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Ann Thorac Surg 1995;59:412-415
© 1995 The Society of Thoracic Surgeons
First Department of Surgery, School of Medicine, Tokai University, Kanagawa, Japan
Accepted for publication September 30, 1994.
Abstract
Immunohistochemical expression of Lewisy, sialyl Lewisx, and sialyl Lewisa were examined in relation to blood vessel invasion and prognosis in 133 patients with stage I non–small cell lung cancer who had a curative resection from 1980 to 1991. Expression of sialyl Lewisx in adenocarcinomas was higher than in squamous cell and large cell carcinomas, and Lewisy immunoreactivity was the highest among the three antigens. The frequency of blood vessel invasion was significantly higher in tumors with expression of Lewisy or sialyl Lewis antigen (sialyl Lewisx or sialyl Lewisa), however, Lewisy expression was even more significant. The postoperative survival was significantly shorter when tumors expressed both the Lewisy and sialyl Lewis antigen. However, the survival of patients with either Lewisy or sialyl Lewis antigen expression was similar to that of patients whose tumors did not express either the Lewisy or sialyl Lewis antigens. These results suggest that Lewisy and sialyl Lewis antigen may be of prognostic value for metastatic potential but have different functional roles in tumor cells.
About 30% of patients with stage I lung cancer who undergo curative resection die of cancer due to minute metastatic foci, which probably are already present at the time of operation [1]. Although minute metastatic foci cannot be detected by any currently available diagnostic or microscopic techniques, the ability to predict the likelihood of metastasis from the resected specimens could present an important contribution to treatment planning. There are several reports that the expression of Lewis-related carbohydrate antigens is associated with various cancers including the lung [2–4]; however, their functional roles for metastatic potential have not been fully established. We therefore have examined retrospectively the immunohistochemical expression of Lewis-related antigens in relation to prognosis in patients with stage I non–small cell lung cancer who had a curative resection.
Patients and Methods
One hundred thirty-three consecutive patients with stage I non–small cell lung cancer according to the TNM classification [5] who underwent a curative tumor resection and lymph node dissection from 1980 to 1991 were included in this study. The surgical protocols were the same for all the patients and none had received any adjuvant therapy.
A streptavidin-biotinyl peroxidase complex method using antibodies against Lewisy (BM-1; Japan Immunoresearch Lab, Takasaki, Japan), sialyl Lewisx (FH6; provided by Otsuka Pharmaceutical, Tokushima, Japan), and sialyl Lewisa (CA19-9; Centocor, Malvern, PA) antigens was performed on fomaldehyde-fixed tissue sections. Each diluted antibody solution (BM-1, 1:100; FH6, 1:10; CA19-9, 1:1) was overlaid on thin-sliced sections and incubated at room temperature overnight. Subsequently, the sections were incubated with a biotinylated sheep anti-mouse immunoglobulin solution and then covered with a streptavidin-biotinyl peroxidase complex (LSAB kit; DAKO, Carpinteria, CA). The sections then were stained with 0.02% 3,3'-diaminobenzidine and 0.06% sodium azide (Wako Pure Chemical, Osaka, Japan) and counterstained with 0.3% methyl green. Immunohistochemical staining was examined in at least 1000 cells over five high-power fields (magnification, x 1,000).
The mean percentage of the cells with Lewisy (Ley), sialyl Lewisx (SLex), and sialyl Lewisa (SLea) staining was 56%, 32%, and 24%, respectively. Of these antigens, positive incidence of Ley staining was significantly higher than SLex and SLea. Thus, the grading of the Ley staining was defined as follows: (+), 50% or more of the cells had membraneous staining; (-), fewer than 50% had staining. The grading of the SLex and SLea staining were as follows: (+), 30% or more had membraneous staining; (-), fewer than 30% had staining. Negative controls were done by omitting the primary antibodies but using the same method mentioned earlier. The pathologic findings were reviewed separately by two pathologists who had no knowledge of the clinical outcome, and the results were taken into account only if the two pathlogists reached consensus. Blood vessel invasion (BVI) was examined by victoria blue-hematoxylin and eosin staining as previously reported [6] and their frequencies were evaluated by the 
2 test. Survivals were calculated by the Kaplan-Meier method, and statistical evaluation was done by the log-rank test.
Results
Profiles of Patient Population
The age, histologic types, tumor stage, BVI, and recurrence in the patient population are summarized in Table 1
. Of the 41 patients with recurrent tumors, 34 (83%) had blood-borne metastases.
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).
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. Patients with each SLex(+), SLea(+), and Ley(+) tumors had significantly shorter survival than those with SLex(-), SLea(-), and Ley(-) tumors (p < 0.02, p < 0.01, and p < 0.01, respectively). Because the expression of SLex and SLea are both significant factors for predicting the survival, and, as will be discussed in the comment section, these antigens are likely to have similar function as adhesion molecules, probably due to the same structures with sialic acid conjugated in the teminal epitope, SLex(+) or SLea(+) tumors are hereafter defined as sialyl Lewis antigen (SLe)(+) tumors.
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. The frequency of BVI was significantly higher in tumors expressing Ley as well as in tumors expressing SLe. However, the difference between the Ley(+) and Ley(-) tumors was even more significant than the difference between SLe(+) and SLe(-) tumors (p < 0.01 and p < 0.05, respectively).
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). Patients with Ley(+)SLe(+) tumors had a significantly shorter survival than those with Ley(-)SLe(-) tumors (p < 0.01), Ley(-)SLe(+) tumors (p < 0.02), or Ley(+)SLe(-) tumors (p < 0.05). However, the survival of patients with Ley(-)SLe(+), Ley(+)SLe(-) and Ley(-)SLe(-) tumors were not significantly different.
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Our present study demonstrates that the expression of Ley, SLex, and SLea may be of prognostic value for predicting survival. As shown in Table 4, Ley, SLex, and SLea have similar structures with sialic acid or fucose conjugated to their terminal epitope. Although these antigens accumulate in tumor tissues of patients with carcinoma [2–4], their functional roles have remained largely unknown. Recently, both SLex and SLea have been shown to be ligands for the cell adhesion molecule called ELAM-1 (E-selectin, endothelial leukocyte adhesion molecule-1) [7–10], which is present on cytokine-activated vascular endothelial cells. Thus, SLex and SLea may contribute to the adhesion of tumor cells to the vascular beds and promote hematogenous metastasis [11]. In addition, others have reported that cells expressing Ley repel each other [12], and may be correlated with cell motility [13]. Thus, Ley may influence the invasive potential of tumor cells and, consequently, prognosis [14]. To assess the contribution of these Lewis-related antigens, we selected patients with stage I non–small cell lung cancer and studied their immunohistochemical expression in relation to prognosis.
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For a distant metastasis to form, the following steps are thought to be important: individual tumor cells first detach from the primary lesion and then invade the blood vessels. Next, they attach to the vascular beds in the target organs after migration in the blood. They then penetrate the capillary walls and finally proliferate in the extracellular matrix. In fact, patients with BVI(+) tumors (n = 58) had a significantly shorter survival than those with BVI(-) tumors (n = 75) (p < 0.01). In addition, we have reported that the disease-free survival of patients with BVI and SLex expression was significantly worse [6]. In the present study, the BVI frequencies were significantly higher when tumors expressed Ley or SLe and the survival was significantly shorter when tumors expressed both Ley and SLe. However, Ley expression was a more significant factor for BVI than SLe. Moreover, the survival of patients whose tumors expressed either Ley or SLe was as long as that of the patients whose tumors did not express either antigen, although Ley and SLe were individually significant factors for the survival. These results suggest that Ley and SLe have a different functional role for distant metastasis. Because SLe is a ligand for the E-selectin receptor, and Ley may be involved with cell motility, it is likely that SLe plays some role in the adhesion of cancer cells to the vascular beds, whereas Ley is involved in invasive potential, namely, blood vessel invasion and transmigration from the site of vascular arrest to the extracellular matrix.
In conclusion, the expression of Ley, SLex, and SLea antigens may be of prognostic value for predicting prognosis in patients with stage I non–small cell lung cancer, but have different functional roles for metastatic potential, possibly in defining adhesion and the motility of cancer cells.
Footnotes
Address reprint requests to Dr Ogawa, First Department of Surgery, School of Medicine, Tokai University, Bohseidai, Isehara, Kanagawa, 259-11, Japan.
References
This article has been cited by other articles:
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  E. Machida, J. Nakayama, J. Amano, and M. Fukuda Clinicopathological Significance of Core 2 {beta}1,6-N-Acetylglucosaminyltransferase Messenger RNA Expressed in the Pulmonary Adenocarcinoma Determined by in Situ Hybridization Cancer Res., March 1, 2001; 61(5): 2226 - 2231. [Abstract] [Full Text]
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