N2 lung cancer is not all the same: an analysis of different prognostic groups

N2 lung cancer is not all the same: an analysis of different prognostic groups Abstract OBJECTIVES The International Association for the Study of Lung Cancer (IASLC) recently proposed a change in the staging system for N2, based on the metastatic station number: N2a1 (a single metastatic station with no hilar involvement), N2a2 (a single metastatic station with hilar involvement) and N2b (multiple metastatic stations). The aim of our study was to validate the IASLC proposal in a cohort of patients with pathological N2 disease. METHODS All patients with pathological T1–T2 N2 non-small-cell lung cancer who were operated on between 2006 and 2010 in our department were enrolled. The patients had lobectomy, bilobectomy or pneumonectomy without induction therapy; patients with any type of extended resection were excluded. All patients had adjuvant treatment. The impact of the new IASLC proposal on the overall and disease-free survival rates was then analysed. RESULTS Ninety-three patients were selected. The median follow-up period and overall survival time were 92 and 28.8 months, respectively. According to the new IASLC proposal, we observed 22 cases of N2a1, 54 N2a2 and 17 N2b. Patients with N2a1 had a significantly better overall survival than those with N2a2 and N2b (P = 0.041); the difference between N2a2 and N2b was not significant (P = 0.19). Patients with N2a1 squamous cell carcinoma had a significantly better overall survival than those with other histological diagnoses (P = 0.046). The disease-free interval was longer in patients with N2a1 than those in other groups (P = 0.021). CONCLUSIONS Our experience partially validates the IASLC proposal; the introduction of quantitative criteria for N staging might improve stratification of patients and the assignment to the correct therapeutic path. Non-small-cell lung cancer , Lymph node metastasis , Staging system , N2 INTRODUCTION Throughout the years, the tumour, node and metastasis (TNM) staging system has been edited several times based on a large international database with data from several nations. Since January 2018, the 8th edition [1] has officially been in use. When compared with the 7th edition, the latest edition has some changes in the T and M descriptors and introduces T1c and M1c; furthermore, Stages IC and IIIC and Stages IVA and IVB have been introduced [2]. Conversely, no changes have been made to the N descriptors, which are the same as those in the 5th edition; the descriptors are based on a pure anatomical rationale, regardless of the number of nodes and the number of stations involved. However, new categories for the stratification of N have been officially proposed, and they could be introduced in the next edition of the TNM if they are validated statistically. This proposal considers N staging from a new perspective: an anatomical point of view and a quantitative measurement. Consequently, lymph node metastases should be divided according to the number of stations involved, both for N1 and N2. In detail, N2 disease would not only be divided into a single station (N2a2) and multiple stations (N2b) but would also include the so-called skip metastasis (involvement of a single mediastinal station with no positive hilar lymph nodes), which would be considered a separate category (N2a1). The aim of our study was to validate the new proposal with an analysis of our recent experience with patients with surgically resected non-small-cell lung cancer (NSCLC). The primary end point of our study was to evaluate the impact of the new proposal on overall survival (OS) and disease-free survival (DFS) rates; second, we analysed possible prognostic factors in this population. MATERIALS AND METHODS Patient selection We retrospectively collected and analysed the data from all patients affected by N2 NSCLC who underwent a surgical resection without induction therapy between January 2006 and December 2010 in our department. We included in our study only patients with pathological T1 or T2 N2 NSCLC (according to the 7th edition of the TNM staging for lung cancer) who underwent a lobectomy, bilobectomy or pneumonectomy; patients with any kind of extended resections were excluded. We also excluded all patients with an active second cancer or with a cancer discovered less than 5 years prior to the lung cancer diagnosis and with a preoperative Eastern Cooperative Oncology Group performance status ≥2. Preoperative workup All patients were first evaluated by our multidisciplinary board. Patients with clinical N2 received neoadjuvant therapy, but patients with an unsuspected N2 or selected cases with a clinical single N2 station had a d’emblé surgical resection, followed by adjuvant therapy. All patients underwent contrast-enhanced chest and abdominal computed tomography (CT) and bronchoscopy. Preoperative histological proof was mandatory only for those patients who had to undergo neoadjuvant therapy. An attempt to obtain a histological diagnosis was always carried out in those who were candidates for surgery, but in case of doubt, a surgical procedure was performed. Positron emission tomography CT was not routinely performed, especially in patients treated during the first period. Pulmonary and cardiac functions were studied using the pulmonary function test, gas analysis and electrocardiography. Further examinations such as the diffusing capacity of the lung for carbon monoxide, echocardiography or a stress test were performed only in patients with important risk factors. Surgical procedure Surgical intervention was performed either via an open thoracotomy or a robotic technique. For open procedures, we mostly used a posterolateral thoracotomy, but a lateral or axillary muscle sparing thoracotomy was occasionally performed; a 3-arm robotic technique was used. Regardless of the technique used, a systematic lymph node dissection was always performed. Postoperative care and follow-up A chest radiograph was performed after surgery and prior to the removal of the chest drains. Two weeks after discharge, the patients were seen in our outpatient clinic to verify the postoperative course. The final pathology report was discussed by the multidisciplinary team, and the patients were then sent to their referring oncologist for the adjuvant treatment. Follow-up was generally carried out by the referring physician, who performed chest and abdominal CT scans every 6 months for the first 2 years and then once a year until the 5th year after the operation. In case of recurrence, the best treatment was discussed by the multidisplinary team. Follow-up ended on 1 April 2016; follow-up information was gathered by the authors from the referring oncologist and by a direct call to the patients or to their relatives. Statistical analyses Statistical analyses were performed using SPSS software, version 18.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables are expressed in terms of the median and interquartile range or the mean value and standard deviation, whereas categorical variables are expressed in terms of frequency and percentage. The OS and the disease-free interval (DFI) were estimated by the Kaplan–Meier method and calculated from the date of the surgical procedure. A comparison of survival rates between groups of patients was performed using the log-rank test; the Cox regression model was used for continuous variables; hazard ratios and 95% confidence intervals were reported for covariates. The Kruskal–Wallis test and the non-parametric median test were used to compare mean and median between groups, respectively. A P-value <0.05 was considered statistically significant. RESULTS From January 2006 to December 2010, we enrolled 1002 patients who underwent a lobectomy for NSCLC in our department. A total of 155 patients were diagnosed with pathological N2 disease according to the 7th edition of the TNM for lung cancer; 58 patients were excluded because they did not fit the inclusion criteria. Among the 97 patients included in the study, 2 patients died within the first 30 days after surgery of non-cancer-related causes and 2 were lost to follow-up after discharge. Table 1 includes all the preoperative clinical details of the 93 selected patients. Table 1: Clinical and surgical characteristics of all patients according to the IASLC proposal Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 CTCAE: Common Terminology for Adverse Events; FEV1: forced expiratory volume in the first second; IASLC: International Association for the Study of Lung Cancer; SD: standard deviation. Table 1: Clinical and surgical characteristics of all patients according to the IASLC proposal Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 CTCAE: Common Terminology for Adverse Events; FEV1: forced expiratory volume in the first second; IASLC: International Association for the Study of Lung Cancer; SD: standard deviation. As shown in Table 1, lobectomies were performed in a majority of cases (92.5%), whereas pneumonectomy was necessary in just 4 cases (4.3%). Forty patients had a clinical N2 diagnosis. The median postoperative hospital stay was 6 days (lower quartile and upper quartile, 5–8). We recorded postoperative complications in 31 cases; 18 were classified as minor complications (Common Terminology for Adverse Events 4.03, Grades 1 and 2). In 13 cases, we recorded a major complication (Common Terminology for Adverse Events 4.03, Grades 3 and 4). Reoperation was required in 3 patients to resolve complications. We recorded 4 early postoperative deaths within 90 days from surgery. The final pathology report revealed squamous cell carcinoma (34 cases, 36.6%) or adenocarcinoma (51 cases, 54.8%) in the majority of cases; large cell carcinoma, sarcomatoid carcinoma and adenosquamous carcinoma were observed in the remaining 8 cases. Thirty-three were T1 and 60 were T2. We resected a median number of 6 lymph node stations (lower quartile and upper quartile, 4–8) and 15 nodes per patient (lower quartile and upper quartile, 11–20); in detail, 6 (lower quartile and upper quartile 4–7) were hilar nodes and 9 (lower quartile and upper quartile 6–14) were mediastinal nodes. All patients were considered as candidates for an adjuvant treatment; in 8 cases, adjuvant therapy was not administered because the patient died or had a poor performance status, 8 patients received only radiotherapy, 59 had platinum-based chemotherapy and 26 patients had both chemotherapy and radiation therapy. Information on chemotherapy regimens was not always available; patients undergoing chemotherapy received mainly cisplatin and gemcitabine or vinorelbine for squamous cell carcinoma and cisplatin and pemetrexed for adenocarcinoma. The median follow-up period was 92 months (range 63–121 months), with a median survival time of the entire cohort of 28.8 months and with 1-, 3- and 5-year survival rates of 74%, 41% and 33%, respectively. When we restaged all patients according to the new International Association for the Study of Lung Cancer (IASLC) proposal for N2 staging, we found N2a1 (22 patients), N2a2 (54 patients) and N2b (17 patients). As shown in Table 1, the groups were significantly different only for the duration of the postoperative hospital stay; none of the patients with N2a1 received either a bilobectomy or a pneumonectomy. Patients who had skip metastasis (N2a1) had a significantly better OS compared with those with N2a2 and N2b (P = 0.045, Fig. 1); in fact, we observed a 36-month median survival in patients with N2a1 (90.9%, 50.0% and 45.5% at 1, 3 and 5 years, respectively), whereas those with N2a2 and N2b had 28- and 16-month median survival rates, respectively (77.8% and 70.6%, 42.6% and 23.5%, 31.5% and 23.5% at 1, 3 and 5 years, respectively). When we compared all patients with an N2a1 nodal stage with all the other patients, we continued to observe a significant difference in OS (P = 0.041). Conversely, no statistically significant difference was found between the OS of patients with N2a2 and N2b (P = 0.19). No statistical difference in OS was found between patients with or without involvement of station 7, calculated both for the whole cohort and for the group with N2a1. Moreover, no significant impact on OS between groups was found when we considered the different histological diagnoses. Figure 1: View largeDownload slide Overall survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Figure 1: View largeDownload slide Overall survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Recurrence was observed in 61 cases (65.6%): 11 cases of local recurrence, 32 cases of distant recurrence, 13 cases of both local recurrence and distant recurrence; in 5 cases no precise information about the localization of the recurrence was available. The median DFS was 19.7 months for the entire cohort. DFS for patients with N2a1 was 40 months, which was significantly higher (P = 0.021, Fig. 2) than those with N2a2 (18 months) and N2b (11 months); conversely, no differences were found when we compared patients with N2a2 and N2b (P = 0.082). Figure 2: View largeDownload slide Disease-free survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Figure 2: View largeDownload slide Disease-free survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. On univariate analysis (Table 2), only patients operated on the right side and younger patients (when age was calculated as a continuous variable) showed a significantly better OS; this significant association was confirmed in the multivariate analysis (hazard ratio for age 1.038, 95% confidence interval 1.006–1.071, P = 0.019; hazard ratio for the right side 0.585, 95% confidence interval 0.366–0.937, P = 0.026). On the other hand, none of the other variables showed a significant association with survival; in particular, we compared the OS of T1 and T2 and found no evidence of significant differences even if a more favourable trend was evident for a smaller cancer; concurrently, radicality of resection was not significantly correlated either with OS or with DFS. We also analysed the impact of the same variables on the DFS rate, but we did not find any significant correlation (Table 2). Table 2: Univariate analysis of variables influencing overall survival and disease-free survival Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 The log-rank test was used to determine categorical variables and the Cox regression analysis was used for continuous variables. P-values <0.05 were considered significant. Values in bold are those which are significant. CI: confidence interval; HR: hazard ratio. Table 2: Univariate analysis of variables influencing overall survival and disease-free survival Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 The log-rank test was used to determine categorical variables and the Cox regression analysis was used for continuous variables. P-values <0.05 were considered significant. Values in bold are those which are significant. CI: confidence interval; HR: hazard ratio. We analysed in more detail the population of 22 patients with a single mediastinal lymph node metastatic station with no hilar lymph node involvement (N2a1). Interestingly, in this subgroup, all metastatic lymph nodes were in so-called lobe-specific stations [3]. The median number of involved nodes was 2. We did not find any significant difference in OS and DFI when we compared different primary tumour locations and lymph node metastatic stations; conversely, we observed a significantly worse prognosis for patients with a histological diagnosis of squamous cell carcinoma versus other histotypes (P = 0.046; Fig. 3). Moreover, among patients who had a recurrence, those affected by squamous cell carcinoma experienced a significantly worse survival rate (29 months vs 72 months, P = 0.047). Figure 3: View largeDownload slide Overall survival according to histological diagnosis in the N2a1 subgroup. Figure 3: View largeDownload slide Overall survival according to histological diagnosis in the N2a1 subgroup. We analysed the impact of the number of metastatic lymph nodes on OS and DFS, using the median value of our cohort (4) as the cut-off value and the lymph node ratio, which is the ratio between the number of metastatic lymph nodes and the total number of harvested lymph nodes. Results (Table 3) showed a significantly better OS and DFS for patients whose number of positive lymph nodes was lower than the median value (P < 0.001 and P = 0.001, respectively) and who had a low lymph node ratio (P = 0.002 and P = 0.002, respectively). When we compared the impact of these 3 classifications on OS, the number of positive lymph nodes was the most significant method. Table 3: Analysis of impact on overall survival and disease-free interval of 3 proposals for quantitative staging of lymph nodes in patients with non-small-cell lung cancer Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Analysis was calculated using the log-rank test for categorical variables and the Cox regression model for continuous variables. CI: confidence interval; HR: hazard ratio; IASLC: International Association for the Study of Lung Cancer. Table 3: Analysis of impact on overall survival and disease-free interval of 3 proposals for quantitative staging of lymph nodes in patients with non-small-cell lung cancer Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Analysis was calculated using the log-rank test for categorical variables and the Cox regression model for continuous variables. CI: confidence interval; HR: hazard ratio; IASLC: International Association for the Study of Lung Cancer. DISCUSSION The 8th edition of the TNM staging system for lung cancer has been in use since January 2018, with some changes in the definitions of the T and M descriptors and some newly defined prognostic groups [2]. Conversely, no changes were made to N descriptors, which have been based only on anatomical criteria since the TNM edition issued in 1982. Nevertheless, the IASLC staging committee [4] reproposed the introduction of new subgroups of N-positive components; similar proposals were promoted in the 7th edition of lung cancer TNM and in several retrospective series [5–8]. Nevertheless, no sufficiently significant data were available to support the introduction of these changes in the official edition of the TNM staging system. The present proposal concerns both N1 and N2 and is no longer based solely on pure anatomical criteria but also on quantitative criteria. Accordingly, N2 would be divided into 3 subgroups: N2a1 for a single involved mediastinal station without hilar involvement (the so-called skip metastasis), N2a2 for a single metastatic mediastinal station with the concurrent involvement of hilar nodes, and finally, N2b for multiple involvement of mediastinal node stations. The aim of our study was to investigate the IASLC proposal in a cohort of patients undergoing multimodal treatment with primary surgery. Asamura et al. [4] found significant differences in terms of OS and DFI between the 3 groups they proposed, with a worse long-term survival for patients with multiple mediastinal station involvement and a significantly better prognosis for patients with skip metastasis and limited involvement of mediastinal lymph nodes; similar results were also reported by other authors [9–11]. An anatomical explanation for this phenomenon lies in the possible direct lymphatic drainage into the mediastinal nodes, completely bypassing the intralobar and hilar stations, but other explanations have been proposed [12]. We consistently observed that patients suffering from skip metastasis and a single metastatic mediastinal lymph node station had a significant survival advantage compared to other groups. Conversely, we did not observe differences in OS rates between patients with N2a2 and those with N2b. These results partially validate the outcomes of the papers mentioned previously, but they point to an important unanswered question concerning the correct stratification of patients with mediastinal lymph node involvement. In fact, it is currently established that patients with a clinical N2 designation, regardless of the extent of lymph node involvement, should receive induction therapy prior to possible surgery and should always be discussed by a multidisciplinary group [13, 14]. Nevertheless, a designation of N2 includes a wide range of clinical situations that might be treated differently with a larger benefit for the patients and similar or better long-term outcomes [15]. In all the patients of our cohort, an N2 diagnosis was clinically unsuspected or, in the case of a clinical single N2 station, a multidisciplinary decision for a surgical resection d’emblé was taken into account. Multimodality treatment was planned for all patients, and all of them received adjuvant chemotherapy except for 8 patients who did not receive postoperative treatment because they died or showed a poor postoperative performance status. Surprisingly, our median 3- and 5-year survival rates for patients diagnosed as N2a1 were considerably better than those reported for N2 patients treated with neoadjuvant therapy and surgery [14, 16]. Similarly, a recent French report [11] on 871 patients advocated for a better stratification of IIIA-N2 NSCLC, because they found a significant difference in OS according to the number and position of the lymph node stations involved. In contrast, Lee et al. [17] did not find any differences in OS and DFS in patients treated with induction chemoradiotherapy followed by surgical resection according to the pretreatment of single- or multistation mediastinal involvement. Finally, a recent match analysis based on a large multi-institutional database [15] found comparable outcomes between patients with N2 NSCLC treated with surgery and adjuvant chemotherapy and neoadjuvant therapy and surgery; in the same study, patients treated with lobectomy and adjuvant therapy for unknown N2 disease also had a significantly better prognosis than those who received radiation or chemoradiation alone. Furthermore, Garelli et al. [10] stressed the importance of not only the number of lymph nodes involved but also the quality of involvement. They showed that microscopic metastases had a significant impact on survival and suggested that this subgroup of patients might not benefit from the use of adjuvant therapy and could be eligible for a clinical follow-up only. Unfortunately, we did not have enough data to discriminate between microscopic lymph node involvement and macroscopic lymph node involvement. On the other hand, the current N1 and N2 division has the crucial advantage of simplifying preoperative staging. A staging system based on the number of positive stations or lymph nodes would be challenging when trying to make a correct, precise preoperative assessment. In fact, such an evaluation would require a pathological confirmation or a detailed positron emission tomography report not only for mediastinal stations but also for Stations 10, 11 and 12. In an interesting report, Lee et al. [9] compared 4 proposed lymph node staging systems [7, 18–20] (based on the metastatic nodal zone, number of lymph nodes involved, lymph node ratio and combination of the number and location of metastatic lymph nodes) and found no significant difference among them in terms of predictive power using the C-index, but they found a higher C-index value for the classification based on the number of metastatic lymph nodes. This evidence should be used to complete the current nodal staging system rather than radically change it. We consistently observed a significant relation of both survival and the DFI with the number of mediastinal lymph node stations involved, the number of positive lymph nodes and the lymph node ratio. To the best of our knowledge, no correlation between histological diagnosis and skip metastasis has been reported so far. We noted that patients affected by squamous cell carcinoma with a pathological N2a1 stage had a significantly worse survival rate compared with patients who had adenocarcinoma or other histological diagnoses. Conversely, no difference was found when we analysed DFS, but, among those who had a recurrence, those with squamous cell carcinoma had a significantly worse survival. A worse survival with a concomitant, similar DFS for patients with squamous cell carcinoma compared to adenocarcinoma has been reported by other authors [21–23], who concluded that the difference in the mortality rate might be associated with non-cancer-related causes; nevertheless, Fukui et al. found more deaths among patients with a recurrent squamous cell carcinoma than among those with adenocarcinoma. They, therefore, proposed a reclassification of T1a-bN0 and T2N0 squamous cell NSCLC as Stage IIA. Moreover, Li et al. [24] reported a retrospective analysis of surgically treated adenocarcinomas of the lung with skip metastasis, finding a higher incidence in acinar subtypes, with no significant differences in the survival rate. Due to the small number of patients, it is difficult to draw conclusions based on our data, but we can speculate that squamous cell carcinomas might be more aggressive than other histological types and should, therefore, be treated with different multidisciplinary protocols. Limitations Our study has some limitations: First, the main weakness is the retrospective nature of the data set, which might have caused accidental selection bias. Second, the number of patients is small and might influence conclusions that have been drawn; in particular, a difference between N2a2 and N2b groups might have been missed due to the small number of patients. Third, detailed information about adjuvant treatments was not always available. Finally, in some cases, lymph nodes were not collected as a single specimen, so pieces of lymph nodes might have been counted as single nodes. CONCLUSIONS Our experience shows that a single-station N2 without hilar node involvement indicates a better outcome and the potential significance of the number of positive lymph nodes and the lymph node ratio. We also noted that patients with squamous cell carcinoma who had an N2a1 diagnosis had worse OS. Our results confirm that the N descriptor should be revised to include quantitative and possibly qualitative criteria along with the existing anatomical criteria to allow better stratification of the heterogeneous group of N2 patients with an N2 diagnosis and better determination of the best therapeutic path for each of them. ACKNOWLEDGEMENTS This research did not involve any studies with human participants or animals. Conflict of interest: none declared. REFERENCES 1 Goldstraw P , Chansky K , Crowley J , Rami-Porta R , Asamura H , Eberhardt WE et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer . J Thorac Oncol 2016 ; 11 : 39 – 51 . Google Scholar CrossRef Search ADS PubMed 2 Rami-Porta R , Asamura H , Travis WD , Rusch VW. Lung cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual . CA Cancer J Clin 2017 ; 67 : 138 – 55 . Google Scholar CrossRef Search ADS PubMed 3 Bille A , Woo KM , Ahmad U , Rizk NP , Jones DR. Incidence of occult pN2 disease following resection and mediastinal lymph node dissection in clinical stage I lung cancer patients . Eur J Cardiothorac Surg 2017 ; 51 : 674 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Asamura H , Chansky K , Crowley J , Goldstraw P , Rusch VW , Vansteenkiste JF et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer . J Thorac Oncol 2015 ; 10 : 1675 – 84 . Google Scholar CrossRef Search ADS PubMed 5 Andre F , Grunenwald D , Pignon JP , Dujon A , Pujol JL , Brichon PY et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications . J Clin Oncol 2000 ; 18 : 2981 – 9 . Google Scholar CrossRef Search ADS PubMed 6 Misthos P , Sepsas E , Kokotsakis J , Skottis I , Lioulias A. The significance of one-station N2 disease in the prognosis of patients with nonsmall-cell lung cancer . Ann Thorac Surg 2008 ; 86 : 1626 – 30 . Google Scholar CrossRef Search ADS PubMed 7 Rusch VW , Crowley J , Giroux DJ , Goldstraw P , Im JG , Tsuboi M et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer . J Thorac Oncol 2007 ; 2 : 603 – 12 . Google Scholar CrossRef Search ADS PubMed 8 Tsitsias T , Boulemden A , Ang K , Nakas A , Waller DA. The N2 paradox: similar outcomes of pre- and postoperatively identified single-zone N2a positive non-small-cell lung cancer . Eur J Cardiothorac Surg 2014 ; 45 : 882 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Lee GD , Kim DK , Moon DH , Joo S , Hwang SK , Choi SH et al. A comparison of the proposed classifications for the revision of N descriptors for non-small-cell lung cancer . Eur J Cardiothorac Surg 2016 ; 49 : 580 – 8 . Google Scholar CrossRef Search ADS PubMed 10 Garelli E , Renaud S , Falcoz PE , Weingertner N , Olland A , Santelmo N et al. Microscopic N2 disease exhibits a better prognosis in resected non-small-cell lung cancer . Eur J Cardiothorac Surg 2016 ; 50 : 322 – 8 . Google Scholar CrossRef Search ADS PubMed 11 Legras A , Mordant P , Arame A , Foucault C , Dujon A , Le Pimpec Barthes F et al. Long-term survival of patients with pN2 lung cancer according to the pattern of lymphatic spread . Ann Thorac Surg 2014 ; 97 : 1156 – 62 . Google Scholar CrossRef Search ADS PubMed 12 Takizawa H , Sakiyama S , Tsuboi M , Tangoku A. Demonstration of the skip metastasis pathway for N2 non-small cell lung cancer . J Thorac Cardiovasc Surg 2014 ; 147 : e50 – 2 . Google Scholar CrossRef Search ADS PubMed 13 Rosell R , Gómez-Codina J , Camps C , Javier Sánchez J , Maestre J , Padilla J et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial . Lung Cancer 1999 ; 26 : 7 – 14 . Google Scholar CrossRef Search ADS PubMed 14 Eberhardt WE , De Ruysscher D , Weder W , Le Péchoux C , De Leyn P , Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer . Ann Oncol 2015 ; 26 : 1573 – 88 . Google Scholar CrossRef Search ADS PubMed 15 Yang CF , Kumar A , Gulack BC , Mulvihill MS , Hartwig MG , Wang X et al. Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: a National Cancer Data Base analysis . J Thorac Cardiovasc Surg 2016 ; 151 : 1380 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Martins RG , D’Amico TA , Loo BW , Pinder-Schenck M , Borghaei H , Chaft JE et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement . J Natl Compr Canc Netw 2012 ; 10 : 599 – 613 . Google Scholar CrossRef Search ADS PubMed 17 Lee H , Ahn YC , Pyo H , Kim B , Oh D , Nam H et al. Pretreatment clinical mediastinal nodal bulk and extent do not influence survival in N2-positive stage IIIA non-small cell lung cancer patients treated with trimodality therapy . Ann Surg Oncol 2014 ; 21 : 2083 – 90 . Google Scholar CrossRef Search ADS PubMed 18 Rami-Porta R , Crowley JJ , Goldstraw P. The revised TNM staging system for lung cancer . Ann Thorac Cardiovasc Surg 2009 ; 15 : 4 – 9 . Google Scholar PubMed 19 Wei S , Asamura H , Kawachi R , Sakurai H , Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol 2011 ; 6 : 310 – 8 . Google Scholar CrossRef Search ADS PubMed 20 Saji H , Tsuboi M , Shimada Y , Kato Y , Yoshida K , Nomura M et al. A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer . Chest 2013 ; 143 : 1618 – 25 . Google Scholar CrossRef Search ADS PubMed 21 Fukui T , Taniguchi T , Kawaguchi K , Fukumoto K , Nakamura S , Sakao Y et al. Comparisons of the clinicopathological features and survival outcomes between lung cancer patients with adenocarcinoma and squamous cell carcinoma . Gen Thorac Cardiovasc Surg 2015 ; 63 : 507 – 13 . Google Scholar CrossRef Search ADS PubMed 22 Nakamura H , Sakai H , Kimura H , Miyazawa T , Marushima H , Saji H. Difference in postsurgical prognostic factors between lung adenocarcinoma and squamous cell carcinoma . Ann Thorac Cardiovasc Surg 2017 ; 23 : 291 – 7 . Google Scholar CrossRef Search ADS PubMed 23 Kawase A , Yoshida J , Ishii G , Nakao M , Aokage K , Hishida T et al. Differences between squamous cell carcinoma and adenocarcinoma of the lung: are adenocarcinoma and squamous cell carcinoma prognostically equal? Jpn J Clin Oncol 2012 ; 42 : 189 – 95 . Google Scholar CrossRef Search ADS PubMed 24 Li H , Hu H , Wang R , Li Y , Shen L , Sun Y et al. Lung adenocarcinoma: are skip N2 metastases different from non-skip? J Thorac Cardiovasc Surg 2015 ; 150 : 790 – 5 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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Abstract

Abstract OBJECTIVES The International Association for the Study of Lung Cancer (IASLC) recently proposed a change in the staging system for N2, based on the metastatic station number: N2a1 (a single metastatic station with no hilar involvement), N2a2 (a single metastatic station with hilar involvement) and N2b (multiple metastatic stations). The aim of our study was to validate the IASLC proposal in a cohort of patients with pathological N2 disease. METHODS All patients with pathological T1–T2 N2 non-small-cell lung cancer who were operated on between 2006 and 2010 in our department were enrolled. The patients had lobectomy, bilobectomy or pneumonectomy without induction therapy; patients with any type of extended resection were excluded. All patients had adjuvant treatment. The impact of the new IASLC proposal on the overall and disease-free survival rates was then analysed. RESULTS Ninety-three patients were selected. The median follow-up period and overall survival time were 92 and 28.8 months, respectively. According to the new IASLC proposal, we observed 22 cases of N2a1, 54 N2a2 and 17 N2b. Patients with N2a1 had a significantly better overall survival than those with N2a2 and N2b (P = 0.041); the difference between N2a2 and N2b was not significant (P = 0.19). Patients with N2a1 squamous cell carcinoma had a significantly better overall survival than those with other histological diagnoses (P = 0.046). The disease-free interval was longer in patients with N2a1 than those in other groups (P = 0.021). CONCLUSIONS Our experience partially validates the IASLC proposal; the introduction of quantitative criteria for N staging might improve stratification of patients and the assignment to the correct therapeutic path. Non-small-cell lung cancer , Lymph node metastasis , Staging system , N2 INTRODUCTION Throughout the years, the tumour, node and metastasis (TNM) staging system has been edited several times based on a large international database with data from several nations. Since January 2018, the 8th edition [1] has officially been in use. When compared with the 7th edition, the latest edition has some changes in the T and M descriptors and introduces T1c and M1c; furthermore, Stages IC and IIIC and Stages IVA and IVB have been introduced [2]. Conversely, no changes have been made to the N descriptors, which are the same as those in the 5th edition; the descriptors are based on a pure anatomical rationale, regardless of the number of nodes and the number of stations involved. However, new categories for the stratification of N have been officially proposed, and they could be introduced in the next edition of the TNM if they are validated statistically. This proposal considers N staging from a new perspective: an anatomical point of view and a quantitative measurement. Consequently, lymph node metastases should be divided according to the number of stations involved, both for N1 and N2. In detail, N2 disease would not only be divided into a single station (N2a2) and multiple stations (N2b) but would also include the so-called skip metastasis (involvement of a single mediastinal station with no positive hilar lymph nodes), which would be considered a separate category (N2a1). The aim of our study was to validate the new proposal with an analysis of our recent experience with patients with surgically resected non-small-cell lung cancer (NSCLC). The primary end point of our study was to evaluate the impact of the new proposal on overall survival (OS) and disease-free survival (DFS) rates; second, we analysed possible prognostic factors in this population. MATERIALS AND METHODS Patient selection We retrospectively collected and analysed the data from all patients affected by N2 NSCLC who underwent a surgical resection without induction therapy between January 2006 and December 2010 in our department. We included in our study only patients with pathological T1 or T2 N2 NSCLC (according to the 7th edition of the TNM staging for lung cancer) who underwent a lobectomy, bilobectomy or pneumonectomy; patients with any kind of extended resections were excluded. We also excluded all patients with an active second cancer or with a cancer discovered less than 5 years prior to the lung cancer diagnosis and with a preoperative Eastern Cooperative Oncology Group performance status ≥2. Preoperative workup All patients were first evaluated by our multidisciplinary board. Patients with clinical N2 received neoadjuvant therapy, but patients with an unsuspected N2 or selected cases with a clinical single N2 station had a d’emblé surgical resection, followed by adjuvant therapy. All patients underwent contrast-enhanced chest and abdominal computed tomography (CT) and bronchoscopy. Preoperative histological proof was mandatory only for those patients who had to undergo neoadjuvant therapy. An attempt to obtain a histological diagnosis was always carried out in those who were candidates for surgery, but in case of doubt, a surgical procedure was performed. Positron emission tomography CT was not routinely performed, especially in patients treated during the first period. Pulmonary and cardiac functions were studied using the pulmonary function test, gas analysis and electrocardiography. Further examinations such as the diffusing capacity of the lung for carbon monoxide, echocardiography or a stress test were performed only in patients with important risk factors. Surgical procedure Surgical intervention was performed either via an open thoracotomy or a robotic technique. For open procedures, we mostly used a posterolateral thoracotomy, but a lateral or axillary muscle sparing thoracotomy was occasionally performed; a 3-arm robotic technique was used. Regardless of the technique used, a systematic lymph node dissection was always performed. Postoperative care and follow-up A chest radiograph was performed after surgery and prior to the removal of the chest drains. Two weeks after discharge, the patients were seen in our outpatient clinic to verify the postoperative course. The final pathology report was discussed by the multidisciplinary team, and the patients were then sent to their referring oncologist for the adjuvant treatment. Follow-up was generally carried out by the referring physician, who performed chest and abdominal CT scans every 6 months for the first 2 years and then once a year until the 5th year after the operation. In case of recurrence, the best treatment was discussed by the multidisplinary team. Follow-up ended on 1 April 2016; follow-up information was gathered by the authors from the referring oncologist and by a direct call to the patients or to their relatives. Statistical analyses Statistical analyses were performed using SPSS software, version 18.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables are expressed in terms of the median and interquartile range or the mean value and standard deviation, whereas categorical variables are expressed in terms of frequency and percentage. The OS and the disease-free interval (DFI) were estimated by the Kaplan–Meier method and calculated from the date of the surgical procedure. A comparison of survival rates between groups of patients was performed using the log-rank test; the Cox regression model was used for continuous variables; hazard ratios and 95% confidence intervals were reported for covariates. The Kruskal–Wallis test and the non-parametric median test were used to compare mean and median between groups, respectively. A P-value <0.05 was considered statistically significant. RESULTS From January 2006 to December 2010, we enrolled 1002 patients who underwent a lobectomy for NSCLC in our department. A total of 155 patients were diagnosed with pathological N2 disease according to the 7th edition of the TNM for lung cancer; 58 patients were excluded because they did not fit the inclusion criteria. Among the 97 patients included in the study, 2 patients died within the first 30 days after surgery of non-cancer-related causes and 2 were lost to follow-up after discharge. Table 1 includes all the preoperative clinical details of the 93 selected patients. Table 1: Clinical and surgical characteristics of all patients according to the IASLC proposal Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 CTCAE: Common Terminology for Adverse Events; FEV1: forced expiratory volume in the first second; IASLC: International Association for the Study of Lung Cancer; SD: standard deviation. Table 1: Clinical and surgical characteristics of all patients according to the IASLC proposal Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 Variables All patients N2a1 N2a2 N2b P-value Gender, n (%)  Male 66 (71.0) 18 (19.3) 37 (39.8) 11 (11.8) 0.419 Age (years), mean ± SD 67.5 ± 7.2 66.4 ± 7.9 67.3 ± 7.3 69.2 ± 5.4 0.506 Smoker, n (%)  Yes 24 (25.8) 6 (6.5) 15 (16.1) 3 (3.2)  No 11 (11.8) 3 (3.2) 6 (6.5) 2 (2.1)  Ex 39 (41.9) 7 (7.5) 23 (24.7) 9 (9.7) 0.827  Not known 19 (20.4) 6 (6.5) 10 (10.7) 3 (3.2) Cardiovascular and respiratory comorbidities, n (%)  Yes 71 (76.3) 13 (14.0) 44 (47.3) 14 (15.0) 0.089 Median FEV1  Value in litres (lower quartile–upper quartile) 2.4 (1.8–2.8) 2.5 (1.9–3.0) 2.4 (1.7–2.8) 2.4 (1.9–3.0) 0.631  Percentage value (lower quartile–upper quartile) 91.0 (75.5–101.5) 94 (71–102) 92 (76–100) 87 (78–96) 0.316 Previous cancers, n (%)  Yes 20 (21.5) 5 (5.4) 13 (14.0) 2 (2.15) 0.761 cN2, n (%)  Yes 40 (43.0) 8 (8.6) 22 (23.6) 10 (10.8) 0.452 Side, n (%)  Right 54 (58.1) 17 (18.3) 28 (30.1) 9 (9.7) 0.112 Surgery, n (%)  Lobectomy 86 (92.5) 22 (23.6) 50 (53.8) 14 (15.0)  Bilobectomy 3 (3.2) 0 2 (2.1) 1 (1.1)  Pneumonectomy 4 (4.3) 0 2 (2.1) 2 (2.1) 0.327 Median number of resected lymph node stations (lower quartile–upper quartile) 6 (4–8) 5 (4–8) 6 (4–8) 7 (5–8) 0.581 Median postoperative hospitalization (lower quartile–upper quartile) 6 (5–8) 6 (5–7) 6 (5–8) 6 (5–12) 0.597 Postoperative complications, n (%)  Yes 31 (33.3) 4 (4.3) 22 (23.6) 5 (5.4) 0.182 CTCAE 4.03, n (%)  Grades 1–2 18 (19.3) 3 (3.2) 14 (15.0) 1 (1.1) 0.285  Grades 3–4 13 (14.0) 1 (1.1) 8 (8.6) 4 (4.3) pT, n (%)  T1 33 (35.5) 10 (10.7) 17 (18.3) 6 (6.4)  T2 60 (64.5) 12 (12.9) 37 (39.8) 11 (11.8) 0.513 Histology, n (%)  Adenocarcinoma 51 (54.8) 14 (15.0) 24 (25.8) 13 (14.0)  Squamous cell carcinoma 34 (36.6) 6 (6.4) 26 (28.0) 2 (2.1)  Sarcomatoid carcinoma 2 (2.2) 1 (1.1) 0 1 (1.1)  Large cell carcinoma 4 (4.3) 1 (1.1) 3 (3.2) 0  Adenosquamous carcinoma 2 (2.2) 0 1 (1.1) 1 (1.1) 0.158 Adjuvant treatment, n (%)  Yes 85 (91.4) 19 (20.4) 51 (54.8) 16 (17.2) 0.616 CTCAE: Common Terminology for Adverse Events; FEV1: forced expiratory volume in the first second; IASLC: International Association for the Study of Lung Cancer; SD: standard deviation. As shown in Table 1, lobectomies were performed in a majority of cases (92.5%), whereas pneumonectomy was necessary in just 4 cases (4.3%). Forty patients had a clinical N2 diagnosis. The median postoperative hospital stay was 6 days (lower quartile and upper quartile, 5–8). We recorded postoperative complications in 31 cases; 18 were classified as minor complications (Common Terminology for Adverse Events 4.03, Grades 1 and 2). In 13 cases, we recorded a major complication (Common Terminology for Adverse Events 4.03, Grades 3 and 4). Reoperation was required in 3 patients to resolve complications. We recorded 4 early postoperative deaths within 90 days from surgery. The final pathology report revealed squamous cell carcinoma (34 cases, 36.6%) or adenocarcinoma (51 cases, 54.8%) in the majority of cases; large cell carcinoma, sarcomatoid carcinoma and adenosquamous carcinoma were observed in the remaining 8 cases. Thirty-three were T1 and 60 were T2. We resected a median number of 6 lymph node stations (lower quartile and upper quartile, 4–8) and 15 nodes per patient (lower quartile and upper quartile, 11–20); in detail, 6 (lower quartile and upper quartile 4–7) were hilar nodes and 9 (lower quartile and upper quartile 6–14) were mediastinal nodes. All patients were considered as candidates for an adjuvant treatment; in 8 cases, adjuvant therapy was not administered because the patient died or had a poor performance status, 8 patients received only radiotherapy, 59 had platinum-based chemotherapy and 26 patients had both chemotherapy and radiation therapy. Information on chemotherapy regimens was not always available; patients undergoing chemotherapy received mainly cisplatin and gemcitabine or vinorelbine for squamous cell carcinoma and cisplatin and pemetrexed for adenocarcinoma. The median follow-up period was 92 months (range 63–121 months), with a median survival time of the entire cohort of 28.8 months and with 1-, 3- and 5-year survival rates of 74%, 41% and 33%, respectively. When we restaged all patients according to the new International Association for the Study of Lung Cancer (IASLC) proposal for N2 staging, we found N2a1 (22 patients), N2a2 (54 patients) and N2b (17 patients). As shown in Table 1, the groups were significantly different only for the duration of the postoperative hospital stay; none of the patients with N2a1 received either a bilobectomy or a pneumonectomy. Patients who had skip metastasis (N2a1) had a significantly better OS compared with those with N2a2 and N2b (P = 0.045, Fig. 1); in fact, we observed a 36-month median survival in patients with N2a1 (90.9%, 50.0% and 45.5% at 1, 3 and 5 years, respectively), whereas those with N2a2 and N2b had 28- and 16-month median survival rates, respectively (77.8% and 70.6%, 42.6% and 23.5%, 31.5% and 23.5% at 1, 3 and 5 years, respectively). When we compared all patients with an N2a1 nodal stage with all the other patients, we continued to observe a significant difference in OS (P = 0.041). Conversely, no statistically significant difference was found between the OS of patients with N2a2 and N2b (P = 0.19). No statistical difference in OS was found between patients with or without involvement of station 7, calculated both for the whole cohort and for the group with N2a1. Moreover, no significant impact on OS between groups was found when we considered the different histological diagnoses. Figure 1: View largeDownload slide Overall survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Figure 1: View largeDownload slide Overall survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Recurrence was observed in 61 cases (65.6%): 11 cases of local recurrence, 32 cases of distant recurrence, 13 cases of both local recurrence and distant recurrence; in 5 cases no precise information about the localization of the recurrence was available. The median DFS was 19.7 months for the entire cohort. DFS for patients with N2a1 was 40 months, which was significantly higher (P = 0.021, Fig. 2) than those with N2a2 (18 months) and N2b (11 months); conversely, no differences were found when we compared patients with N2a2 and N2b (P = 0.082). Figure 2: View largeDownload slide Disease-free survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. Figure 2: View largeDownload slide Disease-free survival for different groups with a diagnosis of N2 according to the International Association for the Study of Lung Cancer proposal. On univariate analysis (Table 2), only patients operated on the right side and younger patients (when age was calculated as a continuous variable) showed a significantly better OS; this significant association was confirmed in the multivariate analysis (hazard ratio for age 1.038, 95% confidence interval 1.006–1.071, P = 0.019; hazard ratio for the right side 0.585, 95% confidence interval 0.366–0.937, P = 0.026). On the other hand, none of the other variables showed a significant association with survival; in particular, we compared the OS of T1 and T2 and found no evidence of significant differences even if a more favourable trend was evident for a smaller cancer; concurrently, radicality of resection was not significantly correlated either with OS or with DFS. We also analysed the impact of the same variables on the DFS rate, but we did not find any significant correlation (Table 2). Table 2: Univariate analysis of variables influencing overall survival and disease-free survival Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 The log-rank test was used to determine categorical variables and the Cox regression analysis was used for continuous variables. P-values <0.05 were considered significant. Values in bold are those which are significant. CI: confidence interval; HR: hazard ratio. Table 2: Univariate analysis of variables influencing overall survival and disease-free survival Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 Variables Overall survival Disease-free survival Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value Age >65 years 24 0.064 28 0.710 Age <65 years 50 18 Age (continuous variable) 1.037 (1.005–1.070) 0.022 1.003 (0.970–1.037) 0.868 Gender  Female 60 31 0.343  Male 23 0.058 18 Right side 31 24 Left side 22 0.027 16 0.176 Lobectomy 28 20 Bilobectomy and pneumonectomy 25 0.142 18 0.499 pT1 42 28 pT2 28 0.481 19 0.528 Adenocarcinoma 29 24 Squamous cell carcinoma 24 18 Other histological diagnoses 29 0.677 12 0.391 Metastasis at station 7 27 18 No metastasis at Station 7 29 0.261 22 0.809 Adjuvant chemotherapy or radiotherapy 31 18 Adjuvant chemoradiation 48 0.951 31 0.627 The log-rank test was used to determine categorical variables and the Cox regression analysis was used for continuous variables. P-values <0.05 were considered significant. Values in bold are those which are significant. CI: confidence interval; HR: hazard ratio. We analysed in more detail the population of 22 patients with a single mediastinal lymph node metastatic station with no hilar lymph node involvement (N2a1). Interestingly, in this subgroup, all metastatic lymph nodes were in so-called lobe-specific stations [3]. The median number of involved nodes was 2. We did not find any significant difference in OS and DFI when we compared different primary tumour locations and lymph node metastatic stations; conversely, we observed a significantly worse prognosis for patients with a histological diagnosis of squamous cell carcinoma versus other histotypes (P = 0.046; Fig. 3). Moreover, among patients who had a recurrence, those affected by squamous cell carcinoma experienced a significantly worse survival rate (29 months vs 72 months, P = 0.047). Figure 3: View largeDownload slide Overall survival according to histological diagnosis in the N2a1 subgroup. Figure 3: View largeDownload slide Overall survival according to histological diagnosis in the N2a1 subgroup. We analysed the impact of the number of metastatic lymph nodes on OS and DFS, using the median value of our cohort (4) as the cut-off value and the lymph node ratio, which is the ratio between the number of metastatic lymph nodes and the total number of harvested lymph nodes. Results (Table 3) showed a significantly better OS and DFS for patients whose number of positive lymph nodes was lower than the median value (P < 0.001 and P = 0.001, respectively) and who had a low lymph node ratio (P = 0.002 and P = 0.002, respectively). When we compared the impact of these 3 classifications on OS, the number of positive lymph nodes was the most significant method. Table 3: Analysis of impact on overall survival and disease-free interval of 3 proposals for quantitative staging of lymph nodes in patients with non-small-cell lung cancer Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Analysis was calculated using the log-rank test for categorical variables and the Cox regression model for continuous variables. CI: confidence interval; HR: hazard ratio; IASLC: International Association for the Study of Lung Cancer. Table 3: Analysis of impact on overall survival and disease-free interval of 3 proposals for quantitative staging of lymph nodes in patients with non-small-cell lung cancer Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Overall survival Disease-free survival N staging system N subdivision Median overall survival (months) HR (95% CI) P-value Median disease-free survival (months) HR (95% CI) P-value IASLC, 8th edition proposal N2a1 36 0.047 40 0.021 N2a2 28 18 N2b 16 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes <4 42 <0.001 31 0.001 Number of total positive lymph nodes ≥4 18 11 Number of metastatic lymph nodes retrieved Number of total positive lymph nodes (continuous variable) 1.039 (1.014–1.065) 0.002 1.046 (1.018–1.076) 0.001 Lymph node ratio Lymph node ratio (continuous variable) 4.333 (1.699–11.048) 0.002 5.151 (1.845–14.378) 0.002 Analysis was calculated using the log-rank test for categorical variables and the Cox regression model for continuous variables. CI: confidence interval; HR: hazard ratio; IASLC: International Association for the Study of Lung Cancer. DISCUSSION The 8th edition of the TNM staging system for lung cancer has been in use since January 2018, with some changes in the definitions of the T and M descriptors and some newly defined prognostic groups [2]. Conversely, no changes were made to N descriptors, which have been based only on anatomical criteria since the TNM edition issued in 1982. Nevertheless, the IASLC staging committee [4] reproposed the introduction of new subgroups of N-positive components; similar proposals were promoted in the 7th edition of lung cancer TNM and in several retrospective series [5–8]. Nevertheless, no sufficiently significant data were available to support the introduction of these changes in the official edition of the TNM staging system. The present proposal concerns both N1 and N2 and is no longer based solely on pure anatomical criteria but also on quantitative criteria. Accordingly, N2 would be divided into 3 subgroups: N2a1 for a single involved mediastinal station without hilar involvement (the so-called skip metastasis), N2a2 for a single metastatic mediastinal station with the concurrent involvement of hilar nodes, and finally, N2b for multiple involvement of mediastinal node stations. The aim of our study was to investigate the IASLC proposal in a cohort of patients undergoing multimodal treatment with primary surgery. Asamura et al. [4] found significant differences in terms of OS and DFI between the 3 groups they proposed, with a worse long-term survival for patients with multiple mediastinal station involvement and a significantly better prognosis for patients with skip metastasis and limited involvement of mediastinal lymph nodes; similar results were also reported by other authors [9–11]. An anatomical explanation for this phenomenon lies in the possible direct lymphatic drainage into the mediastinal nodes, completely bypassing the intralobar and hilar stations, but other explanations have been proposed [12]. We consistently observed that patients suffering from skip metastasis and a single metastatic mediastinal lymph node station had a significant survival advantage compared to other groups. Conversely, we did not observe differences in OS rates between patients with N2a2 and those with N2b. These results partially validate the outcomes of the papers mentioned previously, but they point to an important unanswered question concerning the correct stratification of patients with mediastinal lymph node involvement. In fact, it is currently established that patients with a clinical N2 designation, regardless of the extent of lymph node involvement, should receive induction therapy prior to possible surgery and should always be discussed by a multidisciplinary group [13, 14]. Nevertheless, a designation of N2 includes a wide range of clinical situations that might be treated differently with a larger benefit for the patients and similar or better long-term outcomes [15]. In all the patients of our cohort, an N2 diagnosis was clinically unsuspected or, in the case of a clinical single N2 station, a multidisciplinary decision for a surgical resection d’emblé was taken into account. Multimodality treatment was planned for all patients, and all of them received adjuvant chemotherapy except for 8 patients who did not receive postoperative treatment because they died or showed a poor postoperative performance status. Surprisingly, our median 3- and 5-year survival rates for patients diagnosed as N2a1 were considerably better than those reported for N2 patients treated with neoadjuvant therapy and surgery [14, 16]. Similarly, a recent French report [11] on 871 patients advocated for a better stratification of IIIA-N2 NSCLC, because they found a significant difference in OS according to the number and position of the lymph node stations involved. In contrast, Lee et al. [17] did not find any differences in OS and DFS in patients treated with induction chemoradiotherapy followed by surgical resection according to the pretreatment of single- or multistation mediastinal involvement. Finally, a recent match analysis based on a large multi-institutional database [15] found comparable outcomes between patients with N2 NSCLC treated with surgery and adjuvant chemotherapy and neoadjuvant therapy and surgery; in the same study, patients treated with lobectomy and adjuvant therapy for unknown N2 disease also had a significantly better prognosis than those who received radiation or chemoradiation alone. Furthermore, Garelli et al. [10] stressed the importance of not only the number of lymph nodes involved but also the quality of involvement. They showed that microscopic metastases had a significant impact on survival and suggested that this subgroup of patients might not benefit from the use of adjuvant therapy and could be eligible for a clinical follow-up only. Unfortunately, we did not have enough data to discriminate between microscopic lymph node involvement and macroscopic lymph node involvement. On the other hand, the current N1 and N2 division has the crucial advantage of simplifying preoperative staging. A staging system based on the number of positive stations or lymph nodes would be challenging when trying to make a correct, precise preoperative assessment. In fact, such an evaluation would require a pathological confirmation or a detailed positron emission tomography report not only for mediastinal stations but also for Stations 10, 11 and 12. In an interesting report, Lee et al. [9] compared 4 proposed lymph node staging systems [7, 18–20] (based on the metastatic nodal zone, number of lymph nodes involved, lymph node ratio and combination of the number and location of metastatic lymph nodes) and found no significant difference among them in terms of predictive power using the C-index, but they found a higher C-index value for the classification based on the number of metastatic lymph nodes. This evidence should be used to complete the current nodal staging system rather than radically change it. We consistently observed a significant relation of both survival and the DFI with the number of mediastinal lymph node stations involved, the number of positive lymph nodes and the lymph node ratio. To the best of our knowledge, no correlation between histological diagnosis and skip metastasis has been reported so far. We noted that patients affected by squamous cell carcinoma with a pathological N2a1 stage had a significantly worse survival rate compared with patients who had adenocarcinoma or other histological diagnoses. Conversely, no difference was found when we analysed DFS, but, among those who had a recurrence, those with squamous cell carcinoma had a significantly worse survival. A worse survival with a concomitant, similar DFS for patients with squamous cell carcinoma compared to adenocarcinoma has been reported by other authors [21–23], who concluded that the difference in the mortality rate might be associated with non-cancer-related causes; nevertheless, Fukui et al. found more deaths among patients with a recurrent squamous cell carcinoma than among those with adenocarcinoma. They, therefore, proposed a reclassification of T1a-bN0 and T2N0 squamous cell NSCLC as Stage IIA. Moreover, Li et al. [24] reported a retrospective analysis of surgically treated adenocarcinomas of the lung with skip metastasis, finding a higher incidence in acinar subtypes, with no significant differences in the survival rate. Due to the small number of patients, it is difficult to draw conclusions based on our data, but we can speculate that squamous cell carcinomas might be more aggressive than other histological types and should, therefore, be treated with different multidisciplinary protocols. Limitations Our study has some limitations: First, the main weakness is the retrospective nature of the data set, which might have caused accidental selection bias. Second, the number of patients is small and might influence conclusions that have been drawn; in particular, a difference between N2a2 and N2b groups might have been missed due to the small number of patients. Third, detailed information about adjuvant treatments was not always available. Finally, in some cases, lymph nodes were not collected as a single specimen, so pieces of lymph nodes might have been counted as single nodes. CONCLUSIONS Our experience shows that a single-station N2 without hilar node involvement indicates a better outcome and the potential significance of the number of positive lymph nodes and the lymph node ratio. We also noted that patients with squamous cell carcinoma who had an N2a1 diagnosis had worse OS. Our results confirm that the N descriptor should be revised to include quantitative and possibly qualitative criteria along with the existing anatomical criteria to allow better stratification of the heterogeneous group of N2 patients with an N2 diagnosis and better determination of the best therapeutic path for each of them. ACKNOWLEDGEMENTS This research did not involve any studies with human participants or animals. Conflict of interest: none declared. REFERENCES 1 Goldstraw P , Chansky K , Crowley J , Rami-Porta R , Asamura H , Eberhardt WE et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer . J Thorac Oncol 2016 ; 11 : 39 – 51 . Google Scholar CrossRef Search ADS PubMed 2 Rami-Porta R , Asamura H , Travis WD , Rusch VW. Lung cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual . CA Cancer J Clin 2017 ; 67 : 138 – 55 . Google Scholar CrossRef Search ADS PubMed 3 Bille A , Woo KM , Ahmad U , Rizk NP , Jones DR. Incidence of occult pN2 disease following resection and mediastinal lymph node dissection in clinical stage I lung cancer patients . Eur J Cardiothorac Surg 2017 ; 51 : 674 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Asamura H , Chansky K , Crowley J , Goldstraw P , Rusch VW , Vansteenkiste JF et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer . J Thorac Oncol 2015 ; 10 : 1675 – 84 . Google Scholar CrossRef Search ADS PubMed 5 Andre F , Grunenwald D , Pignon JP , Dujon A , Pujol JL , Brichon PY et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications . J Clin Oncol 2000 ; 18 : 2981 – 9 . Google Scholar CrossRef Search ADS PubMed 6 Misthos P , Sepsas E , Kokotsakis J , Skottis I , Lioulias A. The significance of one-station N2 disease in the prognosis of patients with nonsmall-cell lung cancer . Ann Thorac Surg 2008 ; 86 : 1626 – 30 . Google Scholar CrossRef Search ADS PubMed 7 Rusch VW , Crowley J , Giroux DJ , Goldstraw P , Im JG , Tsuboi M et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer . J Thorac Oncol 2007 ; 2 : 603 – 12 . Google Scholar CrossRef Search ADS PubMed 8 Tsitsias T , Boulemden A , Ang K , Nakas A , Waller DA. The N2 paradox: similar outcomes of pre- and postoperatively identified single-zone N2a positive non-small-cell lung cancer . Eur J Cardiothorac Surg 2014 ; 45 : 882 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Lee GD , Kim DK , Moon DH , Joo S , Hwang SK , Choi SH et al. A comparison of the proposed classifications for the revision of N descriptors for non-small-cell lung cancer . Eur J Cardiothorac Surg 2016 ; 49 : 580 – 8 . Google Scholar CrossRef Search ADS PubMed 10 Garelli E , Renaud S , Falcoz PE , Weingertner N , Olland A , Santelmo N et al. Microscopic N2 disease exhibits a better prognosis in resected non-small-cell lung cancer . Eur J Cardiothorac Surg 2016 ; 50 : 322 – 8 . Google Scholar CrossRef Search ADS PubMed 11 Legras A , Mordant P , Arame A , Foucault C , Dujon A , Le Pimpec Barthes F et al. Long-term survival of patients with pN2 lung cancer according to the pattern of lymphatic spread . Ann Thorac Surg 2014 ; 97 : 1156 – 62 . Google Scholar CrossRef Search ADS PubMed 12 Takizawa H , Sakiyama S , Tsuboi M , Tangoku A. Demonstration of the skip metastasis pathway for N2 non-small cell lung cancer . J Thorac Cardiovasc Surg 2014 ; 147 : e50 – 2 . Google Scholar CrossRef Search ADS PubMed 13 Rosell R , Gómez-Codina J , Camps C , Javier Sánchez J , Maestre J , Padilla J et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial . Lung Cancer 1999 ; 26 : 7 – 14 . Google Scholar CrossRef Search ADS PubMed 14 Eberhardt WE , De Ruysscher D , Weder W , Le Péchoux C , De Leyn P , Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer . Ann Oncol 2015 ; 26 : 1573 – 88 . Google Scholar CrossRef Search ADS PubMed 15 Yang CF , Kumar A , Gulack BC , Mulvihill MS , Hartwig MG , Wang X et al. Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: a National Cancer Data Base analysis . J Thorac Cardiovasc Surg 2016 ; 151 : 1380 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Martins RG , D’Amico TA , Loo BW , Pinder-Schenck M , Borghaei H , Chaft JE et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement . J Natl Compr Canc Netw 2012 ; 10 : 599 – 613 . Google Scholar CrossRef Search ADS PubMed 17 Lee H , Ahn YC , Pyo H , Kim B , Oh D , Nam H et al. Pretreatment clinical mediastinal nodal bulk and extent do not influence survival in N2-positive stage IIIA non-small cell lung cancer patients treated with trimodality therapy . Ann Surg Oncol 2014 ; 21 : 2083 – 90 . Google Scholar CrossRef Search ADS PubMed 18 Rami-Porta R , Crowley JJ , Goldstraw P. The revised TNM staging system for lung cancer . Ann Thorac Cardiovasc Surg 2009 ; 15 : 4 – 9 . Google Scholar PubMed 19 Wei S , Asamura H , Kawachi R , Sakurai H , Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification? J Thorac Oncol 2011 ; 6 : 310 – 8 . Google Scholar CrossRef Search ADS PubMed 20 Saji H , Tsuboi M , Shimada Y , Kato Y , Yoshida K , Nomura M et al. A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer . Chest 2013 ; 143 : 1618 – 25 . Google Scholar CrossRef Search ADS PubMed 21 Fukui T , Taniguchi T , Kawaguchi K , Fukumoto K , Nakamura S , Sakao Y et al. Comparisons of the clinicopathological features and survival outcomes between lung cancer patients with adenocarcinoma and squamous cell carcinoma . Gen Thorac Cardiovasc Surg 2015 ; 63 : 507 – 13 . Google Scholar CrossRef Search ADS PubMed 22 Nakamura H , Sakai H , Kimura H , Miyazawa T , Marushima H , Saji H. Difference in postsurgical prognostic factors between lung adenocarcinoma and squamous cell carcinoma . Ann Thorac Cardiovasc Surg 2017 ; 23 : 291 – 7 . Google Scholar CrossRef Search ADS PubMed 23 Kawase A , Yoshida J , Ishii G , Nakao M , Aokage K , Hishida T et al. Differences between squamous cell carcinoma and adenocarcinoma of the lung: are adenocarcinoma and squamous cell carcinoma prognostically equal? Jpn J Clin Oncol 2012 ; 42 : 189 – 95 . Google Scholar CrossRef Search ADS PubMed 24 Li H , Hu H , Wang R , Li Y , Shen L , Sun Y et al. Lung adenocarcinoma: are skip N2 metastases different from non-skip? J Thorac Cardiovasc Surg 2015 ; 150 : 790 – 5 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: May 19, 2018

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