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Annals of Surgical Oncology 9:388-393 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

RCAS1 Expression as a Prognostic Factor After Curative Surgery for Extrahepatic Bile Duct Carcinoma

Masato Suzuoki, MD, Yasuhiro Hida, MD, Masaki Miyamoto, MD, Taro Oshikiri, MD, Kei Hiraoka, MD, Yoshihiro Nakakubo, MD, Toshiya Shinohara, MD, Tomoo Itoh, MD, Shunichi Okushiba, MD, Satoshi Kondo, MD and Hiroyuki Katoh, MD

From the Department of Surgical Oncology (MS, YH, MM, TO, KH, YN, SO, SK, HK), Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan; Department of Pathology (TS), Teinekeijinkai Hospital, Sapporo, Japan; and Department of Surgical Pathology (TI), Hokkaido University Hospital, Sapporo, Japan.

Correspondence: Address correspondence and reprint requests to: Masato Suzuoki, MD, Department of Surgical Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8648, Japan; Fax: 81-11-706-7158; E-mail: suzuoki@ med.hokudai.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a cancer cell-surface antigen and has been identified as a prognostic factor in several cancers. It is thought that tumor cells escape from immune attack by expressing RCAS1, which induces apoptosis in receptor-positive immune cells. We investigated the relationship between RCAS1 expression and clinicopathologic features and clinical outcome in patients with extrahepatic bile duct carcinoma (EBDC) who underwent curative resection.

Methods: RCAS1 expression was determined by immunohistochemistry in 60 patients with EBDC who underwent curative resection from 1992 to 1999. The patients were divided into two groups on the basis of the extent of RCAS1 expression: a low-expression group (immunoreactivity in <25% of cells) and a high-expression group. Expression was correlated with clinicopathologic features and prognosis.

Results: RCAS1 was expressed in 52 (86.7%) of 60 tumors and at a high frequency in all histopathologic stages. High expression of RCAS1 was detected in 46 (76.7%) of 60 cases. No correlation existed between the pattern of RCAS1 expression and any clinicopathologic feature, although high expression did correlate with poor prognosis. High RCAS1 expression was an independent negative predictor for survival.

Conclusions: RCAS1 expression predicts poor outcome in resectable EBDC.

Key Words: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) • Extrahepatic bile duct carcinoma • Immunohistochemistry • Prognostic factor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Extrahepatic bile duct carcinoma (EBDC) is a relatively uncommon malignancy. Although this tumor is small and progresses slowly, most patients with EBDC have advanced disease at the time of diagnosis because early symptoms are vague and nonspecific. Accordingly, the resectability rate for EBDC is low in most series, despite advances in surgical techniques.1–4 Even in patients fortunate enough to have a resectable lesion, survival remains poor. The 5-year survival rates for patients who undergo surgical treatment ranges from 22% to 31%.1,5,6 Therefore, identification of a novel indicator for EBDC that correlates with its clinicopathologic features and prognosis to help individualize treatment is highly desirable. Several immunohistochemical studies of EBDC have been reported, but it is unclear whether these markers correlate with prognosis, because the study populations were small.7–12

The 22-1-1 monoclonal antibody was elaborated from a human uterine adenocarcinoma cell line, SiSo.13,14 A complementary DNA encoding the antigen recognized by this antibody was isolated and termed RCAS1 (receptor-binding cancer antigen expressed on SiSo cells). RCAS1 is a type II membrane protein that is expressed by a variety of human cancer cells. Expression of RCAS1 inhibits growth and induces apoptosis in immune cell such as T, B, and natural killer cells.15 Immunohistochemical studies have shown that RCAS1 is expressed with a high frequency in uterine, ovarian, and lung cancers and that expression of this antigen correlates with a poor prognosis.14,16–18 We hypothesized that expression of RCAS1 by cancer cells would facilitate tumor progression.

In this study, we investigated RCAS1 expression in tumor specimens from 60 patients with EBDC who underwent curative resection. The relationships between RCAS1 immunopositivity and clinicopathologic features and prognosis were analyzed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Specimens
Tumor specimens were obtained from 60 patients (46 men and 14 women) with EBDC who underwent curative resection at the Second Department of Surgery of Hokkaido University Hospital, the Department of Surgery of Teine Keijinkai Hospital, and the Department of Surgery of Hokkaido Gastroenterology Hospital from 1992 to 1999. Patients who were treated with a palliative procedure and positive margins were excluded from the study. The mean age was 66.2 years (range, 44 to 81 years). Clinicopathologic features were evaluated by using the pathologic tumor-node-metastasis classification of the International Union Against Cancer.19 Twenty-seven patients had grade 1 lesions, 26 had grade 2 lesions, and 7 had grade 3 lesions on the basis of histopathologic findings. Two tumors were stage 0, 6 were stage I, 16 were stage II, 11 were stage III, and 25 were stage IV. Lymphatic metastasis was identified in 25 (41.7%) cases. Two patients had distant metastasis, both of which were microscopic para-aortic lymph node metastases.

All specimens were fixed in 10% formalin and embedded in paraffin wax. Representative blocks were selected (primarily on the basis of the greatest dimension of the tumor), and serial 4-µm-thick sections were examined by immunohistochemistry.

Immunohistochemistry
Immunohistochemical reactions were performed by using the streptavidin-biotin-peroxidase method. Sections were deparaffinized in xylene, washed in phosphate-buffered saline (PBS; pH 7.4), and rehydrated through a graded series of ethanol. Endogenous peroxidase activity was blocked by incubation in 3% hydrogen peroxide methanol for 10 minutes. The specimens were then washed with PBS. The specimens were placed in 10% normal goat serum (Histofine SAB-PO kit; Nichirei Corp., Tokyo, Japan) for 5 minutes and incubated overnight at 4°C with the primary antibodies— anti-RCAS1 (anti-RCAS1 mouse immunoglobulin M monoclonal antibody; Medical & Biological Laboratories Co., Ltd., Nagoya, Japan)—at 1/500 dilution. After washing in PBS, biotinylated goat antibody to mouse immunoglobulin (Histofine SAB-PO kit) was applied and incubated at room temperature for 30 minutes. After washing in PBS, the immunohistochemical reactions were developed in freshly prepared 3,3'-diaminobenzidine tetrahydrochloride (Histofine SAB-PO kit). Slides were counterstained in hematoxylin and coverslipped in a systemic mounting medium. As a positive control, sections of a uterine adenocarcinoma previously found to express RCAS1 protein were affixed to the same slides as the sections of EBDC and were stained in parallel. As a negative control, nonimmune purified mouse immunoglobulin M was substituted for the primary antibody.

The degree of RCAS1 immunoreactivity was classified into four categories: the negative category was assigned when <5% of tumor cells showed immunoreactivity; 5% to 25%, 25% to 50%, and >50% of reactive tumor cells were defined as weak (1+), moderate (2+), and strong (3+), respectively. The 2+ and 3+ categories were considered high-expression patterns, whereas negative and 1+ were considered low expression. Scoring of RCAS1 immunoreactivity was based on examination of 10 high-power (x400) microscopic fields for each section. Immunoreactivity in each section was taken to be the median value of scores assigned by each of three investigators. All specimens were evaluated without any knowledge of the patients’ clinical information.

Statistical Analysis
The relationship between RCAS1 immunoreactivity and clinicopathologic features was evaluated by the {chi}2 test or Fisher’s exact test. The Kaplan-Meier method was used to generate survival curves, and survival differences were analyzed by log-rank test, on the basis of the status of RCAS1 expression. The influence of variables on survival was assessed by using Cox univariate and multivariate regression analyses. Probability values <.05 were considered statistically significant. All analyses were performed with statistical software (StatView, version 5.0; SAS Institute Inc., Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RCAS1 Expression
RCAS1 existed both in the cytoplasm and on the cell membrane of cancer cells. In the 60 cases of EBDC, RCAS1 expression was negative in 8, 1+ in 6, 2+ in 6, and 3+ in 40 (Fig. 1). The incidence of staining was 86.7%, and 46 (76.7%) of 60 tumors showed a high-expression pattern of RCAS1. RCAS1 was not expressed in normal bile duct epithelial cells in any specimens. RCAS1 was expressed at a high frequency in all disease stages (Table 1).



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  		FIG. 1. Immunohistochemical staining for RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) in extrahepatic bile duct carcinoma. (A) RCAS1 was negative in cancer cells. (B) There was strong staining both in the cytoplasm and on the membrane of these cancer cells. More than 50% of tumor cells were reactive (3+). Original magnification, x200.

 

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  		TABLE 1. RCAS1 expression in extrahepatic bile duct carcinoma by tumor stage (pTNM)
 
RCAS1 Expression and Clinicopathologic Parameters
No significant correlation was observed between the patterns of RCAS1 expression and any clinicopathologic feature (age, sex, histopathologic grade, depth of tumor invasion, lymph node metastasis, distant metastasis, lymphatic invasion, venous invasion, perineural invasion, or pathologic tumor-node-metastasis stage; Table 2).


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  		TABLE 2. Correlation between the clinicopathologic features and the expression of RCAS1 in extrahepatic bile duct carcinoma
 
RCAS1 Expression and Prognosis
Figure 2 shows survival curves of patients stratified according to RCAS1 status. Patients whose tumors showed high expression of RCAS1 had a significantly poorer prognosis than those whose tumors showed low expression (3-year survival rate, 35.2% vs. 70.7%, respectively; log-rank test, P = .0221).



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  		FIG. 2. Kaplan-Meier analysis of the overall survival of patients with low (negative/1+) and high (2+/3+) RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) expression (log-rank test; P= .0221).

 
On univariate analysis with Cox’s proportional hazards model, lymph node metastasis (P < .0001), venous invasion (P = .0125), perineural invasion (P = .0028), and RCAS1 status (P = .0305) all decreased survival. Multivariate analysis with Cox’s proportional hazards model showed that high expression of RCAS1 was an independent unfavorable prognostic factor (P = .0324; risk ratio, 3.438; 95% confidence interval, 1.109–10.661), as were the presence of lymph node metastases (P = .0126) and perineural invasion (P = .0379; Table 3).


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  		TABLE 3. Univariate and multivariate analysis using Cox’s proportional hazards model for RCAS1 expression and clinicopathologic features in extrahepatic bile duct carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study showed that (1) RCAS1 expression is common in all stages in EBDC, (2) no significant correlation exists between RCAS1 expression and any clinicopathologic feature, and (3) high expression of RCAS1 is an independent unfavorable prognostic factor. To be successful, a tumor must be able to escape from immune surveillance. Recently, it has been shown that several malignant tumors express Fas ligand to induce apoptosis of Fas-expressing cytotoxic T lymphocytes.20–27 Similarly, RCAS1 acts as a ligand for a receptor present on immune cells. It has been confirmed that a receptor against the RCAS1 antigen exists on normal peripheral immune cells, such as T, B, and natural killer cells. This receptor expression was enhanced by activation of the lymphocytes, and when these receptor-positive immune cells were cultured with RCAS1 peptides, their growth was strongly suppressed, and they were eventually led to apoptotic cell death.15 These results suggest that tumor cells may evade immune surveillance by expressing RCAS1, which acts to suppress clonal expansion and induce apoptosis in RCAS1 receptor–positive immune cells. This hypothesis is supported by the observation that the incidence of apoptosis is increased in tumor-infiltrating lymphocytes that exist in RCAS1-expressing lung cancers.18

RCAS1 is expressed commonly in various cancer tissues. RCAS1 was expressed in 87.5% of uterine cervical adenocarcinomas, 66% of uterine endometrial adenocarcinomas, 58.8% of ovarian carcinomas, and 87.7% of squamous cell carcinomas of the uterine cervix. Among nongynecological cancers, RCAS1 has been detected in esophageal squamous cell carcinoma (2 of 2 cases), gastric adenocarcinoma (3 of 3 cases), colon adenocarcinoma (3 of 3 cases), pancreatic adenocarcinoma (2 of 2 cases), and lung cancer (49 of 66 cases; 74.2%).14,16– 18

Our study established that RCAS1 is expressed frequently in EBDC (86.7%; 52 of 60 cases). Normal bile duct epithelium does not stain for RCAS1. However, this molecule is expressed very frequently in stage I disease (83.3%; Table 1). These data suggest that RCAS1 expression occurs early in the carcinogenesis of EBDC. RCAS1 was expressed in 20% of uterine cervical squamous cell in situ carcinomas, 16.7% of microinvasive carcinomas, and 86.2% of invasive carcinomas. RCAS1 was not detected in the normal or dysplastic uterine cervix.16 These results offer additional evidence that RCAS1 expression is related to tumor progression and invasion.

RCAS1 expression did not correlate with any clinicopathologic feature (Table 2). These results suggest that other molecules, in addition to RCAS1, must be present for tumor growth or adhesion to the vascular endothelial cells. Nevertheless, high expression of RCAS1 was an independent unfavorable prognostic factor in multivariate analysis (Table 3). RCAS1 expression also correlates with poor prognosis in patients with uterine cervical adenocarcinoma and non–small-cell lung carcinoma.17,18 Thus, the capacity to escape immune surveillance conferred by the expression of RCAS1 seems to play an important role in determining the outcome of patients with EBDC and other tumors.

We also have investigated RCAS1 expression in pancreatic cancer and gallbladder cancer28,29 and found that RCAS1 expression is frequent and specific. Thus, this molecule seems to be a useful marker for pancreaticobiliary cancers in general. Recently, it has been reported that K-ras mutational analysis of endobiliary brush cytology and biopsy specimens assisted in the detection of malignancy.30,31 Investigation of RCAS1 expression combined with K-ras might increase the accuracy of these procedures.

Finally, RCAS1 might make an ideal target for anticancer therapy because it is expressed commonly and specifically. Suppression of RCAS1 expression is one potential therapeutic strategy. Constructing a gene therapy vector system that expresses the therapeutic protein driven by the RCAS1 promoter is worthwhile,32 because this would enable transcriptional targeting of RCAS1-expressing tumors.

In conclusion, RCAS1 is expressed frequently and specifically in EBDC, and a high level of RCAS1 expression is an independent poor prognostic factor, even in patients with resectable disease. More aggressive therapy may be necessary for treating patients with EBDC that expresses RCAS1.


   Acknowledgments
 
The authors thank H. Shida, who performed the immunohistochemical studies.

Received for publication June 26, 2001. Accepted for publication February 1, 2002.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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