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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 681-685

The prognostic factors for clinical N1b patients in thyroid papillary carcinoma


Department of General Surgery, Ankara Oncology Training and Research Hospital, Ankara, Turkey

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Ulvi Murat Yuksel
Department of General Surgery, Ankara Oncology Training and Research Hospital, 06200 Demetevler, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1011_16

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 > Abstract 


Background: The aim of this study is to determine the prognostic factors which affect both disease-free survival (DFS) and overall survival (OS) in thyroid papillary carcinoma with clinical lateral lymph node metastasis.
Methods: One hundred and three papillary thyroid carcinomas diagnosed in adult patients received therapeutic lateral neck dissection between December 1989 and June 2010 were analyzed retrospectively. All of the patients were classified as American Thyroid Association (ATA) intermediate risk category. Age, gender, tumor stage and size, multicentricity and bilaterality, vascular invasion and extrathyroidal invasion, ipsilateral/contralateral lymph node involvement, lymph node ratio, extranodal tumor extension, and development of recurrence were the factors which might affect disease-free and OS. Univariate and multivariate analyses were performed. ROC analysis was used to find the cutoff value for lymph node ratio.
Results: One hundred and three patients were followed median 101 months. Locoregional or systemic recurrence developed in 20 patients (19.4%) while 7 patients (6.8%) had persistent disease. In multivariate analysis, lymph node ratio (P = 0.003, relative risk [RR] 5.4, 95% confident interval [CI] 1.7–16.5) and contralateral lymph node involvement (P = 0.02, RR 4.9, 95% CI 1.3–18.5) were the independent factors affecting DFS where contralateral lymph node involvement (P = 0.009, RR 44.4, 95% CI 2.5–765.2) was the only factor which affected OS.
Conclusions: Lymph node ratio and contralateral metastasis affect DFS while contralateral metastases only affect OS in patients with N1b thyroid papillary carcinoma.

Keywords: Lateral lymph node, prognosis, recurrence, thyroid papillary carcinoma


How to cite this article:
Yuksel UM, Turanli S, Acar Y, Berberoglu U. The prognostic factors for clinical N1b patients in thyroid papillary carcinoma. J Can Res Ther 2019;15:681-5

How to cite this URL:
Yuksel UM, Turanli S, Acar Y, Berberoglu U. The prognostic factors for clinical N1b patients in thyroid papillary carcinoma. J Can Res Ther [serial online] 2019 [cited 2019 Dec 13];15:681-5. Available from: http://www.cancerjournal.net/text.asp?2019/15/3/681/231410




 > Introduction Top


Papillary thyroid carcinoma is common among endocrine malignancies. Papillary thyroid carcinoma frequently metastasizes to the regional lymph nodes,[1] and this occurs approximately 30%–80% in papillary thyroid carcinoma patients.[2] According to tumor-node-metastasis staging system of the American Joint Committee on Cancer, regional lymph node metastasis is classified as central lymph node metastasis (N1a) and lateral lymph node metastasis (N1b) due to the location of metastatic lymph nodes.[3]

In addition to this staging system, some other factors have been investigated for the effect on clinical outcomes in various guidelines. These potential prognostic markers are aggressive histology, extrathyroidal extension, incomplete tumor resection, vascular invasion, multifocality, >5 involved lymph node, lymph node metastasis >3 cm, distant metastases, and BRAF and TERT gene mutations.[4] There are some studies investigating prognostic significance of lymph node ratio in disease recurrence as well.[5]

To the best of our knowledge, the presence of cervical lymph node metastasis in papillary thyroid carcinoma has limited prognostic utility for predicting disease-specific survival.[6],[7]

The impact of lymph node metastasis on locoregional recurrence has not been well identified. If the risk factors for poor prognosis in N1b patients are delineated, patients who need aggressive treatment can be identified, risk classifications can be ruled, and optimal management strategies can be stated. Our aim was to determine the prognostic factors which affect both disease-free survival (DFS) and overall survival (OS) in thyroid papillary carcinoma with clinical lateral lymph node metastasis.


 > Methods Top


Ethical consideration

The patients' data were collected retrospectively and approved by our Institutional Ethical Committee.

Study population and postoperative treatment

One hundred and three consecutive adult patients who received therapeutic lateral neck dissection because of papillary thyroid carcinoma, at Ankara Oncology Training and Research Hospital, between December 1989 and June 2010 were analyzed. Patients with gross extrathyroid extension, aggressive variant of papillary thyroid carcinoma and distant metastases at initial were excluded from the study. All of the patients were classified as intermediate risk group according to ATA risk stratification model.

All patients underwent total thyroidectomy at the time of the initial diagnosis. Diagnosis of lateral lymph node metastasis was confirmed with preoperative ultrasonography-guided fine-needle aspiration biopsy or excisional biopsy in most of the patients, and the diagnosis was established clinically (palpable lateral lymph node or suspicious radiological imaging) in a few of them. Lateral neck dissection was performed en bloc including regional lymph node levels of II–IV and V if necessary together with total thyroidectomy. Ipsilateral central lymph node dissection was also added to the surgical procedure. All the patients received I-131 ablative therapy after lateral lymph node dissection under hypothyroid conditions (after levothyroxine withdrawal for at least 4–6 weeks). After I-131 ablative therapy, an I-131 whole body scan was performed to confirm the success of ablation and then thyroid-stimulating hormone suppressive therapy was given. Any patient did not receive external beam radiotherapy during the postoperative period. However, it was used in 2 patients who had either unresectable structural recurrence (structural disease is that either biopsy proven or highly suspicious for disease with or without abnormal serum Tg [4]) or residual disease after re-resection in the follow-up period.

Follow-up procedure

In the postoperative follow-up period, patients received a routine periodic clinical examination (every 3–6 months at the initial year and then yearly interval). Serum thyroglobulin levels with or without thyroid-stimulating hormone stimulation, anti-thyroglobulin antibodies, and thyroid laboratory panel (thyroid-stimulating hormone, free T3 and T4) were measured. For patients suspected for disease recurrence, neck ultrasonography, positron emission tomography, magnetic resonance imaging, and whole body scan were performed. Patients were considered as having no evidence of disease if the stimulated thyroglobulin value was below 2 ng/mL with negative anti-thyroglobulin antibodies and if no tumor was identified on whole-body scan or radiologic imaging. Patients were regarded to have persistent disease if they had stimulated thyroglobulin value of at least 2 ng/mL and/or showed clinical, radiological or pathological evidence of disease during 12 months after lateral lymph node dissection. Subsequently developed disease after lateral neck dissection with no objective criteria for persistent disease was classified as recurrent disease. Recurrence was classified as locoregional if it involved the thyroid bed, trachea, esophagus, midline of the neck in the thyroid region, or nodes of the neck near the previous neck dissection.

Prognostic parameters

We analyzed several clinicopathological features on survival. Age, gender, tumor stage and size, multicentricity and bilaterality of the tumor, vascular invasion and extrathyroidal invasion of the primary tumor, ipsilateral/contralateral lymph node involvement, lymph node ratio, extranodal tumor extension, and development of recurrence were the factors which might affect disease-free and OS. Primary tumor diameter was measured directly on the surgical thyroid specimens. Lymph node ratio was calculated by dividing the number of positive lymph nodes by the total number of lymph nodes removed.

Statistical analysis

The primary end-point of the study was DFS and OS. Lateral lymph node dissection was the starting point for DFS and OS. Patients were followed up until either to death or to the last date the patient was known to be alive. Descriptive statistics were used to calculate frequencies and percentages for all variables involved. Univariate analysis of continuous variables was performed using t-test, and categorical values were determined using the Fisher's exact test. A receiver operating characteristic analysis was used to find the cutoff value with the highest accuracy for lymph node ratio. Univariate survival curves for DFS and death were estimated using the Kaplan–Meier method for the patients without persistent disease; group differences in survival time were tested by the log-rank test. Multivariate Cox regression analysis was carried out to compare and to identify independent prognostic factors for DFS and death. All significant parameters in univariate analysis were used in the multivariate model and excluded for P > 0.05. All analysis was carried out using SPSS software (21.0; SPSS Inc, Chicago, IL, USA).


 > Results Top


This study involved 103 consecutive papillary thyroid cancer patients with clinical N1b lymph node metastasis. According to the American Joint Commission on Cancer 7th edition/TNM Classification System, there were 60 patients in Stage I and 43 patients in stage IVA. The median age of the patients was 42 years (range 19–74 years) when lateral lymph node metastasis diagnosed. The histological subtypes were papillary carcinoma in 89, follicular variant in 12, tall cell variant in 1, and columnar variant in 1 patient. Lateral lymph node dissection was performed bilaterally on 7 patients whereas the rest of the patients received it unilaterally. All the patients those who have unilateral lateral lymph node metastasis received unilateral central dissection together with unilateral lateral lymph node dissection. The rest of the patients (7 patients) underwent bilateral central neck dissection.

The factors related with survival

Patients and tumor characteristics were given in [Table 1]. In 36 patients, the tumor was localized in the right lobe, in 34 patients left lobe, and in 33 patients tumor was confined to both lobes. The tumor size was 1 cm or less in 16 patients, more than 1 cm but not more than 2 cm in 27 patients, more than 2 cm but not more than 4 cm in 46 patients, more than 4 cm in 11 patients, and the primary tumor could not be assessed in 3 patients. There was contralateral metastasis in 4 patients. The median number of metastatic and total removed lymph node was 4 (range 1–41) and 23 (range 12–75), respectively.
Table 1: Patients and tumor characteristics

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Clinical outcomes

The follow-up period of the patients was median 101 months (range 16–308 months). During the follow-up period, locoregional or systemic recurrence developed in 20 patients (19.4%) while 7 patients (6.8%) had persistent disease and any recurrence was not experienced in the rest of the patients. In addition, locoregional structural recurrence was developed in two out of seven patients with persistent disease. Locoregional and systemic recurrence rates were 81.5% and 18.5%, respectively, and repeated operations for disease recurrence in the lateral neck were conducted in 22 patients (21.4%) in median 36.5 months. After central lymph node dissection, structural recurrence in Level VI neck area did not develop in any of the patients. TNM stage did not affect recurrence after lateral lymph node dissection either (16.1% in Stage I patients and 28.2% in Stage IV A patients, P = 0.15). In the follow-up period, I-131 ablative therapy was readministered if needed. The median DFS time after lateral neck dissection was 88.5 months. At the end of the study, only our patients (3.9%) died because of the disease.

Univariate and multivariate analysis

The effective factors on DFS and OS in univariate analysis were given in [Table 2]. Advanced age and lateral lymph node metastasis development in contralateral side had negative effect on OS. In addition, when persistent disease excluded development of locoregional or systemic recurrence after lateral lymph node dissection affected OS adversely compared with progression-free disease.(225.9 ± 13.4 vs. 304.3 ± 3.6 months, P = 0.007). Furthermore, locoregional recurrence development did not affect OS adversely in the whole cohort (P = 0.07). OS was much poorer in case of systemic disease development than both locoregional disease development and in patients with no structural disease (P = 0.002, and P = 0.001 respectively). In multivariate analysis, lymph node ratio (P = 0.003, relative risk (RR) 5.4, 95% confident interval [CI] 1.7–16.5) and contralateral lymph node involvement (P = 0.02, RR 4.9, 95% CI 1.3–18.5) were the independent factors affecting DFS. On the other hand, contralateral lymph node involvement (P = 0.009, RR 44.4, 95% CI 2.5–765.2) was the only factor which affected OS. The prognostic value of lymph node ratio was reasonable in our analysis with a sensitivity of 80.0% and a specificity of 62.0% at a cutoff value of 0.21.
Table 2: Investigated parameters for disease-free survival and overall survival by Kaplan-Meier method

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 > Discussion Top


The incidence of papillary thyroid carcinoma is increasing rapidly worldwide.[8] The tumor spreads mainly by lymphatic route. Central lymph nodes are usually the first station; however, sometimes skip metastasis to the lateral lymph nodes is possible.[9] Studies have shown that N1b stage is an independent prognostic factor for DFS and cause-specific survival of papillary thyroid carcinoma patients, who frequently show recurrence in the lymph nodes.[10],[11] Herein, we investigated the clinicopathological parameters which may have effect on DFS and OS in N1b patients.

Disease recurrence rate was 19.4% in our study for median 101 months. The incidence of disease recurrence ranges between 10% and 28%, in literature.[7],[12],[13],[14] This wide range of recurrence in literature can be attributed to various follow-up periods. Most of other studies have a follow-up period of at least 5 years. When the long follow-up period of this study considered, the recurrence rate seems to be quite better compared with those others. Probably, this is because of younger median age in the present study. Only in univariate analysis, we found age as a significant parameter both in DFS and OS whereas gender affected only DFS. This is compatible with the recent studies.[7],[15],[16],[17] There are also some studies sustaining male gender affecting disease recurrence as well.[7],[16],[18] Tumor size and stage, extrathyroidal invasion, multicentricity and bilaterality of the tumor, extranodal extension of the involved lymph node did not affect DFS and OS in this study. There is no consensus on multicentricity and bilaterality affecting prognosis; however, there is almost an agreement in tumor size and extranodal extension of the involved lymph node affecting survival in literature.[12],[16],[17],[18],[19] There were discordant numbers of patients with and without extranodal extension which may lead to this difference in our study. Furthermore, the fundamental reason may be the heterogeneous conditions of other studies; including all the differentiated thyroid cancers in the study other than papillary thyroid carcinoma, the extent of thyroidectomy and receiving I-131 ablative therapy, and applying prophylactic or therapeutic lateral neck dissection may cause the difference in studies.[20] Our study included only papillary thyroid carcinoma diagnosed patients, and all of them received total thyroidectomy and I-131 ablative therapy. Therefore, also, the significance of tumor size in survival may not be displayed.

Metastatic lymph node ratio is a prognostic factor in most recent studies.[4],[12],[17],[18],[21],[22] There are various cutoff values of 0.26–0.42 for metastatic lymph node ratio in these studies. This difference both depends on the extent of lymph node dissection and surgical practice (prophylactic or therapeutic lateral neck dissection) as well. Metastatic lymph node ratio rather than the number of involved lymph nodes was an independent factor for DFS in our study with a cutoff value of 0.21 (P = 0.001). However, we were not able show the effect of metastatic lymph node ratio on OS. A minority of patients die because of the indolent course and favorable prognosis of papillary thyroid carcinoma. In our study, four patients died due to disease. The length of follow-up period was insufficient to show the effect of metastatic lymph node ratio on OS. For this reason, the effect of metastatic lymph node ratio on OS may not be expressed in our study.

Skip metastases are ipsilateral lymph node metastases without affected central lymph nodes, and they are rarely seen.[9] Contralateral lymph node metastases are more prevalent only in tumors that already had ipsilateral lymph node metastases.[23] However, papillary thyroid carcinoma located in one lobe showing contralateral but not ipsilateral N1b is not impossible. To the best of our knowledge, Ito et al.[24] were the only researchers investigating the relationship between isolated contralateral lymph node metastasis and survival. They claim that isolated contralateral lymph node metastasis causes indolent behavior of the disease and they did not report any recurrence and mortality in those 13 patients in an average follow-up period of 69 months. However, seven out of these 13 patients also revealed ipsilateral lymph node metastasis in postoperative pathology. Furthermore, those patients who had real isolated contralateral lymph node metastasis showed no extrathyroidal extension. There were only four patients of this type in our study. All of them revealed microscopic ipsilateral lymph node metastases. All of them were aged over 45 years and showed extrathyroidal extension as well. In our study, contralateral lymph node metastasis is the only independent factor which affected both DFS and OS (P = 0.003, and P = 0.001).

In literature, most of the studies related to effective parameters on recurrence and survival are not homogeneous when applied surgery, histological type, and postoperative adjuvant treatments considered. This is a single-center study with a long follow-up period which includes homogeneous study population regarding mentioned features. However, small sample size is the weakness of this study.


 > Conclusions Top


The clinical significance of metastatic lymph node ratio and contralateral lymph node metastasis in DFS after long-term follow up are shown in this study. However, contralateral lymph node metastasis was the only independent parameter for OS in patients with clinical N1b patients in papillary thyroid carcinoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Sivanandan R, Soo KC. Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg 2001;88:1241-4.  Back to cited text no. 1
    
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Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: Frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237:399-407.  Back to cited text no. 2
    
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Wang LY, Palmer FL, Nixon IJ, Tuttle RM, Shah JP, Patel SG, et al. Lateral neck lymph node characteristics prognostic of outcome in patients with clinically evident N1b papillary thyroid cancer. Ann Surg Oncol 2015;22:3530-6.  Back to cited text no. 6
    
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Kim SJ, Park SY, Lee YJ, Lee EK, Kim SK, Kim TH, et al. Risk factors for recurrence after therapeutic lateral neck dissection for primary papillary thyroid cancer. Ann Surg Oncol 2014;21:1884-90.  Back to cited text no. 7
    
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Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006;295:2164-7.  Back to cited text no. 8
    
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Lim YC, Koo BS. Predictive factors of skip metastases to lateral neck compartment leaping central neck compartment in papillary thyroid carcinoma. Oral Oncol 2012;48:262-5.  Back to cited text no. 9
    
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Wada N, Masudo K, Nakayama H, Suganuma N, Matsuzu K, Hirakawa S, et al. Recommendation for subclass evaluation of TNM stage iva papillary thyroid carcinomas: T4aN1b patients are at risk for recurrence and survival. Ann Surg Oncol 2008;15:1511-7.  Back to cited text no. 11
    
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Lee CW, Roh JL, Gong G, Cho KJ, Choi SH, Nam SY, et al. Risk factors for recurrence of papillary thyroid carcinoma with clinically node-positive lateral neck. Ann Surg Oncol 2015;22:117-24.  Back to cited text no. 12
    
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Bardet S, Malville E, Rame JP, Babin E, Samama G, De Raucourt D, et al. Macroscopic lymph-node involvement and neck dissection predict lymph-node recurrence in papillary thyroid carcinoma. Eur J Endocrinol 2008;158:551-60.  Back to cited text no. 13
    
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Shah MD, Hall FT, Eski SJ, Witterick IJ, Walfish PG, Freeman JL, et al. Clinical course of thyroid carcinoma after neck dissection. Laryngoscope 2003;113:2102-7.  Back to cited text no. 14
    
15.
Ito Y, Kudo T, Kobayashi K, Miya A, Ichihara K, Miyauchi A, et al. Prognostic factors for recurrence of papillary thyroid carcinoma in the lymph nodes, lung, and bone: Analysis of 5,768 patients with average 10-year follow-up. World J Surg 2012;36:1274-8.  Back to cited text no. 15
    
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Su DH, Chang SH, Chang TC. The impact of locoregional recurrences and distant metastases on the survival of patients with papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2015;82:286-94.  Back to cited text no. 16
    
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Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid 2012;22:1144-52.  Back to cited text no. 19
    
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Lee J, Song Y, Soh EY. Prognostic significance of the number of metastatic lymph nodes to stratify the risk of recurrence. World J Surg 2014;38:858-62.  Back to cited text no. 20
    
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Takada H, Kikumori T, Imai T, Sawaki M, Shibata A, Kiuchi T, et al. Patterns of lymph node metastases in papillary thyroid carcinoma: Results from consecutive bilateral cervical lymph node dissection. World J Surg 2011;35:1560-6.  Back to cited text no. 21
    
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Beal SH, Chen SL, Schneider PD, Martinez SR. An evaluation of lymph node yield and lymph node ratio in well-differentiated thyroid carcinoma. Am Surg 2010;76:28-32.  Back to cited text no. 22
    
23.
Lee KE, Chung IY, Kang E, Koo do H, Kim KH, Kim SW, et al. Ipsilateral and contralateral central lymph node metastasis in papillary thyroid cancer: Patterns and predictive factors of nodal metastasis. Head Neck 2013;35:672-6.  Back to cited text no. 23
    
24.
Ito Y, Higashiyama T, Takamura Y, Kobayashi K, Miya A, Miyauchi A, et al. Prognosis of patients with papillary thyroid carcinoma located in one lobe showing lateral node metastasis in the contralateral but not ipsilateral compartment. J Thyroid Res 2012;2012:953603.  Back to cited text no. 24
    



 
 
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