Tumor location dependent skip lateral cervical lymph node metastasis in papillary thyroid cancer

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1 ORIGINAL ARTICLE Tumor location dependent skip lateral cervical lymph node metastasis in papillary thyroid cancer Yoon Se Lee, MD, PhD, 1,2 Sung-Chan Shin, MD, 1 Yun-Sung Lim, MD, 1 Jin-Choon Lee, MD, PhD, 1 Soo-Geun Wang, MD, PhD, 1 Seok-Man Son, MD, PhD, 3 In-Ju Kim, MD, PhD, 3 Byung-Joo Lee, MD, PhD 1* 1 Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea, 2 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 3 Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea. Accepted 21 May 2013 Published online 4 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Lateral cervical lymph node metastasis without central lymph node (CLN) metastasis is not infrequent in papillary thyroid cancer (PTC). This study was designed to investigate the frequency and pattern of skip metastasis in PTC. Methods. We reviewed 131 patients who underwent total thyroidectomy with CLN dissection and selective lymph node dissection. Tumor location was classified in 3 areas (upper, middle, and lower third) based on preoperative ultrasonographic findings. Results. All skip metastases occurred in patients whose tumors had been on the upper part of the thyroid (p <.001). Among 9 patients with skip metastasis, level III lymph nodes (66.7%) were the lymph nodes that were most frequently involved in skip metastasis. Conclusion. Primary tumors in the upper portion of the thyroid are closely linked to skip metastasis. Careful preoperative evaluation of lateral cervical lymph nodes is suggested when a tumor is in the upper portion. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: papillary thyroid carcinoma, lymphatic metastasis, skip, neck dissection, univariate analysis INTRODUCTION Traditionally, it was suggested that tumors spread in an orderly defined manner based on mechanical consideration and transverse lymphatics to lymph nodes by direct extension. 1 As clinical and laboratory research promotes, Fisher 2 proposed that biological rather than anatomic factors might be responsible for the appearance of metastasis in certain nodes and the lack of metastasis in others and, thus, cancer is not a local disease but a systemic disease. Oligometastases implies that interaction between systemically disseminated cancer cells and host is an important step, and this concept leads to an idea that confined distant metastasis is thoroughly cured by local therapy in some cases. 3 Nodal metastasis of papillary thyroid cancer (PTC) occurs in a stepwise fashion. Spreading from the thyroid gland, the central and lateral lymph node compartments on the ipsilateral side of the thyroid tumor represent the first echelons of lymphatic drainage followed by the mediastinal and opposite lateral lymph node compartments. 4,5 This sequential pattern of lymph node *Corresponding author: B.-J. Lee, Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine and Medical Research Institute, Pusan National University Hospital, 1-10, Ami-dong, Seogu, Pusan , Republic of Korea. voicelee@pusan.ac.kr Contract grant sponsor: This study was supported by Medical Research Institute Grant ( ), Pusan National University Hospital metastasis can help in predicting the central lymph node (CLN) metastasis in the presence of definite metastatic lesions in the lateral cervical lymph nodes. 6 However, this does not apply to all cases of PTC, and we have encountered disarrayed patterns of lymph node metastasis. Discontinuous lymphatic spread, often referred as skip metastasis, is not uncommon in cases of PTC with lateral cervical lymph node metastasis. The frequency of skip metastasis has been reported to vary between 11.1% and 37.5% in node-positive PTC. 7,8 Lymph node metastasis in PTC may be a risk factor for recurrence and further metastasis. Evident CLN metastasis has limited prognostic effect on low-risk patients, although it has been reported to increase the risk of locoregional recurrence. 9,10 Lateral cervical lymph node metastasis also increases the risk of recurrence and distant metastasis, 11,12 and lymph node metastasis on preoperative imaging studies were critical prognostic factors for the survival rate, especially in case of microptc. 13 Repeated operations or radioablation therapy to treat recurrence or distant metastasis may have a negative effect on quality of life. Thus, preoperative detection of lymph node metastasis and subsequent surgical removal are important in preventing later recurrence and avoiding the need for repeated surgery. It is difficult to preoperatively detect lymph node metastasis, especially CLN metastasis, although diagnostic tools such as CT, ultrasonography, and even F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT have undergone HEAD & NECK DOI /HED JUNE

2 LEE ET AL. significant recent advances. 14,15 Ultrasound is most widely used to detect lymph node metastasis, but its sensitivity is variable, ranging from 65% to 93.8%. 16,17 Because the detection rate is influenced by the expertise and the field of the ultrasonographer, some examiners may overlook ambiguous lymph nodes or micrometastasis. Clinical and radiologic findings should be correlated to prevent underdiagnosis of lateral cervical lymph node metastasis. In addition to preoperative radiological imaging, either preoperative or operative findings, that suggest lymph node metastasis in the central or lateral neck compartment may be of value when determining the extent of the surgery required. Thus, the purpose of this study was to investigate the frequency and pattern of skip metastasis in PTC and analyze the relationship between skip metastasis and clinicopathologic factors. PATIENTS AND METHODS A cross-sectional study using medical chart reviews was performed after approval by the institutional review board. We retrospectively reviewed 1787 patients who underwent total thyroidectomy with routine CLN dissection for PTC between January 2004 and June Completion thyroidectomy and revision neck dissection cases were excluded. The patients who underwent selective neck dissection for lateral cervical lymph node metastasis were included in this study (n 5 131; 7.3%). All patients underwent a physical examination, ultrasonography, and CT preoperatively. Lateral cervical lymph node metastasis was confirmed by ultrasound-guided fine-needle aspiration. In addition, if there was either positive or suspicious radiographic finding (central necrosis or cystic change, dense cortical enhancement, or calcification), 18 or aspirated specimen (thyroglobulin >250 ng/ml) in the lateral neck lymph nodes, 19 selective lymph node dissection was performed. Bilateral CLN dissection was performed routinely and selective lymph node dissection was performed for therapeutic purposes. CLN dissection was performed after the thyroid is removed. Both the recurrent laryngeal nerves were dissected retrograde to the point where it courses under the clavicles, the innominate artery, or the right carotid artery. The fibrofatty tissues were dissected off the nerve and usually reflected medially, and then dissected off the trachea. If possible, the specimen should be removed en bloc. However, additional nodal tissues that are deep to the right recurrent laryngeal nerve may be removed separately. Selective lymph node dissection comprehended the levels II, III, IV, and V lymph nodes. Upon selective lymph node dissection, we performed en bloc resection and the specimen was divided into each level on site by the operator. The pathologists examined the nodal metastasis according to the level that was divided previously in the operating room. Negative lateral cervical lymph node metastasis in postoperative histopathologic analyses, revision surgery, and other types of thyroid malignancies were exclusion criteria. Tumor location was classified into 3 areas (upper, middle, and lower third) based on the results of preoperative ultrasonography. We analyzed the relationship between clinicopathological parameters and the rate of skip metastasis. We defined skip metastasis by negative ipsilateral central and positive ipsilateral lateral compartment lymph nodes in postoperative histopathological analyses. Patterns of lateral cervical lymph node metastasis were summarized in cases of skip metastasis and the factors that influenced the location of lateral cervical lymph node metastasis were compared. Association of clinicopathological factors with skip metastasis Associations between nodal metastasis and negative clinicopathological factors including age, sex, extrathyroidal extension, lymphovascular emboli, and multifocality were investigated. The location of the primary tumor was categorized as upper, middle, or lower third based on the results of ultrasonography with a longitudinal view. In multifocal cases, the analysis was based on the largest (dominant) tumor. Patterns of central and lateral lymph node metastasis Nodal sites were defined by the 6-level system, provided by the American Head and Neck Society, which was revised in We investigated patterns of lateral cervical lymph node metastasis according to tumor location and CLN metastasis. Statistical analysis Statistical analysis was performed using the SPSS software (ver. 15.0; Chicago, IL). Rates of skip metastasis for each clinical variable, which contains sex, age (45 years; >45 years), primary tumor size (1 cm; >1 cm), extrathyroidal extension, lymphovascular emboli, tumor multifocality, and tumor location, were compared using the Pearson chi-square tests were applied with a confidence level of 95%. Rate of lateral cervical lymph node metastasis according to tumor location was analyzed using the Fisher exact tests. In all statistical analyses, a 2- tailed p value of <.05 was considered to indicate statistical significance. RESULTS Clinicopathological factors associated with skip metastasis Of enrolled patients, CLN metastasis and lateral cervical lymph node metastasis were confirmed in 698 patients (39.1%) and 131 patients (7.3%), respectively. The patients with lateral cervical lymph node metastasis consisted of 105 women and 26 men. Mean patient age was 50.4 years (range, years). Micropapillary thyroid cancer (1 cm) was found in 34 patients. Extrathyroidal extension was detected in 107 patients and lymphovascular emboli were detected in 34 patients. Solitary tumors (n 5 88) were more common than multifocal tumors (n 5 43). The primary tumor was most frequently located in the upper portion of the thyroid (n 5 52; Table 1). In the present study, skip metastasis was detected in 9 patients (6.8%). Mean tumor diameter was cm. Parameters such as sex, age, primary tumor size, extrathyroidal extension, lymphovascular emboli, and multifocality did not correlate with the rate of positive skip metastasis (Table 1). Individuals with primary tumors in 888 HEAD & NECK DOI /HED JUNE 2014

3 LATERAL METASTASIS IN THYROID CANCER TABLE 1. Factors Factors related to skip metastasis in papillary thyroid cancer. Negative, no. of patients (%) Skip metastasis Positive, no. of patients (%) p value Sex.413 Male 23/26 (88.5) 3/26 (11.5) Female 99/105 (94.3) 6/105 (5.7) Age /59 (93.2) 4/59 (6.8) >45 67/72 (93.1) 5/72 (6.9) Size cm 30/34 (88.2) 4/34 (11.8) >1 cm 92/97 (94.8) 5/97 (5.2) Extrathyroidal extension.495 Present 99/107 (92.5) 8/107 (7.5) Absent 23/24 (95.8) 1/24 (4.2) Lymphovascular emboli.217 Present 33/34 (97.1) 1/34 (2.9) Absent 84/97 (86.6) 8/97 (13.4) Multifocality.340 Present 38/43 (88.4) 5/43 (11.6) Absent 84/88 (95.5) 4/88 (4.5) Location of tumor <.001* Upper 43/52(82.7) 9/52 (17.3) Middle 41/41 (100) 0/41 (0) Lower 28/28 (100) 0/28 (0) *Statistically significant. either the middle or lower portion of the thyroid exhibited lateral cervical lymph node metastasis in the presence of CLN metastasis whereas skip metastasis occurred exclusively in patients whose primary tumor was in the upper part of the thyroid gland (p <.001). Level III nodes (6 of 9) were the nodes most frequently involved in skip metastasis cases, followed by level II nodes (5 of 9), level IV nodes (3 of 9), and level V nodes (3 of 9; Table 2). Patterns of skip metastasis according to the primary tumor location We examined whether CLN metastasis was affected by primary tumor location. CLN metastasis was found in 43 of 52 patients in the upper third group, all 41 in the middle third group, and all 28 in the lower third group. Thus, lateral cervical lymph node metastasis without CLN TABLE 2. Case no. Details of skip metastasis. Tumor location Level II Level III Level IV Level V 1 U U U U U U U U U Abbreviations: U, upper thyroid gland; 1, positive lymph node metastasis; 2, negative lymph node metastasis. TABLE 3. tumor. Pattern of lymph node metastasis with location of primary Location of primary tumor (%, rate of metastasis) Upper Middle Lower p value Involved lateral compartment Level II 35 (67.3) 24 (58.5) 13 (46.4).078 Level III 46 (88.5) 36 (87.8) 21 (75.0).607 Level IV 37 (71.2) 30 (73.2) 23 (82.1).190 Level V 3 (5.8) 7 (17.1) 4 (14.3).215 metastasis was not detected when the primary tumor was located in the middle or lower portion of the thyroid. Skip metastasis was only detected in patients whose primary tumor was located in the upper portion of the thyroid gland. This pattern of nodal metastasis according to primary tumor location was statistically significant (p <.001; Table 1). Pattern of lateral cervical lymph node metastasis according to the location of tumor Next, we investigated the relationship between lateral cervical lymph node metastasis pattern and primary tumor location. We counted and summed up the involved cases to reveal that the distribution of the metastasis is dependent on the location of primary tumor. Table 3 shows the pattern of lateral cervical lymph node metastasis according to the primary tumor location and CLN metastasis. Tumors location was divided into upper (n 5 52), middle (n 5 41), and lower portion (n 5 28). In the upper third group, level III nodes (46 of 52; 88.5%) were the most frequently involved nodes; level IV nodes (37 of 52; 71.2%), level II nodes (35 of 52; 67.3%), and level V nodes (3 of 52; 5.8%) were also involved. In the middle third group, level III nodes (36 of 41; 87.8%) were more frequently involved than level IV nodes (30 of 41; 73.2%), level II nodes (24 of 41; 58.5%), or level V nodes (7 of 41; 17.1%). In the lower third group, level IV nodes (23 of 28; 82.1%) were more frequently involved than level III nodes (21 of 28; 75.0%), level II nodes (13 of 28; 46.4%), or level V nodes (4 of 28; 14.3%). There was no significant difference in the patterns of nodal involvement according to primary tumor location. Lateral cervical lymph node metastasis pattern according to skip metastasis CLN metastasis accompanied by lateral cervical lymph node metastasis was detected in 122 patients. In the CLN-positive group, level III nodes (107 of 122; 87.7%) were involved most frequently, followed by level IV nodes (91 of 122; 74.6%), and level II nodes (64 of 122; 52.5%; Table 3). In contrast, in the skip metastasis group, level III nodes (6 of 9; 66.7%) were involved most frequently followed by level II nodes (5 of 9; 55.6%) and level IV nodes (3 of 9; 33.3%; Table 2). Thus, the rate of level II metastasis tended to be higher in the skip HEAD & NECK DOI /HED JUNE

4 LEE ET AL. metastasis group than in the CLN metastasis group. However, this difference was not statistically significant. DISCUSSION Lymph node metastasis develops in approximately 30% to 80% of patients with PTC. 21 Central lymph nodes are the most frequently involved lymph nodes and their prognostic value is somewhat controversial. 11 In addition to CLN metastasis, other clinical and pathological factors including age, tumor size, extrathyroidal extension, lymphovascular emboli, multifocality, and lateral cervical lymph node metastasis have been proposed to be prognostic factors. 11,22 It is important to reduce the nodal recurrence in PTC 12 because PTC by itself has an excellent prognosis with an overall 10-year survival rate of >90%. 23 Nodal recurrence, which can affect quality of life and results in distant metastasis in patients with PTC, 9,10 can be controlled by either surgical removal or radioiodine ablation therapy. However, radioablation therapy has limited effect on visible metastatic nodes and in older patients. 24 Thus, developing methods to predict, detect, and remove lymph node metastasis is one of key components to control nodal metastasis. In addition to the persistent tumor in the locoregional portion or systemic area, skip metastasis may be one of the factors to explain the recurrence in lateral cervical lymph nodes without CLN metastasis after total thyroidectomy and CLN dissection. We defined skip metastasis by negative ipsilateral central and positive ipsilateral lateral compartment lymph nodes in postoperative histopathologic findings. Machen et al 25 concluded that skip metastasis with its erratic mode of lymphatic spread is an epiphenomenon of low-density nodal dissemination in thyroid cancer. This view was used to explain a case of single lateral nodal metastasis without involvement of CLN. In the present study, the frequency of skip metastasis was 6.8%. This value is lower than some previously reported values (7.7% to 9.9%), 26,27 and much lower than those reported by Ducci et al 8 (11.1%) and Coatesworth et al 7 (37.5%). Recently, many surgeons have advocated CLN dissection. As a result, skip metastasis in PTC was founded less frequently than in the past studies. Among pathological factors, high numbers of CLN metastases can be regarded as a predictive factor for lateral cervical lymph node metastasis. 22 However, there are few reliable clinical factors that predict lateral cervical lymph node metastasis that cannot be detected in preoperative radiologic tests. Although high rate of lateral cervical lymph node metastasis was found in the tumors with extrathyroidal extension and large size (>1 cm; 79.9% and 74.1%, respectively) in this study, those factors were not related to the rate of skip metastasis, significantly. It is likely to be attributed to the small number of skip metastasis cases. Furthermore, sex, age, extrathyroidal extension, lymphovascular emboli, and multifocality were insignificant clinicopathological factors of skip metastasis in PTC. In all 9 patients with skip metastasis, the primary tumor was located on the upper part of the thyroid gland (p <.001). Additionally, CLN dissection should be done if there is an evident metastatic node in the lateral neck area because the rate of skip metastasis is lower than the sequential pattern. These results can be explained by the nature of the lymphatic drainage system of the thyroid gland. Ito et al 28 reported that tumor cells from PTC with an upper pole location were more likely to be transported to the lateral lymph nodes along the superior thyroid artery. However, tumor cells from the mid-lower region of the thyroid gland were more likely to be transported to the tracheoesophageal groove in the CLN. Moreover, lateral cervical lymph node metastasis is detected in twothirds of PTC. 29 This lymphatic drainage system explains why skip metastasis can occur in patients whose primary tumors are in the upper portion of the thyroid. However, other studies showed that the location of PTC was not significantly associated with lateral cervical lymph node metastasis pattern, 30 and that location of the primary tumor did not predict the pattern of lymph node metastasis. 31 Histologic subtype was not included in the pathologic factors in this study. Two cases with skip metastases were sclerosing type and tall cell variant type, respectively, whereas 12 cases of PTC variants were detected in the cases with non-skip metastases. Statistical analysis was not performed because of the low number of cases. Generally, nodal metastasis preferentially occurred along the lymphatic chain. Previous studies showed that level III nodes were the most frequently involved nodes, followed by level IV nodes and level II nodes. 27 In our study, level III, IV, and II nodes were the most frequently involved sites, in that order. The results of the present study are similar to those of previous studies. However, the 9 patients with skip metastasis, all of whose primary tumors were on the upper part of the thyroid gland, had a higher relative rate of level II lymph node involvement. Lymph node metastases arising from primary tumors in the upper portion of the thyroid in patients with CLN metastasis were more frequent in level II nodes than in nodes of other levels. This suggests that the lymphatic drainage system in the upper portion of the thyroid is different from that in other parts of the gland. 29 All surgical findings were not elucidated by the chart review. In addition, there is no measurement to evaluate the adequate dissection and lymph node sampling. Nodal yield is a risk factor and assures thorough dissection. 32 Lack of nodal yield in this article can be compensated by consistent surgical method by 1 surgeon. If clinically N0 cases underwent lateral neck dissection, there might be a higher rate of CLN metastasis and lateral cervical lymph node metastasis than these enrolled cases. Because lateral neck dissection is not indicated for clinical N0, such study design could not be performed. In place of this, we reviewed the chart and intended to find correlation between clinicopathological factors and lateral cervical lymph node metastasis. They are the main limitations of our cross-sectional study. In conclusion, the overall frequency of skip metastasis in the patients in our PTC group was 6.8%. Recurred lateral cervical lymph node metastasis can occur even if there was no CLN metastasis, which was confirmed on previous CLN dissection accompanied with thyroidectomy or no definite CLN metastasis on revision lateral neck dissection. It can be explained by skip metastasis (rather than oligometastasis). Skip metastasis was exclusively observed in individuals whose primary tumors 890 HEAD & NECK DOI /HED JUNE 2014

5 LATERAL METASTASIS IN THYROID CANCER were located in the upper third of the thyroid. We wanted to suggest another possible route of lateral cervical lymph node metastasis beyond CLN, known as primary echelon of thyroid cancer, rather than risk of lateral lymph node metastasis. Surgeons should evaluate lateral cervical lymph nodes carefully with considering the possibility of skip metastasis in patients with lesions in the upper part of the thyroid and without evident CLN metastasis. REFERENCES 1. Halsted WS. The results of radical operations for the cure of carcinoma of the breast. Ann Surg 1907;46: Fisher B. Biological research in the evolution of cancer surgery: a personal perspective. Cancer Res 2008;68: Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8: Machens A, Hinze R, Thomusch O, Dralle H. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 2002;26: Shaha AR. Management of the neck in thyroid cancer. 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