Frequency and pattern of central lymph node metastasis in papillary carcinoma of the thyroid isthmus

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1 ORIGINAL ARTICLE Frequency and pattern of central lymph node metastasis in papillary carcinoma of the thyroid isthmus Chang Myeon Song, MD, 1 Dong Won Lee, MD, 1 Yong Bae Ji, MD, PhD, 1 Jin Hyeok Jeong, MD, PhD, 1 Jung Hwan Park, MD, 2 Kyung Tae, MD, PhD 1 * 1 Department of Otolaryngology Head and Neck Surgery, College of Medicine, Hanyang University, Seoul, Korea, 2 Department of Internal Medicine, College of Medicine, Hanyang University, Seoul, Korea. Accepted 6 January 2015 Published online 29 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate the frequency and pattern of central lymph node metastasis in isthmic papillary thyroid carcinoma (PTC). Methods. We compared the clinical and pathological data of 45 patients with a single isthmic PTC and 149 patients with a single PTC located in the unilateral thyroid lobe, all of whom underwent total thyroidectomy and bilateral central neck dissection. Results. The rates of clinical, pathologic, and occult central lymph node metastasis were higher in the isthmus group than the non-isthmus group. Central lymph node metastasis in the pretracheal and bilateral paratracheal lymph nodes was more frequent in the isthmic PTC group than in the non-isthmus group. On multivariate analysis, isthmic location of the tumor was an independent risk factor for central lymph node metastasis. Conclusion. Complete bilateral central neck dissection should be considered for isthmic PTC because of the high rate of bilateral central lymph node metastasis, especially to pretracheal and bilateral paratracheal lymph nodes. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E412 E416, 2016 KEY WORDS: thyroid neoplasm, papillary thyroid carcinoma, thyroid isthmus, lymph node dissection, lymphatic metastasis *Corresponding author: K. Tae, Department of Otolaryngology Head and Neck Surgery, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, , Korea. kytae@hanyang.ac.kr INTRODUCTION The concept of therapeutic central neck dissection is well-established in the treatment of papillary thyroid carcinoma (PTC). 1 However, the role of prophylactic central neck dissection and the extent of central neck dissection in surgery for PTC remain highly controversial. 2 The support for prophylactic central neck dissection is based on the view that removal of microscopic metastases in the central compartment lymph node prevents recurrence and improves disease-free and overall survival. 3 Prophylactic central neck dissection is also recommended because of the high frequency of lymph node metastasis, 4 and the surgical difficulty and increased risk of complications when tumors recur in the central compartment. 5 Also, pathology reports on nodal status are needed for staging and for evaluating the necessity of radioactive iodine therapy. However, opponents of prophylactic central neck dissection insist that routine central neck dissection increases the risk of hypoparathyroidism and recurrent laryngeal nerve injury, 6 and they argue that no prospective randomized study has established that central neck dissection decreases recurrence or disease-specific mortality. 5 Others recommend that prophylactic central neck dissection should only be considered in patients with high risk factors, such as male sex, younger age, larger tumor size, and extrathyroidal extension. 7 Approximately 3% to 9.2% of all PTCs are located in the thyroid isthmus (isthmic PTC). 8,9 Isthmic PTCs are associated with multiple foci and local invasion to adjacent tissues, such as the trachea and strap muscles. 10 However, the patterns of central compartment lymph node metastasis in isthmic PTC have not been thoroughly evaluated. Therefore, to help to guide the appropriate extent of central neck dissection for such cases, we evaluated the frequency and pattern of central lymph node metastasis in patients with papillary carcinoma arising in the thyroid isthmus. MATERIALS AND METHODS We enrolled 45 patients with a single PTC located in the isthmus who underwent thyroidectomy and neck dissection in a tertiary hospital from January 2008 to June The control group for comparison was comprised of 149 patients who underwent thyroidectomy and neck dissection in the same period for a single PTC located in a unilateral thyroid lobe. All the patients underwent total thyroidectomy and bilateral central neck dissection with or without lateral neck dissection. The central compartment lymph nodes were divided into pretracheal, prelaryngeal, and right and left paratracheal lymph node groups in the operating room. 11 We retrospectively compared patient characteristics, tumor size, extrathyroidal extension, lymphovascular and perineural invasion, and E412 HEAD & NECK DOI /HED APRIL 2016

2 CENTRAL LYMPH NODE METASTASIS OF THYROID ISTHMUS CANCER patterns of lymph node metastasis in the isthmic and nonisthmic groups. We also evaluated potential risk factors for central lymph node metastasis, including isthmic tumor location by univariate and multivariate analysis. This study was approved by the Institutional Review Board of Hanyang University Hospital. All patients underwent preoperative physical examination and imaging studies, including ultrasound and CT scan, to evaluate cervical lymph node metastasis. Ultrasonography-guided fine-needle aspiration cytology (FNAC) was performed in those patients who had positive imaging findings in the central or lateral compartments of the neck. Therapeutic lateral neck dissection was performed in patients with lateral compartment lymph node metastasis suspected on the basis of imaging studies or physical examination, or confirmed by FNAC. We did not perform prophylactic lateral neck dissection in patients with clinically negative lateral compartments. We excluded patients with other pathologic types of thyroid cancer, multiple malignant nodules, recurrent cases, cases with previous neck surgery or history of irradiation involving the neck region, and cases with thyroid lobectomy or unilateral central neck dissection. Isthmic PTC was defined as a single tumor with its boundaries medial to the imaginary lines on the lateral margins of the trachea, based on imaging studies and intraoperative findings. Isthmic PTC was classified as nonmedian and median based on preoperative imaging studies and intraoperative findings. A median tumor was defined as one with its center in the middle of the trachea equal in size to tumors on the right and left sides. The criteria for identifying lymph node metastases in ultrasound images were round shape (long/short diameter ratio <2), calcification (microcalcification), cystic change, hyperechogenicity, and heterogeneous inner structure. The criteria for CT images were enhancement, heterogeneity, calcification, cystic or necrotic change, and round shape. 12 We did not apply size criteria for lymph node metastases in the central compartment. Differences of continuous variables were tested by Student s t test and differences of categorical variables by the chi-square test or Fisher s exact test for small cell sizes. All statistical analysis was performed with SPSS version 18.0 (SPSS, Chicago, IL). A <.05 was considered statistically significant. RESULTS The isthmic PTC consisted of 35 cases in the nonmedian portions of the thyroid isthmus (19 right-sided tumors, 16 left-sided) and 10 cases in the median portion. The non-isthmic control group consisted of 76 right lobe tumors and 73 left lobe tumors. Clinical and pathologic characteristics of the isthmic PTC and non-isthmic PTC groups are listed in Table 1. There were no differences between the 2 groups in age, sex, primary tumor size, T classification, TNM staging (American Joint Committee on Cancer 7th edition), minimal extrathyroidal extension, lymphovascular invasion, and perineural invasion. However, N classification was higher in the isthmus group (p 5.001). Anterior capsule invasion was confirmed by pathological examination in 46.7% (21 cases) of the isthmic PTC, and posterior capsule invasion in TABLE 1. Comparison of clinicopathologic characteristics and surgical complications in isthmic and unilateral non-isthmus papillary thyroid carcinoma. Isthmus cancer (n 5 45) Non-isthmus cancer (n 5 149) Sex Female 35 (77.8) 120 (80.5).832 Male 10 (22.2) 29 (19.5) Age, y, mean <45 17 (37.8) 45 (30.2) (62.2) 104 (69.8) Tumor size, mm, mean cm 19 (42.2) 83 (55.7).127 >1 cm 26 (57.8) 66 (44.3) Extrathyroidal 23 (51.1) 74 (49.7) extension, minimal Lymphovascular invasion 11 (24.4) 26 (17.4).386 Perineural invasion 3 (6.7) 9 (6.0).879 T classification.440 T1 21 (46.7) 69 (46.3) T2 0 7 (4.7) T3 24 (53.3) 73 (49) T4 0 0 N classification.001* N0 13 (28.9) 89 (59.7) N1a 26 (57.8) 44 (29.5) N1b 6 (13.3) 16 (10.7) TNM stage, AJCC.918 I 25 (59.1) 85 (57) II 0 1 (0.7) III 16 (35.6) 53 (35.6) IV 4 (8.9) 10 (6.7) Hypoparathyroidism Transient 12 (26.7) 41 (27.5) Permanent 0 1 (0.7) Recurrent laryngeal nerve palsy.185 Transient 3 (6.7) 3 (2.0) Permanent 0 2 (1.3) Hematoma 1 (2.2) 4 (2.7) Chyle leakage 2 (4.4) 1 (0.7).135 Abbreviation: AJCC, American Joint Committee on Cancer. 4.4% (2 cases). There were no cases of invasion to the trachea or recurrent laryngeal nerve in either group, and no differences in postoperative hypoparathyroidism, recurrent laryngeal nerve palsy, hematoma, or seroma. The rate of clinically positive central lymph node metastasis was higher in the isthmus group (p 5.031; Table 2) and pathologically positive lymph node metastasis in the central compartment were also more common (p <.001; Table 2). In addition, the frequency of metastasis in both the unilateral and bilateral central compartments was higher in the isthmus group than the nonisthmus group (unilateral and bilateral; p and.049, respectively; Table 2). Similarly, the rate of occult central lymph node metastasis was higher in the isthmus group (p 5.003; Table 2). In a subgroup analysis of unilateral and bilateral metastases, unilateral occult metastasis was more common in the HEAD & NECK DOI /HED APRIL 2016 E413

3 SONG ET AL. TABLE 2. Central compartment lymph node metastasis in isthmic and unilateral non-isthmic papillary thyroid carcinoma. Patterns of metastasis Isthmus cancer (n 5 45) Non-isthmus cancer (n5149) Metastasis, clinical 22/45 (48.9) 45/149 (30.2).031* Metastasis, pathologic 32/45 (71.1) 60/149 (40.3) <.001* Unilateral 20/45 (44.4) 39/149 (26.2).026* Bilateral 12/45 (26.7) 21/149 (14.1).049* Occult metastasis in cn0 12/23 (52.2) 21/104 (20.2).003* Unilateral 9/23 (39.1) 15/104 (14.4).015* Bilateral 3/23 (13.0) 6/104 (5.8).207 Metastasis in cn1 20/22 (90.9) 39/45 (86.7).615 Unilateral 11/22 (50.0) 24/45 (53.3).798 Bilateral 9/22 (40.9) 15/45 (33.3).544 Abbreviations: cn0, clinically negative central neck; cn1, clinically positive central neck. isthmus group (p 5.015). Bilateral occult metastasis was also more frequent in the isthmus group, although this effect did not reach statistical significance (p 5.207). The rates of pathologic central compartment lymph node metastasis in clinically positive cases were very high, and similar in the 2 groups (p 5.615; Table 2). We evaluated the distribution of subsites of the central lymph node metastases (Table 3). The most common subsite of central compartment metastasis in isthmic PTC was the pretracheal lymph node, and the isthmic group had higher rates of metastasis to pretracheal and bilateral paratracheal lymph nodes than the non-isthmic control group (pretracheal, 57.8% vs 22.8%; p <.001; bilateral paratracheal, 26.7% vs 14.1%; p 5.049). The rates of metastasis to the contralateral paratracheal lymph node without ipsilateral paratracheal lymph node involvement were similar in the nonmedian isthmic and control cases (2.9% vs 1.3%; p 5.524). Among the 10 cases of median isthmic tumors, positive metastasis in pretracheal lymph nodes was confirmed in 8 cases (80%), in unilateral paratracheal lymph nodes in 6 cases (60%), in bilateral paratracheal lymph nodes in 2 cases (20%), and in prelaryngeal lymph nodes in 2 cases (20%). Among the 35 cases of nonmedian isthmic PTC, pretracheal lymph node metastasis was the most common (51.4%) followed by bilateral paratracheal (31.4%), unilateral paratracheal (17.1%), and prelaryngeal lymph nodes (5.7%). TABLE 3. Subsites of central lymph node metastasis in isthmic and unilateral non-isthmic papillary thyroid carcinoma. Subgroup of lymph nodes Isthmic PTC (n 5 45) Non-isthmic PTC (n 5 145) Pretracheal 26 (57.8) 34 (22.8) <.001* Prelaryngeal 4 (8.9) 5 (3.4).216 Unilateral paratracheal 11 (24.4) 34 (22.8).891 Bilateral paratracheal 12 (26.7) 21 (14.1).049* Only contralateral paratracheal 1 (2.9) 2 (1.3).524 Abbreviation: PTC, papillary thyroid carcinoma. Only nonmedian isthmic PTC cases were evaluated in this category. Univariate analysis of clinicopathological factors showed that central lymph node metastasis was significantly associated with male sex, age <45 years, tumor size >1 cm, minimal extrathyroidal extension, lymphovascular invasion, and isthmic location of tumor (Table 4). In multivariate logistic regression analysis, age <45 years (odds ratio [OR], 3.324), minimal extrathyroidal extension (OR, 3.809), lymphovascular invasion (OR, 8.083), and isthmic location of tumor (OR, 3.998) were independent risk factors for central lymph node metastasis (Table 5). The frequency of lateral lymph node metastasis was similar in the 2 groups. Therapeutic lateral neck dissection including levels II, III, IV, and V was performed in 6 isthmus cases (13.3%) and 16 cases (10.7%) non-isthmus TABLE 4. Univariate analysis of clinicopathological factors associated with central lymph node metastasis. Variables Central lymph node metastasis Absent (n 5 102) Present (n 5 92) Sex.048* Female 87 (56.1) 68 (43.9) Male 15 (38.5) 24 (61.5) Age, y <.001* <45 20 (32.3) 42 (67.7) (62.1) 50 (37.9) Tumor size.001* 1 cm 65 (63.7) 37 (36.3) >1 cm 37 (40.2) 55 (59.8) Extrathyroidal extension <.001* None 66 (68.0) 31 (32.0) Minimal 36 (37.1) 61 (62.9) Lymphovascular invasion <.001* None 96 (61.1) 61 (38.9) Present 6 (16.2) 31 (83.8) Perineural invasion.071 None 99 (54.4) 83 (45.6) Present 3 (25.0) 9 (75.0) Tumor location <.001* Non-isthmus 89 (59.7) 60 (40.3) Isthmus 13 (28.9) 32 (71.1) E414 HEAD & NECK DOI /HED APRIL 2016

4 CENTRAL LYMPH NODE METASTASIS OF THYROID ISTHMUS CANCER TABLE 5. Multivariate logistic regression for central lymph node metastasis. Variables ß SE Exp (ß) 95% CI Exp (ß) Lower Upper Male Age <45 y Tumor size >1 cm Minimal extrathyroidal extension < Lymphovascular invasion < Isthmus tumor Constant < Abbreviations: Exp (ß), odds ratio; CI, confidence interval. cases (p 5.630). Lateral lymph node metastasis was positive on the ipsilateral side in 83.3% (5 cases) of the isthmus tumors and 81.3% (13 cases) of the non-isthmus tumors, and on both sides in 16.7% (1 case) in the isthmus group and 18.7% (3 cases) in the non-isthmus PTC group (p 5.910). Radioactive iodine treatment was performed in 42 patients (93.3%) of the isthmus group and 120 patients (80.5%) of the non-isthmus group (p 5.064). The followup periods were similar in the isthmic and non-isthmic patients ( months vs months; p 5.222). There was no case of recurrence in the isthmic group but there was 1 case in the non-isthmic group (in the contralateral neck). DISCUSSION Thyroid carcinomas are encountered infrequently in the isthmus. The isthmus is located anterior to the second and third tracheal rings connecting the 2 lateral lobes, and is about 20 mm in length and width, with a thickness of 2 to 6 mm. 13 The lymphatic system of the thyroid gland is parallel to the venous drainage system, 14 and drains inferiorly to the pretracheal and paratracheal lymph nodes, followed by the inferior jugular lymphatics and superior mediastinal lymphatics. 15 In addition, the isthmus and upper lobes of the thyroid are drained superiorly to the prelaryngeal lymph nodes. 16,17 Although there are data and overall recommendations for the treatment of differentiated thyroid carcinomas, there are no specific guidelines for thyroid cancers arising in the isthmus. 18,19 Also, there is no consensus on the extent of lymph node dissection that should accompany treatment of isthmic PTC. Because of the unique location, blood supply, and lymphatic drainage of the isthmus, treatment for isthmus cancer may differ from that of PTC located in the thyroid lobe. Some studies have evaluated the appropriate extent of thyroidectomy for differentiated thyroid carcinoma in the isthmus, but they did not focus on management of the lymph nodes and involved small numbers of patients. 9,20,21 One study of a larger series reported central lymph node metastasis in 40.3% of isthmic PTCs. 8 However, the study included multifocal tumors (48.6%) and cases undergoing only unilateral central neck dissection, and the subgroups of central compartment lymph node metastasis were also not evaluated. 8 Another study showed that the risk factors for Delphian lymph node metastasis included tumor location in the isthmus, but no data on lymph node metastasis in other subsites of the central compartment in isthmic PTC were reported. 17 In our study, we enrolled patients with a single tumor located in the isthmus who underwent bilateral central neck dissection and total thyroidectomy. Therefore, although our study is retrospective it has the advantage that it reveals the exact pattern of lymph node metastasis of isthmic PTC in each subdivision of the central compartment. The rate of central lymph node metastasis of isthmic PTC in our study was 71.1%, significantly higher than that of non-isthmus cancer (40.3%; p <.001), and also higher than the rate in a previous study by Lee et al 8 (40.3%). Another study reported central lymph node metastasis in 6 of 12 PTCs in the isthmus. 9 In a retrospective review of patients who underwent Delphian lymph node dissection for PTC, Delphian lymph node metastasis was found in 41.2% of isthmic tumors. 17 A possible explanation for the higher frequency of central lymph node metastasis in our study than in other reports could be that, in our case, only those cases with bilateral central neck dissection, including contralateral paratracheal lymph nodes, were included. In our data, the rates of pathological metastasis in both unilateral and bilateral central compartment lymph nodes were higher in isthmic than in non-isthmic PTC (unilateral, 44.4% vs 26.2%; bilateral, 26.7% vs 14.1%). Bilateral central lymph node metastasis seems to be due to the midline position of isthmus tumors, which are able to spread into both paratracheal lymph nodes. Furthermore, in our study, 42.2% of the isthmus tumors were microcarcinomas. Among the microcarcinoma cases, the rate of central node metastasis in the isthmus group reached 73.7%, much higher than in the non-isthmus group (27.7%; p <.001). In this study, the rate of occult metastasis was 52.2% in the isthmic group, and lower in the non-isthmic control group (20.2%; p 5.003). Of 12 isthmic PTC patients with occult central nodal metastasis, 3 had occult metastases in the bilateral paratracheal lymph node. In 1 case involving a 6 mm non-median isthmic tumor without clinical evidence of nodal metastasis, pathological review revealed metastasis in the contralateral paratracheal lymph node with negative ipsilateral paratracheal lymph node involvement. The rates of metastasis to only the contralateral paratracheal lymph node were similar in nonmedian isthmic and non-isthmic control cases (2.9% vs 1.3%). Among PTCs with clinically positive lymph nodes, the rates of metastasis in the central compartment were high HEAD & NECK DOI /HED APRIL 2016 E415

5 SONG ET AL. in both isthmic and non-isthmic PTC (90.9% and 86.7%, respectively). Moreover, bilateral central lymph node metastasis was common in both groups (40.9% in the isthmic group and 33.3% in the non-isthmic group). Our findings suggest that complete bilateral central neck dissection should be carried out for isthmic PTCs with clinically positive central lymph nodes because of the high rate of bilateral pathologic lymph node metastasis. The pretracheal and bilateral paratracheal lymph nodes, especially, should be carefully dissected during central neck dissection. Although prophylactic central neck dissection is still controversial and our data do not include long-term oncologic outcomes, prophylactic central neck dissection might be considered for isthmic PTC with clinically negative lymph nodes because of the high rate of occult metastasis (52.2%) in the central compartment. Further study with long-term follow-up is needed to establish the exact role of prophylactic central neck dissection in isthmic PTC. In our study, there were no differences of sex, age, tumor size, extrathyroidal extension, lymphovascular or perineural invasion, pathological T classification, TNM stage, and complication rate between the isthmic PTC and non-isthmic PTC groups. Only the rate of lymph node metastasis was higher in isthmic PTCs. To exclude the possibility that clinical and pathological factors might bias lymph node metastasis, we performed a multivariate logistic regression analysis, and isthmic location proved to be an independent risk factor for central lymph node metastasis (OR, 4.00; 95% confidence interval, ; p 5.001) in the multivariate analysis. Extrathyroidal extension was also an independent risk factor in the multivariate analysis. Extrathyroidal extension was found in 51% of isthmus cancers in our study, similar to the proportion in non-isthmus cancers (49.7%). The rate of extrathyroidal extension in our study agreed with that in the literature of 33% to 70.2%. 8,9 We found similar rates of lateral lymph node metastases in isthmic and non-isthmic PTC (13.3% vs 10.7%; p 5.630). The rate of lateral lymph node metastasis in the isthmic PTC was similar to that in the literature (9.4%). 8 Positive metastasis was observed on pathological examination in all cases undergoing lateral neck dissection. Lateral neck dissection can be performed with the same strategy as for thyroid lobe tumors in cases suspected clinically on the basis of imaging studies and confirmed by FNAC Limitations of this study include its retrospective nature, the lack of randomization, and absence of longterm follow-up oncologic data. A randomized controlled trial with a longer period of follow-up is needed. Also, our study was confined to unifocal PTCs, and further studies evaluating multifocal tumors are necessary. CONCLUSION Isthmic PTC has higher rates of clinical, pathologic, and occult central lymph node metastasis than nonisthmic PTC. Complete bilateral central neck dissection should be considered for isthmic PTC because of the high rate of bilateral central lymph node metastasis, especially involving the pretracheal and bilateral paratracheal lymph nodes. REFERENCES 1. Sakorafas GH, Sampanis D, Safioleas M. Cervical lymph node dissection in papillary thyroid cancer: current trends, persisting controversies, and unclarified uncertainties. Surg Oncol 2010;19:e57 e Ji YB, Lee DW, Song CM, Kim KR, Park CW, Tae K. Accuracy of intraoperative determination of central node metastasis by the surgeon in papillary thyroid carcinoma. Otolaryngol Head Neck Surg 2014;150: Grubbs EG, Rich TA, Li G, et al. Recent advances in thyroid cancer. In brief. Curr Probl Surg 2008;45: Machens A, Holzhausen HJ, Dralle H. Skip metastases in thyroid cancer leaping the central lymph node compartment. 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