Abstract
Background/Aim: There are two types of lung cancer cell infiltration into the central airway. One is when a centrally located lung cancer directly infiltrates the central airway and the other is when cancer cells in the metastatic hilar lymph node infiltrate the central airway. We aimed to identify the impact of central airway infiltration type on the clinical features of patients undergoing sleeve lobectomy. Patients and Methods: The clinical courses of 58 primary lung cancer patients who underwent sleeve lobectomy between January 2010 and December 2020 were investigated. Results: Primary tumors directly infiltrated into the central airway in 42 patients, whereas 16 patients had infiltration of cancer cells from the metastatic hilar lymph node. Primary tumor infiltration was a poor prognostic factor according to both univariate (p=0.016) and multivariate analyses (p=0.042). Operation times (p=0.240) and incidences of adverse events (p=0.926) were not associated with the type of central airway infiltration. Conclusion: The type of airway infiltration was an independent poor prognostic factor after sleeve lobectomy in primary lung cancer patients. Our findings may guide the selection of optimal treatments for this patient population.
There are two ways in which lung cancer cells infiltrate into the central airway. One involves a centrally located lung cancer directly infiltrating the central airway. The other is when cancer cells in the metastatic hilar lymph node infiltrate the central airway. Sleeve lobectomy is required to completely remove centrally located lung cancers or lung cancers with hilar lymph node metastasis and to preserve the peripheral lung tissue. The impacts of central airway infiltration type on surgical methods, postoperative courses, and prognosis in patients undergoing sleeve lobectomy have never been investigated.
This study aimed to identify the impact of central airway infiltration type on the clinical features and outcomes of patients undergoing sleeve lobectomy.
Patients and Methods
We retrospectively investigated the clinical courses of 58 lung cancer patients who underwent sleeve lobectomy at our institute from January 2010 to December 2020. Before surgery, all patients gave informed consent for the use of their examination data in clinical studies. This study was approved by the local institutional ethical committee (Approval no. 4403, approval date: 3 October 2019).
Clinical and pathological staging were determined according to the 8th edition of the TMN Classification of Malignant Tumors (1). Mediastinal lymph nodes with a short axis of >10 mm on computed tomography were diagnosed as clinically positive for metastasis. The criteria for surgical resection were absence of distant metastasis, no cancer cell-positive pleural or pericardial effusion, no N2 disease at two or more mediastinal levels, no bulky N2 disease, no N3 disease, and a predicted postoperative percent vital capacity of >40%. Patients with T4 lung cancer, with N0 or N1 nodal extension, and with tumors that could be completely removed were considered candidates for surgery. Bronchial stumps were confirmed to be free of cancer cell infiltration through intraoperative pathological examination.
Because we did not have definitive criteria for providing induction therapy, patients who had undergone any treatments before surgery were excluded from this study. Patients with pathological stage II and III lung cancer received adjuvant platinum-based doublet chemotherapy, while those with stage I lung cancer received oral tegafur adjuvant chemotherapy. Adjuvant chemotherapies were initiated at the discretion of the physician in charge of each case.
After discharge, all patients underwent follow-up chest radiographs and measurement of tumor markers every 2 to 4 months, with computed tomography scans after 6 months and every year thereafter. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). Grade 3 or worse adverse events were recorded in this study.
At our institute, all patients underwent sleeve lobectomy under thoracotomy procedures. Standard sleeve lobectomy was defined as that requiring anastomosis at the lobar bronchus. Other types were defined as complex sleeve lobectomy. Two cases of lower sleeve lobectomy with preservation of the upper and middle lobes by double barreled airway reconstruction were also grouped into the complex type.
Blood samples were obtained within a few days before surgery. Comorbidities were defined as disorders being treated at the time of primary lung cancer diagnosis. Medians were used as the cut-off points for age and tumor size. The cutoffs for tumor markers were calculated in accordance with institutional cutoffs and previous reports (2, 3). Overall survival was calculated using the Kaplan-Meier method, and survival differences were compared using the log-rank test. Independent risk factors associated with survival were calculated using a Cox proportional hazard model. A p-value of <0.05 indicated statistical significance. Statistical analyses were performed using JMP 10 software (SAS Institute, Cary, NC, USA).
Results
Table I shows clinical characteristics of the 58 patients included in this study. Primary tumors directly infiltrated into the central airway in 42 patients, whereas cancer cells in the metastatic hilar lymph node infiltrated into the central airway in 16 patients. Adjuvant chemotherapy was administered to 26 patients (49%). Twenty patients (34%) had recurrence during the study period. Among them, three patients had locoregional recurrence, two had recurrence at the cut end of the chest wall, and one had recurrence around the airway anastomosis.
Characteristics of patients in this study.
Table II shows univariate and multivariate analyses of poor prognostic factors. Primary tumor infiltration and large tumor size were poor prognostic factors according to both univariate and multivariate analyses. Figure 1 shows overall survival curves according to the type of central airway infiltration and tumor size.
Univariate and multivariate analyses of poor prognostic factors.
Overall survival curves according to the type of central airway infiltration (A) and tumor size (B).
Table III shows details of surgical methods and clinical courses according to the type of central airway infiltration. Central location of the primary tumor increased the necessity for additional procedures. Operation times and incidences of adverse events were not affected by the type of central airway infiltration.
Detail of surgery according to the types of central airway infiltration.
Discussion
In this study, we show that primary tumor infiltration as the type of airway infiltration and large tumor size were independent poor prognostic factors after sleeve lobectomy in primary lung cancer patients. During surgery for centrally located lung cancers, tumors, and extensions to neighboring structures prevent attaining an adequate surgical field, which makes the operation more difficult. Sleeve lobectomy for centrally located lung cancers with airway infiltration might require more complex techniques than that for lung cancers with hilar lymph node metastasis. In our study, although central location of the primary tumor increased the necessity for additional procedures, operation times and incidences of adverse events were not significantly different between the different types of airway infiltration. It has been reported that the extent of bronchial resection margin has no clinically relevant impact on surgical outcomes (4, 5). In our cohort, locoregional recurrence at the anastomosis site was observed in only one patient. A more common type was distant organ recurrence. Patient prognosis might not be affected by surgical techniques, but rather by the malignant potential of tumors or anatomical features of the location.
We have previously reported that during sleeve lobectomy, the position of the preserved lung during ligation is important to prevent severe tension at the anastomosis site (6). To keep the preserved lung in the appropriate position, we recommend thoracotomy procedures for most sleeve lobectomies. Poor prognoses after sleeve lobectomy with additional procedures were also reported in our previous article (7). In this study, central location of the primary tumor increased the necessity for additional procedures and contributed to poor prognoses. However, the incidence of adverse events did not increase. For this cohort, all surgical methods were performed under thoracotomy procedures, which might be an important reason why adverse events were avoided.
Clinicopathological features differ between peripherally and centrally located primary lung cancers, with central location being a significant poor prognostic factor in both adenocarcinomas and squamous cell carcinomas (8-10). Moreover, in inoperable stage III/IV advanced lung cancer patients, central location of the tumor was an independent poor prognostic factor (11). These findings revealed that the malignant potential of tumors generated in the central region may contribute to poor prognosis. Tumor growth factor (TGF)-β1 protein expression in non-small cell lung cancers is correlated with prognosis. However, there was no significant difference in cancer cell TGF-β1 expression according to tumor location (peripheral or central) (12). Molecular mechanisms of the malignant behaviors of lung cancers generated in the central region have never been investigated.
Adenocarcinomas located in the main bronchus showed significantly worse patient survival than those in the non-main bronchus, both for all patients and for those undergoing curative resection. Furthermore, adenocarcinomas located in the main bronchus had a significantly higher rate of lymph node metastasis and distant metastasis than those not in the main bronchus (13). Deep infiltration into the airway mucosa was more frequently observed in patients with centrally located lung cancers than in those with hilar lymph node metastasis (14). It has also been reported that subepithelial and submucosal invasion in the bronchus are closely correlated with mediastinal lymph node metastasis (15). In this study, the incidence of mediastinal lymph node metastasis was rare in patients with centrally located lung cancer directly infiltrating the central airway compared with patients with hilar lymph node metastasis. The clinical condition of lympho-venous anastomoses has been reported in patients with malignant disease (16). Lymph-venous anastomoses are commonly caused by obstructed lymph flow (16). Lung tumors within the central region might obstruct lymphatic flow, after which this flow might move into venous networks through the lymph-venous anastomoses. We suggest that this mechanism is highly related with the anatomical features of the hilar portion. Because the hilar portion is a limited area, the lymph flow may be easily obstructed by a centrally located lung tumor. Consequently, cancer cells tend to spread throughout the body though the lymph-venous anastomoses without mediastinal lymph node metastasis in cases of centrally located lung tumors.
This study has several limitations. First, it was a small retrospective study. However, data from more patients are emerging and further analyses are underway. Second, surgical procedures and ancillary treatments were selected at the discretion of the physician in charge of each case. Hence, selection criteria for surgical procedures and perioperative therapy should be established. Third, the molecular mechanisms underlying the malignant behaviors in patients with centrally located lung cancer were not investigated. Molecular targets for anticancer treatment should be established in this patient population.
In conclusion, we found that the type of airway infiltration (primary tumor infiltration) and large tumor size were independent poor prognostic factors after sleeve lobectomy in primary lung cancer patients. These findings could be used to guide the selection of optimal treatments for this subgroup of lung cancer patients.
Footnotes
Authors’ Contributions
Takuma Tsukioka designed the study, analyzed the data, prepared the figures, and wrote the original draft. Hiroaki Komatsu, Hidetoshi Inoue, Ryuichi Ito, and Satoshi Suzuki collected the clinical data. Nobuhiro Izumi and Noritoshi Nishiyama critically reviewed the manuscript. All Authors read and approved the final manuscript.
Conflict of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received August 19, 2022.
- Revision received September 5, 2022.
- Accepted September 6, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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