) 24 (60%)
22 (18.8%) 70 (59.8%)
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve; RLN– RLN, primary RLN anastomosis; Ansa–RLN, ansa cervicalis-to-RLN anastomosis; Implantation, RLN to RLN or ansa cervicalis-to-RLN with neural implantation
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 27 of 31
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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
Abbreviations: LNM, Lymph node metastasis; RLN, recurrent laryngeal nerve
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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
Abbreviation: RLN, recurrent laryngeal nerve
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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)
Right
28 (70%)
54 (46.2%)
Left
12 (30%)
63 (53.8%)
With paralysis
13 (32.5%)
68 (58.5%)#
Laterality*
Condition* Without paralysis 27 (67.5%)
48 (41.5%)
Abbreviations: LNM, lymph node metastasis; RLN, recurrent laryngeal nerve 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.
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Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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
Right
28
10 (35.7%)
18 (63.4%)
Left
12
3 (25%)
9 (75%)
21 ±8 mm
14 ±7 mm
Laterality
LN size*
Abbreviations: LN, lymph node; RLN, recurrent laryngeal nerve 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.
Thyroid Impact of lymph node metastases with recurrent laryngeal nerve invasion on patients with papillary thyroid carcinoma (doi: 10.1089/thy.2014.0152) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 31 of 31
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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
Abbreviations: LN, lymph node
