The prognostic implication of skip metastasis to lateral neck in patients with papillary thyroid cancer

Introduction

The most prevalent kind of differentiated thyroid cancer, papillary thyroid cancer (PTC), is on the rise globally (1). Even with PTC, which has a generally good prognosis, early lymph node metastasis (LNM) may occur. Lymph node (LN) involvement affects 20–60% of PTC patients (1,2). Many studies have shown a connection between PTC patients with LNM and cause-specific death, distant metastases, and local recurrence. Local recurrence control has become a major challenge for most surgeons (3,4). A previous study showed that LNM of PTC occurs in a sequential manner through the lymphatic system: the metastasis involves the central compartment first, followed by the ipsilateral lateral compartment, and finally reaches the contralateral lateral or mediastinal compartment (5). This stepwise pattern of LNM helps predict the central LNM in the presence of specific lateral LNM (6). However, the LNM in lateral compartments that remains negative in the central compartment is referred to as “skip metastasis”, with the incidence of ranging from 1.6% to 21.8% in patients with PTC (7-11). Pre-operative detection of LNM and surgical resection are significant for skip metastasis in preventing recurrence and subsequent re-operation.

Ultrasound is the preferred method to detect cervical LNM in thyroid cancer patients, but it has exhibited a variable and low sensitivity, ranging from 27.3% to 93.8% (12,13). The detection rate of cervical LNM is affected by the experience of sonographers. Some sonographers may miss some suspicious cervical LNs. Clinical and imaging findings should be combined to prevent the misdiagnosis of cervical LNM. Moreover, as a rare event, it might be ignored by radiologists and surgeons who perform routine central LN resection, given that the central compartment is the first compartment of LNM. Few pieces of research have studied the characteristics and prognosis of the skip metastasis, and the available results have varied. This study sought to investigate patterns and the prognosis of skip metastasis in PTC, and assess the relationship between skip metastasis and clinicopathological and sonographic factors. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1737/rc).

Methods

Patient identification

Retrospective identification was performed on 4,265 PTC patients who underwent thyroidectomy at our center between January 2013 and April 2016. The inclusion criteria were as follows: (I) thyroidectomy including central and, if needed, therapeutic lateral neck dissection had been carried out (II) PTC and positive lateral lymph node metastases (LLNM) verified by final histological testing, (III) age above 18 years. Patients who had undergone thyroidectomy at another center were excluded. There were 494 patients in total. Patients were divided into 2 groups according to whether they had skip metastases to the lateral neck. Preoperative imaging suggestive of LLNM, cytologically suggestive of LLNM, or noticeably high thyroglobulin (Tg) in the eluate are among the indications for dissection of the lateral LNs.

Positive LLNM combined with negative nodes in the central compartment was referred to as skip metastasis. Thyroid-stimulating hormone (TSH), anti-Tg antibody, and Tg levels were periodically evaluated in plasma, and conventional ultrasound was conducted as part of the follow-up examinations. Patients underwent whole-body 131-iodine scan, magnetic resonance imaging (MRI), computed tomography (CT), or 18-fluorodeoxyglucose positron emission tomography (PET) if there was a suspicion of cancer recurrence or persistence. An experienced surgeon and radiologist evaluated the Tg level (suppressed Tg >1 ng/mL or stimulated Tg >10 ng/mL) and Tg antibody status (rising Tg antibodies) in conjunction with the persistent or newly discovered loco-regional or distant metastases to determine recurrence/persistence in the current study (1,14). Any disagreements were resolved through discussion.

Data collection

The Philips IU 22 (Philips Healthcare, Eindhoven, Netherlands) and GE Logiq 9 (GE Healthcare, Milwaukee, WI, USA) ultrasound examination machines were utilized, each having a linear-array transducer operating at 5–12 MHz. Preoperative ultrasound was used to assess the location, composition, echogenicity, shape, border, multifocal lesions, microcalcifications, risk stratification of the American Thyroid Association (ATA), and vascularity of thyroid nodules. For multifocal cases, the largest tumor was analyzed. By color Doppler flow (15), vascularity was categorized into 5 patterns: 0 for no flow, 1 for minimal internal flow without peripheral flow, 2 for a peripheral flow with minimal or no internal flow, 3 for a peripheral flow with a small to moderate amount of internal flow, and 4 for extensive internal flow. There were 5 categories for thyroid nodules following the 2015 ATA guidelines (highly suspicious, intermediately suspicious, low-suspicion, very-low suspicion, and benign) (1).

Tumor size, extrathyroidal extension, Hashimoto’s thyroiditis, the status of the center and lateral LNs, and BRAF mutation were from the pathological findings. Lateral neck LNs were classified into levels II, III, IV, and V. Central neck LNs included levels VI and VII LNs. We calculated the number of LNMs in relation to the neck level. According to the 2015 ATA guideline, high-volume LNM is a significant prognostic factor (1). More than 5 metastatic lateral LNs were referred to as high-volume LLNM. A low-volume LLNM was defined as less than or equal to 5 metastatic lateral LNs.

Statistical analysis

Quantitative data were expressed as the mean ± standard deviation (SD). An unpaired t-test was utilized to assess differences between the 2 groups while analyzing parametric data. The Mann-Whitney U test was used to assess group differences in nonparametric data. The chi-square (χ²)-test was used to evaluate the associations between the characteristics and skip metastases. The stepwise regression method was used to create a multivariate logistic regression model based on the parameters from the statistically significant findings of the χ²-tests. The receiver operating characteristic (ROC) curve was plotted by comparing these outcomes. The Kaplan-Meier method and log-rank test were used to analyze recurrence/persistence rates. The software SPSS 19.0 (IBM, Armonk, NY, USA) was used for all statistical analyses. P values less than 0.05 were regarded as statistically significant differences.

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. K2768) and the requirement for individual consent for this retrospective analysis was waived.

Results

Demographic and baseline features of the patient

Among the 4,265 patients with PTC, LLNMs were confirmed in 494 (11.6%) patients. Skip metastasis was detected in 38 patients. The prevalence of skip metastasis was 0.89 % in PTC patients, and 7.7 % in PTC patients with LLNM. The frequency of skip metastasis in patients with metastatic PTC was 7.9% (15/191), and 7.6% (23/303) in patients with tumor size >1 cm.

Clinicopathological and sonographic features of PTC patients with skip metastasis

The patients with skip metastasis consisted of 28 women and 10 men. The majority of the patients were female (73.7%). The mean age of the patients was 42.8±12.4 years (range, 20–69 years). The mean size of the tumor was 1.2±0.5 cm. We observed the ultrasound features of thyroid nodules with skip metastasis. Some 26 individuals (68.4%) developed their largest tumor in the upper lobe, 11 (28.9%) in the middle lobe, and 1 (2.6%) throughout the entire lobe of the thyroid gland. Regarding the echogenicity of the nodules, most of them (35/38, 92.1%) were solid, and 3 (7.9%) had a mixed structure; furthermore, most of them were hypoechoic mass (33/38, 86.8%) with multifocality (27/38, 71.1%), microcalcifications (32/38, 84.2%), taller-than-wide ≤1 shape (33/38, 86.8%), ill-defined border (30/38, 78.9%) and level 0–III vascularity (27/38, 71.1%). All the thyroid nodules were classified as high suspicion by the 2015 ATA guideline. Pathological Hashimoto’s thyroiditis and extrathyroid extension were detected in 36.8% and 50.0% patients, respectively (Table 1).

Distribution features of skip metastasis to the lateral neck

The distribution of pathologic LLNM at the neck level in patients who had skip metastases is displayed in Table 2. The most common distribution model of LLNM in patients with skip metastasis was 1 level (24/38, 63.2%), followed by 2 levels in 8 patients (21.1%), and 3 levels in 6 patients (15.8%). Level III (71.1%, 27/38) was most frequently involved, followed by level IV (47.4%, 18/38), level II (31.6%, 12/38), and level V (2.6%, 1/38).

Among the patients with skip metastasis, 30 cases (78.9%, 30/38) showed lateral LN involvement on preoperative ultrasound. Among these cases, preoperative ultrasound missed 5 (41.7%, 5/12), 5 (18.5%, 5/27), 8 (44.4%, 8/18), and 0 cases of lateral LN involvement for level II, III, IV and V, respectively (Table 3).

Risk factors for skip metastasis

We analyzed the associations of clinical, ultrasound, and pathological features with skip metastasis. Female patients had significantly higher skip metastasis rates than men (9.2% vs. 5.3%, P=0.048). Patient age and tumor size were not correlated with skip metastasis. The tumor located in the upper portion of the thyroid correlated with skip metastasis (19.8% vs. 3.3%, P<0.001). The tumor located in the middle, isthmus, and whole portion of the thyroid was not correlated with skip metastasis (P=0.086; P=0.21; P=0.49). Moreover, the tumor located in the inferior portion of the thyroid was correlated with no skip metastasis (0% vs. 11.3%, P<0.001). The skip metastasis rate was significantly higher in patients with level 0–III vascularity nodules on preoperative ultrasound than those with rich blood flow (level IV vascularity) (9.5% vs. 5.2%, P=0.045). The following features: multifocal lesions, echogenicity, composition, microcalcifications, taller-than-wide ≤1 shape, ill-defined border, and high suspicion of ATA risk stratification of thyroid nodules on preoperative ultrasound were not associated with skip metastasis. Patients with skip metastases had 2.84±2.10 and 5.64±5.55 metastatic LNs in their lateral necks, respectively (P<0.001). When comparing patients with low-volume LLNM to those with high-volume LLNM, skip metastasis was more common in the former group (15.9% vs. 1.7%, P=0.001). Other pathological characteristics such as extrathyroidal extension, BRAF mutation, and Hashimoto’s thyroiditis were not related with skip metastasis (Table 1). Figure 1 shows ultrasound manifestation of a PTC with skip metastasis.

Figure 1 The cervical ultrasound manifestation of a PTC patient with skip metastasis. A 49-year-old woman who was admitted due to neck mass. Ultrasound showed hypoechoic lesions with ill-defined bounder, taller-than-wide >1 and calcifications in the middle of the right lobe (A) and upper of the left lobe (B). The left level III lateral lymph node shows a rounded node with the loss of the fatty hilum (C). The 2 nodules were PTC with 3 metastasized lateral lymph nodes and negative nodes in the central compartment, which was confirmed by histological pathology. The patient experienced suspected cervical lymph node recurrence in the left lateral neck over a 39-month follow-up period. PTC, papillary thyroid carcinoma.

Significant variables, such as sex, pathological low-volume LLNM, tumor location on ultrasound, and tumor vascularity were added to the final models for multivariate testing in order to find independent factors linked to skip metastasis. The model showed significant differences in the location of the tumor on ultrasound and pathological low-volume LLNM for predicting skip metastasis. Patients with the tumor located in the upper portion of the thyroid were likely to have skip metastasis [odds ratio (OR) =8.654, 95% confidence interval (CI): 4.105–18.242, P<0.001]. Patients with pathological low-volume LLNM were more likely to have skip metastasis (OR =5.121, 95% CI: 1.862–14.085, P=0.002) (Table 4).

Clinical courses for patients with skip metastasis

Among the 38 patients with skip metastasis, 30 patients (78.9%) were followed up. The median follow-up period after the initial surgery was 45.2±22.4 months. Recurrence/persistence was found in 5 patients (16.7%), including 4 cases (13.3%) in cervical LN and 1 case (3.3%) in thyroid operative bed. Recurrence/persistence-free survival rates at 3 and 5 years were 93.3% and 74.7%, respectively. Among the 13 patients who received radioiodine (RAI) treatment after primary surgery, 3 (23.1%) were found to have recurrence/persistence. Among the 17 patients who did not receive RAI treatment after primary surgery, 2 (11.8%) were found to have recurrence/persistence. The recurrence/persistence rate of the patients with RAI treatment was equal to that of those without (P=0.372).

Among the 456 patients without skip metastasis, 386 (84.6%) were followed up. The patients without skip metastases had median follow-up durations of 44.7±19.2 months. There were 110/386 (28.5%) patients with recurrence or persistence, including 106 cases (27.5%) in cervical LN, 3 cases (0.78%) in thyroid operative bed, and 1 patient (0.3%) with distant lung metastases. For recurrence/persistence sites, majority of patients (45 cases, 40.9%) had lesions in the primary neck site of LLNM. Recurrence/persistence-free survival rates at 3 and 5 years were 94.5% and 59.0%, respectively. The recurrence/persistence rate of PTC patients with skip metastasis was equal to those without (P=0.077) (Figure 2).

Figure 2 Comparison of recurrence/persistence rates of PTC patients with or without skip metastasis. PTC, papillary thyroid carcinoma.

Discussion

In our analysis, the prevalence of skip metastasis was 0.89% in PTC patients and 7.7% in PTC patients with LLNM, which is consistent with earlier studies that have reported skip metastasis rates ranging from 1.6% to 21.8% (7-11), which could be explained by differences in sample sizes and geographies. Moreover, we showed that the frequency of skip metastasis was not influenced by the tumor size.

Although researchers have explored the prognostic factors of PTC (16), few studies have investigated the prognosis of the patients with skip metastasis. Therefore, the significant association between PTC and skip metastasis has remained unclear. Although a single study found no correlation between skip metastasis and the long-term tumor-free survival rate of PTC patients, the study did not show the prognosis of patients with skip metastasis in detail (7). We showed that the recurrence/persistence-free survival rates at 3 and 5 years were 93.3% and 74.7%, respectively. Among the patients with skip metastasis with a median follow-up of 45.2±22.4 months, recurrence/persistence was found in 16.7% of cases. The recurrence/persistence rate of PTC patients with skip metastasis was equal to that of those without. The results of some studies have suggested that skip metastasis may improve prognosis, which is consistent with skip metastasis in lung cancer and colorectal cancer (17,18). More research is required to determine whether or not this holds significance for PTC patients.

Previous studies have reported that LNM occurred along the lymphatic chain, with level III nodes being the most commonly affected, followed by levels IV, II, and V. In line with our findings, the most common distribution model of skip metastasis was 1 level (63.2%) and level III (71.1%) was most frequently involved, followed by level IV (47.4%), level II (31.6%), and level V (2.6%). Level II and level III are the most commonly impacted locations in skip metastases, according to a comparable conclusion (19,20).

Ultrasound is the most useful modality for preoperative lateral LN evaluation. However, in our study of the patients with skip metastasis, 78.9% of cases showed lateral LN involvement on preoperative ultrasound, meaning that 21.1% of the patients were misdiagnosed via ultrasound. Among these, preoperative ultrasound most frequently missed level II (41.7%) and IV (44.4%), followed by level III (18.5%), indicating that sonographers should pay more attention to levels II and IV. Level III is the least missed area in the preoperative ultrasound. This may be because the preoperative ultrasound examination of level III was less likely to be interfered with by surrounding blood vessels and tissues, compared with level II and IV. Moreover, these misdiagnoses may be due to the low incidence of skip metastasis. Thus, we explored the sonographic features of the primary thyroid nodules with skip metastasis. Most patients developed their carcinoma in the upper lobe. Most of them were a hypoechoic solid mass with microcalcifications, taller-than-wide ≤1 shape, ill-defined border, and level 0–III vascularity. Furthermore, we identified independent factors associated with skip metastasis. We found that the tumor located in the upper portion of the thyroid correlated with skip metastasis, and patients with pathological low-volume LLNM were more likely to have skip metastasis. Age, gender, other features of thyroid nodules on preoperative ultrasound (multifocal lesions, echogenicity, composition, microcalcifications, taller-than-wide ≤1 shape, ill-defined border, and high suspicion of ATA risk stratification), and other pathological features such as Hashimoto’s thyroiditis and extrathyroidal extension were not associated with skip metastasis.

We found that patients with the tumors located in the upper portion of the thyroid were likely to have skip metastasis. A recent meta-analysis supporting this finding found a substantial correlation with skip metastases and the position of the higher pole (9,20,21). This could be explained by the anatomy, whereby malignancies in the upper lobe may spread to lateral LNs via the superior thyroid artery, avoiding central LNs. Patients with pathological low-volume LLNM were more likely to have skip metastasis. This may be because compared to the patients with low-volume LLNM, patients with high-volume LLNM metastasize to different regions (including the central compartment), not just skip metastasis. A previous study also showed that patients with skip metastasis had greater odds of 1 level LNM (7). Older age, female sex, and smaller tumor size were associated with low-volume LNM of PTC (13,22). Combining the 2 results, patients of older age, female sex, and smaller tumor size may be more likely to have skip metastasis. Although the exact etiology of skip metastasis is still controversial, impressive research was published recently which explained the different metastasizing mechanisms of thyroid cancer to cervical LNs. Tumors may migrate along the superior lymphatic channels from the central compartment directly to lateral levels II and III (23).

Our study presents several limitations. Firstly, it may have been affected by selection bias, since patients who underwent thyroidectomy were included. It may have involved disproportionately more patients with larger nodule size and younger age. Secondly, the study was conducted retrospectively; in our center, the II–IV levels of LN were not usually removed separately, but were removed surgically as one piece and then divided to different levels (II, III, IV) afterwards. In the study, the II–IV levels of metastasized LNs were determined by postoperative pathology. Thirdly, the follow-up period was relatively short—the median time of which was 45 months. Further research is required to confirm and expand on our findings.

Conclusions

Our results suggest that patients with tumors located in the upper portion of the thyroid and pathological low-volume LLNM are more likely to have skip metastasis. The most common distribution model of skip metastasis was 1 level, and level III was most frequently involved. Since the postoperative recurrence/persistence incidence of patients with skip metastasis was not lower than that of those with LLNM after treatment and skip metastasis can occur frequently in PTC patients, it should be required to thoroughly examine the lateral LNs prior to surgery.

Acknowledgments

Funding: This research was funded by National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-066), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2016-I2M-1-002), and Fundamental Research Funds for the Central Universities (No. 3332023011).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-23-1737/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1737/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. K2768) and the requirement for individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1-133. [Crossref] [PubMed]
2. Gao L, Wang J, Jiang Y, Gao Q, Wang Y, Xi X, Zhang B. The Number of Central Lymph Nodes on Preoperative Ultrasound Predicts Central Neck Lymph Node Metastasis in Papillary Thyroid Carcinoma: A Prospective Cohort Study. Int J Endocrinol 2020;2020:2698659. [Crossref] [PubMed]
3. Machens A, Dralle H. Correlation between the number of lymph node metastases and lung metastasis in papillary thyroid cancer. J Clin Endocrinol Metab 2012;97:4375-82. [Crossref] [PubMed]
4. Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 2006;106:524-31. [Crossref] [PubMed]
5. Machens A, Hinze R, Thomusch O, Dralle H. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 2002;26:22-8. [Crossref] [PubMed]
6. Koo BS, Choi EC, Yoon YH, Kim DH, Kim EH, Lim YC. Predictive factors for ipsilateral or contralateral central lymph node metastasis in unilateral papillary thyroid carcinoma. Ann Surg 2009;249:840-4. [Crossref] [PubMed]
7. Lei J, Zhong J, Jiang K, Li Z, Gong R, Zhu J. Skip lateral lymph node metastasis leaping over the central neck compartment in papillary thyroid carcinoma. Oncotarget 2017;8:27022-33. [Crossref] [PubMed]
8. Attard A, Paladino NC, Lo Monte AI, Falco N, Melfa G, Rotolo G, Rizzuto S, Gulotta E, Salamone G, Bonventre S, Scerrino G, Cocorullo G. Skip metastases to lateral cervical lymph nodes in differentiated thyroid cancer: a systematic review. BMC Surg 2019;18:112. [Crossref] [PubMed]
9. Qiu Y, Fei Y, Liu J, Liu C, He X, Zhu N, Zhao WJ, Zhu JQ. Prevalence, Risk Factors And Location Of Skip Metastasis In Papillary Thyroid Carcinoma: A Systematic Review And Meta-Analysis. Cancer Manag Res 2019;11:8721-30. [Crossref] [PubMed]
10. Lee YS, Shin SC, Lim YS, Lee JC, Wang SG, Son SM, Kim IJ, Lee BJ. Tumor location-dependent skip lateral cervical lymph node metastasis in papillary thyroid cancer. Head Neck 2014;36:887-91. [Crossref] [PubMed]
11. Feng JW, Qin AC, Ye J, Pan H, Jiang Y, Qu Z. Predictive Factors for Lateral Lymph Node Metastasis and Skip Metastasis in Papillary Thyroid Carcinoma. Endocr Pathol 2020;31:67-76. [Crossref] [PubMed]
12. Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer. Laryngoscope 2011;121:487-91. [Crossref] [PubMed]
13. Huang XP, Ye TT, Zhang L, Liu RF, Lai XJ, Wang L, Yang M, Zhang B, Li XY, Liu ZW, Xia Y, Jiang YX. Sonographic features of papillary thyroid microcarcinoma predicting high-volume central neck lymph node metastasis. Surg Oncol 2018;27:172-6. [Crossref] [PubMed]
14. Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for persistent/recurrent and metastatic differentiated thyroid cancer 2018 (English version). Chin J Cancer Res 2019;31:99-116. [Crossref] [PubMed]
15. Frates MC, Benson CB, Doubilet PM, Cibas ES, Marqusee E. Can color Doppler sonography aid in the prediction of malignancy of thyroid nodules? J Ultrasound Med 2003;22:127-31; quiz 132-4. [Crossref] [PubMed]
16. Zhao W, Chen S, Hou X, Liao Q, Chen G, Zhao Y. Predictive Factors of Lateral Lymph Node Metastasis in Papillary Thyroid Microcarcinoma. Pathol Oncol Res 2019;25:1245-51. [Crossref] [PubMed]
17. Prenzel KL, Mönig SP, Sinning JM, Baldus SE, Gutschow CA, Grass G, Schneider PM, Hölscher AH. Role of skip metastasis to mediastinal lymph nodes in non-small cell lung cancer. J Surg Oncol 2003;82:256-60. [Crossref] [PubMed]
18. Shiozawa M, Akaike M, Yamada R, Godai T, Yamamoto N, Saito H, Sugimasa Y, Takemiya S, Rino Y, Imada T. Clinicopathological features of skip metastasis in colorectal cancer. Hepatogastroenterology 2007;54:81-4. [PubMed]
19. Park JH, Lee YS, Kim BW, Chang HS, Park CS. Skip lateral neck node metastases in papillary thyroid carcinoma. World J Surg 2012;36:743-7. [Crossref] [PubMed]
20. Jin WX, Jin YX, Ye DR, Zheng ZC, Sun YH, Zhou XF, Li Q, Wang OC, Liu HG, Zhang XH. Predictive Factors of Skip Metastasis in Papillary Thyroid Cancer. Med Sci Monit 2018;24:2744-9. [Crossref] [PubMed]
21. Nie X, Tan Z, Ge M. Skip metastasis in papillary thyroid carcinoma is difficult to predict in clinical practice. BMC Cancer 2017;17:702. [Crossref] [PubMed]
22. Oh HS, Park S, Kim M, Kwon H, Song E, Sung TY, Lee YM, Kim WG, Kim TY, Shong YK, Kim WB, Jeon MJ. Young Age and Male Sex Are Predictors of Large-Volume Central Neck Lymph Node Metastasis in Clinical N0 Papillary Thyroid Microcarcinomas. Thyroid 2017;27:1285-90. [Crossref] [PubMed]
23. Likhterov I, Reis LL, Urken ML. Central compartment management in patients with papillary thyroid cancer presenting with metastatic disease to the lateral neck: Anatomic pathways of lymphatic spread. Head Neck 2017;39:853-9. [Crossref] [PubMed]