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J Thorac Cardiovasc Surg 1994;108:684-686
© 1994 Mosby, Inc.
GENERAL THORACIC SURGERY |
Fukuoka, Japan
Supported in part by grant-in-aid for cancer research from the Ministry of Health and Welfare, Japan.
Received for publication Feb. 16, 1994. Accepted for publication June 14, 1994. Address for reprints: Y. Ichinose, MD, Department of Chest Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 815, Japan.
Abstract
We attempted to clarify whether a correlation exists between tumor size and the incidence of lymphatic vessel invasion in peripheral non-small-cell lung cancer without regional lymph node metastasis. The study included 212 resected non-small-cell lung cancers classified as pathologic stage I disease and located on the periphery of the lung. The incidence of lymphatic vessel invasion was relatively correlated with the maximum diameter of the tumor as follows: 25% (1/4) for tumor size 1.0 cm or less, 40% (19/48) for size 1.1 to 2.0 cm, 49% (28/58) for size 2.1 to 3.0 cm, and 57% (58/102) for tumor size 3.1 cm or more. The incidence of lymphatic vessel invasion of tumors measuring 3 cm or less in greatest dimension was 44% (48/110). The degree of lymphatic vessel invasion of 20 resected tumor samples measuring 3 cm or less in greatest diameter with hilar lymph node metastasis was also examined for comparison. This figure was as high as 85%. These observations suggest that even small peripheral tumors without any regional lymph node metastasis have a relatively high rate of lymphatic vessel invasion and thus pose a potential risk of local recurrence after a limited resection, especially in a wedge resection of the tumor. (J THORACCARDIOVASCSURG1994;108:684-6)
The prognosis of non-small-cell lung cancer in patients who undergo a complete resection is largely influenced by the presence or absence of regional lymph node metastasis. In fact, stage I-IIIA of the new International Staging System of Lung Cancer is based mainly on the level of lymph node involvement, such as no metastasis (N0), hilar metastasis (N1), and mediastinal lymph node metastasis (N2). 
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The first step of lymph node metastasis is cancer cell invasion of lymphatic vessels within the tumor. Therefore, tumors found to have lymphatic vessel invasion have a potential risk of local recurrence if the tumor-involved segment(s) of the lung and the regional lymph nodes are not completely removed. Although several studies have been conducted to determine whether patients with small peripheral non-small-cell lung cancer such as T1 N0 disease can be candidates for a limited resection, 2,3 to our knowledge, it has yet to be clarified whether any relation exists between the likelihood of lymphatic vessel invasion and tumor size in N0 disease. We therefore attempted to clarify this issue in the present study.
PATIENTS AND METHODS
Between March 1973 and November 1988, 290 patients who had previously undergone a surgical resection of non-small-cell lung cancer were found to have pathologic stage I cancer by the new International Staging System. The primary tumors of 212 of these 290 patients were peripherally located. Peripheral tumor was defined as a tumor that did not arise grossly from the bronchial tree. The tumors comprised 136 adenocarcinomas, 62 squamous cell carcinomas, and 14 tumors of other histologic types. A lobectomy (188 patients), bilobectomy (12), segmentectomy (6), or pneumonectomy (6) was performed. In the same period, 20 patients whose primary tumor was less than 3 cm in maximum diameter underwent surgical resection for pathologic stage II disease. The tumor was adenocarcinoma in 13 patients, squamous cell carcinoma in 6, and large cell carcinoma in 1. A lobectomy (14 patients), bilobectomy (4), or pneumonectomy (2) was performed. In addition, all patients underwent mediastinal node dissection.
Sections of the tumor were stained with hematoxylin-eosin, alcian blue, and periodic acid-Schiff stains. Any elastic and connective tissue was stained when necessary. Intratumoral or peritumoral vascular invasion was determined by the identification of the tumor cells in the lumen of the endothelium-lined channel. Lymphatic vessel invasion was also morphologically distinguished from venous or arterial invasion.
Differences between the proportions were evaluated with the 
2 test. The data were considered significant when the p value did not exceed 0.05.
RESULTS
Fig. 1 shows a representative photomicrograph of tumor invasion of the lymphatic and blood vessels. The incidence of lymphatic vessel invasion as classified by the size of the primary tumor in the maximum diameter in stage I disease is shown in Table I. The incidence of lymphatic vessel invasion was relatively correlated with the tumor size. The smallest tumor with lymphatic vessel invasion was 1.0 cm in maximum diameter and the histologic type was adenocarcinoma. Of 110 N0 tumors whose greatest dimension was 3 cm or less, 48 tumors (44%) showed lymphatic vessel invasion. For comparison, the incidence of lymphatic vessel invasion of tumors whose size was the same as the above but which had hilar lymph node metastasis (N1) was also examined. As shown in Table I, the incidence of lymphatic invasion was found to be significantly higher in the N1 tumors than in the N0 tumors.
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Table II shows the incidence of blood vessel invasion by tumors larger and smaller than 3 cm. The incidence of blood vessel invasion was significantly lower than that of lymphatic vessel invasion (p < 0.0001). Furthermore, no drastic increase in blood vessel invasion between stages I and II was found, in contrast to that of lymphatic vessel invasion.
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Lymphatic vessels are extremely thin-walled structures in comparison with venous or arterial vessels. 4 This may be one reason why cancer cells easily invade the lumen of lymphatic vessels. In fact, in the present study, the incidence of lymphatic vessel invasion in pathologic stage I tumors was as high as 50%, whereas that of venous and arterial invasion was 11% and 13%, respectively. This difference was statistically significant. However, Macchiarini and colleagues 5 reported completely different findings from those in the present study. In their series of pathologic T1 N0 M0 diseases, no lymphatic vessel invasion was found. However, the incidence of blood vessel invasion was reported to be 17% (16/95), which is similar to our data (21%, 44/212). This difference in the incidence of lymphatic vessel invasion between their study and the present study may be due to a difference in the sample condition or morphologic criteria distinguishing lymphatic vessels. To confirm our judgment on lymphatic vessel invasion in N0 disease, we examined the incidence in N1 disease, in which all tumors can theoretically be thought to have lymphatic vessel invasion, and lymphatic vessel invasion was detected in 85% of the samples. This figure indicates that our morphologic criteria distinguishing lymphatic vessel invasion are reliable.
The Lung Cancer Study Group 3 reported the results of a prospective randomized trial comparing limited resection to lobectomy for the management of patients with T1 N0 disease. A total of 247 patients were eligible for analysis. The limited resection group had a significantly higher local recurrence rate than the lobectomy group. The Lung Cancer Study Group therefore concluded that a limited resection should not be recommended as the resection of choice for patients with T1 N0 disease. These observations seem to be compatible with the findings of the present study, as well as those of Riquet, Hidden, and Debesse. 6 They found that in 9.5% of 483 lung segments, the dye that was injected into the subpleural lymphatics diffused into one or two contiguous segments whereas the lymph drainage followed the pulmonary segmentation in 90.5%. This indicates that segmentectomy is not necessarily a perfect procedure to remove all lesions when a peripheral lung tumor has lymphatic vessel invasion of cancer cells. A wedge resection has even a higher risk of leaving cancer cells because that procedure does not take into account the lymphatic channel in the lung segment. In the present study, we observed lymphatic vessel invasion in 44% of the patients whose peripheral tumor measuring 3 cm or less in maximum diameter without lymph node metastasis was surgically resected. Taken together, even a small peripheral tumor without lymph node metastasis has a potential risk of local recurrence after a limited resection, especially in a wedge resection of the tumor.
Acknowledgments
We acknowledge Brian Quinn for critical review and Yumiko Oshima and Yuko Ishibashi for their help in the preparation of the manuscript.
Footnotes
From the Departments of Chest Surgery a and Pathology, b National Kyushu Cancer Center, Fukuoka, Japan. 
References
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