Accepted 12 August 2013 Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed.23451

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1 ORIGINAL ARTICLE Risk factors and clinical indication of metastasis to lymph nodes posterior to right recurrent laryngeal nerve in papillary thyroid carcinoma: A single-center study in China Zhang Pinyi, MD, Zhang Bin, MD, PhD, * Bu Jianlong, MD, Liu Yao, MD, Zhang Weifeng, MD No. 4 Department of General Surgery, Second Hospital of Harbin Medical University, Harbin, China. Accepted 12 August 2013 Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Lymph nodes posterior to right recurrent laryngeal nerve (PRRLN) may be frequently overlooked during central compartment dissection (CCD) for papillary thyroid carcinoma (PTC). The purpose of this study was to investigate risk factors of lymph node PRRLN metastasis in right-sided PTC, thereby to identify the indications for lymph node PRRLN dissection. Methods. We conducted a retrospective study of patients with rightsided PTC who underwent a thyroidectomy plus lymph node PRRLN dissection during ipsilateral CCD. Results. Overall, 108 patients (26.7%) had lymph node PRRLN metastases, including 26 (6.4%) who presented with solely lymph node PRRLN positivity. Factors of extrathyroidal extension, multifocality, larger tumor (1 cm), level VIa positivity (p <.0001 for each), and lateral compartments positivity (p ) significantly predicted lymph node PRRLN metastasis in right-sided PTC. Conclusion. Lymph node PRRLN should be routinely explored during CCD because of the possibility of only involvement in PTC. Factors of tumors larger than 1 cm, multifocality, and extrathyroidal extension were independent predictors of lymph node PRRLN metastasis in right-sided PTC, and suggested the clinical indications of lymph node PRRLN dissection. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: papillary thyroid carcinoma (PTC), posterior to right recurrent laryngeal nerve (PRRLN), central compartment dissection (CCD), risk factors *Corresponding author: Z. Bin, No. 4 Department of General Surgery, Second Hospital of Harbin Medical University, Harbin/No.246 Xuefu Road, Nan gang District, Harbin, , China. zhangbinletter@yahoo.com.cn INTRODUCTION Papillary thyroid carcinoma (PTC) has a propensity for regional lymphatic spread with the central lymph node most frequently involved. 1 With recognition of the prognostic effect of central lymph node metastasis on locoregional recurrence and survival rate of PTC, 2 consideration of routine central compartment dissection (CCD) has been recommended in the revised guidelines by the American Thyroid Association in Similar to our hospital, routine CCD has been performed as the standard treatment for differentiated thyroid cancer in most hospitals in China and other eastern countries, such as Japan and Korea. However, there remains a common problem with the extent of nodal dissection. Recent studies have shown that the scope of surgery has a major effect on tumor recurrence and survival of PTC. 4,5 Thus, in order to achieve the best chance of cure and effective disease control, it is the thoroughness of dissection, not only the CCD itself, that has to be taken into account. A comprehensive CCD aims at removing all of the lymphatic and fibrofatty tissue within the space of the central neck compartment, which is defined as an area bounded by carotid arteries laterally, hyoid bone superiorly, and innominate artery or brachiocephalic vein inferiorly. 6 Unilaterally, an adequate CCD removes all the lymphatic tissue in the prelaryngeal (Delphian) and pretracheal basins, along with the 1-sided paratracheal basin. 6 Paratracheal lymph node, localizing along the tracheoesophageal groove, is situated in the juxtaposition with the origin of the recurrent laryngeal nerve (RLN), extending down to the rear of the innominate artery. Because of the anatomic differences between the course of right and left RLNs, dissection of paratracheal nodes differ slightly. On the right, paratracheal lymphatic tissues lie both anterior and posterior to the nerve, whereas no lymph nodes are present behind the left nerve. Hence, for a right-sided CCD to be comprehensive, the lymph node posterior to right recurrent laryngeal nerve (PRRLN) should also be removed. Unfortunately, these lymph nodes are overlooked very frequently during CCD. Most of the previous studies on lymph node PRRLN have been related to upper esophageal cancer, being regarded as part of the right RLN lymphatic chain. Lymph node PRRLN positivity in upper esophageal cancer has been demonstrated to be a predictor of early extensive or skip nodal metastases, higher risk of recurrence, and increased morbidity rate, which is of great value in determining the scope of surgery and assessing patient prognosis. In thyroid cancer, however, the clinical significance of lymph node PRRLN has been rarely studied. Therefore, we conducted this study to investigate the frequency and risk factors of lymph node PRRLN HEAD & NECK DOI /HED SEPTEMBER

2 PINYI ET AL. metastasis, thereby to identify the clinical indications for lymph node PRRLN dissection as part of routine CCD in patients with right-sided PTC. MATERIALS AND METHODS Patients A retrospective analysis was performed by using data prospectively collected from the clinical database of the Thyroid Surgery Department in Second Hospital of Harbin Medical University, and through a review of histopathology reports. The study cohort was composed of 405 consecutive patients scheduled to undergo initial surgery for primary PTC from January 2010 to June This study was approved by the Institutional Review Board of the Second Affiliated Hospital of Harbin Medical University. Informed written consent was obtained from all patients before the study. Preoperative examinations consisted of a thorough physical examination, neck ultrasound, and elastography, for a clinical evaluation of thyroid nodules and neck lymph nodes. Neck CT was performed to assess locoregional invasion. Also, blood samples were obtained before surgery to measure the levels of serum thyroid hormone free triiodothyronine and free thyroxine, thyroid stimulating hormone, thyroglobulin, and thyroglobulin antibodies. Vocal cord function was obtained by direct or indirect laryngoscopy. Intraoperative frozen section biopsy was routinely performed to make a diagnosis. With a pathological confirmation of PTC, all the patients received a thyroidectomy with ipsilateral CCD. At the time of initial surgery, a thyroidectomy was performed on the affected lobe diagnosed by the intraoperative frozen section biopsy. Meanwhile, clinical N classification of each patient was determined through the radiological and operative findings suggestive of lymphatic spread. According to the 6th edition of the TNM system, 7 clinical lymph node metastasis of PTC was classified into 3 classifications. Clinically nodenegative (cn0) was defined as no evidence of lymph node metastasis in the central and bilateral lateral compartments on ultrasound. Clinically node-positive (cn1) was defined as suspicious lymph node metastasis in the ipsilateral or contralateral cervical compartment or both, including cn1a for central compartment involved and cn1b for lateral compartment involved. Accordingly, a prophylactic CCD was performed for cn0 patients, and a therapeutic CCD was performed for cn1 patients. In addition, modified radical neck dissection was also selectively performed for cn1b patients. Surgical approach of central lymph node dissection All the operations were performed by the same panel of senior surgeons, with the patients under general anesthesia. Thyroidectomy was performed with a standard technique of fine capsular dissection. RLNs and all parathyroid glands were routinely identified and preserved under direct vision. Any parathyroid gland at risk of viability was excised to mince into several tiny cubes and autotransplanted in the sternocleidomastoid muscle. In the right-sided central compartment, the paratracheal region was divided into an anterior and a posterior subsite by RLN. Level VIa was defined as the right prelaryngeal/ pretracheal, perithyroidal, and anterior paratracheal region. Level VIb was defined as the right posterior paratracheal region alone, namely lymph node PRRLN. Consequently, the right CCD was slightly altered on the basis of the conventional method. Instead of en bloc resection of the entire central lymph nodes, we performed a separated CCD with respect to the sublevels. In this way, the prelaryngeal nodes were removed at the time of isthmectomy or removal of the pyramidal lobe to which the prelaryngeal nodes normally attach. The pretracheal lymphatic tissue was then resected off the tracheal surface down to the level of the brachiocephalic artery. Simultaneously, removal of the perithyroidal nodes was also done during thyroidectomy. At the time when the thyroidectomy was finished, approximately half of the process of CCD had been finished. Afterward, we continued with removing the paratracheal nodes. The dissection of the lymphatic tissue superficial and deep to the nerve included 2 steps with a technique of atraumatic mobilization. Our preference was to remain on the patient s head and to perform paratracheal dissection in a craniocaudal direction. We normally started inferiorly by freeing the deep aspect of the thymic remnant. Then, with the anterior boundary opened, the dissection was performed laterally along the common carotid artery down to the level of innominate vessels. Medially, we retracted the larynx and trachea contralaterally and superiorly to offer an adequate exposure and visualization, the surgeon then used a fine tipped dissector to separate the paratracheal lymphatic tissue from the RLN along the tracheoesophageal groove. Once the superficial lymphatic tissue was freed laterally, medially, and deeply, it was then removed, along with the superior mediastinal nodes and partial thymus. Subsequently, dissection was carried deeply to the esophagus and prevertebral fascia, and the remaining paratracheal tissue was peripherally mobilized from posterior to anterior, transposing from the medial aspects of the nerve (Figure 1). In this fashion, the deep tissue was entirely dissected away from the RLN, without direct retraction or using a nerve hook, thereby to avoid unnecessary manipulation of the nerve (Figure 2). Histopathologic examination All thyroid tumors were confirmed to be primary PTC by paraffin biopsy, in accord with intraoperative frozen section biopsy. For multifocal tumors, the tumor with the largest diameter was chosen as the dominant tumor. All removed lymph nodes were identified according to neck levels and sublevels. CCD specimens were marked and separately removed for histopathology assessment, while the nodal specimens (levels II V) from modified radical neck dissection were assessed altogether as an entirety. All the histopathology examinations were undertaken by the same 2 senior pathologists in a standardized fashion. Clinicopathologic factors for analysis Clinicopathologic variables were prospectively documented. Factors analyzed for association with lymph node PRRLN positivity were divided into 2 sets of variables based on the treatment periods. Clinical factors from 1336 HEAD & NECK DOI /HED SEPTEMBER 2014

3 METASTASIS TO LYMPH NODES POSTERIOR TO RIGHT RECURRENT LARYNGEAL NERVE node metastasis and the number of positive nodes in the level VIa and lateral compartments. FIGURE 1. Schematic representation of lymph node posterior to right recurrent laryngeal nerve (PRRLN; level VIb) dissection during the right-sided central compartment dissection (CCD),! recurrent laryngeal nerve (RLN), W trachea, and $ lymph node PRRLN. The anterior lymph nodes compartment (level VIa) was dissected after identification of RLN. By intraoperative exploration, lymphatic fibrofatty tissue posterior to the nerve (level VIb) likely harboring disease had been partially dissected from the nerve and gently pulled upward. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] preoperative and intraoperative evaluation contained the patient s sex, age at diagnosis, clinical N classification, type of surgery, thyroid function, and coexistent thyroid disease. Histopathologic factors from postoperative pathology examination included tumor focality, (dominant) tumor size, site, laterality, histologic variants, and extrathyroidal extension, as well as the overall lymph Statistics Statistical analysis was conducted by SPSS version 17.0 for Windows (SPSS, Chicago, IL). All variables were summarized in frequency tables by lymph node PRRLN status. Associations of variables with lymph node PRRLN positivity were estimated by univariate analysis, using the Pearson chi-square test or the Fisher exact test for categorical variables, and independent samples t test or the Mann Whitney U test for continuous variables. All the significant factors from univariate analysis were incorporated into multivariate analysis. Binary logistic regression was used to identify independent predictors of positive lymph node PRRLN in all patient populations and repeated in a subgroup of cn0 patients. Statistical significance implies p values of <.05. RESULTS Patients characteristics A total of 405 patients who had initial surgery for PTC were included in this study. There were 90 men and 315 women, with a mean age of 44.8 years (range, years) at the first diagnosis. Most of the patients had normal thyroid functions, except for 32 with hyperthyroidism and 45 with hypothyroidism. No patient was found to have vocal cord paralysis on laryngoscopy. All patients were diagnosed with primary PTC by frozen section biopsy during surgery, also, concomitant thyroid diseases were found in 109 patients. Overall, a total thyroidectomy with bilateral CCD was performed in 171 cases, and a right lobectomy (an isthmectomy or/and pyramidal lobe FIGURE 2. The surgical field after lymph node posterior to right recurrent laryngeal nerve (PRRLN; level VIb) dissection during the right-sided central compartment dissection (CCD)! recurrent laryngeal nerve (RLN), W trachea, and $ lymph node PRRLN. The right paratracheal nodes have been resected superficially and deep to the RLN. (A) The fibrofatty lymph node-bearing tissue of the paratracheal space is marked with the dotted line. (B) The part within the dashed box is magnified to show the detailed anatomic structure of level VIb. The right common carotid artery was retracted laterally with a long-arm retractor. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com] HEAD & NECK DOI /HED SEPTEMBER

4 PINYI ET AL. TABLE 1. Demographics and clinical characteristics of papillary thyroid carcinoma (n 5 405). Variables No. of patients (%) Mean age, y Age at diagnosis (44.9) < (55.1) Sex Male 90 (22.2) Female 315 (77.8) Type of thyroid excision RL 216 (53.3) BST 18 (4.4) TT 171 (42.2) Clinical N classification cn0 285 (70.4) cn1a 53 (13.1) cn1b 67 (16.5) Type of neck dissection Prophylactic CLND 285 (70.4) Therapeutic CLND 120 (29.6) Modified radical neck dissection 67 (16.5) Thyroid function Euthyroidism 338 (83.5) Hyperthyroidism 32 (7.9) Hypothyroidism 45 (11.1) Coexistent thyroid disease Nodular goiter 90 (22.2) Toxic goiter 6 (1.5) Hashimoto s disease 23 (5.7) Absent 286 (70.6) Abbreviations: RL, right lobectomy (an isthmus or/and a pyramidal lobe included); BST, bilateral subtotal thyroidectomy; TT, total thyroidectomy; CLND, central lymph node dissection. included) with right CCD was performed in 216 cases. For the rest of the 18 patients with isthmic tumors, a subtotal thyroidectomy (an isthmectomy included) with bilateral CCD was performed. According to clinical N classification, the procedure of CCD was prophylactic in 285 cn0 patients and therapeutic in 120 cn1 patients. In addition, 67 (cn1b) of the cn1 patients also underwent ipsilateral modified radical neck dissection during the same procedure as the thyroidectomy. The demographics and clinical characteristics are listed in Table 1. Frequency and distribution of lymph node metastasis Table 2 shows the histopathologic characteristics of the tumors and lymph nodes. On postoperative pathology examination, 50.1% of all patients (203 of 405) had lymph node metastasis in the central compartment. Level VIa positivity and level VIb positivity were encountered in 176 patients (43.5%; 176 of 405) and 108 patients (26.7%; 108 of 405) patients, respectively. The mean number of positive nodes in level VIa (n ) was a little more than that in level VIb (n ). In addition, 62.7% of the patients (42 of 67) who underwent modified radical neck dissection were found to have metastatic nodes in lateral compartments, approximately with 5 positive nodes on average. Overall, a total of 7 patterns of lymphatic spread were observed in the patient population TABLE 2. Histopathologic characteristics of papillary thyroid carcinoma (n 5 405). Characteristics No. of patients (%) Tumor Tumor size 1.0 cm 180 (44.4) <1.0 cm 225 (55.6) Tumor focality Multifocality 108 (26.7) Unifocality 297 (73.3) Tumor site Upper one-third 36 (8.9) Middle one-third 172 (42.5) Lower one-third 197 (48.6) Tumor laterality Right lobe 216 (53.3) Isthmus 18 (4.4) Both lobes 171 (42.2) Histologic variants Classic 324 (80) Follicular 45 (11.1) Diffuse sclerosis 28 (6.9) Oncocytic 8 (2.0) Extrathyroidal extension Present 46 (11.4) Absent 359 (88.6) Lymph nodes No. of patients (%) Overall lymph node metastasis Central compartment Level VIa 176 (43.5) Level VIb 108 (26.7) Lateral compartments Levels II V 42 (62.7) No. of resected nodes Mean (95% CI) Central compartment Level VIa 4.85 ( ) Level VIb 3.66 ( ) Lateral compartments Levels II V ( ) No. of positive nodes Mean (95% CI) Central compartment Level VIa 2.78 ( ) Level VIb 2.20 ( ) Lateral compartments Levels II V 5.15 ( ) Abbreviation: CI, confidence interval. (Table 3). Of note, 26 patients (6.4%; 26 of 405) were encountered with lymph node PRRLN metastases in absence of level VIa positivity. Skip lateral metastasis was found in only 1 patient (0.2%; 1 of 405). Predictors of lymph node metastasis posterior to right recurrent laryngeal nerve Initially, data from all patients were analyzed in comparison of positive and negative lymph node PRRLN. On univariate analysis, factors associated with lymph node PRRLN positivity are presented in Table 4, including tumor size, focality, and the presence of extrathyroidal extension. More specifically, patients with larger tumors (1 cm) were more likely to develop lymphatic dissemination to lymph node PRRLN than those who had smaller 1338 HEAD & NECK DOI /HED SEPTEMBER 2014

5 METASTASIS TO LYMPH NODES POSTERIOR TO RIGHT RECURRENT LARYNGEAL NERVE TABLE 3. Patterns and distribution of cervical nodes metastases. Metastatic pattern No. of patients (%) Level VIa 83 (20.5) Level VIa 1 level VIb 53 (13.1) Level VIb 26 (6.4) Level VIa 1 levels II V 12 (3.0) Level Via 1 level VIb 1 level II V 28 (6.4) Level VIb 1 levels II V 1 (0.2) Levels II V 1 (0.2) Note: There are no overlapping numbers among each pattern. carcinomas (42.8% vs 13.8%; p <.0001). This was also true for tumor focality, when comparing multifocal tumors with solitary tumors (50% vs 18.2%; p <.0001). Additionally, the presence of extrathyroidal extension was another parameter that significantly increased the risk of lymph node PRRLN metastasis than intrathyroidal lesions (78.3% vs 20.1%; p <.0001). Conversely, factors including tumor site, laterality, histologic variants, coexistent thyroid disease, and thyroid function all had no significant influence on lymph node PRRLN status (p >.05 for each factor). Likewise, in terms of demographic factors, neither the patients age (p 5.567) nor sex (p 5.058) TABLE 4. Univariate analysis of demographic and clinicopathologic factors for lymph node posterior to right recurrent laryngeal nerve positivity. No. of patients (%) by lymph node PRRLN status Variables Negative (n 5 297) Positive (n 5 108) Chi-square p value Age, y (45.8) 46 (42.3) < (54.2) 62 (57.4) Sex Male 59 (19.9) 31 (28.7) Female 238 (80.1) 77 (71.3) Clinical N classification cn0 221 (74.4) 65 (60.2) cn1a 38 (12.8) 15 (13.9) cn1b 38 (12.8) 28 (25.9) Thyroid function Euthyroidism 241 (81.1) 97 (89.8) Hyperthyroidism 27 (9.1) 5 (4.6) Hypothyroidism 29 (9.8) 6 (5.6) Coexistent thyroid disease Nodular goiter 72 (24.2) 18 (16.7) Toxic goiter 2 (0.7) 4 (3.7) Hashimoto s disease 18 (6.1) 5 (4.6) Absent 205 (69.0) 81 (75.0) Tumor size < cm 103 (34.7) 77 (71.3) <1.0 cm 194 (65.3) 31 (28.7) Tumor focality <.0001 Multifocality 54 (18.2) 54 (50) Unifocality 243 (81.8) 54 (50) Tumor laterality Right lobe 153 (51.5) 63 (58.3) Isthmus 14 (4.7) 4 (3.7) Both lobes 130 (43.8) 41 (38.0) Tumor site Upper one-third 19 (6.4) 17 (15.7) Middle one-third 134 (45.1) 38 (35.2) Lower one-third 143 (48.1) 54 (50) Histologic variant Classic 247 (83.2) 77 (71.3) Follicular 29 (9.8) 16 (14.8) Diffuse sclerosis 16 (5.4) 12 (11.1) Oncocytic 5 (1.6) 3 (2.8) Extrathyroidal extension <.0001 Present 10 (3.4) 36 (33.3) Absent 287 (96.6) 72 (66.7) Lymphatic invasion Level VIa positivity 113 (38.0) 63 (58.3) <.0001 Lateral compartments positivity 13 (4.4) 29 (26.9) <.0001 No. of positive nodes Mean (95% CI) Level VIa 2.08 ( ) 4.34 ( ) <.0001 Lateral compartments 0.98 (0 2.03) 4.96 ( ) <.0001 Abbreviation: CI, confidence interval. HEAD & NECK DOI /HED SEPTEMBER

6 PINYI ET AL. produced differential rates of lymph node PRRLN metastasis. Among lymph node factors, univariate analysis demonstrated that lymph node PRRLN positivity was significantly associated with nodal involvement in level VIa (35.8% vs 19.7%; p <.0001) and in lateral compartments (69.0% vs 21.8%; p <.0001). Also, the positive lymph node PRRLN group had, on average, more metastatic nodes in level VIa (p <.0001) and in lateral compartments (p <.0001) than the negative group. Further, from all significant factors in univariate analysis, multivariate analysis using logistic regression revealed that tumors larger than 1 cm (p <.0001; odds ratio [OR] 5 4.3; 95% [CI] ), multifocality (p <.0001; OR 5 4.4; 95% CI ), the presence of extrathyroidal extension (p <.0001; OR 5 21; 95% CI ), level VIa positivity (p <.0001; OR 5 4.2; 95% CI ), and lateral compartments positivity (p ; OR 5 5.4; 95% CI ) to be significantly predictive of lymph node PRRLN metastasis (Table 5). Surgical complications A total of 5 postoperative complications relating to lymph node PRRLN dissection were registered in 17 patients (4.2%). RLN injury occurred in 4 patients (1.0%) all unilateral involved, who developed transient nerve palsy and showed complete recovery after 3 to 16 weeks. Hypoparathyroidism occurred in 7 patients (1.7%) with transient hypocalcemia postoperatively, and the level of serum calcium returned to normal in 1 to 6 weeks. In addition to the 2 major surgical complications, another 2 patients (0.49%) had wound bleeding, and 2 patients (0.49%) had lymphorrhagia caused by injury of the right lymphatic duct. Horner syndrome was diagnosed in 1 case (0.25%). On univariate analysis, there was no difference between the patients with and without lymph node PRRLN metastasis. DISCUSSION The role of CCD in preventing nodal recurrence of PTC has been an ongoing debate. 8 However, there is now recent compelling data to suggest that the remaining metastatic nodes after initial insufficient CCD are the most common cause of recurrence in PTC. 9 Although surgical therapy has been widely regarded as definitive treatment for recurrent PTC, 10 should reoperation be obviated or reduced, this carries higher risks for hypoparathyroidism and RLN injury. Thus, a thorough resection of the lymphatic tissue in the central compartment may reduce the TABLE 5. Multivariate analysis of predictors for lymph node posterior to right recurrent laryngeal nerve positivity. Variables OR (95% CI) p value Clinical N classification Tumor size (1.0 cm) 4.3 ( ) <.0001 Multifocality 4.4 ( ) <.0001 Extrathyroidal extension 21.0 ( ) <.0001 Level VIa positivity 4.2 ( ) <.0001 Lateral compartment positivity 5.4 ( ).0002 Abbreviations: OR, odds ratio; CI, confidence interval. risks of recurrent or persistent disease through eliminating residual subclinical lymph node metastasis; alternatively, this could effectively minimize the treatment-related morbidity of central neck reoperation. Under such circumstances, attention needs to be directed toward the clinical significance of lymph node PRRLN, which has been frequently overlooked or unrecognized during the right CCD for PTC. The region of lymph node PRRLN was bordered by the junction of inferior thyroid artery and RLN superiorly, the innominate artery inferiorly, the esophagus medially, the carotid artery laterally, and the deep layer of prevertebral fascia dorsally. Although there is no special definition for these lymph nodes in consensus statement on the terminology and classification of neck dissection for thyroid carcinoma, 6 it has been mentioned that lymph nodes behind the right carotid artery should be removed together with the paratracheal nodes during CCD. Nevertheless, the surgical management of lymph node PRRLN for PTC remains unclarified. Consequently, it is imperative to investigate the incidence and predictors of lymph node PRRLN in PTC. In our study, central lymph node positivity was found in 50.1% of all patients (203 of 405), and 66 of them were suspected preoperatively by ultrasound examination. Thus, the predictive positive value of ultrasound N classification was just 32.5% for central lymph nodes, with a false-negative rate of 26.9%. Because of the limited sensitivity of ultrasound for central lymph node metastasis, prophylactic CCD was routinely performed in our center as part of the surgical protocol for PTC. However, ultrasound examination was normally applied to study lymphatic spread to the lateral neck compartment because of a relatively higher sensitivity. In this cohort, 67 patients with cn1b PTC received therapeutic CCD with selective modified radical neck dissection, and 62.7% (42 of 67) of them presented with lateral nodal positivity. According to the outcome of univariate analysis, we found a significant association of lymph node PRRLN metastasis with tumor size and focality, which agreed with the majority studies on central lymph node metastasis. 11 Conversely, Sadowski et al 12 has shown that tumor size was not a risk factor for central lymph node metastasis, and CCD was also recommended to be performed in patients with a PTC tumor smaller than 1 cm. Although our finding was inconsistent with this conclusion, we performed a routine CCD for patients with PTC regardless of the tumor size. Taken into a deep analysis, patients with lymph node PRRLN metastasis who had a smaller tumor were observed to have some features in common, including multifocality and bilateral involvement. This suggested that the 2 factors could possibly enhance the aggressiveness of PTC tumors smaller than 1 cm. As for the remaining solitary smaller tumors, lymph node PRRLN metastasis was probably because of more aggressive phenotype of PTC than these patients may have had. Numerous studies have shown the predictive value of tumor location in the pattern of lymph node metastasis of PTC. According to Zhang et al, 13 primary thyroid tumors originating from the upper lobe mostly had skip metastases in lateral lymph nodes without central nodal involvement, whereas tumors having lymph node metastasis in 1340 HEAD & NECK DOI /HED SEPTEMBER 2014

7 METASTASIS TO LYMPH NODES POSTERIOR TO RIGHT RECURRENT LARYNGEAL NERVE the central neck frequently aroused in the middle or lower lobe. In contrast, Roy et al 14 demonstrated that PTC metastasis would first occur in the RLN lymph nodes chain regardless of the characteristics of the primary tumor. On univariate analyses, we found that there was no association between lymph node PRRLN metastasis with neither tumor location (p 5.379) nor laterality (p 5.471). Another pathological factor of PTC identified to be associated with lymph node PRRLN positivity was the presence of extrathyroidal extension. As an indicator for tumor aggressiveness, the incidence of extrathyroidal extension in well-differentiated thyroid cancer varies in different series, ranging from 5% to 34%. 15 In our cohort, 11.4% of the patients (46 of 405) were observed to have extension of primary tumors, including gross invasion beyond the thyroid into surrounding structures, and microscopic spread out of capsule. Many studies have shown that patients with PTC with extrathyroidal extension had a significant risk of lymph node metastasis. 16 Likewise, in the present study, the incidence of extrathyroidal extension was significantly higher in patients with lymph node PRRLN metastasis than in patients without lymph node PRRLN involvement (33.3% vs 3.4%; p <.0001). In addition to pathological tumor factors, lymph node PRRLN positivity was also significantly associated with lymphatic invasion in level VIa and lateral neck compartments (p <.0001). In clinical factors, we found that only clinical N classification was a risk factor of lymph node PRRLN metastasis (p 5.005). On multivariate analysis, we found that the presence of extrathyroidal extension, tumors larger than 1 cm, multifocality, level VIa positivity, and lateral compartment positivity were independent predictors of lymph node PRRLN metastasis in PTC, but clinical N classification turned out not to be an independent risk factor for lymph node PRRLN positivity. It is noteworthy that overall, solely lymph node PRRLN metastasis is an epiphenomenon of low-intensity nodal disease in PTC. In this category, the presence of discontinuous central lymphatic dissemination was encountered in 26 patients, including 24 cn0 and 2 cn1 patients, and simultaneous lateral lymph node metastasis was found in 1 patient thereof. This suggested that PTC may spread only to the posterior compartment of paratracheal lymph nodes. Despite leaping the anterior compartment of the right paratracheal nodes, lymphatic spread only to lymph node PRRLN may not count as skip metastasis, anatomically because both the posterior and anterior regions of the right paratracheal nodes belong to the central neck compartment. In addition, most of these patients presented with a right-sided tumor larger than 2 cm, extrathyroidal extension, and upper third in the lobe. Although, in this study, there was no evidence of these features to be predictive solely for lymph node PRRLN metastasis in PTC, patients with these features were more likely to benefit from a lymph node PRRLN clearance in case of residual metastatic disease. Very few other studies have produced data on associations with lymph node PRRLN positivity in patients with PTC. To our knowledge, so far, there are only 4 related reports 17 (Table 6) with the lymph nodes deep to the right RLN called right paraesophageal lymph nodes. Unlike our study, Bae et al 18 and Kim and Park 19 defined right paraesophageal lymph nodes as an isolated region from the central compartment. The frequency of lymph node PRRLN positivity in our patient population was a little higher than the 4 previous studies. This may be because of some limitations in our sample selection, in that we excluded patients with tumors only involved in the left lobe. Notably, Kim and Park 19 found that right paraesophageal lymph nodes could be the solely metastatic region from PTC, which was supported by the evidence from both our study (6.4%; 26 of 405) and Bae et al. 18 Of interest, Kim and Park 19 also observed that 1 of the patients with PRRLN positivity had a tumor only in the left thyroid lobe, which thus indicated the necessity for routine detection of right paraesophageal lymph nodes TABLE 6. Summary of studies on right paraesophageal lymph nodes metastasis in papillary thyroid carcinoma. No. of patients by right paraesophageal lymph nodes positivity (%) Authors Patients Overall Solely metastasis Predictors (univariate analysis) Lee et al 17 N (cn0, cn1) right, left 14 (11.4) 0 Tumor size (>1 cm) Tumor site (right) fino. of central lymph node metastases fllateral lymph node metastasis Kim and Park 19 N (cn0, cn1) right, left, isthmus, both 14 (5.8) 2 (0.8) Tumor size (>1 cm) Tumor focality (multifocal) fiextrathyroidal extension fllymphatic invasion Bae et al 18 N (cn0, cn1) right, both 45 (12.2) 8 (2) Tumor size (>1 cm)* Perithyroidal extent ficentral lymph node metastasis* (No. >3) fllateral lymph node metastasis Ito et al 20 N (cn0) right 129 (14.0) 2 Pretracheal and right paratracheal lymph node metastasis Tumor size (2 cm)* fiextrathyroidal extension* * Independent predictors on multivariate analysis. HEAD & NECK DOI /HED SEPTEMBER

8 PINYI ET AL. during PTC surgery regardless of whether tumors were located in the right or left lobe. According to the review by Weber and Holsinger, 21 for a PTC tumor arising in 1 lobe of the thyroid, tumor emboli may traverse the subcapsular lymph nodes and consequently produce metastatic deposits in the contralateral lobe. Although contralateral metastasis of lymph node PRRLN had no statistical significance, it would be important for further understanding the nodal spread pattern of PTC. Together, the 4 studies have only lent coherent credence to the theory that a larger tumor is suggestive of a higher risk of lymph node PRRLN positivity in PTC. As for other clinicopathologic variables, however, no consensus was reached. Lymph node PRRLN may possess higher risks of bleeding and RLN injury. As lymph node PRRLN was located deeply in a confined space between the esophagus and carotid artery, an adequate exposure was hard to reach. Moreover, these lymph nodes lay closely surrounding the RLN and in the fibrofatty tissue with an abundant blood supply. However, Palestini et al 22 indicated that CCD could be performed without increasing the rate of permanent complications, and instead could help to markedly raise the detectable rate of central lymph node metastasis. Similarly, in this study, we found routine detection and elective dissection of lymph node PRRLN can be safely performed without occurrence of permanent RLN paralysis or hypocalcemia. Despite the previous findings, this study still possesses some limitations. In our patient population, lymph node PRRLN metastasis from contralateral tumors failed to be investigated because cases with PTC only in the left lobe were excluded in the sample selection. Notwithstanding our previous cases that PTC only arising from the left lobe had no lymphatic spread to lymph node PRRLN, the patient number was limited to 35 and lack of statistical evidence. In addition, our clinical database of thyroid cancer, as a single-center administrative database, cannot capture every subtle factor, some of which may be critical for clinicians. In addition, we had little information on disease-free survival because of the lack of recurrence records based on long-term follow-up, which failed to evaluate the prognostic significance of lymph node PRRLN dissection. Further investigation for us will also involve experimental research at the molecular level before strict indications for prophylactic lymph node PRRLN dissection are formally defined. CONCLUSION In conclusion, this study demonstrated that larger tumor size, multifocality, extrathyroidal extension, level VIa lymph node metastasis, and lateral lymph node metastasis are significant predictors of lymph node PRRLN metastasis in patients with right-sided PTC. Meanwhile, a noteworthy finding concerns solely lymph node PRRLN metastasis in PTC. 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