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Eur J Cardiothorac Surg 2005;28:33-38
© 2005 Elsevier Science NL

Prognostic factors in surgically resected N2 non-small cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases

^a Department of General Surgery and Surgical Specialties, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41100 Modena, Italy
^b Department of Pathologic Anatomy and Forensic Medicine, Section of Pathology, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41100 Modena, Italy

Received 9 February 2005; received in revised form 14 March 2005; accepted 15 March 2005.

^* Corresponding author. Address: Division of Thoracic Surgery, Policlinico di Modena, Largo del Pozzo 71, 41100 Modena, Italy. Tel.: +39 594 222 257; fax: +39 593 601 59. (Email: u.morandi{at}unimo.it).

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: Patients with non-small cell lung cancer (NSCLC) with metastases to ipsilateral mediastinal lymph nodes (N2) are an heterogeneous group of patients as regard to prognosis and treatment. Indication and timing of surgery remain controversial. The present study investigates the prognostic factors, in order to identify homogenous subgroups of patients. Methods: Histologically proven N2-NSCLC patients, who underwent a complete surgical resection were retrospectively reviewed. Clinical and pathological features were reported and analyzed, and survival study was performed. Results: One hundred eighty-three patients were analyzed. Overall 1.3 and 5 years survival rates were, respectively, 70, 35 and 20%, with a median survival time of 24 months. Univariate analysis showed a significant better prognosis for: incidental N2 respect to clinical N2 (5-years 35.4 vs 17.4%); single level lymph node involvement respect to multiple levels (5-years 23.8 vs 14.7%); metastases to superior mediastinal or aortic nodes respect to lower mediastinal nodes (5-years 32 and 24.3 vs 16.3%); right upper lobe tumors with superior mediastinal nodes and left upper lobe tumors with aortic nodes respect to lower lobes tumors with lower mediastinal nodes (5-years 31.8 and 26.9 vs 15.7%). Skip metastases had not a significant survival advantage respect to continuous lymphatic spread. N2 clinical status, the number of levels involved and the two specific patterns of lymphatic spread resulted significant prognostic factors at multivariate analysis. Conclusions: Clinical N2 status, number of lymph nodes levels involved and specific patterns of lymphatic spread identify homogenous subgroups of patients that can be proposed for different therapeutic strategies.

Key Words: Non-small cell lung cancer • N2 • Mediastinal nodal metastases • Prognosis

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Metastasis to the ipsilateral mediastinal lymph nodes (N2) is the most important prognostic factor in completely resected non-small cell lung cancer (NSCLC). However, resectable N2-NSCLC represents an heterogeneous group of patients; survival rates after surgical treatment range from 6 to 35% [1]. The appearance in literature in the middle 1990s of two randomized trial reporting a survival benefit of neo-adjuvant chemotherapy for N2-NSCLC patients led to change surgical indications for stage IIIA-N2 patients [2,3]. This new approach became more controversial when another randomized trial failed to reveal a significant advantage for preoperative chemotherapy [4]. Moreover, the International Adjuvant Lung Cancer Trial Collaborative Group has recently reported the results of a large randomized trial showing a significant improvement of survival with cisplatin-based adjuvant chemotherapy in completely resected non-small cell lung cancer [5]. To date, the effectiveness and the optimal timing of surgical treatment of resectable N2-NSCLC remain controversial. In order to identify patients that could benefit of different therapeutic strategies, it is important to define homogeneous subgroups of patients according to prognosis. Several prognostic factors in resected N2-NSCLC have been reviewed [1] and different classifications have been proposed [6–8]. The aim of this study is to retrospectively analyze the 10-years experience of surgical treatment of N2-NSCLC at our institution, in order to identify the significant clinical and pathological prognostic factors, with particular regard to lymph nodes related features.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
We retrospectively reviewed the patients with hystologically proven N2 non-small cell lung cancer (pN2 NSCLC) who underwent resection with a curative intent, at the Division of Thoracic Surgery of the University of Modena and Reggio Emilia, from January 1990 to December 2002.

Preoperative staging included: CT scan of the thorax, CT scan of upper abdomen or abdomen ultrasonography and fiberoptic bronchoscopy for all patients. Brain CT scan and bone scintigraphy were performed only in symptomatic patients. Mediastinal lymph nodes with a short-axis diameter of 1cm or more at CT scan evaluation were considered abnormal. Mediastinoscopy was performed only when lymph nodes were abnormal on CT scan. Patients with normal mediastinum on CT and those with abnormal mediastinum but negative mediastinoscopy were considered to have N0–N1 disease. Because only pathological N2 tumors were selected for the study, patients with clinical N0 or N1 (cN0–N1) tumors were considered as having an ‘incidental N2’ disease. Patients with abnormal mediastinum on CT and those with positive medistinoscopy were classified as having clinically N2 disease (cN2).

Complete resection was defined as removal of the primary tumor and all accessible hilar and mediastinal lymph nodes, with no residual tumor left behind (resection of all macroscopic tumor and resection margins free of tumor at microscopic analysis). All patients underwent standard resections (lobectomy, bilobectomy or pneumonectomy). Patients who underwent minor resections were excluded from the study. A complete mediastinal lymph nodes dissection was routinely performed. The following lymph nodes compartments were routinely dissected: superior mediastinal and paratracheal on the right side; aortico-pulmonary window and pre-aortic on the left side, subcarinal and lower mediastinal on both sides. Left paratracheal nodes were not routinely included in the dissection. Only palpable lymph nodes in this region were surgically removed when encountered. For each patient the number of mediastinal lymph nodes resected was recorded. Skip metastases were considered as the presence of mediastinal lymph nodes metastases without intralobar, scissural or hilar lymph node involvement (N2 without N1).

All patients were postsurgically staged according to the 1997-TNM classification [9]. Lymph nodes levels were classified according to the American Thoracic Society system [10].

In order to evaluate the prognostic impact of N2-related factors we proceeded as follows:

(A) We identified five N2-related factors likely having a prognostic influence. (1) clinical N status: cN0–N1 or cN2; (2) N2 topography: superior mediastinal (levels 1–4), aortic (levels 5 and 6), lower mediastinal (levels 7–9); (3) number of mediastinal lymph node stations involved: single or multiples; (4) pattern of lymph nodes metastates, considered as the preferred pathway of mediastinal nodal spread for each of the following tumor location: right upper lobe (RUL) or right middle lobe (RML), left upper lobe (LUL), right lower lobe (RLL) left lower lobe (LLL); (5) presence of skip metastases: continuous or skipped pathway of metastases.

(B) We recorded the following clinico-pathological variables to consider in the analysis: age, sex, smoking history, tumor endoscopy (central and peripheral), tumor location (main bronchus, upper lobes, middle lobe, lower lobes), type of resection, histologic type, histologic grading, post-surgical T status and tumor size (cm).

(C) We matched all the clinical, pathological and N2 related-variables in univariate analysis in order to detect association among them.

(D) Survival analysis was performed for each of the clinical, pathological and N2-related variables.

Adjuvant chemotherapy with cisplatin-based regimens were administered in the whole cohort in different Oncologic Institutes. Since 1996 induction chemotherapy was considered a viable option at our institute, but not routinely performed. To avoid selection bias and to make the whole cohort more homogeneous, patients who underwent induction chemotherapy were excluded from the study.

Follow-up: most patients have been followed up directly at our Institution, with periodic office visits. Information about the remaining patients was obtained from the Oncologic Institutes, which the patients were referred to or by telephone interviews with the patient and/or his/her relatives. Data regarding long-term survival were recorded.

Statistical analysis: the descriptive analysis was expressed in terms of frequency, mean and standard deviation. Frequencies were compared with the chi-square test for categorical variables; Fischer's exact test was used for small samples; phi correlation index was reported when a significant difference was found. T-test and ANOVA were performed when comparing continuous variables. The probability of survival was calculated according to the Kaplan–Meier method; when creating survival curves, deaths for causes other than the tumor and postoperative deaths were considered as withdrawals, the date of death representing the end-point of follow-up. Univariate analysis of survival was performed using the log-rank test. The main prognostic factors were matched in a multivariate analysis, using Cox regression models. Five years survival rates were selected as end point for evaluating the prognosis. A probability value <0.05 was considered statistically significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
One hundred and eighty-three patients with pN2 NSCLC who undergone complete resection entered the study. Patients treated with induction chemotherapy were excluded. Characteristics of the 183 patients are listed in Table 1 . Mean age was 63.3 years (median 64, standard deviation 8.8, range 36–84).

3.1. Analysis of survival
There were three postoperative deaths (1.6%): two ARDS following pneumonectomies, an acute myocardial infarction following inferior bilobectomy. All patients were followed up until death, for a minimum of 5 years. Follow up was complete for all patients within December 2003. It ranged from 9 to 150 months. The overall 1.3 and 5 years survival rates were, respectively, 70, 35 and 20% (standard errors 3.5, 3.7, 3.8%) with a median survival time of 24 months. Seventeen patient (9%) lived more than 5 years.

The results of univariate analysis, respectively, for clinical, pathological and lymph nodes related features are reported in Tables 3 and 4 .

We also performed a univariate analysis of survival for N-clinical status stratified for N2-levels. Four groups were compared: cN0–N1/single station; cN0–N1/multiple stations; cN2/single station and cN2/multiple stations. The better prognosis was recorded for cN0–N1/single station (5-years 38%, median survival 38 months). The group cN2/multiple stations had the poorer outcome results (5-years 1%; median survival 16 months). The difference between the subgroups was highly significant (P=0.0008).

The analysis reached statistical significance for the following lymph-nodes related variables:

1. A significant better prognosis was found for cN0–N1 respect to cN2 (Fig. 1 ).

2. Involvement of a single N2 levels had a better prognosis than multiple N2 levels (Fig. 2 )

3. Lower lymph nodes had negative prognostic impact respect to superior and aortic stations.

4. RUL/RML with superior nodes and LUL with aortic nodes were patterns of metastases related to a better prognosis than lower lobes with lower nodes (Fig. 3 ).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Survival curve of resected N2 non-small cell lung cancer according to N clinical status.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Survival curve of resected N2 non-small cell lung cancer according to the number of N2 levels involved.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Survival curve of resected N2 non-small cell lung cancer according to metastatic pattern of mediatinal lymph node metastases.

All the clinico-pathological features described above were matched in a multivariate analysis. N status, the number of levels involved and the patterns of metastases were confirmed as significant prognostic factors; for N2 topography a trend toward poorer survival for lower levels was recorded (Table 5 ).

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

Some authors have demonstrated the prognostic influence of the relation between primary tumor location and N2 levels involved [17–19]. Patients with RUL tumors with ipsilateral level 4 lymph nodes have better survival compared with patient with RUL tumors and metastases to level 7 [17]. Patients with LUL tumors and metastases to level 5 and 6 have survival similar to N1 patients [18,19]. In our study, three patterns of lymph nodes metastases influenced survival. Patients with right upper lobe tumors and lymphatic metastases to superior mediastinal nodes showed acceptable survival after complete surgical resection, as well as patients with left upper lobe tumors and lymphatic metastases to aortic nodes. On the contrary, lower lobe tumors with lymphatic metastases to subcarinal, esophageal and pulmonary ligament nodes represent metastatic patterns related to very poor prognosis. The pattern of lymphatic spread related to tumor location represents a more important prognostic factor respect to node topography alone (superior and aortic versus lower stations) as demonstrated in multivariate analysis, where node topography does not reach statistical significance in affecting survival.

As recently reported [19], a classification of N2-NSCLC should consider number of lymph node levels involved and pattern of metastases, as well as clinical N2 status. For cN0–N1/single station and for upper lobe tumors with superior or aortic lymph nodes levels, a complete surgical resection with lymph node dissection can be proposed as first treatment. These patients are ideal candidates for randomized trials of adjuvant therapies. Clinical N2 with multiple stations and lower lobes tumors with metastases to lower lymph nodes should not be considered for initial surgery and induction chemotherapy is advisable. Techniques of mediastinal staging play a central role. At present, it is widely accepted to use mediastinoscopy in patients with mediastinal lymph nodes enlargement at CT scan. The usefulness of systematic mediastinoscopy is still debated.

Giving the prognostic importance of lymph nodes levels not accessible to traditional mediastinoscopy, other invasive techniques ought to be considered in mediastinal staging. Videothoracoscopy may play an important role, because it can sample suspected lymph nodes in multiple stations, in particular at aortic and lower levels, not accessible to mediastinoscopy. The effectiveness of videothoracoscopy in the preoperative staging of NSCLC has already been addressed [20]. Its routine use should be considered in patients with NSCLC and lymph nodes enlargement in multiple stations at CT scan.

The different therapeutic strategies that can be proposed to different N2 groups underline the importance of a complete mediastinal lymph node dissection, although a survival advantage of mediastinal lymph node dissection over systematic sampling is not clearly demonstrated [21–24]. The high number of resected lymph nodes for each patient in our series reflects the extensive lymph node dissection we performed.

Skip metastates are thought to derive from subpleural lymphatics that drain directly to the mediastinum. Even if some evidences suggest an increased survival for skip metastases, its prognostic role remains unclear. [23–25]. Pranzel et al. correlated this survival advantage for patients with skip metastasis to an higher expression of antiapoptosis gene BCL2 and lower expression of p21 respect to patients with sequential N1–N2 lymphatic spread [24]. Otherwise, other authors failed to find difference in survival between skip metastases and continuous spread [25]. In our series, we found skip metastases in 34% of surgically resected N2-NSCLC, which is similar to what is reported in literature. As previously reported by other authors [24,25], we confirmed that skip metastases were more frequently associated to squamous cell carcinoma than to other histologic subtypes. Though a trend was present in our study, a survival advantage for skip metastases compared to continuous pathways of lymphatic spread was not recorded. To date the prognostic role of skip metastases remains controversial. Further studies are needed.

In conclusion, the intraoperative detection of previously undiagnosed mediastinal lymph nodes metastases (incidental N2), the number of mediastinal lymph nodes levels involved by the tumor and specific patterns of lymphatic spread to mediastinal nodes are significant prognostic factors. They are useful to classify N2-NSCLC patients into homogeneous groups. These different subtypes of patients are ideal candidates for further randomized clinical trial regarding the timing of surgery in relation to chemotherapy.

	References

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