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Risk factors for right paraesophageal lymph node metastasis in papillary thyroid carcinoma: A meta-analysis
Surgical Oncology 32 (2020) 90–98
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Risk factors for right paraesophageal lymph node metastasis in papillary thyroid carcinoma: A meta-analysis Liang Shao, Wei Sun, Hao Zhang *, Ping Zhang, Zhihong Wang, Wenwu Dong, Liang He, Ting Zhang, Yuan Qin Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, 110001, Liaoning Province, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords: Papillary thyroid carcinoma Right paraesophageal lymph node Risk factors
Objective: Prophylactic dissection of the right paraesophageal lymph node (RPELN) in thyroid cancer is controversial. We performed a meta-analysis to provide evidence for RPELN dissection in thyroid cancer. Methods: We searched the PubMed and Science Citation Index Expanded (SCIE) databases for relevant studies published up to January 31, 2019. The patients involved all had a pathological diagnosis of papillary thyroid cancer (PTC) and had undergone total thyroidectomy or right lobectomy with central compartment lymph node dissection. The RPELNs had been kept aside during the operation. Results: Fourteen cohort studies involving 11,090 patients with PTC were included in the meta-analysis. There was RPELN metastases (RPELNM) in 1038 patients (9.36%). The factors related to RPELNM were: age <45 years, male sex, right lobe tumor, tumor >1 cm, extrathyroidal extension, capsular invasion, right paratracheal lymph node metastasis (RPTLNM), central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), and tumor multifocality. There was no association between RPELNM and Hashimoto’s thyroiditis (HT) and inferior pole tumors or tumor in the middle of the gland. With superior pole tumors, there was even less RPELNM. Conclusions: The clinical features related to RPELNM are age <45 years, male sex, tumor >1 cm, tumor diameter >2 cm, right lobe tumor, RPTLNM, extrathyroidal extension, capsular invasion, CLNM, CLNM �3, LLNM and multifocality, which should be considered when evaluating RPELN dissection.
1. Introduction Thyroid cancer is the most prevalent endocrine malignancy [1]. It is the fifth most common cancer in women in the USA [2] and the fourth most common cancer in China, increasing by 20% every year. In recent years, thyroid cancer morbidity has increased by three times in recent years [3]. Up to 80–85% of all primary thyroid cancers are papillary thyroid carcinoma (PTC) [1]. The prognosis of PTC is favorable, with 10-year survival >91% and 15-year survival >87% [4,5], but tumors frequently spread to the lymph nodes even when the primary tumor is small and intrathyroidal [6–8]. Up to 20–90% of patients present with central lymph node metastasis (CLNM) [9–11]. There is controversy regarding prophylactic central compartment lymph node dissection (PCLND). Nixon et al. found that the 5- and 10-year disease-specific survival of patients with PTC who did not undergo PCLND was 100%; they considered dynamic observation of CLN safe and that it should be
recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis [12,13]. A prospective study by Viola et al. reported that PCLND had no effect on outcome [14]. Besides this, many researchers believe that PCLND may increase the complication rate of recurrent laryngeal nerve(RLN)and parathyroid gland injury by about two times [15–17]. On the other hand, most scholars agree that CLNM is a vital prognostic factor of locoregional recurrence and mortality only second to distant metastasis [10]. Barc zynski et al. acknowledged that PCLND can improve both 10-year disease-specific survival and locoregional control without increasing the risk of permanent morbidity [18]. In summary, PCLND is increasing worldwide and has become a conventional treatment for patients with PTC in many Asian countries such as China, Japan, and Korea. The right paraesophageal lymph node (RPELN) is formed from fibrofatty tissue and is located between the right recurrent laryngeal nerve and the central esophagus; the carotid arteries form the lateral boundaries, the
* Corresponding author. Department of Thyroid Surgery, The First Hospital of China Medical University, 155 Nanjing Bei Street, Shenyang, Liaoning, 110001, PR China. E-mail address: [email protected] (H. Zhang). https://doi.org/10.1016/j.suronc.2019.11.007 Received 4 June 2019; Received in revised form 15 October 2019; Accepted 25 November 2019 Available online 2 December 2019 0960-7404/© 2019 Published by Elsevier Ltd.
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tracheal margins form the medial boundaries, the hyoid bone forms the superior boundary, the suprasternal fossa forms the inferior boundary, the anterior surface of the thyroid gland forms the anterior boundary, and the prevertebral fascia forms the posterior boundary. Several studies have reported lower metastasis rates in PTC, which ranges from 2.6% to 26.7% [19,20]. RPELN dissection is also hotly debated, given the low rate of metastases to this region, the greater technical difficulty involved, and the resulting higher incidence of complications [21]. Many surgeons often overlook this dissection. However, if metastatic lymph nodes are missed, locoregional recurrence or subsequent metas tases to the lateral lymph node (LLNM) and distant locations will affect overall survival. So et al. reported that reoperation of the central compartment may cause more complications for the RLN and para thyroid glands [22]. It is essential to evaluate RPELN dissection preop eratively. In the present meta-analysis, we attempted to analyze the risk factors of RPELN metastases (RPELNM) in PTC and to identify the in dications for RPELN dissection.
3. Result After filtering out studies, 159 articles were initially included. Sub sequently, 65 articles were excluded for duplication and language, and 74 reviews and irrelevant studies were excluded after careful reading of the titles and abstracts. The full text of the remaining 20 articles was evaluated. A total of 14 studies involving 11,090 patients were finally included in our meta-analysis based on the inclusion criteria; four studies were prospective and 10 studies were retrospective. Table 1 shows the basic characteristics of the articles, and S1 Table presents the original data. Begg’s funnel plots are presented in the Supporting In formation section. Fig. 1 depicts the flow chart of the article selection process. 3.1. Age A fixed-effects model was used (P ¼ 0.67, I2 ¼ 0%). There was RPELNM in 7.01% and 9.09% of patients aged �45 years and <45 years, respectively. This indicates that age <45 years may be closely related with RPELNM in patients with PTC (OR ¼ 0.76, 95% CI ¼ 0.64–0.90, P ¼ 0.001) (Fig. 2).
2. Materials and methods This meta-analysis was performed in accordance with the guidelines proposed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [23].
3.2. Sex We used a fixed-effects model to analyze the data (P < 0.65, I2 ¼ 0%). There was RPELNM in 8.62% of women and 12.47% of men. This shows that RPELNM is more common in male patients (OR ¼ 0.58, 95% CI ¼ 0.50–0.68, P < 0.00001) (Fig. 3).
2.1. Search strategy PubMed and Science Citation Index Expanded (SCIE) were system atically searched for relevant studies published up to January 31, 2019. The keywords for the search strings were ([thyroid carcinoma] OR thyroid neoplasm) AND (posterior to the right recurrent laryngeal nerve OR right paraesophageal lymph node). Two reviewers (Shao L and Sun W) performed the selection independently, and discrepancies were resolved through discussion.
3.3. Tumor location A random-effects model and 10 articles involving 4143 patients was used to determine whether foci location affected the rate of RPELNM. There was RPELNM in 18.82% of patients with right lobe foci, which was higher than the 12.07% of patients with tumors in other foci (P < 0.00001, I2 ¼ 78%), indicating that tumor location on the right lobe plays a positive role in metastasis (OR ¼ 1.66, 95% CI ¼ 1.01–2.73, P ¼ 0.04) (Fig. 4).
2.2. Inclusion criteria We selected studies that met the following criteria: (i) prospective or retrospective original literature; (ii) published in the English language; (iii) all patients had undergone thyroidectomy plus unilateral or bilat eral PCLND, and the RPELNs were kept aside during the operation; (iv) PTC was pathologically confirmed intraoperatively or postoperatively; (v) complete medical records were available for data extraction. Articles were excluded from the meta-analysis if: (i) they were abstracts, com ments, reviews, and editorials; (ii) patients had undergone completion thyroidectomy after primary surgery; (iii) lacked complete clinical data or follow-up information.
3.4. Size Twelve articles involving 9573 patients were used to analyze the relationship between tumor size and RPELNM using a fixed-effects model (P ¼ 0.60, I2 ¼ 0%). There was RPELNM in 14.84% of patients with tumor >1 cm and in 4.84% of patients with tumor �1 cm. This indicates that tumor >1 cm (OR ¼ 3.76, 95% CI 3.20–4.41, P < 0.00001) is significantly associated with RPELNM (Fig. 5). Furthermore, we investigated whether there was a difference when the tumor diameter was >2 cm, analyzing five studies using a random-effects model (P ¼ 0.02, I2 ¼ 66%). RPELNM was more common in patients with tumor diameter >2 cm (OR ¼ 4.21, 95% CI ¼ 1.92–9.26, P ¼ 0.0003) (Fig. 6).
2.3. Data extraction and quality assessment Two investigators independently extracted the relevant data from the included articles. The following information was extracted: authors, publication year, country of study, study design, case number, and surgical approach. The following possible risk factors and corresponding numbers of patients were recorded independently: age, sex, size, loca tion, extrathyroidal extension, capsular invasion, CLNM, LLNM, multi focality, and HT.
3.5. Extrathyroidal extension A random-effects model was used to compare the rate of RPELNM in patients with and without extrathyroidal extension (P ¼ 0.0001, I2 ¼ 73%). This involved 7 studies and the 7515 patients, and the results showed that extrathyroidal extension of tumor can significantly promote RPELNM (OR ¼ 3.70, 95% CI ¼ 1.89–7.23, P ¼ 0.0001) (Fig. 7).
2.4. Statistical analysis All statistical analyses were performed using RevMan version 5.3. The results are presented as odds ratios (ORs) with a 95% confidence interval (CI); P < 0.05 was considered statistically significant except where otherwise specified. Heterogeneity was quantified using the Qtest and the I2 statistic. When P > 0.1 and I2 < 50%, a fixed-effect model was used; otherwise, a random-effects model was applied. Possible publication bias was tested with Begg’s funnel plot.
3.6. Capsular invasion We analyzed eight articles involving 3656 patients using a randomeffects model to estimate the heterogeneity of the capsular invasion data (P < 0.0003, I2 ¼ 75%). The rate of RPELNM in the patients with and without capsular invasion was 21.82% and 13.39%, respectively, 91
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Table 1 Basic characteristics of the included studies. Author 19
Bae, S.Y Chang, H34 Ito, Y35 Kim, Y.S36 Lee, B37 Liu, Z38 Luo, D.C39 Luo, Y42 Park, Y. M45 Pinyi, Z43 Qu, Y44 Yu, Q40 Yuan, J41 Zhang, L20
Year
Country
Study design
Case number
Surgical intervention
Prevalence of RPELNM(%)
Quality assessment
2012 2015 2013 2012 2009 2016 2017 2018 2017 2013 2017 2018 2017 2016
Korea Korea Japan Korea Korea China China China Korea China China China China China
retrospective study retrospective study retrospective study prospective retrospective study prospective study prospective study prospective study retrospective study retrospective study retrospective study retrospective study retrospective study retrospective study
369 5556 922 243 123 145 306 595 1107 405 163 829 81 246
TT þ BCLND or RTL þ CLND TT þ ipsilateral/bilateral CLND TT/NTT/RTL þ ipsilateral/bilateral CLND TT þ ipsilateral/bilateral CLND TT þ ipsilateral/bilateral CLND TT þ BCLND TT/RTL þ ipsilateral/bilateral CLND TT/RTL þ ipsilateral/bilateral CLND TT þ BCLND or TT þ RCLND or RTL þ RCLND TT þ ipsilateral/bilateral CLND TT/RTL þ ipsilateral/bilateral CLND TT þ BCLND or RTL þ RCLND or NTT þ BCLND TT/NTT þ BCLND TT þ BCLND
12.2 2.7 14 5.8 36.6 42.1 16.7 17.14 15.4 26.7 12.3 19.1 38.3 13.4
7 8 6 7 7 8 7 7 7 8 7 7 7 8
CLND, central lymph node dissection; BCLNDL, bilateral central lymph node dissection; NTT, near total thyroidectomy; RTL, right thyroid lobectomy; TT, total thyroidectomy.
factors, using 10 and six articles, respectively (P < 0.00001, I2 ¼ 87%; P < 0.00001, I2 ¼ 91%, respectively). The significant differences indicate that CLNM and RPTLNM are both vital risk factors for RPELNM (OR ¼ 10.34, 95% CI ¼ 4.94–21.67, P < 0.00001; OR ¼ 9.06, 95% CI ¼ 3.13–26.23, P < 0.00001, respectively) (Fig. 9, Fig. 10). Based on the number of metastatic CLNs, analysis of five articles with a randomeffects model (P ¼ 0.12, I2 ¼ 45%) showed that CLNM � 3 was a posi tive factor of RPELNM (OR ¼ 6.89, 95% CI ¼ 4.58–10.35, P < 0.00001) (Fig. 11). 3.8. Lateral lymph node metastasis To assess the relationship between LLNM and RPELNM, 12 articles were analyzed using a random-effects model (P ¼ 0.01, I2 ¼ 53%), LLNM was identified as a risk factor for RPELNM (OR ¼ 6.89, 95% CI ¼ 4.58–10.35, P < 0.00001) (Fig. 12), with 4.23-fold higher morbidity. 3.9. Multifocality A random-effects model was used to evaluate the influence of mul tifocality on RPELNM (P < 0.00001, I2 ¼ 74%). There was more RPELNM in patients with >1 foci, indicating that multifocality is a risk factor for RPELNM (OR ¼ 1.91, 95% CI ¼ 1.31–2.47, P ¼ 0.0001) (Fig. 13).
Fig. 1. Flow chart of the meta-analysis.
indicating that patients with capsular invasion had more propensity for RPELNM (OR ¼ 2.78, 95% CI ¼ 1.80–4.30, P < 0.00001) (Fig. 8).
3.10. Hashimoto’s thyroiditis
3.7. Central lymph node metastasis
A fixed-effects model was used to assess the effect of HT on RPELNM (P ¼ 0.91, I2 ¼ 0%), and showed that HT had no significant effect on RPELNM (OR ¼ 0.78, 95% CI ¼ 0.61–1.00, P ¼ 0.05) (Fig. 14).
A random-effects model was used to determine whether CLNM or right paratracheal lymph node metastasis (RPTLNM) are RPELNM risk
Fig. 2. Forest plots of the association between age (PTC) and RPELNM in PTC patients. 92
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Fig. 3. Forest plots of the association between sex (PTC) and RPELNM in PTC patients.
Fig. 4. Forest plots of the association between right lobe and RPELNM in PTC patients.
Fig. 5. Forest plots of the association between tumor >1 cm and RPELNM in PTC patients.
3.11. Sub-location of right lobe tumor (SLRLT)
was even less metastasis to the superior pole (OR ¼ 2.16, 95% CI ¼ 1.44–3.25, P ¼ 0.002) (Fig. 17).
To clarify whether SLRLT affected the rate of RPELNM, a fixedeffects model was used to analyze the superior pole (P ¼ 0.87, I2 ¼ 0%) and inferior pole tumors (P ¼ 0.94, I2 ¼ 0%), and a random-effects model was used for the tumors in the middle of the gland (P ¼ 0.02, I2 ¼ 62%). Six articles involving 1283 patients were analyzed, and we found that there was no influence when the tumor was in the inferior pole (OR ¼ 1.02, 95% CI ¼ 0.72–1.43, P ¼ 0.93) (Fig. 15) or the middle of the right lobe (OR ¼ 0.74, 95% CI ¼ 0.41–1.36, P ¼ 0.33) (Fig. 16); there
4. Discussion Although most PTC follows an indolent course and has an optimistic prognosis [24,25], it is prone to spreading to the CLN earlier [6]; in the present study, a total 45.57% of patients had CLNM. It is debated whether PCLND should be routinely implemented. The American Thy roid Association (ATA) guidelines for differentiated thyroid cancer 93
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Fig. 6. Forest plots of the association between tumor >2 cm and RPELNM in PTC patients.
Fig. 7. Forest plots of the association between extrathyroidal extension and RPELNM in PTC patients.
Fig. 8. Forest plots of the association between capsular invasion and RPELNM in PTC patients.
Fig. 9. Forest plots of the association between central lymph node metastasis and RPELNM in PTC patients.
(DTC) recommend PCLND only for stage T3–4 patients with cN0 and all cN1b disease [26]. The National Comprehensive Cancer Network (NCCN) states that PCLND can be considered but is not required for all patients with cN0 PTC. Many scholars believe that PCLND cannot yield more benefit but frequently increases complications. However, Hartl et al. found that PCLND did not increase the incidence of complications, especially permanent morbidity [27]. This is because surgeons’ metic ulous surgical technique and surgical skill competency can also decrease complications. It is well-known that revision surgery in the scarred area presents a high risk for RLN, the parathyroid gland, and its blood supply.
A meta-analysis of 17 articles by Zhao et al. suggested that PCLND can decrease lymph node recurrence in an obvious manner, especially for CLN [28]. Furthermore, PCLND can help surgeons ascertain the tumor-node-metastasis (TNM) stage of patients with PTC to plan for follow-up radioactive iodine (RAI) therapy [29]. In addition, ascer taining CLNM can help predict LLNM to evaluate whether LLN dissec tion should be implemented [30]. Overall, PCLND is vital but should be implemented with caution. It is important to diagnose CLNM preoperatively to evaluate the necessity of the operation. Although the ATA recommends using preoperative 94
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Fig. 10. Forest plots of the association between right paratracheal lymph node metastasis and RPELNM in PTC patients.
Fig. 11. Forest plots of the association between central lymph node metastasis number�3 and RPELNM in PTC patients.
Fig. 12. Forest plots of the association between lateral lymph node metastasis and RPELNM in PTC patients.
Fig. 13. Forest plots of the association between multifocality and RPELNM in PTC patients.
ultrasound (US) and contrast-enhanced computed tomography (CT) to detect the relevant lymph node [26], B ultrasonography has 27.5% sensitivity for detecting CLNM [31]; US and CT have limited diagnostic value. Besides, US-guided fine-needle aspiration cytology (FNAC) was always been proposed as the gold-standard technique for suspicious or
malignant-appearing thyroid nodules and lymph nodes [32], but FNAC has false negative rates of 6–18% and up to 20% in non-diagnostic specimens [33]. The right central neck lymph nodes are divided into posterior and anterior parts. The RPELN is located posterior to the right RLN and is difficult to expose; complete dissection requires entire 95
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Fig. 14. Forest plots of the association between Hashimoto’s thyroiditis and RPELNM in PTC patients.
Fig. 15. Forest plots of the association between tumor in inferior of right lobe and RPELNM in PTC patients.
Fig. 16. Forest plots of the association between tumor in middle of right lobe and RPELNM in PTC patients.
Fig. 17. Forest plots of the association between tumor in superior of right lobe and RPELNM in PTC patients.
dissociation of the right RLN, which may cause more complications. Several studies have investigated the risk factors for RPELNM in patients with PTC, but the results were inconsistent [19,20,34–45]. Specific prospective cohort studies should be performed to establish the criteria for RPELN dissection. Here, we attempted tried to identify the risk fac tors for RPELNM to help evaluate the necessity of PCLND. Traditionally, the age of 45 years was of concern as a cut-off for evaluating the disease stage in patients. Many studies have reported that age <45 years is a risk factor for CLNM [46,47], but that mortality is lower in younger patients. In the present meta-analysis, we obtained the
same result: more patients with PTC aged <45 years had RPELNM. Although most thyroid cancer cases are diagnosed in women, ma lignancy and mortality are obviously higher in men [48]; this may be due to the high stress and unhealthy lifestyle, such as smoking and drinking, men face. The authors concluded that male patients with PTC had poorer prognosis. Similar with the conclusion of Besic et al. [49], we found in the pooled studies that more men had RPELNM. Tumor size is widely used in many staging systems such as that of American Joint Committee on Cancer (AJCC), International Union Against Cancer (UICC), MACIS (metastasis, age, completeness of 96
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resection, invasion, size), and NTCTCS (National Thyroid Cancer Treatment Cooperative Study), and the most-used cut-off in risk strati fication is 1 cm, which is accepted as a risk factor for CLNM and is related to higher mortality [50]. Large tumors are prone to being more aggressive [51]. Our data drew the coherent conclusion that RPELNM is increased when the tumor diameter is > 1 cm; the conclusion remained valid even when we increased the cut-off to 2 cm. In general, although skip metastasis exists, the CLN are generally the first and most commonly involved in metastasis [52]; we found more RPELNM in patients with right lobe tumor than in other sites. When we focused on the SLRLT, there was no difference between the middle and inferior pole locations. Moreover, there was less metastasis when the tumor was in the superior pole. PTC is multifocal in 18–87% of patients [32,33]. The relationship between multifocality and recurrence and mortality has long been controversial; multifocality was first considered to be intraglandular spread of the primary tumor initially [53]. Moreover, most studies agree that patients with multifocal tumors had more CLNM and worse TNM stage [54]. Many surgeons administer more radical treatment for such patients [55–57]. However, some researchers have argued that it has no impact on recurrence and overall survival in PTC after propensity score–matched analysis [58]. Our pooled data showed that patients with multifocal tumors had 1.2-fold more RPELNM than patients with single tumor foci. PTC has a slow and long course; tumors may break through the capsule of the gland and may invade the capsule or surrounding muscles, blood vessels, or even recurrent laryngeal nerves. There is consensus that extensive extrathyroidal extension has an important effect on lymph node metastasis and poor prognosis [59]; our data demonstrate that patients with both capsular invasion and extrathyroidal extension have more RPELNM. The RPELN is divided out of the CLN separately because of its special anatomic features, but its metastasis is linked with CLNM. Here, RPTLNM obviously indicated RPELNM; we also determined the rela tionship between CLNM and RPELNM, which we identified to be posi tive; >3 metastatic lymph nodes indicated a higher risk of RPELNM. Furthermore, analysis of LLNM yielded a similar result, i.e., if certain lymph nodes were metastatic and when there were >3, the patient may already have RPELNM. HT is common in people; the frequency of the association between PTC and HT ranges from 9% to 58% [60]. Most scholars agree that HT is a risk factor for the rate of PTC, but that it usually leads to a better clinical outcome [61,62]. Donangelo et al. have suggested that patients with HT have fewer metastatic cervical lymph nodes and more benign cervical lymph nodes [63], but we found no connection between HT and RPELNM. The different findings between our study and previous studies may be due to the different study designs. We noticed Dr. Park and colleagues performed a meta-analysis of RPENLM in their article [45]. After careful comparison, our main advantage lies in the following: Park et al. included a total of six articles involving 2308 patients, while we included a total of 14 articles involving 11,090 patients in our article, and our article includes more risk factors, including 2-cm diameter, tumor sublocation in the glan dular lobes, ETE, multifocal, and HT, so we believe that our article is a more comprehensive analysis of the risk factors of RPELNM, and pro vides more powerful evidence for surgeons to develop surgical strategies. Our study has several limitations. First, most of the pooled studies were not prospective or randomized case–control trials. Second, the studies were all from Asia. Third, we did not analyze whether left par atracheal lymph node metastasis can affect RPELNM. Fourth, the oper ative method in several studies included lobectomy and bilateral CLN dissection was not performed, which may disrupt the final result. In conclusion, our meta-analysis demonstrates the following risk factors for RPELNM: age <45 years, male sex, tumor <1 cm and diam eter <2 cm, right lobe tumor, extrathyroidal extension, capsular
invasion, RPTLNM, CLNM and CLNM >3, LLNM and multifocality. HT and right lobe foci have no effect on RPELNM. Although CLN and RPELN dissection presents complications, the operation should be evaluated and implemented more actively when �1 risk factors are found in pa tients with PTC. Author contributions L S,H Z, P Z, W S, W W D, Z H W, L H, T Z, Y Q contributed to this study. L S, W S performed the study. L S, W S analyzed the data. L S, H Z contributed materials, analysis tools. L S wrote the paper. Funding This work was supported by the Protect Funded by China Post doctoral Science Foundation (NO. 2018M641739), Natural Science Foundation of Liaoning Province (20180530090) and Science and Technology Project of Shenyang City (No. F16-205-1-41). Data availability statement The dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgments The authors declare that no conflicts of interest exist regarding the publication of this study. We would like to thank the native English speaking scientists of Elixigen Company (Huntington Beach, California) for editing our manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.suronc.2019.11.007. References [1] C.I. Lundgren, P. Hall, P.W. Dickman, J. Zedenius, Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested casecontrol study, Cancer-Am Cancer Soc 3 (2006) 524–531. [2] M.E. Cabanillas, D.G. McFadden, C. Durante, Thyroid cancer, Lancet 10061 (2016) 2783–2795. [3] D.S. Cooper, G.M. Doherty, B.R. Haugen, et al., Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer, Thyroid 11 (2009) 1167–1214. [4] R. Sciuto, L. Romano, S. Rea, F. Marandino, I. Sperduti, C.L. Maini, Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution, Ann. Oncol. 10 (2009) 1728–1735. [5] A. Toniato, I. Boschin, D. Casara, R. Mazzarotto, D. Rubello, M. Pelizzo, Papillary thyroid carcinoma: factors influencing recurrence and survival, Ann. Surg. Oncol. (2008) 1518–1522. [6] S.M. Chow, S.C. Law, J.K. Chan, S.K. Au, S. Yau, W.H. Lau, Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality, Cancer-Am Cancer Soc 1 (2003) 31–40. [7] S.K. Grebe, I.D. Hay, Thyroid cancer nodal metastases: biologic significance and therapeutic considerations, Surg. Oncol. Clin. N. Am. 1 (1996) 43–63. [8] I.D. Hay, C.S. Grant, J.A. van Heerden, J.R. Goellner, J.R. Ebersold, E.J. Bergstralh, Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period, Surgery 6 (1992) 1139–1146, 1146-7. [9] V.A. Smith, R.B. Sessions, E.J. Lentsch, Cervical lymph node metastasis and papillary thyroid carcinoma: does the compartment involved affect survival? Experience from the SEER database, J. Surg. Oncol. 4 (2012) 357–362. [10] Y.D. Podnos, D. Smith, L.D. Wagman, J.D. Ellenhorn, The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer, Am. Surg. 9 (2005) 731–734. [11] L. Rotstein, The role of lymphadenectomy in the management of papillary carcinoma of the thyroid, J. Surg. Oncol. 4 (2009) 186–188. [12] I.J. Nixon, L.Y. Wang, I. Ganly, et al., Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection, Br. J. Surg. 3 (2016) 218–225.
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Surgical Oncology journal homepage: http://www.elsevier.com/locate/suronc
Risk factors for right paraesophageal lymph node metastasis in papillary thyroid carcinoma: A meta-analysis Liang Shao, Wei Sun, Hao Zhang *, Ping Zhang, Zhihong Wang, Wenwu Dong, Liang He, Ting Zhang, Yuan Qin Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, 110001, Liaoning Province, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords: Papillary thyroid carcinoma Right paraesophageal lymph node Risk factors
Objective: Prophylactic dissection of the right paraesophageal lymph node (RPELN) in thyroid cancer is controversial. We performed a meta-analysis to provide evidence for RPELN dissection in thyroid cancer. Methods: We searched the PubMed and Science Citation Index Expanded (SCIE) databases for relevant studies published up to January 31, 2019. The patients involved all had a pathological diagnosis of papillary thyroid cancer (PTC) and had undergone total thyroidectomy or right lobectomy with central compartment lymph node dissection. The RPELNs had been kept aside during the operation. Results: Fourteen cohort studies involving 11,090 patients with PTC were included in the meta-analysis. There was RPELN metastases (RPELNM) in 1038 patients (9.36%). The factors related to RPELNM were: age <45 years, male sex, right lobe tumor, tumor >1 cm, extrathyroidal extension, capsular invasion, right paratracheal lymph node metastasis (RPTLNM), central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), and tumor multifocality. There was no association between RPELNM and Hashimoto’s thyroiditis (HT) and inferior pole tumors or tumor in the middle of the gland. With superior pole tumors, there was even less RPELNM. Conclusions: The clinical features related to RPELNM are age <45 years, male sex, tumor >1 cm, tumor diameter >2 cm, right lobe tumor, RPTLNM, extrathyroidal extension, capsular invasion, CLNM, CLNM �3, LLNM and multifocality, which should be considered when evaluating RPELN dissection.
1. Introduction Thyroid cancer is the most prevalent endocrine malignancy [1]. It is the fifth most common cancer in women in the USA [2] and the fourth most common cancer in China, increasing by 20% every year. In recent years, thyroid cancer morbidity has increased by three times in recent years [3]. Up to 80–85% of all primary thyroid cancers are papillary thyroid carcinoma (PTC) [1]. The prognosis of PTC is favorable, with 10-year survival >91% and 15-year survival >87% [4,5], but tumors frequently spread to the lymph nodes even when the primary tumor is small and intrathyroidal [6–8]. Up to 20–90% of patients present with central lymph node metastasis (CLNM) [9–11]. There is controversy regarding prophylactic central compartment lymph node dissection (PCLND). Nixon et al. found that the 5- and 10-year disease-specific survival of patients with PTC who did not undergo PCLND was 100%; they considered dynamic observation of CLN safe and that it should be
recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis [12,13]. A prospective study by Viola et al. reported that PCLND had no effect on outcome [14]. Besides this, many researchers believe that PCLND may increase the complication rate of recurrent laryngeal nerve(RLN)and parathyroid gland injury by about two times [15–17]. On the other hand, most scholars agree that CLNM is a vital prognostic factor of locoregional recurrence and mortality only second to distant metastasis [10]. Barc zynski et al. acknowledged that PCLND can improve both 10-year disease-specific survival and locoregional control without increasing the risk of permanent morbidity [18]. In summary, PCLND is increasing worldwide and has become a conventional treatment for patients with PTC in many Asian countries such as China, Japan, and Korea. The right paraesophageal lymph node (RPELN) is formed from fibrofatty tissue and is located between the right recurrent laryngeal nerve and the central esophagus; the carotid arteries form the lateral boundaries, the
* Corresponding author. Department of Thyroid Surgery, The First Hospital of China Medical University, 155 Nanjing Bei Street, Shenyang, Liaoning, 110001, PR China. E-mail address: [email protected] (H. Zhang). https://doi.org/10.1016/j.suronc.2019.11.007 Received 4 June 2019; Received in revised form 15 October 2019; Accepted 25 November 2019 Available online 2 December 2019 0960-7404/© 2019 Published by Elsevier Ltd.
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tracheal margins form the medial boundaries, the hyoid bone forms the superior boundary, the suprasternal fossa forms the inferior boundary, the anterior surface of the thyroid gland forms the anterior boundary, and the prevertebral fascia forms the posterior boundary. Several studies have reported lower metastasis rates in PTC, which ranges from 2.6% to 26.7% [19,20]. RPELN dissection is also hotly debated, given the low rate of metastases to this region, the greater technical difficulty involved, and the resulting higher incidence of complications [21]. Many surgeons often overlook this dissection. However, if metastatic lymph nodes are missed, locoregional recurrence or subsequent metas tases to the lateral lymph node (LLNM) and distant locations will affect overall survival. So et al. reported that reoperation of the central compartment may cause more complications for the RLN and para thyroid glands [22]. It is essential to evaluate RPELN dissection preop eratively. In the present meta-analysis, we attempted to analyze the risk factors of RPELN metastases (RPELNM) in PTC and to identify the in dications for RPELN dissection.
3. Result After filtering out studies, 159 articles were initially included. Sub sequently, 65 articles were excluded for duplication and language, and 74 reviews and irrelevant studies were excluded after careful reading of the titles and abstracts. The full text of the remaining 20 articles was evaluated. A total of 14 studies involving 11,090 patients were finally included in our meta-analysis based on the inclusion criteria; four studies were prospective and 10 studies were retrospective. Table 1 shows the basic characteristics of the articles, and S1 Table presents the original data. Begg’s funnel plots are presented in the Supporting In formation section. Fig. 1 depicts the flow chart of the article selection process. 3.1. Age A fixed-effects model was used (P ¼ 0.67, I2 ¼ 0%). There was RPELNM in 7.01% and 9.09% of patients aged �45 years and <45 years, respectively. This indicates that age <45 years may be closely related with RPELNM in patients with PTC (OR ¼ 0.76, 95% CI ¼ 0.64–0.90, P ¼ 0.001) (Fig. 2).
2. Materials and methods This meta-analysis was performed in accordance with the guidelines proposed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [23].
3.2. Sex We used a fixed-effects model to analyze the data (P < 0.65, I2 ¼ 0%). There was RPELNM in 8.62% of women and 12.47% of men. This shows that RPELNM is more common in male patients (OR ¼ 0.58, 95% CI ¼ 0.50–0.68, P < 0.00001) (Fig. 3).
2.1. Search strategy PubMed and Science Citation Index Expanded (SCIE) were system atically searched for relevant studies published up to January 31, 2019. The keywords for the search strings were ([thyroid carcinoma] OR thyroid neoplasm) AND (posterior to the right recurrent laryngeal nerve OR right paraesophageal lymph node). Two reviewers (Shao L and Sun W) performed the selection independently, and discrepancies were resolved through discussion.
3.3. Tumor location A random-effects model and 10 articles involving 4143 patients was used to determine whether foci location affected the rate of RPELNM. There was RPELNM in 18.82% of patients with right lobe foci, which was higher than the 12.07% of patients with tumors in other foci (P < 0.00001, I2 ¼ 78%), indicating that tumor location on the right lobe plays a positive role in metastasis (OR ¼ 1.66, 95% CI ¼ 1.01–2.73, P ¼ 0.04) (Fig. 4).
2.2. Inclusion criteria We selected studies that met the following criteria: (i) prospective or retrospective original literature; (ii) published in the English language; (iii) all patients had undergone thyroidectomy plus unilateral or bilat eral PCLND, and the RPELNs were kept aside during the operation; (iv) PTC was pathologically confirmed intraoperatively or postoperatively; (v) complete medical records were available for data extraction. Articles were excluded from the meta-analysis if: (i) they were abstracts, com ments, reviews, and editorials; (ii) patients had undergone completion thyroidectomy after primary surgery; (iii) lacked complete clinical data or follow-up information.
3.4. Size Twelve articles involving 9573 patients were used to analyze the relationship between tumor size and RPELNM using a fixed-effects model (P ¼ 0.60, I2 ¼ 0%). There was RPELNM in 14.84% of patients with tumor >1 cm and in 4.84% of patients with tumor �1 cm. This indicates that tumor >1 cm (OR ¼ 3.76, 95% CI 3.20–4.41, P < 0.00001) is significantly associated with RPELNM (Fig. 5). Furthermore, we investigated whether there was a difference when the tumor diameter was >2 cm, analyzing five studies using a random-effects model (P ¼ 0.02, I2 ¼ 66%). RPELNM was more common in patients with tumor diameter >2 cm (OR ¼ 4.21, 95% CI ¼ 1.92–9.26, P ¼ 0.0003) (Fig. 6).
2.3. Data extraction and quality assessment Two investigators independently extracted the relevant data from the included articles. The following information was extracted: authors, publication year, country of study, study design, case number, and surgical approach. The following possible risk factors and corresponding numbers of patients were recorded independently: age, sex, size, loca tion, extrathyroidal extension, capsular invasion, CLNM, LLNM, multi focality, and HT.
3.5. Extrathyroidal extension A random-effects model was used to compare the rate of RPELNM in patients with and without extrathyroidal extension (P ¼ 0.0001, I2 ¼ 73%). This involved 7 studies and the 7515 patients, and the results showed that extrathyroidal extension of tumor can significantly promote RPELNM (OR ¼ 3.70, 95% CI ¼ 1.89–7.23, P ¼ 0.0001) (Fig. 7).
2.4. Statistical analysis All statistical analyses were performed using RevMan version 5.3. The results are presented as odds ratios (ORs) with a 95% confidence interval (CI); P < 0.05 was considered statistically significant except where otherwise specified. Heterogeneity was quantified using the Qtest and the I2 statistic. When P > 0.1 and I2 < 50%, a fixed-effect model was used; otherwise, a random-effects model was applied. Possible publication bias was tested with Begg’s funnel plot.
3.6. Capsular invasion We analyzed eight articles involving 3656 patients using a randomeffects model to estimate the heterogeneity of the capsular invasion data (P < 0.0003, I2 ¼ 75%). The rate of RPELNM in the patients with and without capsular invasion was 21.82% and 13.39%, respectively, 91
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Table 1 Basic characteristics of the included studies. Author 19
Bae, S.Y Chang, H34 Ito, Y35 Kim, Y.S36 Lee, B37 Liu, Z38 Luo, D.C39 Luo, Y42 Park, Y. M45 Pinyi, Z43 Qu, Y44 Yu, Q40 Yuan, J41 Zhang, L20
Year
Country
Study design
Case number
Surgical intervention
Prevalence of RPELNM(%)
Quality assessment
2012 2015 2013 2012 2009 2016 2017 2018 2017 2013 2017 2018 2017 2016
Korea Korea Japan Korea Korea China China China Korea China China China China China
retrospective study retrospective study retrospective study prospective retrospective study prospective study prospective study prospective study retrospective study retrospective study retrospective study retrospective study retrospective study retrospective study
369 5556 922 243 123 145 306 595 1107 405 163 829 81 246
TT þ BCLND or RTL þ CLND TT þ ipsilateral/bilateral CLND TT/NTT/RTL þ ipsilateral/bilateral CLND TT þ ipsilateral/bilateral CLND TT þ ipsilateral/bilateral CLND TT þ BCLND TT/RTL þ ipsilateral/bilateral CLND TT/RTL þ ipsilateral/bilateral CLND TT þ BCLND or TT þ RCLND or RTL þ RCLND TT þ ipsilateral/bilateral CLND TT/RTL þ ipsilateral/bilateral CLND TT þ BCLND or RTL þ RCLND or NTT þ BCLND TT/NTT þ BCLND TT þ BCLND
12.2 2.7 14 5.8 36.6 42.1 16.7 17.14 15.4 26.7 12.3 19.1 38.3 13.4
7 8 6 7 7 8 7 7 7 8 7 7 7 8
CLND, central lymph node dissection; BCLNDL, bilateral central lymph node dissection; NTT, near total thyroidectomy; RTL, right thyroid lobectomy; TT, total thyroidectomy.
factors, using 10 and six articles, respectively (P < 0.00001, I2 ¼ 87%; P < 0.00001, I2 ¼ 91%, respectively). The significant differences indicate that CLNM and RPTLNM are both vital risk factors for RPELNM (OR ¼ 10.34, 95% CI ¼ 4.94–21.67, P < 0.00001; OR ¼ 9.06, 95% CI ¼ 3.13–26.23, P < 0.00001, respectively) (Fig. 9, Fig. 10). Based on the number of metastatic CLNs, analysis of five articles with a randomeffects model (P ¼ 0.12, I2 ¼ 45%) showed that CLNM � 3 was a posi tive factor of RPELNM (OR ¼ 6.89, 95% CI ¼ 4.58–10.35, P < 0.00001) (Fig. 11). 3.8. Lateral lymph node metastasis To assess the relationship between LLNM and RPELNM, 12 articles were analyzed using a random-effects model (P ¼ 0.01, I2 ¼ 53%), LLNM was identified as a risk factor for RPELNM (OR ¼ 6.89, 95% CI ¼ 4.58–10.35, P < 0.00001) (Fig. 12), with 4.23-fold higher morbidity. 3.9. Multifocality A random-effects model was used to evaluate the influence of mul tifocality on RPELNM (P < 0.00001, I2 ¼ 74%). There was more RPELNM in patients with >1 foci, indicating that multifocality is a risk factor for RPELNM (OR ¼ 1.91, 95% CI ¼ 1.31–2.47, P ¼ 0.0001) (Fig. 13).
Fig. 1. Flow chart of the meta-analysis.
indicating that patients with capsular invasion had more propensity for RPELNM (OR ¼ 2.78, 95% CI ¼ 1.80–4.30, P < 0.00001) (Fig. 8).
3.10. Hashimoto’s thyroiditis
3.7. Central lymph node metastasis
A fixed-effects model was used to assess the effect of HT on RPELNM (P ¼ 0.91, I2 ¼ 0%), and showed that HT had no significant effect on RPELNM (OR ¼ 0.78, 95% CI ¼ 0.61–1.00, P ¼ 0.05) (Fig. 14).
A random-effects model was used to determine whether CLNM or right paratracheal lymph node metastasis (RPTLNM) are RPELNM risk
Fig. 2. Forest plots of the association between age (PTC) and RPELNM in PTC patients. 92
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Fig. 3. Forest plots of the association between sex (PTC) and RPELNM in PTC patients.
Fig. 4. Forest plots of the association between right lobe and RPELNM in PTC patients.
Fig. 5. Forest plots of the association between tumor >1 cm and RPELNM in PTC patients.
3.11. Sub-location of right lobe tumor (SLRLT)
was even less metastasis to the superior pole (OR ¼ 2.16, 95% CI ¼ 1.44–3.25, P ¼ 0.002) (Fig. 17).
To clarify whether SLRLT affected the rate of RPELNM, a fixedeffects model was used to analyze the superior pole (P ¼ 0.87, I2 ¼ 0%) and inferior pole tumors (P ¼ 0.94, I2 ¼ 0%), and a random-effects model was used for the tumors in the middle of the gland (P ¼ 0.02, I2 ¼ 62%). Six articles involving 1283 patients were analyzed, and we found that there was no influence when the tumor was in the inferior pole (OR ¼ 1.02, 95% CI ¼ 0.72–1.43, P ¼ 0.93) (Fig. 15) or the middle of the right lobe (OR ¼ 0.74, 95% CI ¼ 0.41–1.36, P ¼ 0.33) (Fig. 16); there
4. Discussion Although most PTC follows an indolent course and has an optimistic prognosis [24,25], it is prone to spreading to the CLN earlier [6]; in the present study, a total 45.57% of patients had CLNM. It is debated whether PCLND should be routinely implemented. The American Thy roid Association (ATA) guidelines for differentiated thyroid cancer 93
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Fig. 6. Forest plots of the association between tumor >2 cm and RPELNM in PTC patients.
Fig. 7. Forest plots of the association between extrathyroidal extension and RPELNM in PTC patients.
Fig. 8. Forest plots of the association between capsular invasion and RPELNM in PTC patients.
Fig. 9. Forest plots of the association between central lymph node metastasis and RPELNM in PTC patients.
(DTC) recommend PCLND only for stage T3–4 patients with cN0 and all cN1b disease [26]. The National Comprehensive Cancer Network (NCCN) states that PCLND can be considered but is not required for all patients with cN0 PTC. Many scholars believe that PCLND cannot yield more benefit but frequently increases complications. However, Hartl et al. found that PCLND did not increase the incidence of complications, especially permanent morbidity [27]. This is because surgeons’ metic ulous surgical technique and surgical skill competency can also decrease complications. It is well-known that revision surgery in the scarred area presents a high risk for RLN, the parathyroid gland, and its blood supply.
A meta-analysis of 17 articles by Zhao et al. suggested that PCLND can decrease lymph node recurrence in an obvious manner, especially for CLN [28]. Furthermore, PCLND can help surgeons ascertain the tumor-node-metastasis (TNM) stage of patients with PTC to plan for follow-up radioactive iodine (RAI) therapy [29]. In addition, ascer taining CLNM can help predict LLNM to evaluate whether LLN dissec tion should be implemented [30]. Overall, PCLND is vital but should be implemented with caution. It is important to diagnose CLNM preoperatively to evaluate the necessity of the operation. Although the ATA recommends using preoperative 94
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Fig. 10. Forest plots of the association between right paratracheal lymph node metastasis and RPELNM in PTC patients.
Fig. 11. Forest plots of the association between central lymph node metastasis number�3 and RPELNM in PTC patients.
Fig. 12. Forest plots of the association between lateral lymph node metastasis and RPELNM in PTC patients.
Fig. 13. Forest plots of the association between multifocality and RPELNM in PTC patients.
ultrasound (US) and contrast-enhanced computed tomography (CT) to detect the relevant lymph node [26], B ultrasonography has 27.5% sensitivity for detecting CLNM [31]; US and CT have limited diagnostic value. Besides, US-guided fine-needle aspiration cytology (FNAC) was always been proposed as the gold-standard technique for suspicious or
malignant-appearing thyroid nodules and lymph nodes [32], but FNAC has false negative rates of 6–18% and up to 20% in non-diagnostic specimens [33]. The right central neck lymph nodes are divided into posterior and anterior parts. The RPELN is located posterior to the right RLN and is difficult to expose; complete dissection requires entire 95
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Fig. 14. Forest plots of the association between Hashimoto’s thyroiditis and RPELNM in PTC patients.
Fig. 15. Forest plots of the association between tumor in inferior of right lobe and RPELNM in PTC patients.
Fig. 16. Forest plots of the association between tumor in middle of right lobe and RPELNM in PTC patients.
Fig. 17. Forest plots of the association between tumor in superior of right lobe and RPELNM in PTC patients.
dissociation of the right RLN, which may cause more complications. Several studies have investigated the risk factors for RPELNM in patients with PTC, but the results were inconsistent [19,20,34–45]. Specific prospective cohort studies should be performed to establish the criteria for RPELN dissection. Here, we attempted tried to identify the risk fac tors for RPELNM to help evaluate the necessity of PCLND. Traditionally, the age of 45 years was of concern as a cut-off for evaluating the disease stage in patients. Many studies have reported that age <45 years is a risk factor for CLNM [46,47], but that mortality is lower in younger patients. In the present meta-analysis, we obtained the
same result: more patients with PTC aged <45 years had RPELNM. Although most thyroid cancer cases are diagnosed in women, ma lignancy and mortality are obviously higher in men [48]; this may be due to the high stress and unhealthy lifestyle, such as smoking and drinking, men face. The authors concluded that male patients with PTC had poorer prognosis. Similar with the conclusion of Besic et al. [49], we found in the pooled studies that more men had RPELNM. Tumor size is widely used in many staging systems such as that of American Joint Committee on Cancer (AJCC), International Union Against Cancer (UICC), MACIS (metastasis, age, completeness of 96
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resection, invasion, size), and NTCTCS (National Thyroid Cancer Treatment Cooperative Study), and the most-used cut-off in risk strati fication is 1 cm, which is accepted as a risk factor for CLNM and is related to higher mortality [50]. Large tumors are prone to being more aggressive [51]. Our data drew the coherent conclusion that RPELNM is increased when the tumor diameter is > 1 cm; the conclusion remained valid even when we increased the cut-off to 2 cm. In general, although skip metastasis exists, the CLN are generally the first and most commonly involved in metastasis [52]; we found more RPELNM in patients with right lobe tumor than in other sites. When we focused on the SLRLT, there was no difference between the middle and inferior pole locations. Moreover, there was less metastasis when the tumor was in the superior pole. PTC is multifocal in 18–87% of patients [32,33]. The relationship between multifocality and recurrence and mortality has long been controversial; multifocality was first considered to be intraglandular spread of the primary tumor initially [53]. Moreover, most studies agree that patients with multifocal tumors had more CLNM and worse TNM stage [54]. Many surgeons administer more radical treatment for such patients [55–57]. However, some researchers have argued that it has no impact on recurrence and overall survival in PTC after propensity score–matched analysis [58]. Our pooled data showed that patients with multifocal tumors had 1.2-fold more RPELNM than patients with single tumor foci. PTC has a slow and long course; tumors may break through the capsule of the gland and may invade the capsule or surrounding muscles, blood vessels, or even recurrent laryngeal nerves. There is consensus that extensive extrathyroidal extension has an important effect on lymph node metastasis and poor prognosis [59]; our data demonstrate that patients with both capsular invasion and extrathyroidal extension have more RPELNM. The RPELN is divided out of the CLN separately because of its special anatomic features, but its metastasis is linked with CLNM. Here, RPTLNM obviously indicated RPELNM; we also determined the rela tionship between CLNM and RPELNM, which we identified to be posi tive; >3 metastatic lymph nodes indicated a higher risk of RPELNM. Furthermore, analysis of LLNM yielded a similar result, i.e., if certain lymph nodes were metastatic and when there were >3, the patient may already have RPELNM. HT is common in people; the frequency of the association between PTC and HT ranges from 9% to 58% [60]. Most scholars agree that HT is a risk factor for the rate of PTC, but that it usually leads to a better clinical outcome [61,62]. Donangelo et al. have suggested that patients with HT have fewer metastatic cervical lymph nodes and more benign cervical lymph nodes [63], but we found no connection between HT and RPELNM. The different findings between our study and previous studies may be due to the different study designs. We noticed Dr. Park and colleagues performed a meta-analysis of RPENLM in their article [45]. After careful comparison, our main advantage lies in the following: Park et al. included a total of six articles involving 2308 patients, while we included a total of 14 articles involving 11,090 patients in our article, and our article includes more risk factors, including 2-cm diameter, tumor sublocation in the glan dular lobes, ETE, multifocal, and HT, so we believe that our article is a more comprehensive analysis of the risk factors of RPELNM, and pro vides more powerful evidence for surgeons to develop surgical strategies. Our study has several limitations. First, most of the pooled studies were not prospective or randomized case–control trials. Second, the studies were all from Asia. Third, we did not analyze whether left par atracheal lymph node metastasis can affect RPELNM. Fourth, the oper ative method in several studies included lobectomy and bilateral CLN dissection was not performed, which may disrupt the final result. In conclusion, our meta-analysis demonstrates the following risk factors for RPELNM: age <45 years, male sex, tumor <1 cm and diam eter <2 cm, right lobe tumor, extrathyroidal extension, capsular
invasion, RPTLNM, CLNM and CLNM >3, LLNM and multifocality. HT and right lobe foci have no effect on RPELNM. Although CLN and RPELN dissection presents complications, the operation should be evaluated and implemented more actively when �1 risk factors are found in pa tients with PTC. Author contributions L S,H Z, P Z, W S, W W D, Z H W, L H, T Z, Y Q contributed to this study. L S, W S performed the study. L S, W S analyzed the data. L S, H Z contributed materials, analysis tools. L S wrote the paper. Funding This work was supported by the Protect Funded by China Post doctoral Science Foundation (NO. 2018M641739), Natural Science Foundation of Liaoning Province (20180530090) and Science and Technology Project of Shenyang City (No. F16-205-1-41). Data availability statement The dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgments The authors declare that no conflicts of interest exist regarding the publication of this study. We would like to thank the native English speaking scientists of Elixigen Company (Huntington Beach, California) for editing our manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.suronc.2019.11.007. References [1] C.I. Lundgren, P. Hall, P.W. Dickman, J. Zedenius, Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested casecontrol study, Cancer-Am Cancer Soc 3 (2006) 524–531. [2] M.E. Cabanillas, D.G. McFadden, C. Durante, Thyroid cancer, Lancet 10061 (2016) 2783–2795. [3] D.S. Cooper, G.M. Doherty, B.R. Haugen, et al., Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer, Thyroid 11 (2009) 1167–1214. [4] R. Sciuto, L. Romano, S. Rea, F. Marandino, I. Sperduti, C.L. Maini, Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution, Ann. Oncol. 10 (2009) 1728–1735. [5] A. Toniato, I. Boschin, D. Casara, R. Mazzarotto, D. Rubello, M. Pelizzo, Papillary thyroid carcinoma: factors influencing recurrence and survival, Ann. Surg. Oncol. (2008) 1518–1522. [6] S.M. Chow, S.C. Law, J.K. Chan, S.K. Au, S. Yau, W.H. Lau, Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality, Cancer-Am Cancer Soc 1 (2003) 31–40. [7] S.K. Grebe, I.D. Hay, Thyroid cancer nodal metastases: biologic significance and therapeutic considerations, Surg. Oncol. Clin. N. Am. 1 (1996) 43–63. [8] I.D. Hay, C.S. Grant, J.A. van Heerden, J.R. Goellner, J.R. Ebersold, E.J. Bergstralh, Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period, Surgery 6 (1992) 1139–1146, 1146-7. [9] V.A. Smith, R.B. Sessions, E.J. Lentsch, Cervical lymph node metastasis and papillary thyroid carcinoma: does the compartment involved affect survival? Experience from the SEER database, J. Surg. Oncol. 4 (2012) 357–362. [10] Y.D. Podnos, D. Smith, L.D. Wagman, J.D. Ellenhorn, The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer, Am. Surg. 9 (2005) 731–734. [11] L. Rotstein, The role of lymphadenectomy in the management of papillary carcinoma of the thyroid, J. Surg. Oncol. 4 (2009) 186–188. [12] I.J. Nixon, L.Y. Wang, I. Ganly, et al., Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection, Br. J. Surg. 3 (2016) 218–225.
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