Impact of tumor location and pleural invasion on the frequency of skip hilar lymph node metastasis in lung cancer

Introduction

The standard surgical procedure for non-small cell lung cancer (NSCLC) has been lobectomy with systematic hilar and mediastinal lymph node (LN) dissection for more than half a century (1,2). This is because the systematic dissection of regional LNs susceptible to metastasis from lung cancer enables accurate staging and improves the patient’s prognosis. The association between the pattern of LN metastasis and tumor localization has been studied intensively for many years. Hata et al. analyzed intrathoracic lymphatic flow by lymphoscintigraphy and demonstrated that the pattern of lymphatic flow differed greatly for each pulmonary lobe (3,4). Since the 1990s, various studies have reported that metastasis from upper lobe lung cancers to the subcarinal LN is rare and that the prognosis in such cases is precarious, giving rise to the concept of selective LN dissection (5-10). A phase III randomized controlled trial (JCOG1413) was conducted to evaluate the validity of lobe-specific selective LN dissection compared with systematic LN dissection (11). Case collection is now complete, and prognostic tracking is ongoing.

A phase III randomized controlled trial comparing lobectomy with segmentectomy for small lung cancer with tumors measuring ≤2 cm in diameter (JCOG0802) showed that overall survival was better in the segmentectomy group than in the lobectomy group (12). Segmentectomy is now recommended as a standard procedure for small-sized peripheral lung cancer, as long as sufficient margins can be secured. The number of segmentectomies for compromised patients is also expected to increase. Mediastinal LN dissection can be performed in segmentectomy to the same extent as it can be performed in lobectomy. However, the appropriate extent of hilar LN dissection in segmentectomy has not yet been fully investigated. The European Society of Thoracic Surgeons expert consensus (13) recommended that all LN stations draining the target segment should be removed. A frozen section of the LNs at the foot of the corresponding segmental bronchus should be obtained. In case any LN station tests positive for cancer, a lobectomy should be performed instead of a segmentectomy. Lobar LNs (#12) and segmental LNs (#13) located around the bronchus of the tumor-bearing segment can be removed simultaneously during segmentectomy, whereas interlobar LNs (#11) and hilar LNs (#10) that are not adjacent to the affected segment need to be dissected separately. Recently, a supplemental analysis of the JCOG0802 trial has revealed that 55 (10.4%) of 523 patients with pure-solid tumors measuring ≤2 cm had LN metastases, and 5 (1.0%) had metastases to nonadjacent interlobar LNs (14). Besides tumor localization, pleural invasion is an important factor in determining the pattern of LN metastasis. Although some studies have suggested that the presence of the subpleural lymphatic pathway causes skip metastasis to the mediastinal LNs (15-17), it remains unclear whether the pleural invasion status influences the incidence of skip metastasis to the hilar LNs.

This study aimed to investigate whether the appropriate extent of LN dissection depends on the affected segment and pleural invasion. We analyzed the patterns of LN metastasis using Cytoscape (18), a network analysis software commonly used in bioinformatics. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-944/rc).

Methods

Ethics statement

In this study, all procedures were conducted per the ethical standards of the institutional and national committees on human experimentation and the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board for Clinical Research of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research on October 5, 2023 (Referral No. 2023-GB-078). The requirement for informed consent was waived because of the retrospective study design.

Study design

This retrospective study reviewed patients who underwent anatomical resection for NSCLC with tumor diameters of ≤30 mm between 2005 and 2022 (Figure 1). We excluded the following categories of patients: patients without nodal metastasis, patients without an identifiable primary tumor, and patients with centrally located primary tumors. Data on patient characteristics (including age, sex, pack-year smoking history, pathological tumor size, invasive tumor size, pleural invasion, intrapulmonary metastasis, pT stage, pN stage, number of metastatic nodal stations, surgical procedure, extent of lymphadenectomy, histology, and localized segment of primary tumor) were collected. Pathological staging was defined per the eighth edition of the tumor-node-metastasis (TNM) classification system (19). The histological pleural invasion was classified as follows: pl1: tumor invades beyond the elastic layer of the visceral pleura; pl2: tumor invades the visceral pleura surface; and pl3: tumor invades any component of the parietal pleura (20). Intrapulmonary metastasis was divided as follows: pm1: tumors with same-lobe separate tumor nodules with the same histologic appearance; pm2: tumors with same-side nodules (21).

Figure 1 Flowchart of patient selection process. NSCLC, non-small cell lung cancer.

LN assessment

The LN stations used in this study followed the LN map definitions of the International Association for the Study of Lung Cancer (22). Hilar nodes (#10) are adjacent to the mainstem bronchus, and interlobar nodes (#11) are between the origins of the lobar bronchi. On the right side, the #11 nodes are between the upper lobe bronchus and bronchus intermedius, and the #11i nodes are between the middle and lower lobe bronchi. The hilar LNs were removed along with the affected lung during surgery, and the mediastinal LNs were dissected separately with the surrounding connective tissue and fat. LNs were separated one by one by a thoracic surgeon from the removed specimen and classified into lobar (#12), interlobar (#11), hilar (#10), and mediastinal (#2R, #4R, #4L, #5, #6, #7, #8, #9) categories. Peripheral LNs from segmental LNs (#13) were fixed in formalin along with the lung and sectioned by a pathologist to evaluate for metastases. Therefore, segmental LNs (#13) and subsegmental LNs (#14) were not distinguished. In this study, lobar LNs (#12), segmental LNs (#13), and subsegmental LNs (#14) were treated together, and all were denoted as #12.

Network analysis

Patterns of LN metastasis were analyzed using Cytoscape (18). This software visualizes the interactive network by designating each factor as a node and the strength of the association between the node and the node as an edge. First, the assumed lymphatic flow pathways were established based on the known anatomical findings separately for the left and right sides (Figure 2). For example, if a right upper lobe (RUL) lung cancer developed metastasis to #12u and #11s, we considered that the cancer cells metastasized from the primary tumor to #12u and then from #12u to #11s. Metastasis to #11 or #10 without metastasis to #12 was defined as skip N1 metastasis, and mediastinal LN metastasis without metastasis to any of the hilar LNs was defined as skip N2 metastasis. Each LN is considered a node, and the frequency of metastasis occurring among the two nodes is set as an edge to illustrate the LN metastatic patterns by performing network analyses according to the segment containing the tumor (Figure 3 and Figure S1). In the figures, each LN is represented by a circle. The size and color of the circle represent the frequency of metastasis to a particular LN. A line connecting a circle to another one indicates that cancer cell metastasis has occurred between the two LNs. The width of the line and the red number represent the frequency of metastasis through a particular pathway. For example, the red number 4 on the line connecting the tumor and #10 in the figure titled Rt. S1 in Figure 3 represents four cases with lung cancer in the right S1 that had skip metastases to #10 without metastases in the pathway to #10 (that is, #11s, #12, and more peripheral LNs). Based on the figures, the frequencies of skip N1 and skip N2 metastases were calculated. The stations with the highest incidence of skip metastasis were also examined. Furthermore, the same analysis was performed only for cases with pathologic pleural involvement, and the frequency of skip metastasis was compared with that of cases without pleural invasion.

Figure 2 The assumed lymphatic flow pathways established based on known anatomical findings. The lymph node stations used in this study followed the International Association for the Study of Lung Cancer lymph node map definitions. Hilar nodes (#10) are adjacent to the mainstem bronchus, and interlobar nodes (#11) are between the origin of the lobar bronchi. On the right side, the #11s nodes are between the upper lobe bronchus and bronchus intermedius, and the #11i nodes are between the middle and lower lobe bronchi. Lobar lymph nodes (#12), segmental lymph nodes (#13) and subsegmental lymph nodes (#14) were treated together and all were denoted as #12 in this study.

Figure 3 Patterns of lymph node metastasis illustrated using Cytoscape. Each lymph node is represented by a circle. The size and color of the circle represent the frequency of metastasis to a particular lymph node. A line connecting a circle to another one indicates that cancer cell metastasis has occurred between the two lymph nodes. The width of the line and the red number represent the frequency of metastasis through a particular pathway. The figure showing nodal metastasis patterns in right middle lobe lung cancer is included in Figure S1. Rt., right; Lt., left.

Statistical analysis

Continuous variables were expressed as means ± standard deviations, while categorical variables were expressed as frequencies and percentages. The χ² test was used to compare categorical variables, while Student’s t-test was used to compare continuous variables. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). P values <0.05 were considered statistically significant.

Results

A total of 2,904 patients underwent anatomical lung resection for NSCLC with tumors measuring ≤3 cm in diameter between 2005 and 2022. After excluding ineligible patients per our exclusion criteria, the remaining 322 patients were included in this study (Figure 1). The demographic characteristics of patients with nodal metastasis of NSCLC are shown in Table 1. The mean age of our participants was 64±10 years, and the mean smoking index was 25±31 pack-years. The mean pathological invasive tumor size was 19±6 mm. A total of 123 patients (38%) had invasive pleural tumors and 32 patients (10%) had intrapulmonary metastases. Therefore, although all patients had a tumor diameter of ≤3 cm, 140 patients (43%) had a pT2 or greater disease. Of the 37 patients with pT3, eight had parietal pleural involvement (pl3), while 29 had same-lobe intrapulmonary metastases (pm1). All three patients with pT4 had same-side intrapulmonary metastases (pm2). There were 130 patients (40%) with pN1 disease and 192 patients (60%) with pN2 disease. The number of metastatic nodal stations was 2.2±1.4. Three hundred and thirteen patients (97%) underwent lobectomy or more and 305 patients (95%) underwent systematic or lobe-specific selective mediastinal LN dissection. The histological diagnosis was adenocarcinoma in 277 cases (86%). The distribution of the localized segment of the primary tumor is shown in Table 1. Because there were only a few cases with primary lesions in right S4 and S5, S7 and S8, S9 and S10, left S4 and S5, and S9 and S10, they were treated as a group of sums. There were 45 cases (14%) with primary tumors in right S1, which was the most common.

The patterns of nodal metastasis according to the localized segment of the primary tumor were illustrated using Cytoscape (Figure 3 and Figure S1). Figure 3 shows that, in lung cancers of RUL, there was a high frequency of skip metastasis to #10 and #4R, whereas skip metastasis to #11s was rare. In contrast, in right lower lobe (RLL) lung cancer, the frequency of skip metastasis to #11s and #11i was high. It is especially noteworthy that skip metastasis to #11i from the segments not directly adjacent to #11i (right S6, S9, and S10) was unexpectedly frequent. In left upper lobe (LUL) lung cancer, nodal metastasis patterns differed significantly between left upper division segment lung cancer and left lingular segment lung cancer. Skip metastases to #11 were rare in left upper division segment lung cancer but skip mediastinal metastases to #5 were more common. However, metastases to #11 and #7 were frequent in left lingular segment lung cancer. In left lower lobe (LLL) lung cancer, similar to RLL lung cancer, the frequency of skip metastasis to #11 was high.

Table 2 shows the frequency of skip N1 and skip N2 metastases calculated according to the tumor localized segment based on Figure 3 and Figure S1. The overall proportion of patients with metastases in the peripheral zone (#12 or #13) was 67%. Skip N1 metastasis was significantly more frequent in patients with RLL tumors than in those with RUL tumors (40% vs. 10%, P<0.001). The rates of skip metastasis to #11i in the right S6 tumor and in the right S9–10 tumor were high (22% and 17%, respectively). Similarly, skip N1 metastasis was relatively more frequent in patients with LLL tumors than in those with LUL tumors (20% vs. 9%, P=0.07). The rate of skip metastasis to #11 in the left S6 tumor was high (16%). The overall rate of patients with skip N2 metastasis was 16%, which was higher in patients with RUL tumors (19%) and LUL tumors (21%). Patients with lower lobe tumors had more frequent skip N1 metastasis than those with upper lobe tumors (31% vs. 10%, P<0.001) but had less frequent skip N2 metastasis (10% vs. 20%, P=0.02).

In addition, the same analysis was performed for the 123 cases with pathologic pleural invasion (Figure S2). The frequency of skip metastasis according to the location of the tumor in cases with pleural invasion is shown in Table 3. There was a significant difference in the frequency of skip LN metastasis between tumors with and without pleural invasion (44% vs. 27%, P=0.001). In cases with pleural invasion, as in the total cohort, skip N1 metastasis was more frequent in patients with lower lobe tumors. In particular, skip N1 metastasis was present in half of the 20 patients with RLL tumors.

The skip N1 and skip N2 rates for each pT factor are summarized in Figure 4. Interestingly, while the skip N2 frequency increased with T factor advancement, the skip N1 rate was the highest (24%) in the case of pT2a, perhaps because all patients with pT2a had visceral pleural invasion. The correlation between pleural involvement and the risk of skip LN metastasis has been demonstrated.

Figure 4 The skip N1 and skip N2 rates for each pT factor. The gray bars indicate the number of cases (left-side axis) and the line graphs indicate the skip N1 and skip N2 rates (right-side axis).

Discussion

In this study, the patterns of nodal metastasis according to the localized segment of the primary tumor and the status of pleural invasion were illustrated using Cytoscape. The results revealed that the overall proportion of patients with skip N1 metastasis was 17%. Patients with lower lobe tumors had more frequent skip N1 metastasis than those with upper lobe tumors but had less frequent skip N2 metastasis. Skip metastasis was more frequent in tumors with than in those without pleural invasion.

Numerous studies have been conducted on the relationship between tumor localization and mediastinal LN metastatic patterns to optimize the extent of mediastinal LN dissection in lobectomy (4-6,8-10). However, now that an increasing number of small lung cancer cases are being resected by segmentectomy (23,24), there is a need to optimize the extent of hilar and mediastinal LN dissection in this surgical procedure. The results of this study will be useful when performing segmentectomy for lung cancer because there is a lack of studies examining in detail the pattern of N1 metastasis according to the segment in which the primary tumor is located. A particular concern with segmentectomies is the possibility of skip metastasis to interlobar LNs (#11) that are not adjacent to the affected segment (25). In this study, skip metastases to #11s from right S1 and S3 tumors and to #11 from left S1+2 and S3 tumors were rare, and the need for the dissection of these LNs seems to be relatively low. Meanwhile, skip metastases to #11i from the right S6 tumor and #11 from the left S6 tumor were unexpectedly common, and the dissection of these LNs should not be easily omitted. For S6 lung cancers with a relatively high risk of nodal metastasis, either segmentectomy followed by additional interlobar LN dissection or lobectomy instead of segmentectomy should be performed.

The relationship between pleural invasion and patterns of nodal metastasis is also of interest. The presence of subpleural lymphatic channels may be responsible for skip metastasis to mediastinal LNs. Takeda et al. evaluated the existence of subpleural lymph flow in vivo using indocyanine green fluorescence in 100 cases and detected subpleural lymph flow in 58 of them (15). The rate of detection to the mediastinal lymph flow without hilar LN staining was 11%. Gorai et al. (16) reported that the incidence of skip N2 metastasis was significantly associated with visceral pleural invasion in patients with cIA NSCLC. Similarly, in the present study, there was a significant difference in the frequency of skip N2 metastasis between tumors with and without pleural invasion (22% vs. 12%, P=0.02). Our study further demonstrated that the frequency of skip N1 metastasis also tends to be higher in tumors with pleural invasion (22% vs. 15%, P=0.09). The extent of LN dissection for patients with tumors involving the pleura should be determined with attention to the risk of nodal metastasis not only via lymphatic channels along the bronchi but also skip metastasis via the subpleural lymphatic channels.

Nevertheless, this study had a few limitations. It was a retrospective, single-institution study, which means its findings are not generalizable. The location of the tumor within the segment was not considered; therefore, cases in which the tumor partially invaded adjacent segments were also included. The frequency of metastasis to LNs in the undissected area may be underestimated because 58% of cases underwent lobe-specific selective mediastinal LN dissection and 5% omitted mediastinal lymphadenectomy. However, the metastatic pattern of hilar LNs, which was the objective of this study, was investigated in all cases. Since 86% of the cases included in this study were adenocarcinomas, its findings may not be applicable to other tumors. Because we did not investigate the location of the metastatic LNs within the lobar LNs (#12), it is unknown whether they were included in the tumor-bearing segment or whether they could not be removed via segmentectomy. This study includes cases in which complete resection cannot be performed by segmentectomy in practice; therefore, one cannot determine whether segmentectomy is appropriate for these patients based on the results of this study. Further prospective studies and randomized controlled trials are needed to answer the question of whether or not hilar LNs apart from the resected segment should be dissected.

Conclusions

The pattern of nodal metastasis differed according to the segment containing the tumor and the pleural invasion status. The frequency of skip N1 metastases was higher in lower lobe tumors than in upper lobe tumors. The rate of skip metastasis was associated with pleural invasion. To determine the extent of LN dissection during segmentectomy, tumor location and pleural invasion should be considered in addition to the expected malignancy of the tumor based on imaging findings.

Acknowledgments

We presented this study at the 2023 World Conference on Lung Cancer, Singapore, September 9–12, 2023. We would like to thank Enago (www.enago.jp) for English language editing.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-944/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-944/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-944/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-944/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 Institutional Review Board for Clinical Research of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research on October 5, 2023 (Referral No. 2023-GB-078) and 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/.

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