Ann Thorac Surg 1997;64:809-813
© 1997 The Society of Thoracic Surgeons
Original Article: General Thoracic
Postoperative Prognosis in Patients With Non–Small Cell Lung Cancer With Synchronous Ipsilateral Intrapulmonary Metastasis
Ichiro Yoshino, MD,
Ryoichi Nakanishi, MD,
Toshihiro Osaki, MD,
Shota Hasuda, MD,
Satoshi Taga, MD,
Mitsuhiro Takenoyama, MD,
Takashi Yoshimatsu, MD,
Kosei Yasumoto, MD
Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Accepted for publication January 29, 1997.
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Abstract
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Background. Non–small cell lung cancer with intrapulmonary metastasis (PM) was recently reclassified according to the revision of the TNM classification. To determine whether the new staging system is appropriate, we analyzed the postoperative prognosis of patients with synchronously detected and resected PM lesions.
Methods. Of 509 patients with non–small cell lung cancer who underwent surgical resection, 42 patients were revealed to have synchronous and ipsilateral PM. Their survival was compared with that of matched stage groups (without PM) by Kaplan-Meier test and log rank test.
Results. Two patients who were classified as stage I survived 40 and 30 months after operation, respectively. One patient was determined to be stage II, and survived 100 months postoperatively. Thirty-eight patients were classified as stage IIIA/IIIB (19 each) (90.5% of all cases with PM). There was no significant difference between 3- and 5-year survival rates of the PM stage IIIA group (34.2% and 34.2%) and those of the other IIIA (144 patients; 37.9% and 31.6%). Survival rates of such stage IIIA subgroups as PM, T3 and N2, were comparable. No significant differences were observed between the 3- and 5-year survival rates of the PM stage IIIB (16.6/16.6%) and those of the other stage IIIB (45 cases; 11.7% and 0.0%). The survival rates of such stage IIIB subgroups as PM, T4 and N3 were also similar.
Conclusions. The new staging system for patients with synchronous resectable PM appears to be reasonable regarding survival. Most cases of PM are categorized as locally advanced disease; however, stage IIIA/IIIB cases have become a more heterogeneous population.
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Introduction
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See also page 813.
The lung is one of the most common sites (20% to 44%) of metastasis in non–small cell lung cancer (NSCLC) [1–3]. Deslauriers and collegues [4] reported the presence of satellite lesions associated with lung cancer to be a factor of poor prognosis. Thereafter, several clinicopathologic analyses revealed the prognosis of patients with intrapulmonary metastasis (PM) to be better than that of other stage IV patients if PM is totally removed and no other distant metastasis is observed at the time of operation [5, 6].
Recently, the Union Internationale Contre le Cancer [7] and American Joint Committee on Cancer [8] proposed that ipsilateral PM should not be defined as distant metastasis but instead as local progression because of the favorable clinical outcome of PM, and revised the TNM classification of NSCLC with ipsilateral PM by upgrading the T factor instead of classifying the disease as stage IV. As a result of the revision of the TNM classification, the majority of patients with PM were reclassified as stage IIIA/B in other studies [9, 10]. To determine whether the new staging system is appropriate, we analyzed the postoperative prognosis of the patients with synchro-nously detected and resected ipsilateral PM lesions compared with the same stage group without PM (referred to as the others), especially with stage IIIA/IIIB.
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Patients and Methods
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Patients
During the period between January 1979 and January 1995, a total of 509 patients with non–small cell lung cancer underwent a surgical resection at the Department of Surgery II, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Of them, 42 patients were pathologically shown to have ipsilateral and synchronous PM. Cases of synchronous multiple primary lung cancer were excluded according to the criteria proposed by Martini and Melamed [11]. The histologic diagnosis of the tumors was based on the criteria of the World Health Organization [12]. The patients with PM ranged in age from 38 to 82 years, with a mean age of 60.6 ± 8.6 years. The patients consisted of 28 men and 14 women; the diagnosis were: adenocarcinomas (31 patients), squamous cell carcinomas (9), and large cell carcinoma and undifferentiated carcinoma (1 patient each). Standard operations, such as a lobectomy or pneumonectomy with a complete dissection of the hilar and mediastinal lymph nodes, were performed in 20 patients, a lobectomy without mediastinal dissection was performed in 21 patients, and a partial resection was performed in 1 patient.
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TNM System
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The TNM stage was determined by a preoperative examination comprising a chest roentgenogram, computed tomography of the brain, chest, and abdomen, and a bone scan, and a pathologic examination of surgical specimens. According to the revised TNM system [7, 8], the incidence of PM in the ipsilateral lung was alternatively included in the T factor instead of the M factor. Briefly, the T factor was upgraded if PM was located at the primary lobe (T4 at most), or was determined as T4 if PM was located at the other lobes of the ipsilateral lung. Before the revision of the TNM system the T factors [13] were T1 in 7 patients, T2 in 19, T3 in 7, and T4 in 9 patients, whereas after revision the T factors were T2 in 6 patients, T3 in 17, and T4 in 19 patients. N factors were N0 in 17 patients, N1 in 9, N2 in 15, and N3 in 1 patient.
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Follow-up of Patients
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A follow-up examination was, in general, done every 1 or 2 months for the first 2 years and every 3 to 4 months thereafter. The examination included a physical examination, a complete blood count, blood chemistry, and chest radiography. In addition, all patients routinely received screening examinations by computed tomography or radionuclide bone scanning once or twice per year after operation. Recurrent disease was confirmed by biopsy whenever clinically feasible. In patients in which a biopsy was not feasible, radiographic evidence (roentgenography, computed tomography, or radionuclide scan) was accepted for the diagnosis of recurrence. The final date of evaluation in this study was December 31, 1995. The follow-up times ranged from 1 to 16 years.
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Statistical Analysis
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The survival curves were determined by the Kaplan-Meier method, and comparisons among the survival curves were made using the log rank test. The data were considered significant when the p value did not exceed 0.05.
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Results
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Reclassification of the Old Stage IV Including Intrapulmonary Metastasis
The previous (before revision) stage IV group who underwent a surgical resection comprised 50 patients including 42 patients with PM. After reclassification of the 42 patients with PM, 2 patients were categorized as stage I, 1 as stage II, 19 as stage IIIA, 19 as stage IIIB, and 1 as stage IV (Fig 1
). Forty-one patients (97.6%) showed a reduced stage; however, most of them (38 patients; 90.5%) were categorized as stage IIIA/IIIB.
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Fig 1. . Revision of the classification for non–small cell lung cancer with intrapulmonary metastasis (pm).
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Overall Survival
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The 2 patients at PM stage I and the 1 at PM stage II are alive without any recurrent diseases for 40, 30, and 100 months after operation, respectively. The survival curves of the PM stage IIIA group and the other stage IIIA group are shown in Figure 2. The survival rates at 3 and 5 years of the PM stage IIIA group and the other stage IIIA were 34.2% and 34.2%, and 37.9% and 31.6%, respectively. The mean survival time (MST) was 15 months in the PM stage IIIA group and 24 months in the other stage IIIA. The difference was not statistically significant (p = 0.1965). The survival rates at 3 and 5 years were 45.6% an 39.1% (MST, 26 months) in the T3 N0–1 stage IIIA (T3-IIIA) subgroup (n = 41), and 33.3% and 26.4% (MST, 24 months) in the T1–3 N2 stage IIIA (N2-IIIA) subgroup (n = 38). In addition, no statistical significance was observed among the three new stage IIIA subgroups as shown in Figure 3.
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Fig 2. . The survival curves of the new intrapulmonary metastasis (PM) stage IIIA and the old stage IIIA.
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The survival curves of the PM stage IIIB group and the other stage IIIB are shown in Figure 4. The survival rates at 3 and 5 years of the PM stage IIIB group and the other stage IIIB were 16.6% and 16.6% (MST, 13 months), and 11.7% and 0.0% (11 months), respectively, and no statistically significant difference was observed between the survival rates of the two groups (p = 0.4455). The survival rates at 3 and 5 years were 15.5% and 15.5% (MST, 13 months) in the T4 N0–2 stage IIIB (T4-IIIB) subgroup (n = 29), and 33.3% and 26.4% (MST, 24 months) in the T(any) N3 stage IIIB (N3-IIIB) subgroup (n = 15). There were no statistical significance among the three stage IIIB subgroups (Figure 5).
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Fig 4. . The survival curves of the new intrapulmonary metastasis (PM) stage IIIB and the old stage IIIB.
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The 1 patient with PM and brain metastasis, classified as stage IV, died of multiple recurrence at 23 months after undergoing a pulmonary resection. The present (revised) stage IV group (n = 9) showed 3- and 5-year survival rates of 6.2% and 0% (MST, 14 months). The survival rates at 3 and 5 years of the previous stage IV group including the 42 patients with PM (n = 50) were 63.4% and 23.7% (MST, 14 months). Although no significant difference was seen between the two groups, no long-term survivor (>2 years) was included in the present stage IV group (Fig 6).
As shown in Figure 7, when survival curves of the PM stage IIIA/IIIB groups and the present stage IV group were compared, incidence of long-term survivors were the highest in the PM stage IIIA group, and the next highest in the PM stage IIIB group; however, there were no long-term survivors in the new stage IV group as mentioned above, although no significant difference was observed in the overall survival rate among the groups.
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Fig 7. . The overall survival curves of intrapulmonary metastasis (PM) stage IIIA, intrapulmonary metastasis stage IIIb, and the present (new) stage IV groups.
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Incidence and the First Site of Recurrence
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In the 38 patients with PM stage IIIA/IIIB disease, 19 patients died due to a relapse of NSCLC, 5 died of non–tumor-related disease, and 3 died of unknown causes. Of the 11 survivors, 5 patients demonstrated recurrence, whereas the other 6 patients are all in a disease-free condition. Of the 24 patients who had a relapse, information regarding the first site of recurrence was available in 14 patients based on the follow-up data. The sites included distant organs in 4 patients: the brain in 2 and the bone and the liver in 1 patient each. Intrathoracic recurrences were observed in 8 patients: ipsilateral or bilateral lung in 3, lymph node in 3, and pleuritis and pericarditis in 1 patient each. In 2 patients, recurrences were detected in both distant and intrathoracic sites: the brain and lymphangiosis carcinomatosa in 1, and the bone and PM in the other.
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Comment
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The various routes of metastasis to the lung from primary lung cancer are considered to be as follows: (1) lymphatic spread from tumor embolus in the pulmonary artery; (2) pulmonary circulation from hilar/mediastinal lymphatic drainage chains, the thoracic/right lymphatic ducts, and the brachiocephalic veins; (3) retrograde migration from metastatic lymph nodes; (4) systemic venous circulation from distant metastasis or primary tumors showing a high degree of invasion to the neighboring organs; and (5) aerial metastasis [14–16]. Deslauriers and colleagues [4] proposed that the PM may be established by the migration of cancer cells in the peripheral pulmonary artery as 63% of all satellite nodules were located either near to or at the periphery of main tumors. Yano and associates [17] advocated that PM may be prevalently established by the pulmonary circulation of cancer cells through a mediastinal lymphatic drainage chain because the incidence of intrapulmonary recurrence was significantly higher in pN2 patients than in pN0 patients. Based on the anatomic aspects mentioned above, PM is possibly the intrathoracic disease if no distant disease or invasion to the neighboring structures is observed. In fact, NSCLC patients with PM have shown a better prognosis than those with other types of distant metastasis if a surgical resection is possible [4–6]. As a result of these factors, the Union Internationale Contre le Cancer and the American Joint Committee on Cancer revised the TNM classification of primary lung cancer in 1993 and 1994 [7, 8], in which they categorized ipsilateral PM as the factor of primary lesion (T factor).
In our study, to investigate the propriety of the new classification, we evaluated the prognosis of NSCLC patients with PM. Based on the new classification, the majority of ipsilateral PMs was reclassified to be IIIA/B (90.5%), and the prognosis of patients with PM was also comparable with that of other subgroups in the same stage (IIIA/IIIB). When we further studied the first recurrent site of the patients with PM, the first recurrence was detected in the intrathoracic area in 8 of 14 patients followed up. On the basis of these results, we consider the new classification for PM to be acceptable in terms of postoperative survival data; in addition, NSCLC with ipsilateral PM is also thought to represent locally advanced disease rather than systematic disease.
The only problem arising from the new classification is that the stage IIIA/B groups become larger and heterogeneous. In the previous revision of the TNM classification in 1987, the "heterogeneous" stage III NSCLC had been divided into stages IIIA and IIIB (ie, resectable disease and non- (or hardly) resectable disease) [13]. This classification makes it clearer to plan the therapeutic strategy and management of these diseases. The new stage IIIA/B appears to be more complicated by including PM. For example, a case with a "previous" T3 lesion plus PM lesion in the same lobe is now classified as T4 stage IIIB, but is it nonresectable? Patients with synchronous as well as metachronous PM (recurrence) showed favorable prognosis if a resection is performed [18, 19]. Therefore, the strategy for the therapy or management of PM would more frequently be based on operation, whereas irradiation or operation with induction therapy would be indicated for other instances of locoregional advanced disease.
Recently, several investigators reported on the prognostic factors of NSCLC patients with PM. In the study by Shimizu and colleagues [20], a multivariate analysis identified a significant correlation between poor prognosis and blood/lymphatic vessel invasion from the primary lesions, but not based on the size/number of all PM lesions or T factor. Nakajima and associates [21] stated in their detailed histopathologic study that 30% of PM lesions may be adenomatous or atypical adenomatous hyperplasias, and patients with such lesions also exhibited a long postsurgical survival. Several researchers [12, 22] have proposed various criteria to define multiple primary lung cancer; however, it is still difficult to distinguish multicentric lung cancer from PM when the histologic type is identical. As a result, the possibility that a contamination of double or triple primary lung cancers may exist in patients with PM. The development of accurate diagnostic method based on a genetic analysis may resolve these problems.
In conclusion, the present staging for patients with synchronous and ipsilateral resectable PM was found to be acceptable in terms of survival; however, the stage IIIA/IIIB patients, in which the majority of the PM were observed, were found to be a more heterogeneous population.
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Acknowledgments
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We thank Dr Brian T. Quinn, Kyushu University, for his critical review.
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Abstract
Introduction
