Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death in the world (1). Approximately 30% of the NSCLC were locally advanced at the time of diagnosis (2). The most important risk factor in completely resected NSCLC is metastasis to the mediastinal lymph nodes (N2). The survival rates of N2-NSCLC after surgical treatment ranged from 19.2 to 40% which means that there was a large heterogeneity among N2-NSCLC (3–5). Skip metastases (pN0N2), pathological N2 NSCLC without hilar lymph nodes involvement (N1), were an important subgroup of N2-NSCLC. It was reported that skip N2 occurred in approximately 17.2–42.7% of surgically resected N2-NSCLC (6, 7). Skip N2 was reported to be an independent prognostic factor for better overall survival (OS) of the NSCLC (8, 9). However, the prognostic impact of skip N2 metastases was still under debate. The aim of this study was to elucidate the prognostic impact of skip N2 lymph node metastases on the OS of NSCLC through a meta-analysis of the published studies.

The literature search identified 409 relevant studies for review. Based on the title and abstracts, 60 studies were selected and reviewed for full text. Six studies were excluded for including patients with lymph node sampling. Nine studies were eliminated for the duplicated data. A total of five studies not providing survival information were excluded. Three studies including patients of not pathologically N2 were excluded. Five studies were eliminated because of including operation technique of segmentectomy or wedge resection. Lack of operation information was excluded in one study and three studies were eliminated for low quality scores. Three studies with patients of R1 or R2 resection were excluded. The full text was not available for four studies.

A total of 21 studies with 6,806 patients were included for the meta-analysis (Figure 1) (7, 9, 13–31). All the studies were retrospective studies. The clinical information of 2,258 patients of skip N2 and 4,548 patients of non-skip N2 were retrieved for further analysis. A total of 21 studies were performed in China (8), Japan (6), Italy (2), Germany (1), France (1), Turkey (1), Poland (1), and Croatia (1). All the studies were published between 1999 and 2020. Seven studies were published before 2010. Baseline characteristics in one study were adequately matched for age, gender, surgical procedure, tumor size, histology, T stage, and use of adjuvant therapy. The detailed baseline information was summarized in Table 1. The results of the quality assessment of the studies were shown in Table 2.

Pathological N2 involvement is an important prognostic factor for NSCLC. Skip N2 disease is an important subclassification of N2 disease and accounts for 17.2–42.7% of resected N2 NSCLC (6, 7). The impact of skip N2 metastases on survival remains controversial. Several studies found a better OS for skip N2 disease than the non-skip N2 disease (17, 32). However, other studies did not find a significant difference in 5-year OS between the two groups (33, 34). Recently, the International Association for the Study of Lung Cancer suggested that the skip N2 should be treated as a new pN subclassification because of its better survival (35, 36). However, the evidence was based on the analysis of the patients from the cancer registry database and the clinical characteristics and operation details were not provided which still casts doubt on the conclusion. The present meta-analysis demonstrated that the skip N2 disease provided a better survival for NSCLC with a pooled analysis of the 24 studies.

The relationship is close in anatomy between N1 and N2 disease and the prognosis is also similar in some subgroups of N1 and N2 disease. It was reported that patients of N1 with hilar nodal involvement and patients of single N2 station metastasis had a comparable prognosis (37). Another recent study found that the 5-year OS was similar between patients with N1 metastasis and single skip N2 station metastasis, significantly better than the patients with single non-skip N2 station metastasis (15). Our study showed that the better prognostic impact is consistent in the single N2 station metastasis subgroup.

Multiple N2 stations involvement was reported to be a poor prognostic factor for survival (14, 31, 38). The new 8th tumor, node, metastasis (TNM) staging system for lung cancer did not further classify the N2b group into multiple skip N2 stations and multiple non-skip N2 station diseases. Our result showed that the influence of skip N2 in multistation metastases was not significant for OS although there were only two studies providing the survival information on the subgroup of N2 multistation metastases. Large studies may be needed to further elaborate the prognostic factor of multiskip N2 stations on survival.

Adenocarcinoma is an important histology subtype of NSCLC and the incidence has increased fast and accounted for almost one-half of all lung cancer in recent years (35, 39, 40). There was a higher risk of lymph node metastasis associated with adenocarcinoma compared with squamous cell cancer (41). Histological and molecular heterogeneity also existed in adenocarcinoma (42). The subgroup analysis of our study showed that skip N2 was also a benefit prognostic factor for adenocarcinoma.

The result of our study supported the 8th edition of the American Joint Committee on Cancer TNM staging system which classified the N2 into N2a1 (skip single station involved), N2a2 (non-skip single station involved), and N2b (multiple stations involved). Our result suggested that these patients with skip N2 metastases should be carefully recognized and surgery is an optimal option for these patients.

At first, this study is the first meta-analysis focusing on the prognosis of skip N2 lymph node metastasis on NSCLC and provides a convincing result that the prognosis of skip N2 lymph node metastasis NSCLC is better compared with that of non-skip N2 lymph node metastasis. Second, all the studies were retrospective studies. Third, the baseline clinical characteristics and adjuvant therapy in skip N2 and non-skip N2 were not matched among studies. Fourth, a high degree of heterogeneity and publication bias was found. Despite the use of meta-regression and numerous sensitivity analyses, significant heterogeneity remained. The results should be interpreted with caution. At last, most of the patients were Asians and the result may not be applicable for other ethnicities.

The present meta-analysis suggests that the skip N2 lymph node metastases are a prognostic factor for better survival in N2-NSCLC.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

XW drafted the manuscript. BC revised the manuscript. HG and XW extracted the data and XW did the analysis. QH and YY assessed the quality of the included studies. All authors contributed to the article and approved the submitted version.

The work was supported by the Taizhou Municipal Science and Technology Bureau (No. 1801ky09) and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2019KY773).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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