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10.1245/s10434-006-9200-z
Annals of Surgical Oncology 14:960-967 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Expression of Carbohydrate Antigens in Human Esophageal Squamous Cell Carcinoma: Prognostic Application and Its Diagnostic Implications

Ahmad Faried, MD1,3, Hitoshi Kimura, MD1, Leri S. Faried, MD2, Nurhayat Usman, MD3, Tatsuya Miyazaki, MD, PhD1, Hiroyuki Kato, MD, PhD1, Shin Yazawa, PhD1,4 and Hiroyuki Kuwano, MD, PhD1

1 Department of General Surgical Science (Surgery I), Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
2 Department of Gynecology and Reproductive Medicine, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
3 Department of Surgery, Padjadjaran University Faculty of Medicine, Hasan Sadikin Hospital, 38 Pasteur Street, Bandung 40161, Indonesia
4 Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan

Correspondence: Address correspondence and reprint requests to: Ahmad Faried, MD; E-mail: afaried{at}med.gunma-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Tumor markers whose antigenic determinants have been demonstrated to consist of carbohydrates are probably one of the most extensive tools that have been used in routine cancer diagnosis. In this study, the relevance of carbohydrate antigen expression profile was examined in esophageal squamous cell carcinoma together with prognosis in 130 patients.

Methods: The expression of carbohydrate antigens was estimated immunohistochemically by anti–sialyl Lewis a (sialyl Lea) and anti–sialyl Lewis x (sialyl Lex) monoclonal antibodies, and correlation between their staining and clinicopathological status was examined. In addition, the correlation of both carbohydrate antigens expression was evaluated with microvessel density (MVD).

Results: Expressions of sialyl Lewis antigens and MVD were associated with several clinicopathological features that reflect the tumor aggressiveness in esophageal cancer. The 5-year survival rate of patients was found to be associated with expression of sialyl Lea and sialyl Lex antigens and with MVD; thus, all of them were revealed to be independent prognostic factors.

Conclusions: Combination of these factors offered a better prediction of prognosis of esophageal squamous cell carcinoma. Further, carbohydrate antigens represent a promising target for therapeutic approaches against the disease.

Key Words: Carbohydrate antigens • Esophageal squamous cell carcinoma • ESCC • Microvessel density • MVD • Sialyl Lea • Sialyl Lex • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal cancer is the ninth most common malignancy worldwide1 and is one of the most aggressive and lethal malignancies. The mortality rates of this cancer are similar to its incidence rates.2 Adenocarcinoma is the most common histologic presentation of esophageal cancer in North America, whereas squamous cell carcinoma is predominant in geographic regions of the world where esophageal cancer is endemic (e.g., Japan and China).3

Altered histoblood group antigens consisting of a family of carbohydrate epitopes are frequently over-expressed in malignant tissues.4 Oligosaccharides containing antigenic determinants of sialyl Lewis a (Lea) (NeuAc{alpha}2,3Galß1,3[Fuc{alpha}1,4] GlcNAc) and si-alyl Lewis x (Lex) (NeuAc{alpha}2,3Galß1,4[Fuc{alpha}1,3]Glc-NAc) are commonly present as glycoproteins and/or glycolipids on the surface of the tumor cells.5 Malignant transformation is associated with increased and abnormal glycosylation, resulting in the accumulation of tumor-associated antigens and the expression of altered carbohydrate determinants such as sialyl Lea and sialyl Lex antigens. Activities of a-sialyltransferases and {alpha}1,3(4)fucosyltransferases that related to the synthesis of the aforementioned sialylated and fucosylated antigens have already been demonstrated to be increased in patients with cancer, depending on the presence of tumor.6–8 To date, correlations of hematogenous recurrence with degrees of expression of both of these carbohydrate antigens on esophageal squamous cell carcinoma (ESCC) have been reported.9

Angiogenesis, which is essential for tumor growth and metastasis, has been found to be associated with the overall survival of patients with a variety of malignancies. The antigenic activity determined by degrees of microvessel density (MVD) has been found to correlate with vascular endothelial growth factor and poor prognosis in ESCC.10,11

Although the tumor markers mentioned above have been reported to be good predictors of ESCC, to our knowledge, a comprehensive study of these markers has never been carried out. We thus performed an immunohistological study to analyze the correlation between expression of sialyl Lea, sialyl Lex, and MVD with clinicopathological status and prognosis in patients with ESCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Clinical Samples
Surgical specimens were obtained from 130 patients (114 men and 16 women) who had ESCC and who underwent potentially curative surgery at the Gunma University Hospital, Department of General Surgical Science, Maebashi, Japan, between 1983 and 2004. The age of the patients ranged from 40 to 80 years with a mean of 62 years. The tumor stage and disease grade were classified according to the 6th edition of the tumor, node, metastasis system (TNM) classification of the International Union Against Cancer.12 None of the patients had received irradiation or chemotherapy before surgery, and none of them had hematogenic metastases at the time of surgery. Patients who underwent noncurative surgery and/or who had received inadequate follow-up were excluded. Postoperative chemotherapy and/or radiotherapy were not performed until recurrence of the tumor was confirmed by radiologic or endoscopic examination.

Immunohistochemistry for Sialyl Le
Immunohistochemical staining of anti–sialyl Lea and anti–sialyl Lex antibodies was performed by a streptavidin-biotin method as described previously.13 Paraffin was removed from 4-µm-thick sections, and sections were incubated with fresh .3% hydrogen peroxide in methanol for 30 minutes at room temperature. After rinsing in phosphate-buffered saline (PBS; pH 7.4), nonspecific binding sites were blocked by incubation with 10% normal rabbit serum for 30 minutes. The specimens were then incubated with anti–sialyl Lea and anti–sialyl Lex antibodies (the gift of Dr. T. Tachikawa) as the primer antibody at a dilution of 1:100 in PBS containing 1% bovine serum albumin at 4°C overnight. Specimens were washed with PBS and incubated with anti-mouse immunoglobulin M for 30 minutes at room temperature, then treated with a Histofine SAB-PO (M) kit (Nichirei, Tokyo, Japan). The chromogen was a .02% 3.3'-di-aminobenzidine tetrahydrochloride solution containing .005% H2O2 in a 50 mM ammonium acetate–citric acid buffer, pH 6.0. The specimens were lightly counterstained with hematoxylin. Negative controls were prepared by substituting normal mouse serum for each primary antibody; no detectable staining was evident.

The staining evaluation was scored as follows: total staining was scored as the product of the staining intensity (on a scale of 0 to 3) times the percentage of cell stained, resulting in a scale of 0 to 300. Staining intensity was scored as follows: 0, no appreciable staining; 1, barely detectable staining in cytoplasm or membrane compared with stromal; 2, readily appreciable brown staining distinctly making tumor cell cytoplasm or membrane; and 3, dark brown staining in tumor cells completely obscuring cytoplasm and membrane. The data were then classified as null (0), weak (1 to 100), moderate (101 to 200), or strong (201 to 300). For the purpose of statistical analysis, all specimens staining as null or weak were grouped as negative, and all specimens staining as moderate or strong were grouped as positive. When the interpretation differed between observers, reevaluation was performed for a final decision on a conference microscope. The degree of staining was scored as previously described with some modification.9 The sections were evaluated independently by two investigators without knowledge of the clinical and pathological background of the patients.

Immunohistochemistry for MVD
Immunohistochemical detection of the MVD was carried out by a streptavidin-biotin method as described above with anti-CD34 monoclonal antibody (NU-4A1, Nichirei Co., Tokyo, Japan) at a dilution of 1:50. The levels of MVD were calculated as the mean of the number of CD34-labeled vessels within five of the most vascular areas in tumor specimens examined under x200 magnification, and they were graded as either low or high.11

Statistical Analysis
Statistical analysis was performed by Stat View software, version 5 (SAS Institute, Cary, NC). The correlation between the parameters was determined by the {chi}2 method, Fisher’s exact test, and the Mann-Whitney U-test. Survival rates of the patients were calculated by the Kaplan-Meier method. A Cox proportional hazard model for the risk ratio was used to assess survival in univariate and multivariate analyses. The risk factors affecting the recurrence of ESCC were evaluated by logistic regression analysis. P < .05 was considered to be significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The correlation between clinical parameters and expression of sialyl Lea and sialyl Lex antigens was examined in 130 patients with ESCC (Table 1Go). In normal esophageal epithelium, sialyl Lea and sialyl Lex antigens were slightly expressed. On the other hand, specimens from 41 (31.5%) of 130 patients were stained with anti–sialyl Lea antibody and showed diffused staining on the cytoplasm and membrane (Fig. 1AGo). Comparison between the expression of sialyl Lea and clinicopathological characteristics in 130 patients revealed a significant association of expression of sialyl Lea antigen with TNM clinical classification (tumor status [T], P = .0011; lymph node metastasis [N], P = .0001; distant metastasis [M], P = .0001; staging [S], P = .0001) and lymphatic invasion (P = .0009). In agreement with these findings, the survival rate of patients whose tumor tissues was stained with sialyl Lea was significantly lower than that of the patients whose tumor tissues did not stain with the same antibody, and the overall 5-year survival rates were 15% and 61%, respectively (log rank P < .0001; Fig. 2AGo).


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  		TABLE 1. Clinicopathological characteristics of sLea, sLex, and MVD in 130 patients with esophageal squamous cell carcinoma
 

Figure 1
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  		FIG. 1. Representative photomicrographs of tissue sections stained for sialyl Lewis a (Lea), sialyl Lewis x (sialyl Lex), and CD34. (A) Primary esophageal cancer positive for sialyl Lea was detected in cytoplasm and membrane of cancer cell nest (original magnification, x200). (B) Primary esophageal cancer negative for sialyl Lea in cancer cell nest (original magnification, x100). (C) Primary esophageal cancer positive for sialyl Lex was detected in cytoplasm and membrane of cancer cell nest (original magnification, x200). (D) Primary esophageal cancer negative for sialyl Lex in cancer cell nest (original magnification, x100). (E) CD34 staining was detected in vascular endothelial cells. Primary esophageal cancer with high microvessel density (original magnification, x100). (F) Primary esophageal cancer with low microvessel density (original magnification, x100).

 

Figure 2
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  		FIG. 2. Overall survival rate. (A) Sialyl Lewis a (Lea)-negative and sialyl Lea–positive cancers. Patients with sialyl Lea–positive tumors had a far worse prognosis than those whose tumors did not express sialyl Lea; 5-year survival rates were 61% and 15%, respectively. (B) Sialyl Lewis x (Lex)-negative and sialyl Lex–positive cancers. Patients with sialyl Lex-positive tumors had a far worse prognosis than those with sialyl Lex–negative tumors; 5-year survival rates were 66% and 10%, respectively. (C) Low–microvessel density (MVD) and high-MVD cancers. Patients with high MVD had far worse prognosis than those with low MVD; 5-year survival rates were 62% and 27%, respectively.

 
Expression of sialyl Lex antigen was observed both in cytoplasm and membranous area of cancer cells (Fig. 1CGo). The expression of sialyl Lex was observed in 40 patients (30.8%), and the presence of this antigen was found to be strongly associated with their TNM clinical classification (T, P = .0027; N, P = .0001; M, P = .0001; S, P = .0001), and lymphatic (P = .0001) and blood vessel invasion (P < .0001) (Table 1Go). The survival rate of patients whose tumors expressed sialyl Lex was statistically significantly lower than that of the patients whose tumors were not expressed by the same antigen, and the overall 5-year survival rates were 10% and 66%, respectively (log rank P < .0001; Fig. 2BGo).

Next, the correlation between the MVD and clinical parameters in 130 patients with ESCC was examined. The MVD determined with anti-CD34 was detected in vascular endothelial cells (Fig. 1E, FGo). The mean ± SD and the median level of the MVD were 25.7 ± 11 and 24.9, respectively. Comparison of the MVD level and clinicopathological characteristics revealed a significant association between the MVD level and grading (P = .0467), distant metastasis (P = .0122), staging (P = .0196), and blood vessels invasion (P < .0001), respectively (Table 1Go). The survival rate of patients with high MVD was significantly lower than that of patients with low MVD (P = .0004; Fig. 2CGo), and the overall 5-year survival rates were 27% and 62%, respectively.

A significant correlation was observed between the expression of sialyl Lea and sialyl Lex antigens (P < .0001; Table 2Go). The expression of sialyl Lex antigen was significantly correlated with the level of MVD (P = .0429; Table 3Go). In contrast, the correlation between sialyl Lea antigen and the level of MVD was not statistically significant. The 3-year survival rates were 82% in patients with low MVD and no expression of sialyl Lex (n = 51) and 58% in patients with high MVD and no expression of sialyl Lex (n = 39), respectively. The same survival rates were 34% in patients with low MVD and positive sialyl Lex expression (n = 15) and 18% in patients with high MVD and positive sialyl Lex expression (n = 25). Therefore, patients with the combination of high MVD and positive sialyl Lex expression had the worst prognosis (P = .0001; Fig. 3Go).


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  		TABLE 2. Correlation between sLea and sLex
 

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  		TABLE 3. Correlation between sLea, sLex, and MVD
 

Figure 3
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  		FIG. 3. Postoperative overall survival rate shown according to expression of sialyl Lewis x (Lex) antigen and microvessel density (MVD).

 
Furthermore, by multivariate analysis, level of MVD was identified as an independent prognostic factor for survival, along with primary tumor (T), blood vessel invasion, and expression of sialyl Lea and sialyl Lex antigens (Table 4Go). With regard to the hematogenous recurrence, the following were statistically significant predictive factors: tumor status ( > T2; P = .0003), lymph node metastasis (N1; P = .0012), distant metastasis (M1; P = .0002), MVD (high; P = .0007), expression of sialyl Lea antigen (positive; P = .002), and expression of sialyl Lex antigen (positive; P = .0003) (Table 5Go).


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  		TABLE 4. Univariate and multivariate analyses of prognosis factor by Cox proportional hazard model
 

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  		TABLE 5. Logistic regression analysis (hematogenous recurrence)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Among the many factors predicting tumor metastasis and prognosis reported to date, tumor-associated expressions of carbohydrate antigens from cancer cells have received much attention,4,14 and thus tumor markers to detect such expression are probably the most extensive tools used in routine cancer diagnosis. The occurrence of tumor-associated expression has led us to study them further to learn their pathophysiology and for clinical applications. An increasing body of evidence has proved that these determinants play a role in hematogenous metastasis and tumor prognosis.4,9 All these observations should enable us to predict the risk of metastasis in patients with cancer.

There have been few reports describing expressions of carbohydrate antigen in esophageal cancer. The expression of both sialyl Lea antigens and sialyl Lex antigens seems to reflect hematogenous recurrence, although diagnosis of ESCC could not be predicted.9 However, in our study, unlike previous observations, expressions of sialyl Lea and sialyl Lex antigens and MVD were identified as independent prognostic factors for survival. This controversial result perhaps occurred because the antibody used in both studies was different and must have a different specificity, and because the observation time (survival rate) of each case involved differed in each study. Further study is needed to elucidate the role of carbohydrate antigens for evaluating patient prognosis in ESCC.

Four distinct ligands for L-selectin including CD34 have been identified in mouse high endothelial venules.15 CD34 is a mucin-like glycoprotein that is widely expressed on vascular endothelium.16 The mucin domain of CD34 is characterized by a high content of serine, threonine, and proline.17 We found that the angiogenic activity (positive expression of CD34) was observed in all cases from patients with ESCC, and these data are in agreement with the findings of previous studies.11,18,19 We and others showed that MVD was associated with clinicopathological parameters and the prognosis of patients with ESCC, and that increased MVD counts might be due to increased activities of angiogenic stimulatory factors such as thymidine phosphorylase expression, resulting in the contribution of tumor growth.20

Simultaneous evaluation of the degree of sialyl Lea and sialyl Lex antigen expression and MVD in cancer cells might be useful for predicting the risk of tumor progression and prognosis. Regarding MVD, a series of {alpha}-fucosyltransferases may contribute to the increased expression of {alpha}-fucosylated antigen, which could be related by the AAA binding carbohydrates and sialyl Lea and sialyl Lex antigens,14,21 and it may be possible that selectins in the vascular system share the route to metastasis of cancer cells through carbohydrates in ESCC.22 To our best knowledge, we are the first to show a correlation between the expression of sialyl Lea and sialyl Lex antigens and MVD with clinicopathological parameters and prognosis of esophageal carcinoma.

In conclusion, the expression of carbohydrate antigens such as sialyl Lea and sialyl Lex and MVD (CD34) was associated with several clinicopathological features that reflect tumor aggressiveness in esophageal cancer. Multivariate analysis revealed that expression status of sialyl Lea, sialyl Lex, and CD34 antigens was an independent prognostic factor in patients with ESCC. Further, the two carbohydrate antigens, sialyl Lea and sialyl Lex, also contribute a hematogenous recurrence in esophageal cancer. All these data may have diagnostic implications and clinical applications. Further studies are in progress to evaluate the promising anticancer agent, chemically synthesized oligosaccharides, as a specific and sensitive target to be used as therapeutic modalities in ESCC cells.


   ACKNOWLEDGMENTS
 
The authors thank Dr. T. Tachikawa for providing the antibodies, T. Aoyagi for technical assistance, and Professor T. Nakajima (Department of Tumor Pathology, Gunma University, Japan) for supervising this study. A.F. is supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan; and in part by the 21st Century Center of Excellence (COE), Japan.

Received for publication July 9, 2006. Accepted for publication July 13, 2006.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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