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Ann Thorac Surg 2007;84:1818-1824. doi:10.1016/j.athoracsur.2007.07.015
© 2007 The Society of Thoracic Surgeons
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Right arrow Lung - cancer

Original Articles: General Thoracic

Completely Resected Non-Small Cell Lung Cancer: Reconsidering Prognostic Value and Significance of N2 Metastases

Marc Riquet, MD, PhDa,*, Patrick Bagan, PMDa,b, Françoise Le Pimpec Barthes, MDa, Eugeniu Banu, MDa, Florian Scotte, MDa, Christophe Foucault, MDa, Antoine Dujon, MDb, Claire Danel, MDa,b

a Departments of Thoracic Surgery and Pathology, G. Pompidou European Hospital, Paris
b Department of Surgery, Cedre Surgical Center, Boisguillaume, France

Accepted for publication July 6, 2007.

* Address correspondence to Dr Riquet, Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, Paris, 75015, France (Email: marc.riquet{at}egp.aphp.fr).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Non-small cell lung cancer (NSCLC) mediastinal (N2) metastases are indicators of poor prognosis. Survival rates decrease with increasing number of N2 stations and involved lymph nodes as well as lymph node size and capsular invasion. Our purpose was to elucidate the impact lymph node–related variables on the outcome after surgical resection.

Methods: We reviewed data of 2344 NSCLC patients who underwent curative resections with mediastinal lymphadenectomy, and 586 (25%) had N2 metastases. We studied the overall survival of N2 patients according to some important covariates.

Results: Metastases involved single N2 stations in 386 patients (66%) and two or more in 200 (34%). Survival was not related with histology or pathologic tumor (pT), but was better when only one N2 station was involved (5-year overall survival 28.5% [median, 24 months] versus 17.2% [median, 14 months] respectively; p = 0.0002. For single N2 stations, capsular rupture, number, and size of lymph nodes were not significant prognostic factors. When the size of lymph node was analyzed (micrometastases, 53; nonbulky, 207; or bulky metastases, 126), overall survival differences between nonbulky and bulky N2 were significant: 5-year overall survival was 34% (median, 28 months) versus 23% (median, 23 months), respectively (p = 0.026). Presence of micrometastases was associated with a poor prognosis: 5-year overall survival of 21.4% (median, 23 months).

Conclusions: Prognosis was better for patients with single N2 stations when metastatic lymph nodes were not enlarged. However, the presence of lymph nodes micrometastases does not seems associated with a better outcome.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Patients with clinically N2 disease are often not amenable to have a complete resection and are associated with a poor outcome even when surgical resection is complete. The concept of "resectable N2 disease" is based on reports demonstrating late survival in 20% to 30% of patients with favorable pathologic features such as a single lymph node or single-station involvement, microscopic or intracapsular metastases, N2 confined to lower stations, and left upper pulmonary lobe tumors with N2 limited to the subaortic level [1]. Other factors that have been variably reported to be significant include the extent and anatomic location of N2 metastases, skip metastases, and the tumor (T) classification and histologic type [1].

In a previous study, we reviewed survival of patients with resected N2 non-small cell lung cancer (NSCLC) [2]. The mediastinal lymph node stations were labeled according to their anatomic location in corresponding lymph node chains. We observed that survival was significantly better when lymph node metastases involved a single chain, with the number of involved lymph nodes and the presence of extracapsular extension having no prognostic value. Shortly thereafter, Andre and colleagues [3] reported that clinical N2 disease was a negative prognostic factor compared with "minimal N2" disease, with the best results observed when micrometastases were located in only one station. The purpose of the present analysis was to further elucidate the meaningful variables that impact the overall survival of N2 patients after complete resection.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
We reviewed the hospital records of NSCLC patients who underwent a complete pulmonary resection with mediastinal lymphadenectomy in two centers in France (Georges Pompidou European Hospital and Bois-Guillaume Clinic) between 1984 and 2003. The preoperative work-up included chest roentgenogram, bronchoscopy, computed tomography (CT) scan of the chest, spirometry, lung perfusion scan, and positron emission tomography, in recent years. Mediastinoscopy was performed to exclude N3 disease and to better assess N2 disease in patients treated with neoadjuvant regimens (depending on different referring centers). Those patients were excluded from the analysis. All other patients thought to have completely resectable tumors with no distant metastases and who could tolerate the projected resection underwent thoracotomy. Patients with a history of cancer or with residual disease (R1 and R2) and those with neuroendocrine tumors were excluded.

Our local Ethics Committee approved this retrospective study and waived the need for patient consent. Data of 2344 patients were available, and their pN status was N0, 1294 (55.2%); N1, 464 (19.8%); and N2, 586 (25%). The 586 pN2 patients were the cohort of interest for this analysis. Postoperative treatment was performed in a nonrandomized fashion, according to specific local guidelines.

Methods
The regional lymph node classification of Mountain and Dresler [4] was used. The N2 population was divided in single N2 stations, defined as one station involved in superior mediastinal nodes (2R + 4R, or 3, or 4L), aortic nodes (5 or 6), or inferior mediastinal nodes (7, 8, or 9), and multiple-N2 stations corresponding to the involvement of two or more of any mentioned stations. The 2R and 4R stations were grouped because they form the same anatomic lymph node chain [5].

Single and multiple N2 categories were compared in terms of the patient’s age and sex, type of pulmonary resection, location of the primary tumor, histology (including adenocarcinoma components such as solid and papillary), pT as provided by the international staging system [6], overall and cancer-specific survival.

Single N2 patients were further analyzed according to more detailed criteria of size and number of involved lymph nodes and lymph node capsular rupture. Metastases were subdivided in three groups according to the size:

• group 1 (G1): micrometastases within macroscopic normal lymph node (minimal metastases);
• group 2 (G2): metastases encompassing the whole lymph node, with a size below 2 cm in greatest diameter (nonbulky metastases);
• group 3 (G3): lymph node metastases larger than 2 cm in diameter (bulky metastases).

Each category was analyzed according to the histology, pT [6], intrapulmonary lymph node involvement (skip metastases), location of the primary tumor and the N2 station, and overall and cancer-specific survival.

Follow-up information was obtained from hospital case records or a questionnaire completed by the local chest physician or the general practitioner (for censored patients), or from death certificates.

Univariate analyses were conducted between groups, as previously described. Actuarial survival probabilities were estimated by Kaplan-Meier method, and statistical comparisons were made by using an unstratified log-rank test. Multivariate analysis was performed by using the Cox proportional hazards regression method. The covariates used were sex, age, type of surgical resection, histological type, pT and pN status, and tumor size. Two-sided tests were used for all statistical analyses, and a value of p < 0.05 was considered as statistically significant. The statistical software used for the analysis was SEM (Cancer Centre J. Perrin, Clermont-Ferrand, France) [7].


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Comparisons between single and multiple N2 patients are presented in Table 1. These groups did not differ in age, sex, postoperative complications and mortality, pT, histology, and adjuvant treatment distribution. Single N2 was more frequent when the tumor was right-sided and located in the right upper lobe. Significant differences in favor of single N2 were the number of lobectomies, visceral pleural involvement (21% versus 7.5%, p = 0.0003), and skip metastases (33.7% versus 17.5%, p = 0.000007). The 5-year survival rate for single N2 patients was higher compared with multiple N2: 28.5% (median, 24 months) versus 17.2% (median, 14 months; p = 0.0002; Fig 1). Univariate and multivariate analyses demonstrated that age, pT, single N2 stations, and adjuvant treatment were independent prognostic factors.


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  		Table 1 Surgical Characteristics of Single and Multiple N2 Patients, Location of Tumors and Stations
 

Figure 1
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  		Fig 1. Five-year and 10-year survival rates of single N2 patients (curve 1) and multiple N2 patients (curve 2). Survival difference were similar when postoperative and cancer-unrelated deaths were excluded: single N2 (n = 305), 32.2% (median, 28 months); multiple N2 (n = 167), 19% (median, 17 months; p = 0.00008.)

 
Single N2 metastases consisted of micrometastases in 13.7%, nonbulky lymph node metastases in 53.7%, and bulky metastases in 32.6%. Characteristics of these groups according to histology, pT, visceral pleural invasion, site of the primary tumor, involved lymph node station, and postoperative complications and deaths were not significantly different. Significant differences were observed for type of procedure, adjuvant treatment, tumor size, capsular rupture, and the number of metastatic lymph nodes (Table 2), including larger tumor size in G3, adjuvant treatment infrequently performed in G1, capsular rupture quasi-absent in G1 and absent when only one lymph node was metastatic, and tendency for more involved lymph node in G3. Capsular rupture was more frequent in cases of multiple metastatic lymph nodes, and the difference was significant, 52.1% versus 32.1% (p = 0.018), when three or more lymph nodes were involved. Frequency was similar when one and two lymph nodes were involved (p = 0.66).


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  		Table 2 Characteristics of Non-Small Cell Lung Cancer Patients According to the Three Different Subgroups of Single N2 Metastasis
 
Survival of single N2 patients was not associated with histology, visceral pleural involvement, location of the primary tumor, involved N2 station, adjuvant treatment, capsular rupture, and number of metastatic lymph nodes. Five-year overall survival was better in cases of skip metastases (38% versus 23.3%, p = 0.004), and was highly statistically related with pT, with pT3 to pT4, 16.3%; pT2, 27.7%; and pT1, 42.9% (p = 0.00004). There was a tendency for better survival for G2 patients. The difference was significant compared with G3 (p = 0.026) but not significant when compared with G1 (Fig 2). When cancer-unrelated deaths were excluded (Fig 3), the difference was significant (p = 0.03). However, when survival rates of patients with only one metastatic lymph node were compared (47 of 53 micrometastases were located in a single lymph node), prognosis of G1 patients was significantly poorer compared with G2 patients (p = 0.02), whereas the difference between G2 and G3 was no longer significant (Fig 4).


Figure 2
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  		Fig 2. Five-year survival rates according to the size of lymph nodes. Nonbulky N2 (curve 2) demonstrated the best prognosis with a 5-year overall survival of 34% (median, 28 months). Micrometastases (curve 1) and bulky metastases (curve 3) demonstrated similar 5-year survival rates: 21.4% (median, 23 months) and 23% (median, 23 months), respectively. Difference between curve 2 and 3 was significant (p = 0.026).

 

Figure 3
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  		Fig 3. Five-year survival rates according to the size of lymph node metastases when cancer-unrelated causes of death (postoperative and known medical causes) were excluded. Differences between the three subgroups were not significant: 5-year overall survival (median) were 24.4% (24 months), 40.1% (35 months), and 26.1% (24 months), respectively; the difference between G2 and G3 was significant (p = 0.03).

 

Figure 4
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  		Fig 4. Five-year survival rates when only one lymph node was metastatic within the station: survival of micrometastases group (curve 1, 5-year overall survival, 16.6%; median, 23 months) was poorer (p = 0.02), whereas significance between the nonbulky metastases (curve 2; 5-year, 32.5%; median, 30 months) and bulky (curve 3; 5-year, 27.6%; median 23 months) was not significant (p = 0.12).

 
Causes of death are summarized in Table 3. Death was more often related to NSCLC in patients with micrometastases. Adjuvant treatment did not affect the survival rates of G2 and G3 patients. For G1 patients, there was a tendency to a better prognosis after adjuvant treatment, with 5-year overall survival rates of 22% (median, 32 months) versus 8.9% (median, 18 months; p = 0.098). Multivariate analysis demonstrated that age, pT, and presence of skip metastases were independent prognostic factors, and the presence of micrometastases was a borderline factor (p = 0.07).


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  		Table 3 Causes of Death
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Resection remains the most effective therapy in NSCLC patients with tumors limited to the lung. In many centers, patients with N2 tumors are currently treated with neoadjuvant chemotherapy, followed by surgical resection. As a consequence, pathologic reports are profoundly modified, and the natural history of the lymphatic spread can no longer be analyzed. In our department, therapeutic strategy depends on previous treatments performed in different oncology centers referring patients, and many N2 patients still undergo a surgical procedure as their first treatment. Reviewing such patients, managed by the same team during a 20-year period, offers the opportunity to reconsider the mediastinal lymphatic spread pathway at a stage that is still resectable.

Commonly recognized favorable features of resected N2 disease are [1]: single node or level involvement, skip metastases, microscopic or intracapsular metastases, N2 confined to lower stations, and left upper lobe tumors with N2 limited to the subaortic level. Our study confirms that single lymph node or level involvement and skip metastases are associated with a better prognosis, but other factors require reconsideration.

1 Location of the involved N2 station within the mediastinum does not have a prognostic value.
• N2 involvement located to the lower mediastinum, and more particularly to subcarinal nodes (station 7), is reported to be often associated with lower survival than other locations [8, 9]. In fact, station 7 appeared more often involved in case of multiple N2 stations (always on the right and in most cases on the left, Table 1). The prognostic value is more likely explained by the multiple N2 status than by the station location itself: station 7 is involved in 34.5% of single N2 involvement and in 73% of multiple N2 involvement.
• N2 involvement located to the subaortic nodes (station 5) in patients with left upper lobe tumors was reported to provide more chance of cure [9–13]. These reports often deal with small series that take into account station 5 single N2 involvement and compare it with the other N2 stations. Neither our series nor other series have confirmed these results [14, 15].
• N2 involvement of the highest mediastinal lymph node is considered as a marker of incomplete resection [16]. Sakao and colleagues [18] report that it was the only significant factor of poor prognosis in multivariate analysis in a review of 53 N2 patients. In that series, 14 patients (26.4%) had metastases to the highest mediastinal lymph nodes: 37.5% were on the left and 21.7% on the right side. However, that was observed when multiple lymph node stations were involved. Left lung tumors were operated according to the method of Hata and colleagues [19], an extended lymphadenectomy by sternotomy. It was difficult to distinguish the ipsilateral from contralateral lymph node (N3) in dissected tissues, and in that case, lymph nodes around the trachea were considered as N2. Lacasse and coworkers [17] report that such lymph node involvement has not a poor prognosis. In our study, the outcome was not modified by the involved highest mediastinal lymph nodes when a single N2 station was concerned: we suggest that Sakao and colleagues’ [18] findings may be related to included N3 and multiple N2 patients.

2 Involvement of a single N2 station [8, 10, 20, 21], as well as a low number of involved lymph nodes [19], has a better prognosis. No late survivors had been observed when the number of involved levels has exceeded four [22]. However, we observed that several lymph nodes may be involved within the same chain without worsening prognosis, whereas a single node involvement in two chains was of poor prognosis. In fact, involvement of only one mediastinal lymph node chain is the main factor offering chances for cure, with 5-year overall survival of 29.6% (up to 33.2% when causes of death other than cancer were excluded), which is no longer the case when two or more chains are involved (19% in both conditions). The number of involved lymph nodes must not be confused with the number of involved lymph node stations or chains.
A common pattern of metastasis for carcinomas is that regional lymph nodes are often the first organs to develop metastases. This is a poorly understood mechanism that may be explained by lymphangiogenesis [23]. Regional lymph node metastases act as a bridgehead that constitutes a reservoir of tumor cells that have many of the properties required for metastases to further secondary sites [24]. Regarding NSCLC lymphatic spread, the mediastinal lymph node chains drain the lymph into the blood circulation, either at the venous confluences of the neck or through the thoracic duct in the mediastinum [25], and at the same moment into neighboring ipsilateral and contralateral mediastinal lymph node chains by anastomotic lymphatics [26]. When disease is located in only one lymph node chain, tumor cells with potentially metastatic properties may be absent or controlled within the lymph nodes; when disease is present in multiple lymph node chains, cells have escaped from their bridgehead lymph node, they have more distant metastatic properties and may have disseminated into the blood stream directly and by way of the thoracic duct.
3 Other N2 prognostic characteristics that are discordant with common knowledge must be reconsidered in case of single N2 station involvement.
• Capsular rupture and number of metastatic lymph nodes have no significant relationship with the prognosis of single N2 station patients. Capsular rupture is an important prognostic factor when invading mediastinal structures [12, 27], so exposing patients to the risk of incomplete surgery. When it is confined to the fatty tissue surrounding lymph nodes, capsular rupture will be completely removed by lymphadenectomy.
• The increasing number of metastatic lymph nodes within single N2 stations should indicate more selected cells with metastatic properties; however, the number and size of N2 stations vary within a chain from an individual to another and behave as an unique anatomic entity [25], which explains the lack of prognostic value of that lymph node pattern.
• Micrometastases indicate a poor outcome, the most surprising of our findings. Previous reports suggest a better prognosis for that subgroup of patients [3] and for those whose N2 disease is not apparent by clinical staging but is confirmed by pathologic staging [1]. Also, clinical N2 is associated with a higher rate of incomplete resections. Selecting patients by mediastinoscopy permits a lower rate of useless resections [28], but minimal N2 metastases still appears to have a better prognosis [29]. We observed that bulky N2 metastases were associated with a poor prognosis compared with nonbulky N2 metastases. On the other hand, survival curves of G1 and G3 categories were similar. These findings bring up the hypothesis of a higher tumor cell aggressiveness in case of micrometastases, which is also supported by more cancer-related deaths and the responsiveness to adjuvant treatment observed in that group.

Roh and colleagues [29] report a relationship between the micropapillary component and micrometastases in regional lymph nodes of patients with stage I NSCLC, an indicator of the aggressive behavior, which may be reflected by the frequency of micrometastases. In our study, micrometastases were present regardless of histology. We suggest that micrometastasis have a specific aggressiveness independently of histology or macroscopic features, with particular biologic properties. This gives a new light inside the prognostic value of micrometastases, permits a better understanding of some controversial data [30, 31], and supports the interest for further research in biomolecular direction.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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