Eur J Cardiothorac Surg 2008;33:480-484. doi:10.1016/j.ejcts.2007.12.005
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment
Jin Gu Lee,
Chang Young Lee,
Dae Joon Kim,
Kyung Young Chung,
In Kyu Park*
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, Republic of Korea
Received 24 July 2007;
received in revised form 14 November 2007;
accepted 10 December 2007.
* Corresponding author. Tel.: +82 2 2228 2140; fax: +82 2 393 6012. (Email: ik2653{at}yumc.yonsei.ac.kr).
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Abstract
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Objective: Although designated as T4 or M1 in the current TNM classification system revised in 1997, non-small cell lung cancer with ipsilateral pulmonary metastases is treated as a locally advanced disease and reported survival rates are relatively good. We intended to analyze the prognosis of ipsilateral pulmonary metastases and validate current TNM classification system. Methods: Data of 1213 surgically treated patients with non-small cell lung cancer from January 1990 to December 2004 were retrospectively reviewed. Overall and disease-free survival rates of patients with ipsilateral pulmonary metastases and other T stages were obtained by the Kaplan–Meier method and compared by the log rank test. Prognostic impact of ipsilateral pulmonary metastases on disease-free survival was sought by multivariate analysis. Results: Among 49 patients with ipsilateral pulmonary metastases (IPM), 23 patients had metastasis in primary lobe (IPM1) and 26 had metastasis in non-primary lobe (IPM2). Five-year overall and disease-free survival rates of IPM1 and IPM2 were not significantly different (30.3% vs 30.7%, p
= 0.95, 21.9% vs 23.1%, p
= 0.78). Prognoses of IPM1 and IPM2 were not significantly different than those of T3 disease (30.1%, 26.6%). Resected T4 disease excluding IPM1 had a tendency to show the worse prognosis (16.2%, 7.5%) without significant difference with IPM1 and IPM2. In the univariate analysis of prognostic factors for disease-free survival, IPM1 and IPM2 were prognostic factors. In the multivariate analysis, IPM2 (1.554, 1.02–2.34, p
= 0.039) was one of independent negative prognostic factors. However, IPM1 was not an independent prognostic factor (1.31, 0.84–2.04, p
= 0.23). Conclusions: Regarding prognosis, prognostic strength, extent of disease and surgical treatment the current TNM classification system may be inappropriate in designation of ipsilateral pulmonary metastases and needs revision. The authors suggest that the IPM1 should be staged as T3 or designated as upstaging co-parameter of T stage as like in 1992 TNM classification and IPM2 can be staged as T4 as like in 1992 TNM classification.
Key Words: Ipsilateral pulmonary metastasis • Non-small cell lung cancer • Staging
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1. Introduction
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Non-small cell lung cancer (NSCLC) with ipsilateral pulmonary metastases (IPM) in the primary lobe is designated as T4 and IPM in the non-primary lobe is designated as M1 according to the international lung cancer staging system revised in 1997, which means staged IIIb and IV, respectively [1]. Although, there were reports supporting validity of the current TNM classification [2,3], many authors reported that survival rates of patients with IPM were better than other subgroup of stage IIIb or IV, thus suggested that the current TNM classification for IPM needs revision [4–6]. Previous TNM classification revised in 1992, which regarded all IPM as a T factor thus designated T1 and T2 tumors with IPM in the primary lobe as T2 and T3 (one grade upward shift of T stage) and all other IPM including IPM in the non-primary lobe as T4 [7], is suggested to be more appropriate for classification of IPM [4,5], especially for IPM in the primary lobe. We intended to analyze the prognosis of IPM and prognostic effect of IPM, thus validating current TNM classification and previous TNM classification.
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2. Materials and methods
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This study was designed to evaluate survival rates and prognostic impacts of surgically resected IPM1 and IPM2 and compare with survival rates of other T stages according to the current TNM classification system. One thousand, two hundred and thirteen patients, who underwent surgical resection for NSCLC from January 1990 to December 2004 in our institute, were retrospectively reviewed. This study was approved by the institutional review board. Lobectomy and systematic lymph node dissection was the procedure of choice regardless of clinical stage. Pathological stages were determined based on histological findings of resected specimens according to the current TNM classification revised in 1997 [1]. Histologically identical synchronous ipsilateral intraparenchymal nodules without connection with the primary tumor were defined as ipsilateral pulmonary metastasis. The following patients were excluded from survival analysis: (1) in-hospital mortalities or mortalities before postoperative day 30; (2) histologic types other than squamous cell carcinoma, adenocarcinoma, large cell carcinoma and adenosquamous cell carcinoma; (3) limited resection or palliative surgery; and (4) N3 disease or distant M1 disease. Demographic and clinical data were collected from a preexisting lung cancer data registry and review of medical records. The survival time was counted from the day of surgery to the day of last follow-up or the day of death in months. The disease-free time was designated as months from the date of surgery to the date of detection of recurrence. The follow-up was completed in November 2006. Patients with IPM in the primary lobe were designated as IPM1 and patients with IPM in the non-primary lobe were designated as IPM2. Others without IPM were designated as IPM0. Overall and disease-free survival rates of IPM1 and IPM2 were separately compared with other T stages. Prognostic impacts of IPM1 and IPM2 on the disease-free survival were investigated by univariate and multivariate analysis after adjusting the T stage of IPM1 based on the pathologic findings of the primary tumor. Age, gender, neoadjuvant treatment, adjuvant treatment, extent of resection, T stage, N stage, histologic type, grade of differentiation, microvascular invasion, lymphatic permeation and each IPM were selected for potential prognostic factors. Categorical variables were compared by the 
2 and Fisher's exact tests. Student's t-test or ANOVA was used for comparison of continuous variables. The cumulative probability of survival was assessed by the Kaplan–Meier method and differences in survival were evaluated by the log rank test. The Cox proportional hazard model was used for multivariate analyses of prognostic factors. A p-value less than 0.05 was considered statistically significant. All statistical analyses were performed with the Statistical Package for Social Science (SPSS 12.0, Chicago, IL, USA).
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3. Results
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Out of 1028 eligible patients, 808 were male and 220 were female with a median age of 61 years. Five hundred and forty-eight patients had squamous cell carcinoma and 394 had adenocarcinoma. Stage distribution was as follows: Ia – 115, Ib – 305, IIa – 22, IIb – 181, IIIa – 310, IIIb – 61, IV – 34. Pneumonectomy was performed in 432 (42%) patients and others underwent lobectomy or bilobectomy (Table 1
). The median follow-up time was 35.4 months. Five-year overall and disease-free survival rates were 46.7% and 41.7%, respectively. In IPM0, there were 172 patients with T1, 596 with T2, 173 with T3 and 38 with T4 disease. IPMs were discovered in 49 patients. 23 patients had IPM1 and 26 patients had IPM2. Demographic and clinical characteristics of IPM1 and IPM2 were not statistically significantly different from IPM0, except the proportion of pneumonectomy. Pneumonectomy was performed in the majority of IPM2 patients (85%), but less performed (36%) in IPM1. Five-year overall survival rate was 30.3% in IPM1 and 30.7% in IPM2 (p
= 0.95). Five-year disease-free survival rates were 21.9% in IPM1 and 23.1% in IPM2 (p
= 0.78) (Table 2
). The prognosis of each IPM was significantly worse than IPM0 (Fig. 1
). T1 and T2 stages showed significantly better survival than IPMs. (Table 2) However, there was no evidence of significant survival differences between IPMs and T3 and T4 stages (Fig. 2
). After adjusting the T stage of IPM1 based on the status of the primary mass, prognostic factors for disease-free survival were age 
65, pneumonectomy, IPM1, IPM2, T stage, N stage, microvascular invasion and lymphatic permeation in the univariate analysis. But, IPM1, microvascular invasion and lymphatic permeation were excluded in the multivariate analysis. IPM2 was an independent prognostic factor also in the multivariate analysis (Table 3
).
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4. Discussion
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In 1989 Deslauriers and colleagues reported that the 5-year survival rate of NSCLC with satellite pulmonary nodules was not different from that of stage IIIa (21.6% and 20.3%) and satellite pulmonary nodules were negative prognostic factor for survival. They suggested that a tumor accompanied by satellite nodules to be classified as T3 and staged as IIIa [8]. Watanabe and colleagues reported that the prognosis of NSCLC with IPM was better than stage IIIb and not different from stage IIIa. Also they suggested that IPM should be staged as T3 [9]. In 1992, the American Joint Committee on Cancer proposed a new TNM classification system that IPM was regarded as a T factor. T1 and T2 tumors with IPM1 were designated as T2 and T3 respectively, which means one grade upward shift of T stage and all other IPMs including IPM2 were designated as T4 [8]. Early in 1997, Yoshino and colleagues [10] and Fukuse and colleagues [11] ascertained that TNM classification in 1992 is a reasonable and useful system for staging of IPMs regarding postoperative prognosis. Fukuse and colleagues reported that the 5-year survival of IPM was better than distant organ metastasis (25.8% vs 0%, p
= 0.001) and there was no evidence of survival difference between IPM1 and IPM2. However, the TNM classification system revised in 1997 designated IPM1 as T4 and IPM2 as M1, thus staged as IIIb and IV, respectively [1]. Subsequently, there were a number of supportive reports toward a new revision and several skeptical reports regarding the validity of the revision. From a large volume single center study, Naruke and colleagues reported that 5-year survival rates were 17.8% in IPM1, 8.3% in IPM2, 11.8% in T4, 9.8% in IIIb and 11.2% in M1 and concluded that the revision in 1997 was appropriate [2]. Five-year survival rates in Okumura and colleagues’ report were 34% in IPM1, 34% in resected T4 disease without IPM, 11% in IPM2 and 6% in distant M1 disease [3]. These authors conclude that the current TNM classification was appropriate. Contrarily, Urschel and colleagues reported that the 5-year survival rate of 552 IPMs cases was 20% by meta-analysis and concluded that designating IPM1 as T4 may unjustifiably upstage IPM1. Therefore, these authors suggested that the TNM classification in 1992 or the recommendation of Deslauriers appeared to be appropriate. But they concluded that the designation of IPM2 as M1 was consistent with reported survival results and the pathophysiologic concept of systemic metastatic disease [12]. Okada and colleagues reported that 5-year survival rates were 29.6% in IPM1 and 23.4% in IPM2 without significant difference, thus regarded IPM as representing a locally advanced disease rather than a systematic disease [5]. Recently there were two reports focused on IPM1. Bryant and colleagues reported in a case-control study that the 5-year survival rate of IPM1 with N0 (57%) was significantly better than that of other subsets of T4N0 disease (30%, p
= 0.009) [6]. In Port and colleagues’ study, the 5-year overall survival rate of IPM1 was 47.6% and especially 58.4% in N0 patients [13]. Both reports suggested that the current TNM classification might be inappropriate for the staging of IPM1. The most recent report was a national data base study by the Japan Lung Cancer Registration Committee [14]. This was the largest study, enrolling 317 patients with IPM1, 128 patients with IPM2 and 6080 patients without IPM. Five-year survival rates were 26.8% in IPM1 and 22.5% in IPM2 with no statistically significant difference between two groups. The survival of IPM1 was between that of the T3 and the T4 excluding IPM1. Large number of patients with IPM in the Japanese study resulted in the survival difference in relation to the N status being recognized. To categorize a specific clinico-pathologic finding as a staging parameter, the prognosis of that subgroup is most important as shown in previous reports. The 5-year overall survival rate of IPM1 in our study was 30.3% and compatible with previous reports. Overall and disease-free survival rates of IPM1 were worse than T2 disease without evidence of significant difference with T3 disease. Resected T4 diseases excluding IPM1 showed a tendency of worse prognosis than IPM1 and T3 without statistically significant difference. But this result cannot be generalized because patients with resected T4 disease excluding IPM1 in this study were a selected group and cannot represent whole T4 disease. Secondary, the prognostic effect should be considered for staging. In the univariate analysis after adjusting T stage of IPM1 to the status of the primary tumor, presence of IPM1 was a significant prognostic factor. However, the multivariate analysis revealed that IPM1 is not an independent prognostic factor. The prognostic effect of IPM1 was significantly influenced by the N stage in additional analysis. But the negative prognostic effect of IPM1 was independent to T stage. These findings suggest that although IPM1 cannot be categorized as an independent staging parameter, IPM1 can be a co-parameter of T staging. Finally, the extent of the disease and surgical treatment should be considered for staging. IPM1 is a disease in the same anatomical compartment of the primary tumor and can be resected without further resection of other vital organs (such as great vessels, left atrium, etc) as in T4. This is a significantly different feature of IPM1 from T4. Furthermore, T4 stage comprises many unresectable and prognostically worse subsets, so designating IPM1 as T4 may increase the heterogeneity of T4 stage regarding prognosis and extent of surgical treatment. However, if IPM1 is designated in T3 or considered as an upstaging co-parameter, the heterogeneity of each T stage would not increased. Considering these findings, IPM1 can simply be designated as T3 as in the report of Deslauriers and colleagues or an upstaging co-parameter of T stage as in the 1992 TNM classification. Overall and disease-free survivals of IPM2 in this study provided no evidence of difference from resected T4 disease and T3 disease. We did not compare the prognosis of IPM2 and surgically treated distant M1 disease, because eight patients with surgically treated distant M1 diseases could not represent whole M1 disease. But, the overall survival of IPM2 is better than the expected survival of distant M1 disease. Therefore, designation of IPM2 as M1 and staging as stage IV is not relevant as shown in many other reports. Furthermore, IPM2 is an independent negative prognostic factor. So IPM2 can be considered as an independent parameter for staging. IPM2 is an intrathoracic disease in an anatomically separated compartment from the primary lobe and cannot be resected without resection of separated vital anatomical compartment (non-primary lobe) as in other T4 diseases. Considering these findings, it is reasonable to designate IPM2 as T4 as in the 1992 TNM classification. Due to the retrospective nature of this study, there is limitation to generalize results and the small number of patients in the study groups may erode statistical validity. But, these are inevitable because the number of patients with surgically treated IPM is small and many other reports had the same limitations. Without an international multi-institutional study, only various institutional experiences can be relied on. Hopefully, in the near future more confident results can be obtained by a well-controlled international multi-institutional study. In conclusion, the current TNM classification is inappropriate for the classification of IPM and needs revision regarding prognosis, prognostic effect, extent of disease and extent of surgical treatment. The authors of this study suggest that the IPM1 should be staged as T3 or designated as upstaging co-parameter of T stage as in the 1992 TNM classification and IPM2 should be staged as T4 as in the 1992 TNM classification.
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Appendix A
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Conference discussion
Dr A. Oliaro (Torino, Italy): You have reported a very high percentage of pneumonectomy, 85%, in IPM2. Generally the metastases in the other lobe is small, and it's superseded to perform a typical resection or segmentary resection. Why did you perform the pneumonectomy?
Dr Lee: The percentage of pneumonectomy of IPM2 was 85% in our data. Yes, sometimes it is reasonable to resect the lung cancer with resection and segmentectomy. But we are in favor of pneumonectomy based on the oncologic principle.
Dr P. van Schil (Antwerp, Belgium): I would like to know how many of the nodules were diagnosed before the operation. I understood this is a retrospective study of operated patients. So, how many of the metastases in the same lobe or another lobe were known before surgical resection? Did you observe any survival difference between those nodules that were detected before the operation and those that were incidental findings on pathological examination?
Dr Lee: In most of the cases the nodal number was one. But I don’t have data about the survival between them.
Dr R. Rami-Porta (Barcelona, Spain): With your relatively small series, you have reached the same conclusions that the International Staging Committee of the International Association for the Study of Lung Cancer reached after analyzing the international database. So changing additional nodules in the same lobe from T4 to T3, and additional nodules in different ipsilateral lobe from M1 to T4, is exactly the same recommendation that we gave to the UICC for the next edition of the TNM classification for lung cancer.
As you did, the recommendation of the IASLC was also driven by pathologically staged cases, because most of the clinically staged cases have no pathologic diagnosis of the additional nodules. So the information derives from the surgical cases.
Dr T. Dosios (Athens, Greece): If you see a nodule in the contralateral lung, do you define it as M1 or T4? And what is the difference between a nodule in the contralateral lung and a nodule in the ipsilateral lung but in different lobe?
Dr Lee: I think it is more reasonable to define them as M1. I think it is distant metastasis such as brain metastasis, bone metastasis.
Dr Dosios: But both of them, in the contralateral lung and in the ipsilateral lung but in different lobe, are hematogenous metastases. You consider both of them as hematogenous metastases, don’t you?
Dr Lee: I have no idea about that matter.
Dr Dosios: I mean, that the metastases were done by the bloodstream. Do you agree?
Dr Lee: I think lymphatic spread is more reasonable.
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Footnotes
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Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
This study was supported by a faculty research grant of Yonsei University College of Medicine for 2006.
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Abstract
1. Introduction
