Ann Thorac Surg 2009;88:1583-1588. doi:10.1016/j.athoracsur.2009.04.065
© 2009 The Society of Thoracic Surgeons
Original Articles: General Thoracic
The Prognostic Impact of Main Bronchial Lymph Node Involvement in Non-Small Cell Lung Carcinoma: Suggestions for a Modification of the Staging System
Yoshihisa Shimada, MD,
Masahiro Tsuboi, MD, PhD*,
Hisashi Saji, MD, PhD,
Kuniharu Miyajima, MD, PhD,
Jitsuo Usuda, MD, PhD,
Osamu Uchida, MD, PhD,
Naohiro Kajiwara, MD, PhD,
Tatsuo Ohira, MD, PhD,
Takashi Hirano, MD, PhD,
Harubumi Kato, MD, PhD,
Norihiko Ikeda, MD, PhD
Department of Thoracic Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
Accepted for publication April 16, 2009.
* Address correspondence to Dr Tsuboi, Department of Thoracic Surgery and Oncology, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan (Email: mtsuboi{at}za2.so-net.ne.jp).
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Abstract
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Background: The therapeutic strategies for non-small cell lung carcinoma (NSCLC) with N1 and N2 disease differ remarkably. Debate exists about the definition of the borderline between N1 and N2 stations. This study evaluated the prognostic effect of N1 disease, especially focused on the significance of the main bronchial node (No. 10) vs N2 disease.
Methods: The records of 1601 patients who underwent complete pulmonary resection for NSCLC were reviewed to examine the clinical features of lymph nodal involvement.
Results: There were 1086 patients (67.8%) with pN0 disease, 202 (12.6%) with pN1, and 274 (17.1%) with pN2 disease; overall 5-year survival rates were 74.7%, 56.1% and 28.9%, respectively (p < 0.001). Overall 5-year survival rates were 60.2% in hilar N1 and 49.6% in intralobar N1. Overall 5-year survival rates were 58.6% in N1 without node 10 and 35.1% in N1 with node 10. A significant difference was observed between N0 and N1 without node 10 (p < 0.001), and N1 without node 10 and N1 with node 10 (p = 0.033); however, the difference between N1 with node 10 and N2 was not significant. The status of node 10 involvement was an independent prognostic factor of pN1 patients, as well as age and gender.
Conclusions: Patients with node 10-positive N1 disease have an unfavorable prognosis, and the disease behaves like N2 disease. The definition of clear borderline between N1 and N2 is mandatory to achieve a uniform classification map. This study offers further information for clinical and therapeutic purposes.
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Introduction
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Staging of lung cancer based on the T N M classification is the method internationally accepted for the clinical setting of the disease to evaluate the prognosis, decide appropriate management, and analyze the results of treatment. The current T N M classification was initially proposed by Mountain in 1986 [1] and revised in 1997 [2].
Although this staging classification has been accepted, the anatomic definition of lymph node location—especially the boundary between N1 and N2 stations—has not been completely accorded. Currently, some variations of the lymph node map can be found, and thus considerable discordance exists regarding the designation of sites among investigators in the United States, Europe, and Japan [3]. The American Joint Committee on Cancer (AJCC) [4], Naruke and colleagues [5], and The American Thoracic Society (ATS) [6] introduced the concept of lymph node maps in 1973, 1978, and 1983, respectively.
The Mountain and Dresler modification of the ATS (MD-ATS) map was promulgated in 1997 [2]. Mountain and coworkers defined the boundary between N1 and N2 at the pleural reflection. The Naruke-Japanese map did not mention pleural reflection, however; they defined the lymph node station in relation to the bronchial tree and mediastinal structures [5, 7]. The main discrepancy between these two maps is that the Narke-Japanese map considers lymph nodes around the main bronchus and in the subcarinal space among the inferior border of the main bronchus to be station 10 (N1), whereas most of those are labeled as station 4 or 7 (N2) in the MD-ATS map [8].
A rational approach to the management of lung cancer requires accurate staging to plan the most appropriate treatment and to estimate the prognosis. Patients with pathologically proven N2 are no longer indicated for initial resection. Chemotherapy, chemoradiotherapy, or induction therapy, followed by resection, is the standard treatment of choice [9, 10]. Because the therapeutic strategies for patients with N1 and N2 disease differ greatly, the boundary between N1 and N2 stations where metastasis is confirmed pathologically is most essential. Moreover, these discordant classifications may lead to a non-univocal staging, rendering the comparison of different clinical studies difficult. Therefore, we need to define the boundary of lymph node location more precisely and reach consensus on the basis of the most recent evidence.
We reviewed the records of patients with completely resected non-small cell lung cancer (NSCLC) to examine the clinical features of lymph nodal involvement. The purpose of our study was to evaluate the prognostic impact of N1 disease, with a special focus on the significance of involvement of the main bronchial node (No. 10) compared with N2 disease.
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Patients and Methods
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Of 1601 patients who underwent complete pulmonary resection for NSCLC from 1990 to 2004 at Tokyo Medical University, 202 pN1 patients (12.6 %) without distant metastasis were the focus. Data collection and analyses were approved, and the need for obtaining informed consent from each patient was waived by the Institutional Review Board.
All of those patients underwent lobectomy or pneumonectomy with systemic lymph nodal dissection of the hilum and mediastinum. The histologic tumor type was determined according to the World Health Organization classification. Staging was determined according to the international T N M staging system [2]. All dissected lymph nodes were pathologically examined and classified according to anatomic location by the numbering system of Naruke and colleagues [5].
The station of N1 lymph nodes were classified main bronchial lymph node as No. 10, interlobar as No. 11, lobar bronchial as No. 12, segment bronchial as No. 13, and subsegmental as No. 14. N1 lymph nodes were generally classified into two groups as follows, hilar lymph nodes as No. 10 and 11, and intralobar lymph nodes as No. 12, 13, and 14. We further classified N1 lymph nodes involvement into two groups: pN1 disease who were No. 10-positive as the No. 10+ N1 group, and pN1 disease who were No. 10-negative as the No. 10– N1 group. Single-station metastasis was defined as involvement of only one station, whereas multiple-station metastasis was defined as involvement of more than one station.
For staging, all patients underwent a physical examination, chest roentgenogram, computed tomography (CT) imaging of the thorax, brain, and upper abdomen; bone scintigraphy, and bronchoscopy. The tumor marker, carcinoembryonic antigen (CEA) was also examined preoperatively. Serum CEA levels were measured using Latex photometric immunoassay (Mitsubishi Chemical Medience, Tokyo, Japan), and the upper limit of normal serum CEA levels was 3.0 ng/mL according to the manufacturers.
After resection, the patients were examined at 3-month intervals for 3 years, at 6-month intervals for the next 2 years, and thereafter at 1-year intervals in general. The evaluations included physical examination, chest roentgenogram, CT of the chest, and tumor marker measurement. Abdominal and brain CT as well as bone scintigraphy were done each year.
Patients with cancer recurrences were carefully divided into two groups according to the site of initial relapse: locoregional or distant. Locoregional recurrence was defined as any recurrent site within the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes. All other sites of recurrence were considered distant metastases.
Survival was calculated by the Kaplan-Meier method, and differences in survival were determined by log-rank analysis in which the initial day of treatment was the day of operation. The cause of death was recorded as cancer-related, due to other diseases, or unknown. Deaths that were not because of cancer were censored. Multivariate analysis of clinicopathologic factors was performed using the Cox proportional hazard regression model. A value of p < 0.05 was considered statistically significant. Hazard ratios (HR) and 95% confidence intervals (CI) are presented.
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Results
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Demographics
Of 1601 patients who underwent complete pulmonary resection for NSCLC from 1990 to 2004 at Tokyo Medical University, lymph node involvement was recognized in 1086 (67.8 %) as pN0, 202 (12.6 %) as pN1, and 274 (17.1 %) as pN2 disease. The 202 pN1 patients (158 men, 44 women) were a median age of 64 years (range, 31 to 82 years). Operative procedures included 177 lobectomies and 25 pneumonectomies. The histologic classification was adenocarcinoma in 94 patients, squamous cell carcinoma in 84, large cell carcinoma in 14, adenosquamous in 3, and others in 7. The median value of preoperative serum CEA was 3.0 ng/mL (range, 1.0 to 213.5 ng/mL) (Table 1).
The distribution of pathologic T status was 72 pT1, 99 pT2, 19 pT3, and 12 pT4. The mean value of preoperative serum CEA was 3.0 ng/mL (range, 1.0 to 213.5 ng/mL). Among 202 patients with p-N1 disease, 124 had metastasis of intralobar nodes but not hilar nodes. Patients with hilar N1 nodes metastases were further categorized as 21 with No. 10+ N1 disease and 181 with No. 10– N1 disease (Table 2).
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Table 2 Survival at 5 Years in Patients with pN1 Non-Small Cell Lung Cancer According to Prognostic Factors, 1994 to 2002
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Prognosis
The median follow-up for survivors was 55 months (range, 1 to 200 months). The survival curves for the 1086 pN0, 202 pN1, and 274 pN2 patients are shown in Figure 1. The overall 5-year survival rates were 74.7%, 56.1%, and 28.9%, respectively, and this difference was statistically significant (p < 0.001).
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Fig 1. Kaplan-Meier curves show cumulative survival of patients undergoing complete resection for non-small cell lung carcinoma according to pathologic nodal status.
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The association of various prognostic factors was examined by univariate analysis in 202 pN1 patients. Age and gender had a significant effect on survival (p = 0.006 and p = 0.007, respectively). The 21 No. 10+ N1 patients had significantly worse outcome than the 181 No.10– patients (p = 0.033). The overall 5-year survival of No. 10+ N1 patients was 35.1%, which was similar to that of pN2 patients (28.9%; Fig 2;
Table 2). However, there was no significant difference in survival when pN1 patients were divided into hilar N1 (No. 10 and No. 11; n = 78) and intralobar N1 (No. 12, 13, and 14; n = 124; p = 0.146; Fig 3). There were also no significant differences on survival between the 156 patients with pN1 disease who had single-station metastasis and the 46 with multiple-station metastasis (p = 0.742; data not shown). This result implied that lymph node involvement of No. 10 is a poor prognostic marker in pN1 patients compared with No. 10 and No. 11 hilar lymph nodes. In multivariate analysis, the status of No. 10 lymph node involvement was an independent prognostic factor of pN1 patients as well as age and gender (HR, 1.933; 95% CI, 1.089 to 3.430; p = 0.024; Table 3).
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Fig 2. Kaplan-Meier curves show cumulative survival of patients undergoing complete resection for pN1 non-small cell lung carcinoma according to pathologic nodal status. Disease was classified as pN0, intralobar pN1, hilar pN1, and pN2. (Intralobar = No. 12, 13, 14 regional lymph nodes; hilar = No. 11, 10 regional lymph nodes.)
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Fig 3. Kaplan-Meier curves show cumulative survival of patients undergoing complete resection for pN1 non-small cell lung carcinoma according to pathologic nodal status. Disease was classified as pN0, pN1 without No. 10 lymph nodes metastasis, pN1 with No. 10 lymph nodes metastasis, and pN.
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We evaluated postoperative cancer recurrence in 100 pN1 patients for limited period, from 1996 to 2002, and 43 (43.0%) had cancer recurrence. Detailed data on cancer recurrence were not available for 6 patients. The initial relapse site was analyzed in the remaining 37 patients. The recurrences were locoregional in 10 (27.0%) and distant in 27 (73.0%). No statistical difference was observed in the distribution of the site of recurrence, locoregional or distant, between No. 10+ N1 and No. 10– N1 patients. Locoregional relapse occurred in 2 No. 10+ N1 patients (33.0%) and distant metastasis occurred 4 patients (67.0%). For those without No. 10 lymph node involvement, locoregional relapse occurred in 8 patients (25.8%) and distant metastasis in 23 (74.2%). The lung was the most common site for distant metastasis in both groups (data not shown).
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Comment
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During the past 30 years, different types of lymph node maps have been proposed. The distinction of lymph node stations is a most crucial topic that is still not entirely resolved by many lung cancer surgeons. One of the most significant problems concerning lymph node involvement under debate among thoracic oncologists is the definition of the borderline between N1 and N2 stations, which must be clarified, because this discordance could distort therapeutic strategies and stages reported in different studies.
In Naruke's map, lymph nodes in the subcarinal space along the inferior border of the mainstem bronchus are station No. 10 [5], whereas in MD-ATS map, these are labeled as level 7, hence N2 nodes [8]. The borderline between the N1 and N2 station is not clearly defined in Naruke's map. The No. 10 station is defined simply as "nodes around the main bronchus," and adjacent No.4 and No.7 were defined as "nodes at the tracheobronchial angle" and "nodes below tracheal carina," respectively [7].
In the MD-ATS map, the pleural reflection was set as a clear borderline for N1-N2 stations [8], with N1 nodes as those located distal to the mediastinal pleural reflection and within visceral pleura. This definition involves the proximal part of the hilar lymph nodes being classified within the N2 category because the proximal part of the mainstem bronchus lies within the mediastinal pleural envelope. However, concerning the borderline between N1 and N2 station, Asamura and colleagues [11] reported that the pleural reflection is recognized as a plane rather than as a line, and the reflecting line can be easily moved by retracting the lung anteriorly or posteriorly.
Some patients considered to have T1 2N1 M0 stage II disease in Japan would be considered to have T1 2N2 M0 stage IIIA disease in all other countries. This difference in nodal diagnosis might be a cause of staging migration.
In this study, we used Naruke's lymph node map to review the records of 1601 consecutive patients who had undergone complete resection for NSCLC. We also examined the spread pattern of lymph node metastases and investigated the outcome according to the level of the involved nodes.
Some investigators reported hilar lymph node metastasis is a significant unfavorable prognostic factor in p-N1 disease [12–18]. First, we divided N1 lymph nodes into two stations as follows, hilar lymph nodes (No. 10 and 11) and intralober lymph nodes (No. 12, 13, and 14). However, the difference in survival between hilar N1 and intralobar N1 was not significant.
Second, we further categorized patients with hilar N1 node metastases as those with and those without main bronchus node (No. 10) involvement. Among the 202 p-N1 patients, the 21(10.4%) identified with No. 10-positive N1 disease had a significantly worse prognosis than those with No. 10– N1 disease (p = 0.031). Moreover, the overall 5-year survival of patients with No. 10+ N1 disease was 35.1%, which was similar to the 28.9% survival in N2 disease. Multivariate analysis demonstrated that No. 10 lymph node involvement was one of the independent prognostic factors of pN1 patients as well as age and gender. Although the number of patients who were No. 10+ in this study is relatively small, we found that pN1 with No. 10+ disease behaves like a more advanced stage. Matsuoka and colleagues [19] reported the same results, including multivariate analysis, as ours concerning the survival benefit for the N1 disease with or without No. 10 involvement.
Several authors reported that the mode of metastasis in interlobar N1 tended to resemble that of N0, whereas that of hilar N1 behaved like N2 disease [12, 13, 15, 17, 18]; however, the modality of recurrence in our study for the limited period was not affected by the level of pN1 involvement. Our result that distant metastasis was predominant in the recurrent pattern over locoregional recurrence in p-N1 patients implies that nodal involvement might be a surrogate marker for distant metastasis, even if the site of metastasis is the interlobar lymph nodes.
Previous studies suggest that multiple levels of N1 stations are associated with a worse outcome than single-level disease [14, 20–23]. We were unable to identify the differences. Concerning the prognostic effect of the number of involved N1 stations, which may be one of the strong predictable factors for poor survival, it is possible that these analysis did not include enough patients to lead to a valid conclusion.
When taken together, the discrepancy between the Naruke map and the MD-ATS map might contribute to borderline cases between N1 and N2, such as multiple-station N1 disease or hilar N1 disease. The staging committee of the International Association for the Study of Lung Cancer (IASLC) is proposing a new international lymph node map that provides very precise definitions of the anatomic boundaries of each lymph node station and reconciles the differences between the Naruke map and the MD-ATS map [22].
The nodes around the junction of the hilum and mediastinum are key points at issue. Indeed, one of the most important problems is to decide whether the main bronchus nodes belong to the N1 or N2 station in relation to prognosis as well as anatomy. In this study, we found a difference in survival among patients with nodal metastasis up to either station 11 or station 10, whereas survival did not differ among patients with nodal metastases up to either station 10 or N2 station. This result suggested that nodes could be designated as intermediate between N1 and N2 and that there might be a borderline between N1 and N2 nodes around the main bronchus in accordance with the Naruke map. Moreover, our study demonstrated that the involvement of main bronchial nodes has a prognostic significance similar to that of single-station N2 and could be considered as an early N2 disease.
We fervently hope to have a single, accurate map of lymph node stations that can be used universally. Otherwise, it will be difficult to make progress in therapeutic strategies for lung cancer.
In conclusion, survival in patients with pN1 disease differs according to the type of lymph node involvement. Patients with No. 10 involvement have an unfavorable prognosis, and the disease behaves like N2 disease. The definition of a clear borderline between N1 and N2 is mandatory to achieve a uniform classification map. Further clinical studies may give more accurate information about the real prognostic value of No. 10 involvement to improve the clinical assessment and therapeutic strategies.
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Acknowledgments
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We are indebted to Professor J. Patrick Barron of the International Medical Communication Center of Tokyo Medical University for his review of this manuscript.
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References
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Abstract
Introduction
