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Clinical Cancer Research Vol. 9, 6453-6460, December 15, 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Expression of the MAGE-A4 and NY-ESO-1 Cancer-Testis Antigens in Serous Ovarian Neoplasms

Evgeny Yakirevich1, Edmond Sabo1, Ofer Lavie2, Salam Mazareb1, Giulio C. Spagnoli3 and Murray B. Resnick1

1 Department of Pathology and
2 Division of Gynecologic Oncology, Carmel Medical Center and Rappaport Faculty of Medicine, Technion University, Haifa, Israel, and
3 Department of Surgery, Division of Research, University Hospital, Basel, Switzerland


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms and is silent in normal tissues, except for the testis. Expression of two members of this family, MAGE-A4 and NY-ESO-1, has been described in melanomas, germ cell tumors, certain carcinomas and sarcomas, and more recently in uterine neoplasms. The objective of this study was to evaluate the extent and prognostic significance of CT antigen expression in ovarian serous neoplasms.

Experimental Design: Seventy-four patients with ovarian neoplasms, including 10 with serous cystadenomas, 11 with serous tumors of borderline malignancy, and 53 with serous carcinomas, were studied. Immunohistochemistry was performed with the 57B monoclonal antibody, which recognizes predominantly the MAGE-A4 antigen and the D8.38 antibody that recognizes NY-ESO-1.

Results: MAGE-A4 expression was found to be present in 57% of the serous carcinomas and only in 9% of the serous tumors of borderline malignancy. No staining was detected in serous cystadenomas or in the normal ovary. In 8 of 30 positively stained serous carcinomas, >50% of the tumor cells expressed MAGE-A4. NY-ESO-1 expression was seen in 19% of the serous carcinomas, whereas serous tumors of borderline malignancy and cystadenomas were negative. A significant inverse correlation was found between MAGE-A4 expression and patient survival (P = 0.016). Multivariate analysis revealed that both tumor stage and MAGE-A4 expression were independent predictors of patient survival (P = 0.022 and P = 0.013, respectively).

Conclusions: Cancer-testis antigen expression in ovarian serous neoplasms correlates directly with their degree of malignancy. MAGE-A4 expression, and to a lesser degree NY-ESO-1 expression, is characteristic of the majority of serous carcinomas. Determining the degree of MAGE-A4 expression in these tumors may provide important prognostic information. Finally, MAGE-A4 may represent a novel target for immunotherapy in serous ovarian neoplasms.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovarian cancer is the leading cause of death from gynecological cancer in the western hemisphere. The majority of ovarian tumors, including serous carcinomas, occur in elderly women and have a poor prognosis with an overall 5-year survival of only 25% (1 , 2) . The high mortality rate is usually ascribed to late diagnosis of this tumor, which lacks early symptoms. Well established conventional prognostic factors that correlate with outcome of patients with ovarian carcinoma include International Federation of Gynecology and Obstetrics (FIGO) stage and grade and the presence or absence of residual tumor after surgery (3 , 4) . A number of studies have investigated the prognostic value of histopathological and molecular parameters in women with ovarian carcinoma. Among these nontraditional predictors of survival are intratumoral T lymphocytes (5) , expression of the cell cycle inhibitor p27 KIP1 (6) , human kallikrein gene 9 (7) , vascular endothelial growth factor (8) , matrix metalloproteinases (9) , and CD24 (10) .

The cancer/testis (CT) family of antigens is the focus of intense research interest because it is expressed by a variety of malignant neoplasms and by normal germ cells of the testis and placenta but not in other normal human tissues (11 , 12) . Patients with tumors expressing CT antigens are able to elicit specific cellular and humoral immune responses to these antigens (12 , 13) . Because of their unique expression pattern, the CT antigens are considered ideal candidates for novel cancer immunotherapies with encouraging preliminary results (12 , 14) .

The MAGE genes are the best characterized members of the CT antigen family (15, 16, 17) . Currently, there are 23 related MAGE genes divided into four clusters on chromosome X (16 , 17) . Although originally described in melanomas, these genes have since been found to be expressed by a wide range of solid tumors, certain hematological and lymphoid neoplasms, and several tumor cell lines (11 , 12) . Expression of MAGE antigens was initially detected using the semiquantitative reverse-transcription PCR (16) . More recently, monoclonal antibodies to certain MAGE antigens have been developed, allowing for their immunohistochemical localization within neoplastic tissues. The 57B monoclonal antibody is a recently characterized antibody that recognizes most of the MAGE-A family members in Western blots and immunohistochemistry but predominantly the MAGE-A4 protein in paraffin-embedded sections (18 , 19) . Using this antibody, expression of MAGE antigens have been detected in a variety of tumor types (20 , 21) . Recently, the pattern of MAGE-A4 antigen expression was described in a subset of uterine malignancies (22) . A few studies have identified MAGE expression in ovarian neoplasms at the mRNA and protein level, however, the prognostic significance of CT antigen expression in ovarian neoplasms is unknown (23, 24, 25) .

NY-ESO-1 is another member of the CT family that seems to be one of the most immunogenic CT antigens known to date. NY-ESO-1 elicits a strong, integrated humoral and cellular immune response in a high proportion of patients with NY-ESO-1-expressing tumors (13 , 26) . Similar to most of the MAGE genes, expression of NY-ESO-1 is restricted to the testis in normal tissues and has been found to be expressed at the mRNA level in a range of malignancies including melanomas, carcinomas of the breast, lung, urinary bladder, ovary, and in synovial sarcomas (27) . More recently, immunohistochemical analysis of NY-ESO-1 expression in normal and malignant human tissues has confirmed these findings (28 , 29) . The expression of NY-ESO-1 protein has not been described in ovarian neoplasms.

In this study, we examined the expression of the MAGE-A4 and NY-ESO-1 CT antigens in a wide range of ovarian serous neoplasms and demonstrated that strong expression of these antigens is present in the majority of serous carcinomas. Moreover, a strong negative correlation was found between MAGE-A4 expression and patient survival.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Selection.
Seventy-four cases of ovarian neoplasms were retrieved from the archives of the Carmel Medical Center between 1992 and 2002. The tissues examined were obtained by oophorectomy. Approval was obtained from the Local Research Ethics Committee for this retrospective study. The cases were stratified into the following groups: 10 serous cystadenomas, 11 serous tumors of borderline malignancy, and 53 serous carcinomas. None of the patients underwent radiation or chemotherapy before surgery. All patients with serous carcinomas underwent staging laparotomy, including radical surgical debulking, followed by adjuvant first-line chemotherapy that included six to eight cycles of paclitaxel (175 mg/m2) and carboplatin (AUC 6). Optimal surgical debulking was defined by residual individual tumor nodules measuring <=1 cm in diameter. Clinical assessment of response was recorded according to the WHO criteria. The histopathological subtype of the tumors was determined by three pathologists (M. B. R., E. Y., and E. S.) according to the guidelines of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract (30) . The stage and grade of tumors were assessed according to the FIGO guidelines (4) . Patients were stratified further by FIGO stage into two groups: early stage (stage I and II) and advanced stage (stage III and IV). In addition, 10 cases of normal ovarian tissue from hysterectomy specimens resected for nonovarian disease were also studied.

Immunohistochemical Staining.
Immunohistochemical staining was performed according to the following protocol. Consecutive sections from paraffin-embedded tissue blocks were cut at 4 µm, deparaffinized, and rehydrated with xylene and graded alcohol. Microwave epitope retrieval was performed in 1 mM EDTA buffer (pH 8.0), followed by cooling for 15 min at room temperature. Immunohistochemical staining was performed using the Ventana ES automated staining system and Ventana Basic DAB detection kit with endogeneous biotin-blocking kit (Ventana Medical Systems, Tucson, AZ). Mouse monoclonal antibodies against MAGE-A4 (clone 57B) or NY-ESO-1 (clone D8.38; Refs. 20 and 29 ) were used at 1:20 and 1:10 dilutions, respectively. Sections of normal human testes were used as a positive control. An unrelated murine IgG1 antibody was used as a negative control.

The level of MAGE-A4 and NY-ESO-1 expression was described semiquantitatively using a four-grade scoring system (+, <25%; ++, 25–49%; +++, 50–75%; ++++, >75% of cells stained). Focal staining of single cells or small clusters (<5% total) was considered negative.

Statistical Analysis.
Statistical analyses were performed using SPSS version 10.0 software. Associations between categorical groups (i.e., CT antigen expression and clinicopathological parameters) were tested using the {chi}2 test or Fisher’s exact test, as appropriate. Survival analysis was performed on 53 papillary serous carcinoma patients. For the univariate analysis, Kaplan-Meier analysis survival curves were constructed using the product-limit method. The log-rank test was applied to assess the statistical significance of the association between the variables and patient survival. To determine independent predictors of survival, multivariate analysis was performed using the Cox proportional hazard model. Two-tailed P <= 0.05 was considered to be statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathological Parameters.
The clinicopathological characteristics of the patients with ovarian carcinoma are summarized in the Table 1Citation . In the ovarian carcinoma group, the median patient age was 63 years. Clinical follow-up was available for all cases. The median follow-up period was 42 months (range, 4–104).


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  		Table 1 Clinicopathological characteristics of the patients with ovarian serous neoplasms

 
CT Antigen Expression in Normal Ovarian Tissue.
No reactivity of normal ovarian tissue was seen using either the MAGE-A4 or NY-ESO-1 monoclonal antibodies. Furthermore, no staining of normal tissue adjacent to the positively stained tumors was detected.

CT Antigen Expression in Benign and Borderline Serous Neoplasms.
The results of immunohistochemical staining with the MAGE-A4 and NY-ESO-1 monoclonal antibodies are shown in Tables 2Citation and 3Citation . No staining of epithelial or stromal cells was seen in all 10 cases diagnosed as serous cystadenomas.


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  		Table 2 MAGE-A4 expression in ovarian serous neoplasms

 

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  		Table 3 NY-ESO-1 expression in ovarian serous neoplasms

 
One of 11 (9.1%) serous tumors of borderline malignancy exhibited weak cytoplasmic MAGE-A4 expression (Fig. 1A)Citation . None of the borderline tumors stained with the NY-ESO-1 antibody.



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  		Fig. 1. A, weak MAGE-A4 expression in a serous tumor of borderline malignancy. B, well differentiated papillary serous carcinoma exhibiting strong expression of MAGE-A4 antigen. C, diffuse strong expression of MAGE-A4 in a poorly differentiated serous carcinoma. D, focal strong expression of NY-ESO-1 in a poorly differentiated serous carcinoma. The arrow indicates unstained tumor cells.

 
CT Antigen Expression in Papillary Serous Carcinomas.
Immunohistochemical analysis revealed MAGE-A4 immunoreactivity in a large proportion of the serous carcinomas. As shown in the Table 2Citation , 30 of 53 (56.6%) of the serous carcinomas expressed MAGE-A4 antigen. The staining pattern was cytoplasmic and nuclear (Fig. 1, B and C)Citation . The majority of cases exhibited a heterogenous pattern of staining. In 22 of 30 (73.4%) positively stained tumors, <50% of the malignant cells were immunoreactive (Table 2)Citation .

In contrast to the MAGE-A4 expression, NY-ESO-1 staining was seen in only 10 of 53 serous carcinomas (18.9%; Table 3Citation ). The pattern of the NY-ESO-1 immunoreactivity resembled that seen with MAGE-A4 antibody (Fig. 1D)Citation . As seen in Table 3Citation , the extent of NY-ESO-1 expression was limited to <=50% of the malignant cells in 7–10 (70%) positive cases, whereas in three of these tumors, >50% of the malignant cells exhibited a strong diffuse homogenous staining. A trend toward a positive association between MAGE-A4 and NY-ESO-1 expression was seen in individual serous carcinoma cases (P = 0.09). Thirty-two (60.4%) cases stained with either CT antibody and eight cases were immunoreactive with both antibodies. In the majority of these cases, areas of MAGE-A4 and NY-ESO-1 coexpression were seen on serial sections.

In two cases, serous tumors of borderline malignancy were seen adjacent to the invasive serous carcinomas. In these cases, MAGE-A4 expression was observed in the carcinomatous component, whereas no staining of the borderline component was seen. None of these cases stained with the NY-ESO-1 antibody.

The relationship between CT antigen expression and other clinicopathological parameters was investigated by univariate analyses. As shown in the Table 4Citation , no significant association was found between CT antigen expression and tumor grade, FIGO stage, debulking efficiency, or response to chemotherapy (P > 0.05). However, significantly more frequent MAGE-A4 expression was observed in patients older than 60 years (P = 0.02). In the tumors containing areas with different histological grades, CT antigen expression was seen in both well differentiated papillary areas and in poorly differentiated solid areas (Fig. 1, B and C)Citation .


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  		Table 4 Relationship between cancer-testis antigen expression and other clinicopathological characteristics in serous carcinoma

 
CT Antigen Expression and Survival in Patients with Serous Carcinoma.
To evaluate the impact of conventional prognostic predictors on patient outcome, the univariate analysis of survival was applied to the serous carcinoma group. Kaplan-Meier survival curves were constructed, followed by the log-rank test (Fig. 2Citation and Table 5Citation ). FIGO stage, tumor grade, and debulking efficiency significantly influenced patient survival (P = 0.018, P = 0.047, and P = 0.029, respectively; Table 5Citation ).



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  		Fig. 2. Univariate analysis of survival in serous carcinoma. A, International Federation of Gynecology and Obstetrics (FIGO) stage. B, FIGO grade. C, debulking efficiency. D, MAGE-A4 expression. E, NY-ESO-1 expression. F, MAGE-A4-positive and advanced stage.

 

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  		Table 5 Univariate survival analysis (log rank test)

 
A significant correlation was found between MAGE-A4 expression and poor patient survival (Table 5)Citation . Thus, by the end of the follow-up period, higher survival rates were seen in MAGE-A4-negative tumors compared with MAGE-A4-positive tumors (58 and 9%, respectively; P = 0.016). Moreover, advanced stage cases (FIGO stage III and IV) expressing MAGE-A4 exhibited the poorest prognosis. Fifty-three percent of the MAGE-A4-negative advanced stage cases survived by the end of follow-up, whereas none of the MAGE-A4-positive advanced stage cases were alive (P = 0.001). Although higher survival rates were seen in NY-ESO-1-negative tumors compared with NY-ESO-1-positive tumors, the difference was not statistically significant (P = 0.16; Table 5Citation ).

To detect independent predictors of survival, the multivariate analysis of prognostic variables based on the Cox proportional hazard model was performed. The multivariate survival analysis revealed that MAGE-A4 expression and FIGO stage were the only independent predictors of survival (MAGE-A4: P = 0.013, relative risk = 3.20; FIGO stage: P = 0.022, relative risk = 5.52; Table 6Citation ).


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  		Table 6 Multivariate survival analysis (Cox regression model)

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The CT family of genes is expressed in certain malignant neoplasms but not in normal tissues, except for the testis and placenta. This is the first report to describe the immunohistochemical pattern of expression of two members of this family, MAGE-A4 and NY-ESO-1, in a series of ovarian serous neoplasms. Ovarian serous carcinomas exhibited a high frequency of MAGE-A4 (and to a lesser degree NY-ESO-1) expression, and MAGE-4 expression was a negative independent predictor of survival in these tumors.

Expression of MAGE antigens in normal and neoplastic ovarian tissue was detected previously using semiquantitative reverse-transcription PCR (23, 24, 25) . Yamada et al. (23) described that the majority of the MAGE mRNA-positive tumors were histologically surface epithelial-stromal tumors (12 of 17, 71%), encompassing serous, mucinous, endometrioid, clear cell, and transitional cell carcinomas. An increased frequency of MAGE expression was observed in the serous carcinoma group. Rarely, sex cord-stromal tumors, including yolk sac tumor and fibrosarcoma, expressed MAGE genes (23) . Russo et al. (24) demonstrated that MAGE, BAGE, and GAGE genes are expressed at the mRNA level in epithelial ovarian carcinomas (24) . Of the 54 ovarian carcinoma samples, 28% expressed MAGE-1 and 17% expressed MAGE-3. Gillespie et al. (25) demonstrated frequent MAGE-1 gene expression in 15 of 27 (56%) malignant ovarian tissue specimens. As described here and in the study by Yamada et al. (23 , 25) , preferential expression of the MAGE-1 gene was observed in 10 of 14 serous carcinomas with relatively infrequent expression in other tumors of epithelial origin.

More recently, antibodies to specific CT antigens have been developed, allowing for immunohistochemical analysis of archival pathological material. The 57B monoclonal antibody recognizes most of the MAGE-A family members in Western blots and immunohistochemistry but predominantly the MAGE-A4 protein in paraffin-embedded sections (18 , 19) . The D8.38 clone recognizes the NY-ESO-1 antigen and also works well on paraffinized tissues (28) .

Few immunohistochemical studies have examined the levels of CT antigen expression in gynecological neoplasms in general and ovarian neoplasms specifically. Recently, we described increased frequency of MAGE-A4 and NY-ESO-1 expression in malignant uterine neoplasms, particularly in carcinosarcomas and papillary serous carcinomas (22) . Jungbluth et al. (21) described that three of four ovarian papillary serous carcinomas exhibit staining with the 57B MAGE-A4 antibody. Recently, Bolli et al. (31) , using tissue microarray technology, evaluated MAGE-A4 expression in an extensive panel of normal and neoplastic tissues. Among the tumor specimens, 18% of ovarian serous carcinomas exhibited MAGE-A4 immunoreactivity; however, correlation with tumor grade, stage, or patient survival was not performed. Our observation of more frequent MAGE-A4 expression in ovarian serous carcinomas may be related to the heterogeneous expression pattern of this antigen. Sample bias by inclusion of MAGE-A4-negative areas in tissue microarrays is the most likely explanation for the more frequent MAGE-A4 expression in serous carcinomas seen here compared with the study by Bolli et al. (31) . To our knowledge, expression of the NY-ESO-1 antigen by ovarian carcinomas has not been reported.

Several observations suggest the role of CT antigens in carcinogenesis. First, CT antigens are expressed exclusively by malignant tumors but not in normal tissues, except for testicular and ovarian germ cells and placenta (32) . In this study, MAGE-A4 and NY-ESO-1 exhibited only rare expression in tumors of borderline malignancy and were not expressed in benign ovarian tumors or in the normal ovary. Second, a correlation was found between CT antigen expression and tumor progression. The correlation between MAGE expression and tumor stage seems to be dependent on tumor type. In melanoma, the relationship between MAGE expression and stage is controversial (19 , 33) . A direct correlation between CT antigen expression and tumor stage has been reported in tumors of the bladder (34, 35, 36) and in multiple myeloma (37) but not in squamous carcinomas of the head and neck (20) , seminoma (38) , esophagus (39) , gastrointestinal tract, or breast (40) . These findings suggest that CT antigen expression may be a relatively late event in tumor progression, although other studies have shown that activation of MAGE is seen in early carcinogenesis (41) .

Few studies have addressed the relationship of CT antigen expression to patient survival. Expression of CT antigens correlated with poor survival of patients with squamous cell carcinoma of the lung and transitional cell carcinoma of the urinary bladder (31 , 36) . Our study demonstrates, for the first time, a highly significant prognostic importance of MAGE-A4 antigen expression in ovarian serous carcinoma.

In conclusion, MAGE-A4, and to a lesser degree NY-ESO-1 antigen, expression is characteristic of the majority of serous carcinomas of the ovary. On the basis of these results, MAGE-A4 may prove to be a novel reliable prognostic factor for patients with serous carcinoma, suggesting that a more aggressive regimen in patients with tumors expressing MAGE-A4 is appropriate. Furthermore, our findings may have important clinical implications in immunotherapy trials targeted toward CT antigens in these aggressive ovarian neoplasms.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Murray Resnick, Department of Pathology, Carmel Medical Center, 7 Michal Street, Haifa, Israel 34362. Phone: 972-4-8250373; Fax: 972-4-8250816; E-mail: mresnick{at}life span.org.

Received 3/24/03; revised 8/20/03; accepted 9/ 3/03.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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