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Ann Thorac Surg 1996;61:158-162
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Excellent Survival in a Subgroup of Patients With Intrapulmonary Metastasis of Lung Cancer

Departments of Cardiothoracic Surgery and Pathology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Accepted for publication June 30, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Recently, intrapulmonary metastases in non-small cell lung cancer have been considered to have less influence on prognosis than extrapulmonary metastases. We report a subgroup found among patients with intrapulmonary metastases showing a good prognosis.

Methods. A retrospective study was performed on 236 consecutive patients with non-small cell lung cancer who underwent surgical resection of their tumors. Intrapulmonary metastases were found histopathologically in 50 of them, and their clinicopathologic features were investigated.

Results. Analysis of postsurgical results revealed a subgroup of patients showing excellent prognosis (n = 15). They had well-differentiated adenocarcinomas with bronchioloalveolar spread and pT1-2 N0, without vascular or lymphangitic invasion. Their actuarial 5-year survival rate was 100%, with a mean survival interval to date of 28 months. However, none of the other 35 patients survived for 5 years, with a mean survival interval to date of 11 months.

Conclusions. We have clarified that patients with histopathologically diagnosed intrapulmonary metastases from non-small cell lung cancer do not constitute a homogeneous group. Pulmonary metastases with good prognosis, which are considered to be hematogenous metastases, may be benign lesions such as adenomatous or atypical adenomatous hyperplasias mimicking malignant tumors.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
See also page 162.

Intrapulmonary metastases (PM) in non-small cell lung cancer have previously been thought to influence adversely the postoperative prognosis, as in metastases spread hematogenously to other organs. However, PM may have less impact on prognosis than extrapulmonary metastases, as shown in a recent report from the Union Internationale Contre le Cancer, which upgraded the staging of the primary tumor in cases of ipsilateral multiple tumors instead of classifying it as stage IV [1]. In the present study, we report a subgroup found among patients with PM showing a good prognosis. Clinicopathologic characteristics responsible for the improved survival rate in this subgroup are described.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
A retrospective study was performed on 236 consecutive patients with non-small cell lung cancer who had undergone surgical resection at this institution between January 1, 1983, and December 31, 1993. Patients who died of postoperative complications were excluded from the analysis. The final date for evaluation was December 31, 1994. Pathologic diagnosis and staging of the resected specimens were carried out according to the General Rule for Clinical and Pathological Record of Lung Cancer (3rd ed) [2]. This system is identical to the International System for Staging Lung Cancer [3] and is accepted by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer with regard to the tumor, nodes, metastasis (TNM) classification. Vascular or lymphangitic invasion was defined as positive when carcinoma cells were present in the vessel wall or lumen in at least one cross section of a tumor.

Intrapulmonary metastasis was defined according to the criteria of Chaudhuri [4], Deslauriers and associates [5], and Kunitoh and co-workers [6] as an independent tumor mass having the same histopathologic features as the primary tumor (Fig 1). Pathologic type, pathologic-TNM (p-TNM) grade, and the presence of vascular or lymphangitic invasion, as well as their accompanying clinical features, were assessed in both the main tumor and PM.

View larger version (230K): [in this window] [in a new window]   Fig 1. . Histopathologic findings of an intrapulmonary metastasis (PM) and atypical adenomatous hyperplasia (AAH). (A) Main tumor showing well-differentiated adenocarcinoma from a patient with PM. (B) Pulmonary metastasis from the same patient. (C) Higher magnification of the PM. (D) Main tumor showing well-differentiated adenocarcinoma from another patient with AAH. (E) Atypical adenomatous hyperplasia from the patient. (F) Higher magnification of the AAH.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Among the 236 cases, 86 were classified as p stage I, 26 as stage II, 53 as stage IIIA, 17 as stage IIIB, and 54 as stage IV. The actuarial 5-year survival rates were 82.6% in stage I, 54.8% in stage II, 51.5% in stage IIIA, 0% in stage IIIB, and 30.0% in stage IV (Fig 2). Pathologic examination revealed PM in 50 (21.2%) of the 236 cases (Table 1). Among these 50 patients, pneumonectomy was performed in 3 and lobectomy was performed in 47, along with hilar and mediastinal lymph node dissection. Furthermore, extrapulmonary metastasis was observed in the brain in 2 patients and in the lumbar spine in 1 at the time of pulmonary resection. The age of these patients ranged from 24 to 80 years, with an average of 61 years. Thirty-four were male and 16 were female.

View larger version (21K): [in this window] [in a new window]   Fig 2. . Actuarial survival for 236 patients with resection of non-small cell lung cancer according to pathologic staging as defined by the General Rule for Clinical and Pathological Record of Lung Cancer [2].

Among the 50 patients with PM, the actuarial survival curves were analyzed using three different criteria, as follows: (1) The 5-year survival of patients with well-differentiated adenocarcinoma with bronchioloalveolar spread (46.1%, n = 29) was significantly better than that of patients with other histology (0%, n = 21) (Fig 3). (2) The 5-year survival of patients without vascular or lymphangitic invasion (72.7%, n = 18) was significantly better than that of patients who did show invasion (0%, n = 32) (Fig 4). (3) The 5-year survival of patients with pT1-2 (main tumor) and N0 (68.6%, n = 20) was significantly better than that of more advanced cases (0%, n = 30) (Fig 5). Fifteen patients fulfilled all three criteria, and their actuarial 5-year survival rate was 100%, with a mean survival interval to date of 28 months. This survival was significantly better than that of cases of p stage IIIA (p = 0.024) and p stage IIIB (p < 0.0001). None of the other 35 patients survived for 5 years (Fig 6). Their actuarial survival curve was significantly worse than that of patients in p stage I (p < 0.0001), p stage II (p < 0.0001), or p stage IIIA (p = 0.0001). Other factors such as sex, age, diameter of the main tumor, the location of PM, and the number of PM did not influence the actuarial survival rate.

View larger version (15K): [in this window] [in a new window]   Fig 3. . Actuarial survival for patients with non-small cell lung cancer and intrapulmonary metastases. Patients with well-differentiated adenocarcinoma with bronchioloalveolar spread (n = 29) are compared with patients with other histopathologic findings (n = 21).

View larger version (15K): [in this window] [in a new window]   Fig 4. . Actuarial survival for patients with non-small cell lung cancer with intrapulmonary metastases. Patients without vascular or lymphangitic invasion (n = 18) are compared with patients with vascular or lymphangitic invasion (n = 32).

View larger version (13K): [in this window] [in a new window]   Fig 5. . Actuarial survival for patients with non-small cell lung cancer with intrapulmonary metastases. Patients with primary tumors classified as T1-2 N0 are compared with patients with more advanced primary tumors.

View larger version (16K): [in this window] [in a new window]   Fig 6. . Actuarial survival for patients with non-small cell lung cancer with intrapulmonary metastases. Patients fulfilling all three selected criteria (see text) (n = 15) are compared with the other patients (n = 35).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

It should be pointed out that the histopathology of adenomatous hyperplasia and atypical adenomatous hyperplasia (AAH) is similar to that of PM of adenocarcinoma. We sometimes failed to distinguish PM from adenomatous hyperplasia or AAH when the main lesion was a particular type of well-differentiated adenocarcinoma, such as type II cell carcinoma or Clara cell adenocarcinoma. In fact, AAH of the lung has been regarded as a precancerous lesion, and the morphology of AAH is very similar to that of the peripheral part of well-differentiated adenocarcinoma showing bronchioloalveolar spread.

Miller [11] defined the bronchioloalveolar cell adenomas of the lung as precancerous lesions. Histologically, these lesions consist of enlarged atypical bronchioloalveolar epithelial cells lining the alveolar walls and lacking a central scar. We have not regarded lesions with these histopathologic features as PM, but classified them as typical or atypical adenomatous hyperplasias.

Morphometric studies have been performed to distinguish AAH from adenocarcinoma. Kodama and associates [12] reported that the mean and standard deviation of the nuclear area were significantly greater in adenocarcinoma than in hyperplastic epithelial lesions. Nakanishi [13] also reported that the standard deviation of the nuclear area was greater in adenocarcinoma than in AAH or adenomatous hyperplasia. However, Mori and colleagues [14] concluded from a morphometric study that adenocarcinoma and AAH were indistinguishable. Carey and associates [15] and Ichinose and co-workers [16] reported that differences in the DNA ploidy pattern between the main tumor and satellite lesions were helpful in defining PM. Analysis of the p53 gene mutation in the satellite lesion may also be helpful. When conventional pathologic examination fails to diagnose intrapulmonary satellite lesions in patients with lung cancer, clinical follow-up is the only way to distinguish PM from adenomatous hyperplasia or AAH.

Deslauriers and associates [5] and Mountain and colleagues [1] have recommended that the primary tumor stage be extended to reflect the poorer survival when there are multiple intraparenchymal tumors. However, we found that non-small cell lung cancer cases with PM were divisible into two subgroups of patients, one with a good postsurgical prognosis and one with a poor outcome. The tumors in the subgroup with a good prognosis were well-differentiated adenocarcinoma with bronchioloalveolar spread and without vessel invasion, belonging to T1 N0 or T2 N0. The prognosis of this patient subgroup was as good as that of stage I cases in this study. Therefore, these PM, which have been presumed to be hematogenous metastases, may be benign lesions such as adenomatous hyperplasia or AAH. However, patients with PM of the other subgroup showed an extremely poor prognosis, which was significantly worse than that in p stages I, II, or IIIA. These PM may be ``true'' hematogenous metastases like those in other extrapulmonary organs.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Nakajima, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jun Nakajima Akira Furuse Tadasu Kohno Toshiya Ohtsuka Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakajima, J. Articles by Ohtsuka, T. Search for Related Content PubMed PubMed Citation Articles by Nakajima, J. Articles by Ohtsuka, T. Related Collections Related Article