Clinical implications of Delphian lymph node metastasis in papillary thyroid carcinoma: a single-institution study, systemic review and meta-analysis

Background To evaluate the possible predictive value and clinicopathological characteristics of Delphian lymph node metastasis in papillary thyroid carcinoma. Methods A retrospective analysis of papillary thyroid carcinoma patients with Delphian lymph node metastasis in a single institution and meta-analysis of literature reports were performed. Results In own series, Delphian lymph node metastasis was detected in 19 (9.9%) of 192 papillary thyroid carcinoma patients and was significantly associated with tumor size≥1 cm (P = 0.003), multifocality (P = 0.006) and extrathyroid extension (P < 0.001) in the multivariate analysis. Female was a protective factor for Delphian lymph node metastasis (P = 0.001). Delphian lymph node metastasis was highly predictive of further central lymph node metastasis (positive predictive value = 89.5%, negative predictive value = 67.6%) and moderately predictive of lateral lymph node metastasis (positive predictive value = 26.3%, negative predictive value = 95.4%). In this meta-analysis, there was a strong correlation between Delphian lymph node metastasis and aggressive clinicopathologic characteristics with regards to multifocality (P = 0.0008), bilaterality (P = 0.04), extrathyroid extension (P < 0.00001), lymphovascular invasion (P < 0.00001), further central lymph node metastasis (P < 0.00001) and lateral lymph node metastasis (P < 0.00001). Conclusions This single-institution observational study and meta-analysis identified that Delphian lymph node metastasis was significantly associated with unfavorable clinicopathological characteristics and had a strong predictive power for further disease in the central compartment. Trial registration The clinical study was retrospectively registered to UMIN clinical trials registry (the registry number: UMIN000033835). Electronic supplementary material The online version of this article (10.1186/s40463-019-0362-7) contains supplementary material, which is available to authorized users.


Introduction
The Delphian lymph node (DLN), also called the prelaryngeal or cricothyroid node, locates in the fascia above the thyroid isthmus and lies between the cricoid and thyroid cartilages [1,2]. The DLN receives afferent lymph flow from the larynx and the thyroid gland, then flows towards the central and lateral lymph nodes [2]. Therefore, DLN status should be critically evaluated in patients with cancers involving the larynx, hypopharynx and thyroid. Most studies to date on the DLN address its significance in laryngeal and hypopharyngeal carcinoma and emerging evidence suggests that the positive DLN is a poor prognostic factor in laryngeal and hypopharyngeal cancers [1,[3][4][5][6][7][8][9]. Unlike laryngeal cancer, the clinicopathologic factors of the positive DLN in thyroid cancer are still not completely understood. To our knowledge, there are 9 reports addressing the predictive value of DLN metastasis in papillary thyroid carcinoma (PTC) [10][11][12][13][14][15][16][17][18] and most of these studies were published in recent years. The clinical data from some studies indicate that DLN metastasis is a predictor of further disease in the central compartment and in the lateral compartment. However, some investigators contended that the DLN is frequently found without extensive lymph node disease and even argued that DLN involvement is a misleading and unreliable sign [19,20].
Because of inconsistent results and lack of meta-analyses to systematically review the significance of the DLN in PTC, we report the outcomes of a single-institution case series and present the first meta-analysis of the clinical characteristics of PTC patients with DLN metastasis.

Single-institution observational study
We retrospectively reviewed the medical records of 192 patients with a final diagnosis of PTC who underwent total thyroidectomy and central lymph node dissection (CLND) with or without lateral lymph node dissection (LLND) in Shanghai Changzheng Hospital (Shanghai, China) between July 2017 and August 2018. The protocol for this research project was approved by the local Clinical Ethics Committee and written informed consent was obtained from each participant. The clinical study was registered to UMIN clinical trials registry (the registry number: UMIN000033835) (Additional file 3).
CLND was performed routinely on the affected side. CLND on the contralateral side was performed when any of the central lymph nodes were found to be suspicious on preoperative imaging examination or upon intraoperative inspection. LLND was performed only if preoperative fine needle aspiration cytology confirmed evidence of metastasis. The soft tissue and lymph nodes between the thyroid and cricoid cartilage were excised in all 192 cases, then were routinely labeled as DLNs and examined by frozen section evaluation and separate histopathological examinations. Most of the frozen sections were interpreted by three subspecialty pathologists who all had rich experiences with the pathological diagnosis of PTC and lymph nodes.

Systematic review and meta-analysis
Electronic searches were performed for relevant reports in two databases (PubMed and Embase) with publication date before August 2018. The search strategy used the following terms: (Delphian lymph node OR prelaryngeal lymph node OR cricothyroid lymph node) AND (thyroid tumor OR thyroid cancer OR thyroid carcinoma OR thyroid neoplasm). The abstracts of all potential articles, references, and related articles were reviewed according to their titles and each article was independently assessed for eligibility using inclusion criteria.
Inclusion criteria were as follows: (1) comparative studies of the clinicopathologic parameters of the positive DLN and the negative DLN in PTC; (2) articles published in English before August 2018 and (3) exact and intact dichotomous-type or continuous-type data with standard deviations. The literature search was independently performed by 2 authors. The third author determined whether to include the study when controversy occurred.
Two investigators independently extracted and collected data using a standardized data-extraction protocol. For repeated publications, the latest data about interesting outcomes were extracted. For example, Zheng et al. reported their results twice at different periods of the same trial [18,21]. Two authors (BinWang and Xing-zhu Wen) independently assessed the quality of the included studies according to the Newcastle-Ottawa Scale (NOS) [22]. Disagreements regarding methodological assessment were discussed and resolved through consensus.

Statistical analysis
For our single-institution experience, the database was exported to SPSS software (version 19.0; IBM-SPSS, Inc., Chicago, IL, USA). Continuous data was compared using Student t-test and categorical variables were compared using Pearson's chi-squared or Fisher's exact test. Variables with p < 0.15 in univariate analysis were considered statistically significant and included in the multivariate analysis. Differences were considered significant when P < 0.05.
Regarding meta-analysis, data extracted from the included trials were integrated with Review Manager Software version 5.3 (Cochrane Collaborative, Oxford, UK). The odds ratio (OR) was used for dichotomous-type data. The ORs were combined using a random-effects model. Heterogeneity among articles was quantitatively assessed using the Q test and I 2 statistic [23]. A significant heterogeneity was defined as I 2 > 50% or Q-test reporting a P value < 0.05. Sensitivity analysis was applied by removing individual studies from the data set and evaluating the effect of their removal on the pooled OR. Publication bias was examined by Begg's funnel plot as well as Egger's linear regression test.

Single-institution experience
All patients underwent CLND and 13 patients underwent LLND. DLN metastasis was observed in 19 patients (9.9%) and only 1 patient (0.5%) had DLN metastasis without other compartments metastasis. A total of 101 lymph nodes among the patients with DLN metastasis and 799 lymph nodes among the patients without DLN metastasis were detected. No significant difference existed between the 2 groups regarding the mean number of detected lymph nodes (P = 0.320). Histopathological examination proved 65 metastatic lymph nodes among the patients with DLN metastasis and 145 metastatic lymph nodes among the patients without DLN involvement. The mean number of metastatic lymph nodes among the patients with DLN metastasis was significantly higher than that among patients without DLN involvement (P < 0.001).
In univariate analysis, female, age ≥ 45 years, tumor size, multifocality, bilaterality, ETE and Hashimoto's thyroiditis showed a p < 0.15. These factors thus were included in the multivariate analysis ( Table 2). The multivariate analysis revealed that tumor size≥1 cm (P = 0.003), multifocality (P = 0.006) and ETE (P < 0.001) were found to be independent risk factors of DLN metastasis. Female was a protective factor for DLN metastasis (P = 0.001
The sensitivity analyses revealed that the study of Zheng et al. [18] influenced the bilaterality result. After exclusion of this study, the prevalence of bilaterality failed to show significant difference between DLN-positive PTCs and DLN-negative PTCs (OR, 1.43; P = 0.195; see Additional file 1: Figure S1). The study of Chai et al. [12] influenced the heterogeneity of further CLNM. After exclusion of this study, the significant heterogeneity vanished statistically (P for heterogeneity =0.22, I 2 = 29%) and no change in the result with regard to CLNM (OR, 12.02; 95% CI, 6.78-21.32, P < 0.00001; see Additional file 2: Figure S2) was observed. Other studies did not affect the pooled ORs. In the funnel plots and the Egger's regression tests, there was no evidence of publication bias (Fig. 5).

Discussion
This single-institution observational study and metaanalysis showed that DLN metastasis was less common in women with PTC but had a positive association with aggressive clinicopathological characteristics of PTC such as larger primary tumor, ETE, multifocality, and other compartment metastasis.
The name "Delphian" originated from a priestess in Delphi who can foresee the future and was first used to name the lymph node by Raymond B. Randall, a senior student of Harvard Medical School, in 1948 [1,17]. As its name indicates, the DLN can predict the progression   [11] indicated that DLN positivity predicted a 9-fold higher frequency of LLNM, and a 40-fold higher frequency of any nodal disease. This meta-analysis revealed a strong correlation between DLN metastasis and aggressive clinicopathologic characteristics such as ETE, multifocality, lymphovascular invasion, and further central and lateral compartment metastasis. In own series, tumor size≥1 cm, multifocality and ETE were found to be independent risk factors of DLN metastasis. Previous studies also investigated the risk factors for DLN metastasis but the conclusions were inconsistent. Oh et al. [16] revealed that lymphovascular invasion and tumor size played key roles in the occurrence of DLN metastasis. Chai et al. [12] found that tumor location in the isthmus or upper third of the thyroid was a predictor for DLN metastasis. Tan et al. [17] identified capsular invasion as an independent risk factor for DLN metastasis by multivariate analysis. Zheng et al. [18] reported that BRAF mutation was correlated with DLN metastasis. Kim et al. [14] demonstrated thyroiditis contributes to inhibiting DLN metastasis. This single-institution study showed that female played a role in impeding DLN metastasis. The inconsistent results may be attributed to the differences in sample size or demographics of patients included in each study.
In laryngeal cancer, the presence of DLN metastasis increases LLNM, resulting in a high recurrence rate and low survival rate [1,24]. In PTC with DLN metastases, lymph node metastasis are detected in up to 95.9% of the central lymph nodes [16] and 47.2% of  the lateral lymph nodes [14]. According to nodal staging for thyroid cancer, N1a refers to metastatic disease in the central compartment and N1b refers to metastasis to the lateral nodal chains. Because DLN positivity is predictive of lateral compartment disease, Delbridge et al. have suggested that nodal metastasis to the DLN should be upstaged to N1b [10]. DLN status has important implications in extending the scope of surgical procedures, planning radiotherapy, and determining outcome. Current methods for evaluating preoperative DLN status such as ultrasonography, computed tomography, or magnetic resonance imaging are imperfect [12,25] because the median size of the positive DLN is small [13]. Intraoperative frozen section is generally accepted as one of the sensitive and useful tools for evaluation of nodal status of DLN. The current American Thyroid Association guidelines [26] do not recommend prophylactic CLND for small tumors (T1 or T2 classification). However, even in cases of PTC with small tumors, there was a high rate of CLNM [27]. Therefore, DLN could be sent for frozen section evaluation because of its predictive value for widespread nodal metastasis [13]. If the DLN is positive, CLND should be carefully considered even in clinically node-negative PTC.
There are few reports addressing the recurrence of PTC with DLN metastasis [12,16,18]. Studies showed that PTC recurrence was slightly higher in DLN-positive than in DLN-negative patients, although the difference did not reach statistical significance [12,16]. However, Zheng et al. [18] showed that DLN-positive patients had a significantly higher rate of unstimulated Tg ≥1 ng/ml than DLN-negative patients during a median follow-up duration of 14 months and 11 months for DLN-positive patients and DLN-negative patients, respectively. Metastasis to the DLN is a poor prognostic factor in many malignant neck cancers [24,25], and it is associated with several poor prognostic factors in PTC, including ETE [28], and a heavier nodal burden, in terms of number of metastatic nodes and node size [29]. These factors could act as confounders for the relationship between DLN metastasis and PTC prognosis [30]. To date, there is no published evidence or definitive studies on the association between survival and DLN involvement in PTC. Owing to the limited data on long-term follow-up of DLN metastasis in PTC, its relationship with the recurrence and survival of PTC patients remains unclear. Therefore, further studies with longer follow-up periods are warranted to explore the prognostic significance of DLN metastasis in PTC.
The present study had several limitations. First, this study was a 1 year retrospective study in a single institution. Some new findings in this study such as female as a protective factor for DLN metastasis might be not completely convincing and needed more perspective studies with large sample size and relatively long-term follow-up periods to confirm. Second, the sample size in the metaanalysis and the single-institution observational study was not well-matched because the rate of DLN metastasis was low. In this study, the ratio of DLN positive and negative patients was 19/173, which resulted to the low power of test statistic. Third, most studies were performed in Korea and China. Therefore, the results may not accurately reflect the clinical characteristics of PTC in another region.    Funnel plot of standard error by log odds ratio data of this single-institution observational study and meta-analysis regarding the clinicopathological characteristics of papillary thyroid carcinoma patients with Delphian lymph node metastasis and the ability of positive Delphian lymph node for predicting central lymph node metastasis and lateral lymph node metastasis. BW and X-zW wrote the manuscript. MQ made the critical revision of the manuscript. All authors read and approved the final manuscript.

Funding
The work was supported by the National Natural Science Foundation of China under Grant no. 81703854.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The protocol for this research project was approved by the local Clinical Ethics Committee and written informed consent was obtained from each participant.

Consent for publication
Not applicable.