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Eur J Cardiothorac Surg 2005;28:635-639
© 2005 Elsevier Science NL
Original articles |
Department of Thoracic Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan
Received 17 May 2005; received in revised form 4 July 2005; accepted 7 July 2005.
* Corresponding author. Tel.: +81 86 422 0210; fax: +81 86 421 3424. (Email: tn8336{at}kchnet.or.jp).
Abstract
Objective: Pulmonary metastasis of non-small cell lung cancer is classified as an advanced disease stage, with limited indications for surgical treatment. However, the prognosis of patients with pulmonary metastasis of non-small cell lung cancer is better than that of patients with distant metastases. The purpose of the present study was to analyze and detect possible prognostic factors in surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer. Methods: Among 1198 patients with non-small cell lung cancer who underwent surgery at Kurashiki Central Hospital (Okayama, Japan) from April 1982 to March 2004, a total of 48 (4.0%) patients with pathologically diagnosed ipsilateral pulmonary metastasis were retrospectively evaluated. The median follow-up time was 20.5 months (range 1–103 months) and 37 patients (77.1%) were completely followed up until their death or more than 5 years after the operation. Results: Among the 48 patients, 31 (64.6%) patients had metastatic nodules in the same lobe as the primary tumor (PM1) and 17 (35.4%) patients had metastatic nodules in different ipsilateral lobes (PM2). There was no significant difference in survival between patients with PM1 and the other patients with pT4-stage IIIB, or between patients with ipsilateral PM2 and the other patients with stage IV. Univariate analysis of postoperative survival stratified according to clinicopathologic factors revealed significant differences for the radicality of resection (complete vs. incomplete), tumor size (0–30 vs. >30mm) and pathological nodal (pN) factor (among pN0, pN1 and pN2–3). Multivariate analysis revealed that tumor size (0–30 vs. >30mm) and pN factor (pN0–1 vs. pN2–3) were independent prognostic factors. Conclusions: The results of our study suggest that undergoing a complete resection, having a tumor size of 30mm or less and having no mediastinal lymph node metastases were better prognostic factors for surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer.
Key Words: Non-small cell lung cancer • Ipsilateral pulmonary metastasis • Surgery • Prognostic factor
Abbreviations: NSCLC = non-small cell lung cancer • PM = pulmonary metastasis • BAC = bronchiolo-alveolar carcinoma
1. Introduction
In non-small cell lung cancer (NSCLC), pulmonary metastasis (PM), which is one of the most common types of metastasis in lung cancer [1,2], has previously been considered to be a poor prognostic factor and was designated as distant metastasis (M1) in the 1987 revision of the TNM staging system for lung cancer [3]. However, some clinicopathologic studies have revealed that the prognosis of patients with PM is better than that of patients with distant metastasis if the PM is totally resected and no other distant metastases are detected at the time of the operation [4,5]. The 1997 revision of the TNM staging system ruled that PM should be classified as T4 if the metastatic nodules are only within the same lobe as the primary tumor (PM1) and classified as M1 if the metastases extend to different ipsilateral lobes or the contralateral lung (PM2) [6]. In this system, PM is therefore classified as T4-stage IIIB or M1-stage IV, which are generally thought to be advanced stages with limited indications for surgical treatment. There are still controversies regarding this staging system because some patients with PM could be candidates for surgical treatment with a relatively better prognosis, especially cases of PM1 disease [7–10]. Moreover, some studies have revealed that certain clinicopathologic factors, such as the lymph node status and vascular or lymphatic vessel invasion, have an impact on the prognosis of PM [10–13], suggesting that PM may be a heterogeneous category of patients with NSCLC. In the present study, we retrospectively analyzed clinicopathologic factors to identify possible prognostic factors in surgically treated patients with ipsilateral PM of NSCLC.
2. Patients and methods
From April 1982 to March 2004, a total of 1198 patients were surgically treated for NSCLC at Kurashiki Central Hospital (Okayama, Japan). Among these 1198 patients, 48 (4.0%) patients were pathologically diagnosed to have ipsilateral PM at the initial operation. No distant metastases were detected preoperatively in any of these patients. PM was defined as a parenchymatous lesion that was histologically distinct from the main tumor, and was discriminated from synchronous multiple primary lung cancers on the basis of the criteria established by Martini and Melamed [14]. Complete resection was defined as follows: (1) all tumors in the ipsilateral lung that were identified preoperatively by chest computed tomography or during the operation were resected with both macroscopically and microscopically negative surgical margins; (2) all metastatic lymph nodes in the performed level of node dissection were resected with macroscopically and microscopically negative surgical margins; (3) no evidence of malignant pleural effusion or pleural dissemination was present. Radical dissection or systematic sampling of mediastinal lymph nodes at specified levels was performed in 36 (75.0%) patients and non-systemic sampling was performed in eight (16.7%) patients. No pathologic evaluation was performed in the remaining four (8.3%) patients. Pathologic typing and staging were re-determined according to the current General Rules for Clinical and Pathological Record of Lung Cancer (6th ed.) [15], which are identical to the International System for Staging Lung Cancer [6]. Vascular or lymphatic invasion was defined as positive when carcinoma cells were present in the vessel wall or lumen. The median follow-up time was 20.5 months (range 1–103 months). Of the 48 patients, 38 (77.1%) patients were completely followed up until their death or more than 5 years after the operation.
Comparisons between two groups were performed by Pearson's chi-square test for counts data and Student's t-test for continuous data if the distribution of the samples was normal or by the Mann–Whitney U-test if the distribution of samples was not normal. For univariate analysis, all the cumulative survival rates after the operation were calculated by the Kaplan–Meier method and any differences were evaluated by the log-rank test. Multivariate analysis of independent prognostic factors was conducted by Cox's proportional hazards regression model. Differences were considered significant when the P-value was less than 0.05. All statistical analyses were performed using the SPSS statistical software program package (SPSS ver. 12.0 for windows; SPSS, Inc., Chicago, IL).
3. Results
The backgrounds of the 48 patients are shown in Table 1 . Among the 48 patients, 31 (64.6%) patients had PM1 diseases and 17 (35.4%) patients had PM2 diseases. Of the 48 patients, nine (16.7%) patients were preoperatively diagnosed to have PM disease, while 39 (83.3%) patients were diagnosed intraoperatively or postoperatively. Regarding the histologic type, 31 (64.6%) patients had adenocarcinoma and 11 (22.9%) patients had squamous cell carcinoma. Among the 31 patients with adenocarcinoma, two patients had bronchiolo-alveolar carcinoma (BAC) and the remaining 29 patients had mixed subtypes of adenocarcinoma.
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In the present study, we analyzed postoperative prognostic factors for patients with PM of NSCLC. This study is unique and valuable on the point that an extensive analysis of 15 clinicopathologic factors was performed on the controversial topic of PM of lung cancer. The postoperative survival of patients with PM1 was comparable to that of the other patients with T4-stage IIIB, and furthermore the postoperative survival of patients with ipsilateral PM2 was comparable to that of the other patients with stage IV. Regarding this point, the current TNM staging system may be acceptable in terms of prognosis. However, we revealed that radicality of resection, tumor size and pN factor were significant prognostic factors for surgically treated patients with ipsilateral PM. The importance of these results is that tumor size and pN factor, which are common and important descriptions for staging NSCLC, had an impact on the prognosis for patients with ipsilateral disease, whereas PM factors, such as the distribution (PM1 or PM2) and number of metastatic lesions, did not. Shimizu et al. [13] reported that pN0 and T1 were significantly better prognostic factors in a retrospective study of 42 surgically treated patients with ipsilateral PM of lung cancer. Okada et al. [10] also reported that the survival rates of patients with pN0 or pN1 disease were significantly better than those of patients with N2 or N3 disease in a retrospective study of 89 surgically treated patients with ipsilateral PM disease. These results are similar to our current results, and suggest that the prediction of prognosis would be more precise if tumor size, as a part of the T factor and pN factor, was reflected in the staging for patients with PM. On the other hand, Fukuse et al. [16] reported that there was no significant prognostic difference in relation to the pN factor, whereas a significant correlation was identified between survival and the T factor. Okumura et al. [17] reported that no significant difference in survival was observed among patients with PM according to either the nodal or T status. These studies were conducted retrospectively and involved relatively small study populations, which may partly account for the differences in these results.
The question usually arises as to whether one tumor is a metastasis from another tumor, or whether both tumors are synchronous primary lesions, especially if both tumors have the same histologic features. Although Martini and Melamed [14] defined synchronous multiple primary lung cancers and some other researchers have proposed modified criteria [18,19], it is still difficult to completely differentiate PM from synchronous multiple primary lung cancers. PM has been reported to account for 4.1–10.1% [4,10,13,16,17] of surgically treated patients with NSCLC. The incidence of PM may partly depend on how carefully the detection was carried out, as proposed by Okada et al. [10]. Moreover, contamination of synchronous multiple primary disease may affect the ratio of PM. The difficulties associated with precise detection and making a definitive pathologic diagnosis may be another reason for the contradictory results of the above-mentioned studies. On the other hand, there have been some reports of experimental trials for the discrimination of multiple primary lung cancers from PM using novel techniques such as immunohistochemistry or molecular biology [20–22]. Although complete discrimination may still be difficult to perform, these techniques may contribute to upgrading the accuracy of PM diagnosis.
With the recent prevailing use of high-resolution CT scanning, small peripheral carcinomas have become more frequently detected, most of which represent adenocarcinomas, including BAC [23,24]. It is well known that BAC sometimes shows multifocality with the possibility of synchronous multiple primary lesions [20,21]. Nonami et al. [21] concluded that if either of the multiple pulmonary nodules show type A or B in Noguchi's classification [25], which are thought to be minimally invasive BAC, it is highly likely that they comprise synchronous multiple primary lung cancers. In our study, two patients were pathologically diagnosed as BAC, neither of whom were classified as type A or type B in Noguchi's classification. One patient had diffuse multiple nodules in the whole lung, while the other had localized multiple small nodules around the main tumor, strongly suggesting PM rather than multiple primary cancers.
In conclusion, the results of the present study indicate that undergoing a complete resection, having a tumor size of 30mm or less in diameter and having no mediastinal lymph node metastasis were favorable prognostic factors for surgically treated patients with ipsilateral PM of NSCLC. Although PM is classified as an advanced disease stage according to the current TNM staging system, it should be remembered that PM in itself does not preclude surgical treatment for NSCLC. Since difficulties for a complete diagnosis of PM still remain, further investigations are needed to increase the accuracy of PM diagnosis in the fields of immunohistochemistry or molecular biology as well as morphology. Finally, the patient number in the present study was relatively small, and investigations involving a large number of patients are necessary to confirm the current results.
Acknowledgments
We are especially grateful to Dr Chyotatsu Tsukayama, Dr Youji Wani and Dr Kenji Notohara in the Department of Pathology for the pathologic reviewing and their kind advice.
References
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J. Rao, R. A. Sayeed, S. Tomaszek, S. Fischer, S. Keshavjee, and G. E. Darling Prognostic Factors in Resected Satellite Nodule T4 Non-Small Cell Lung Cancer Ann. Thorac. Surg., September 1, 2007; 84(3): 934 - 939. [Abstract] [Full Text] [PDF]
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