Metastatic lymph node status in the central compartment of papillary thyroid carcinoma: A prognostic factor of locoregional recurrence

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1 ORIGINAL ARTICLE Metastatic lymph node status in the central compartment of papillary thyroid carcinoma: A prognostic factor of locoregional recurrence Young Min Park, MD, PhD, 1 Soo-Geun Wang, MD, PhD, 2 Jin-Choon Lee, MD, PhD, 3 Dong Hoon Shin, MD, PhD, 4 In-Ju Kim, MD, PhD, 5 Seok-Man Son, MD, PhD, 6 Mijin Mun, MD, 7 Byung-Joo Lee, MD, PhD 2 * 1 Department of Otorhinolaryngology, Pundang Jesaeng Hospital, Deajin Medical Center, Seongnam, Gyeonggi, Korea, 2 Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea, 3 Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea, 4 Department of Pathology, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea, 5 Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea, 6 Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea, 7 Department of Otorhinolaryngology Head and Neck Surgery, Busan St. Marry s Medical Center, Busan, Korea. Accepted 3 July 2015 Published online 13 August 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to present our focus on the lymph node status in the central compartment and evaluate the relevant factors and disease recurrence. Methods. Between January 2004 and December 2009, 1040 patients were diagnosed with papillary thyroid carcinoma (PTC) and underwent surgery. Results. The number of metastatic lymph nodes was a significant predictor for recurrence conferring a hazard ratio of 1.36 (confidence interval ; p 5.004). The receiver operating characteristic (ROC) curve was calculated to determine the cutoff number of lymph nodes that predicted recurrence with the highest sensitivity and specificity (area under the ROC curve, 0.794; SE, 0.077; p 5.001). The sensitivity/specificity of >3 metastatic lymph nodes for predicting recurrence was 63.6%/77.0%, respectively. Conclusion. The number of metastatic lymph nodes in the central compartment was a statistical significant predictive factor associated with disease recurrence. Further study is required to confirm the relationship between the number of lymph nodes and disease recurrence. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E1172 E1176, 2016 KEY WORDS: lymphatic metastasis, recurrence, papillary thyroid cancer, lymph node status, prognostic factor INTRODUCTION Papillary thyroid carcinoma (PTC) is the most common malignancy occurring in the thyroid gland, the prognosis of which is generally very good because of its insidious growth and progression. 1 Although PTC metastasizes primarily to central lymph nodes (CLNs), the necessity of CLN dissection in the treatment of PTC has not been established. 2 4 Several investigators reported that a positive cervical lymph node was an independent risk factor for disease relapse, and that disease-free survival was worse in patients with metastatic lymph nodes in the lateral compartment. 5 8 Additionally, Ito et al 5 8 reported that the risk of recurrence is high if 5 or more metastatic lymph nodes are present in the lateral compartment. However, to our knowledge, few studies of the relationship between disease recurrence and lymph node metastases in the central compartment, especially lymph node status, including the number of metastatic lymph nodes, lymph *Corresponding author: B.-J. Lee, Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, 1-10 Ami-Dong, Seo-Gu, Busan , Korea. voiceleebj@gmail.com node ratio, unilaterality/bilaterality, and extracapsular spread (ECS), have been published. The present TNM staging system developed by the American Joint Commission on Cancer (2010, 7th edition) is used commonly for PTC staging. The staging system proposed lymph node metastasis in the central compartment as N1a and lymph node metastasis in the lateral compartment as N1b. 9 The system considered only the location of the metastatic lymph, excluding other factors, such as the number of metastatic lymph nodes, lymph node ratio, ECS, and unilaterality/bilaterality. In this study, we focused on the lymph node status in the central compartment in patients with PTC and evaluated the associated factors, recurrence rate, and disease-free survival. MATERIALS AND METHODS Patients Between January 2004 and December 2009, 1040 patients were diagnosed with PTC at Pusan National University Hospital. We analyzed their clinical records retrospectively. The Institutional Review Board approved this retrospective study. High-resolution ultrasound and CT scans were performed preoperatively in all patients to evaluate the extent of E1172 HEAD & NECK DOI /HED APRIL 2016

2 CENTRAL LYMPH NODE METASTASIS IN PTC following were defined as disease recurrence: histological evidence of newly developed lesions, enlarged lymph nodes observed on ultrasound with increased Tg levels, and recurrent lesions detected on diagnostic whole-body scan or positron emission tomography with increased Tg levels. FIGURE 1. Inclusion and exclusion criteria. PTC, papillary thyroid carcinoma; ECS, extracapsular spread; 1LN, positive lymph node; LNR, lymph node ratio. disease. Based on the results of these studies and the guidelines of the American Thyroid Association (2006), all patients routinely received total thyroidectomy with bilateral CLN dissection. As described previously, bilateral CLN dissection was performed to completely remove the CLN. 10 All fibro-fatty tissues containing lymph nodes from the hyoid bone superiorly to the innominate artery inferiorly and the common carotid artery laterally were removed. First, we removed ipsilateral paratracheal and pretracheal lymph nodes along the boundary of the central compartment, as described above. Then, contralateral paratracheal lymph nodes were removed separately. Patients with N0 or with lateral neck metastasis were excluded from the study. Patients were also excluded if distant metastasis was found at the time of diagnosis (see Figure 1). After all exclusions, 430 patients among a total of 1040 patients were included in the study. Follow-up strategies after the initial surgery I-131 thyroid remnant ablation was performed in all patients who underwent a surgery. Ablative dosage varied from 30 to 100 mci. Levothyroxine was stopped before ablation therapy to elevate endogenous thyroid stimulating hormone. After the surgery, thyroglobulin (Tg) and thyroid stimulating hormone levels were measured and ultrasound was performed at 3 to 6-month intervals to detect disease recurrence. Outcome measurements The main outcome measurements were disease recurrence, mean time to disease recurrence, and disease-free survival. Disease-free survival was defined as a period without disease recurrence after an initial treatment. The Relationship between lymph node status in the central compartment and recurrence The relevance of metastatic lymph node status in the central compartment to recurrence was analyzed. First, we analyzed the relationship between disease relapse and the number of metastatic CLNs; moreover, the number of metastatic lymph nodes with the highest sensitivity and specificity for predicting recurrence was evaluated using a receiver operating characteristics (ROC) curve. Lymph node ratio for each patient was calculated by dividing the number of metastatic lymph nodes by the total number of lymph nodes removed. Then, the relationship between disease relapse and lymph node ratio was evaluated and the cutoff level of lymph node ratio with the highest sensitivity and specificity for predicting recurrence was calculated using an ROC curve. Last, the relevance of recurrence, unilaterality/bilaterality, and ECS was evaluated. Statistical analysis Chi-square or Fisher s exact test was used to evaluate differences in categorical variables between 2 independent groups. An independent 2-sample t test was used to assess differences in continuous variables between 2 independent groups. Multivariate logistic regression analysis was performed to model dichotomous variables using the Cox proportional hazards model. Categorical cutoff values for the number of metastatic CLNs and lymph node ratio were based on frequently used cutoffs from the literature as well as ROC curves. ROC curves were plotted for the number of lymph nodes and lymph node ratio cutoff points. The value at which sensitivity and specificity were maximized for disease-free survival was selected for analysis. The Kaplan Meier curve was used to analyze disease-free survival and the survival outcomes were assessed using a log-rank test. A p value <.05 was considered to indicate statistical significance. Statistical analyses were performed using SPSS 18.0 for Windows (SPSS, Chicago, IL). RESULTS The medical records of 430 patients with pn1a were analyzed retrospectively. The median follow-up period was 74 months (range, months). The patients clinical information is summarized in Table 1. All patients received total thyroidectomy with bilateral CLN dissection. The median number of dissected lymph nodes was 9 (range, 1 31). Disease relapse was observed in 11 patients (2.6%) during the follow-up period. Recurrence of CLN metastasis occurred in 1 patient and lateral lymph node metastasis occurred in 10 patients. The recurrence pattern was analyzed based on the number of metastatic CLNs (Table 2). These recurrent lesions were histologically confirmed by ultrasonographyguided fine-needle biopsy. These 11 patients underwent HEAD & NECK DOI /HED APRIL 2016 E1173

3 PARK ET AL. TABLE 1. survival. Clinical variables Univariate analysis of clinical variables on recurrence free No. of patients (%) No. of events 5-y RFS p value Age, y.445 < (38) (62) Sex.057 Male 58 (16) Female 296 (84) Tumor size cm 305 (86) >2 cm 49 (14) Extrathyroidal extension.052 No 135 (38) Yes 219 (62) CLN metastasis.070 Unilateral 224 (63) Bilateral 130 (37) No. of metastatic CLN (76) >3 86 (24) (90) <.001 >5 36 (10) (97) <.001 >8 10 (3) Lymph node ratio (70) > (30) ECS.195 No 175 (75) Yes 58 (25) Abbreviations: RFS, recurrence-free survival; CLN, central lymph node; ECS, extracapsular spread. reoperations to remove the recurrent lesions and they received therapeutic dosage of I-131 ablation therapy. Univariate analyses demonstrated that the number of metastatic CLNs and lymph node ratio were significantly associated with disease recurrence (Table 1). Because of the correlation between the number of metastatic CLNs and lymph node ratio (R ; p <.001), multivariate logistic regression analysis using the Cox proportional hazards model was performed separately for each variable. Multivariate analysis only indicated a significant association between the number of metastatic CLNs and disease recurrence. The number of metastatic lymph nodes was the only significant predictor for recurrence, conferring a hazard ratio of 1.36 (confidence interval ; p 5.004). Next, the ROC curve was calculated to determine the cutoff number of metastatic lymph nodes that predicted recurrence with the highest sensitivity and specificity (area under ROC curve, 0.794; SE, 0.077; p <.001). Based on the ROC curve, the sensitivity/specificity of >3 metastatic lymph nodes for predicting recurrence was 63.6%/77.0%, respectively. The disease-free survival of patients with >3 metastatic lymph nodes was lower than that of patients with 1 to 3 metastatic lymph nodes (p 5.003; Figure 2A). The 5-year disease-free survival of patients with PTC with 0 to 3 metastatic lymph nodes and >3 metastatic lymph nodes was 98.5% and 89.2%, respectively. Next, the ROC curve was calculated to determine the cutoff level of lymph node ratio that predicted recurrence with the highest sensitivity and specificity (area under ROC curve, 0.746; SE, 0.084; p 5.005). Based on the ROC curve, the sensitivity/specificity of lymph node ratio >0.43 for predicting recurrence was 72.7%/71.7%, respectively. The disease-free survival of patients with lymph node ratio >0.43 was lower than that of patients with lymph node ratio 0.43 (p 5.003; Figure 2B). The 5-year disease-free survival of patients with PTC with lymph node ratio 0.43 and lymph node ratio >0.43 was 98.8% and 90.6%, respectively. In patients with CLN metastasis, no significant relationship between unilaterality/bilaterality and disease recurrence was detected on multivariate analysis and ECS of CLN was not significantly associated with disease recurrence on multivariate analysis. With regard to postoperative complications, temporal paralysis of the vocal cords occurred in 5 patients, and permanent paralysis occurred in 4 patients (2.5%). There were 13 cases (3.7%) of permanent hypocalcemia. There were no other significant complications. DISCUSSION Because PTC progresses and grows slowly, the prognosis in most cases is generally very good. However, several investigators reported a recurrence rate of 30% after an initial treatment. Shen et al 11 reported that reoperative CLN dissection has a lower rate of hypocalcemia and the same rate of other complications compared to initial CLN dissection. Kim et al 12 stated that revision surgery in the central compartment of the neck is compatible with successful eradication of disease and acceptable morbidity. However, reoperation is related to high morbidity in recurrent cases. 13,14 Postoperative complications, such as recurrent laryngeal nerve paralysis and hypoparathyroidism, occur frequently when reoperation is performed along the previously dissected surgical plane, decreasing patients quality of life. Because most patients with PTC live longer after treatment, these surgical complications are a significant burden to the patient and surgeon. Accordingly, determining predictive factors for disease recurrence is important as it would facilitate application TABLE 2. Recurrence events according to the number of metastatic central lymph node. No. of metastatic CLNs Recurrence events (%) No. of patients 1 1 (0.8) (1.3) (3.4) (3.0) (0) (0) (25) (14.3) (0) (100) (0) (50) 2 Abbreviation: CLNs, central lymph nodes. E1174 HEAD & NECK DOI /HED APRIL 2016

4 CENTRAL LYMPH NODE METASTASIS IN PTC FIGURE 2. (A) A Kaplan Meier curve was used to analyze disease-free survival; the survival outcomes were assessed using a log-rank test. Disease-free survival of patients with >3 metastatic lymph nodes was significantly different from that of patients with 1 to 3 metastatic lymph nodes (p 5.003). (B) A Kaplan Meier curve was used to analyze disease-free survival; the survival outcomes were assessed using a log-rank test. Disease-free survivalof patients with lymph node ratio >0.43 was significantly different from that of patients with lymph node ratio 0.43 (p 5.003). CLN, cervical lymph node; LNR, lymph node ratio. of more aggressive treatment strategies and close followup in high-risk patients. Early detection and treatment of disease relapse would also enhance treatment outcomes and reduce surgical morbidity. Although cervical lymph node metastasis occurs in 11% to 80% of patients with PTC, controversies remain regarding the relevance of lymphatic metastasis to prognosis In the current American Joint Commission on Cancer TNM staging, lymph node metastasis is reflected in staging only when patients are older than 45 years. Additionally, only the location of metastatic lymph nodes is considered; other node factors are excluded. Because the staging system was designed to predict mortality, the risk of recurrence was not predicted. In previous studies, lymph node metastasis was related to locoregional recurrence; indeed, lymph node metastasis in the lateral compartment was highly associated with disease relapse. 5 8 However, to our knowledge, few studies have evaluated the relevance of CLN metastasis and disease relapse. In our study, the number of metastatic lymph nodes and lymph node ratio were found to be significantly associated with recurrence in the multivariate analysis in patients with PTC. Specifically, the presence of >3 metastatic lymph nodes in the central compartment was related to worse disease-free survival. Previously, we mentioned that the probability of lateral neck node metastasis increases with the number of CLN metastases. Specifically, in patients with 3 nodal metastases of the central compartment, the risk of lateral neck node metastasis is higher than in patients with 0 to 2 nodal metastases. 19 Such an increased risk of lateral node metastasis could influence disease relapse and disease-free survival in patients with >3 CLN metastasis in this study. However, even though Ito et al 5 8 reported that ECS of metastatic lymph nodes was associated with disease relapse, our results did not confirm this. Although, I-131 ablation therapy is not administered routinely after surgery to patients with PTC in Japan. However, we administered it routinely to all patients, which may have led to the difference in recurrence between our study and the report by Ito et al. 5 8 Recently, Wang et al 20 studied CLN characteristics related to the prognosis of patients with PTC. They examined whether the number of positive lymph nodes, size of the largest lymph node, or ECS was related to recurrencefree survival. Unlike our results, a cutoff value of 8 or fewer positive lymph nodes was determined by ROC analysis in their study and only ECS was a statistically significant predictor of recurrence-free survival. In their study, central lymph nodes were dissected in cases of macroscopic lymph nodes on clinical or radiologic examination. However, in our institution, bilateral central lymph nodes were dissected in all cases. These aggressive surgical strategies could have an influence on the differences between our results and those of previous research. Several investigators reported recently that lymph node ratio was superior to the previous TNM staging system for predicting the prognosis of patients with carcinomas of the pancreas, stomach, and colon. 16,21,22 Although Ryu et al 23 reported an increased risk of locoregional recurrence in patients with pn1a disease with lymph node dissection >0.65, the result was significant only if at least 3 lymph nodes were removed. In the present study, irrespective of the number of lymph nodes removed, we confirmed that the risk of recurrence was increased if lymph node ratio was >0.43. Also, the disease-free survival of patients with PTC with lymph node ratio >0.43 was significantly lower than that of patients with PTC with lymph node ratio Because this study involved a retrospective analysis of patients medical records, limitations related to its design existed. However, considering the characteristics of PTC, performing a prospective, randomized clinical trial with a sufficient number of patients and a long-term follow-up period would be highly problematic. In addition, the HEAD & NECK DOI /HED APRIL 2016 E1175

5 PARK ET AL. follow-up period in our study was relatively short for evaluating recurrence and survival rates. However, compared with previous studies, a sufficient number of patients was included for analysis of the association between metastatic lymph node status in the central compartment and disease recurrence, which has not been investigated previously Additionally, more aggressive surgeries were performed in our institution, even for micro-ptc. In this study, total thyroidectomy and bilateral CLN dissection were performed in all patients. This treatment approach is questionable over the extent of surgery, especially in micro-ptc. Although other factors such as age, tumor size, and extrathyroidal extension are known to be prognostic factors of PTC, these factors were not statistically significant in this study. However, 5-year recurrence-free survival was worse with increasing age, tumor size, and extrathyroidal extension, although the relationships were not significant. 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