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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1242-1252 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.034 Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial CancerFrom the Department of Pathology, the Gade Institute, and the Department of Obstetrics and Gynecology, University of Bergen, Haukeland University Hospital, Bergen, Norway. Address reprint requests to Lars A. Akslen, MD, PhD, Department of Pathology, the Gade Institute, Haukeland University Hospital, Bergen, Norway; e-mail: lars.akslen{at}gades.uib.no
PURPOSE: Reduced tumor cell adhesion is associated with invasive growth and unfavorable prognosis. In endometrial carcinoma, the prognostic impact of adhesion markers (E-cadherin, beta-catenin [ß-catenin], P-cadherin, and p120ctn) is partly unknown. We wanted to examine the expression pattern and prognostic value of these molecules in a population-based series of endometrial carcinoma patients. PATIENTS AND METHODS: All patients diagnosed with endometrial carcinoma between 1981 and 1990 in Hordaland County, Norway, were included. Paraffin-embedded tumor tissue was available for 96% of the patients (n = 286), and was studied immunohistochemically for expression of E-cadherin, ß-catenin, P-cadherin, and p120ctn. The tissue microarray technique was used for P-cadherin and p120ctn. Median follow-up time for survivors was 9 years (range, 4 to 16 years) and follow-up was complete. RESULTS: Pathologic expression of P-cadherin, E-cadherin, and ß-catenin was associated with a majority of the clinicopathologic variables. In univariate survival analyses, all adhesion markers influenced survival significantly (P < .05). Tumors with pathologic expression of both E-cadherin (low expression) and P-cadherin (high expression; 19%), and ß-catenin (low expression) and P-cadherin (high expression; 16%), had significantly reduced survival compared with the remaining samples (P < .001 for both). In multivariate models, all markers except E-cadherin showed independent prognostic significance in addition to the traditional tumor features. CONCLUSION: Differential expression of P-cadherin and ß-catenin seems to be important in endometrial carcinoma and is associated with aggressive subgroups. Our findings also indicate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.
Endometrial carcinoma is among the most common malignancies of the female genital tract in Western countries, with several well-established prognostic factors.1–3 Still, especially for patients with localized tumors, identification of additional prognostic markers is important for a better detection of patients with high risk of relapse or death from the disease. Alterations in cellular adhesion molecules are important for the development of invasion and metastatic capacity in human cancers.4 Among these, cadherins represent a group of Ca-dependent cell surface molecules, and to date, E-cadherin is the best known.5,6 Altered E-cadherin expression has been related to a more infiltrative growth pattern in cancers of the breast,7,8 stomach,9 lung,10 large bowel,11 and prostate.12 In endometrial carcinoma, studies have shown an association between reduced or absent E-cadherin expression and high International Federation of Gynecology and Obstetrics (FIGO) grading system, deep myometrial invasion, risk of tumor recurrence, and metastatic disease.13–17 The intracellular domain of E-cadherin connects to the actin cytoskeleton via the catenins.4 In addition to this role, beta-catenin (ß-catenin) activates the Wingless-Wnt (Wnt) signaling pathway, acting as an oncogene.18 Mutations in the ß-catenin gene (CTNNB1) have been reported in 14% to 44% of endometrial carcinomas,19–21 but none of these studies have focused on the prognostic relevance of altered ß-catenin expression. Another component of this complex, catenin p120ctn, also binds to the cytoplasmic tail of E-cadherin.22 Alterations of p120ctn seem to be frequent in human tumors,23–26 and loss of or reduced expression has been associated with poor prognosis.27–29 In endometrial carcinomas, one small study reported a different cellular distribution of p120ctn in well-differentiated compared with poorly differentiated tumors,30 whereas a recent study found no difference between endometrioid and nonendometrioid subtypes.31 To our knowledge, the prognostic relevance of p120ctn has not been studied previously in endometrial tumors. P-cadherin is expressed in the basal layers of stratified epithelia, indicating a role in cell growth and differentiation.32 Its expression pattern has been linked to a more dedifferentiated stem-cell-related population of tumor cells,32 although the importance of P-cadherin in different tumors is not well understood. A few studies on breast cancer have reported upregulation as an indicator of poor survival.33,34 P-cadherin is normally expressed in the endometrium,35 and upregulation was found in nonendometrioid carcinomas in one series.31 Patient survival or other clinicopathologic associations have not been examined previously. The aim of this study was to investigate the expression patterns and prognostic significance of the cellular adhesion markers E-cadherin, P-cadherin, ß-catenin, and p120ctn, within a well-defined population-based series of endometrial carcinoma, with complete follow-up.
Patients All patients diagnosed with endometrial carcinoma in Hordaland county, Norway, in the 10-year period 1981 to 1990 have been studied. Hordaland county has approximately 400,000 inhabitants, representing approximately 10% of the total population of Norway, and has a similar age-adjusted incidence rate of endometrial cancer.36 The treatment protocol was constant during this study period, and consisted of abdominal hysterectomy with bilateral salpingo-oophorectomy as initial treatment. Adjuvant radiation therapy was recommended for all patients with myometrial tumor infiltration without distant metastases. Intravaginal radiation was given to patients with highly or moderately differentiated tumors infiltrating less than half of the myometrium. For the remaining patients, external radiation to the pelvis (50 Gy) was recommended. For some patients, however, older age or intercurrent disease resulted in less aggressive treatment, and gestagens were given as part of the primary treatment to some of these patients. The Norwegian Data Inspectorate and the Regional Ethical Committee, Health Region III, approved the research. Paraffin-embedded tumor tissue, available in 96% of the total population (n = 286), was studied, and original microscopic slides were reviewed by one pathologist (I.M.S.). All patients were staged retrospectively according to the FIGO 1988 criteria,37 and the following histologic characteristics were recorded: histologic type; FIGO grade in accordance with established criteria;38 nuclear grade according to Zaino;39 solid growth, necrosis, and growth pattern according to Lax;40 myometrial infiltration, measured as less than or equal to versus more than half of the myometrial thickness; vascular invasion, recorded as no invasion, tumor tissue in one vascular space, or in more than one vascular space; and mitotic count, recorded as the number of mitoses in 10 high-power fields (x400), examined within the most active area.
Follow-Up
Tissue Microarray (TMA)
Immunohistochemistry p120ctn and P-cadherin. A sufficient amount of tumor tissue was available in 276 patient samples using the tissue-conserving TMA technique. Immunohistochemical staining procedures were as described above. Antigen retrieval was performed by boiling for 10 minutes at 750 W and 15 minutes at 500 W in Target Retrieval Solution (TRS; DAKO) buffer, pH 6.0, in a microwave oven. An Autostainer (DAKO) was used for staining. The slides were incubated for 1 hour at room temperature with a monoclonal antibody for p120ctn (clone 98, catalog no. 610134, dilution 1:3200; BD Transduction Laboratories) and with a monoclonal antibody for P-cadherin (clone 56, catalog No. 610228, dilution 1:100; BD Transduction Laboratories) for 1 hour at room temperature. Immunoperoxidase staining was carried out using the Envision Kit (DAKO) with diaminobenzidine tetrachloride peroxidase as substrate before counterstaining with Mayer's hematoxylin. In every run, control slides with benign endometrial epithelium and endometrial carcinoma tissue were included for comparison.
Evaluation of Staining Results Immunohistochemical registration was performed blinded to patient characteristics and outcome for all four markers.
For internal validation, 20 regular slides were randomly selected and stained for both P-cadherin and p120ctn. SIs for TMA sections were then compared with the regular slides, with 90% correspondence in SI for both markers (P < .0001 by
In subsequent statistical analyses, cutoff points for SI categories mainly were based on median or quartile values, considering also the frequency distribution for each marker. Categories with similar survival estimates were merged. E-cadherin and ß-catenin SIs were categorized by median values; E-cadherin SI was categorized as high (> 3) or low (0 to 3), whereas ß-catenin SI was categorized as high (> 2) or low (0 to 2). For P-cadherin, tumors were classified by the upper quartile as high expressing (SI
Statistical Methods
E-Cadherin Expression Reduced or low membranous expression of E-cadherin (n = 159; 56%) was significantly associated with the serous or papillary type (P = .002), high FIGO grade (P = .04), vascular invasion (P = .04), deep myometrial invasion (  50%; P = .02), and high FIGO stage (P = .01), as listed in Table 1. Low E-cadherin expression was also associated with high nuclear grade (P = .002), solid growth more than 50% (P = .01), diffusely infiltrative growth pattern (P = .01), and high mitotic count (P = .03, Mann-Whitney test; data not shown).
Examples of the different expression patterns for the investigated adhesion markers are illustrated in Figure 1.
ß-Catenin Expression Reduced membranous expression of ß-catenin (53%) was found significantly more often among tumors with vascular invasion (P < .001), deep myometrial invasion (P = .002), and high FIGO stage (P = .03; Table 1). No significant associations were found with histologic type or FIGO grade, whereas low expression was more frequent in tumors showing solid growth more than 50% of the tumor area (P = .002) and a diffusely infiltrative growth pattern (P = .005). Nuclear ß-catenin expression was detected in 27% of the endometrioid tumors, whereas no serous or clear-cell tumors showed this feature (P = .001). There were no other significant associations between nuclear ß-catenin expression and the studied features, except that 83% of tumors expressing nuclear ß-catenin had nuclear grade 1 or 2, compared with 61% of tumors without nuclear ß-catenin expression and nuclear grade 1 or 2 (P = .001; data not shown). The percentage of tumor cells with nuclear ß-catenin expression varied from 5% to 90%, and often was found in areas with squamous differentiation.
P-Cadherin Expression
Combined low expression of E-cadherin and high expression of P-cadherin was found in 52 tumors (19%), and was significantly associated with high mitotic count (P = .001, Mann-Whitney test), vascular invasion (P = .01), and deep myometrial infiltration (P < .001). Thirty-eight patient samples (15%) of the endometrioid subgroup showed this low expression of E-cadherin and high expression of P-cadherin, with a significant association to high mitotic count (P = .02, Mann-Whitney test) and deep myometrial infiltration (P = .002).
p120ctn Expression
Associations Among Cell Adhesion Markers
Associations With Other Biomarkers
Univariate Survival Analysis
A combination of low expression of ß-catenin and high expression of P-cadherin was seen in 46 tumors (16%). This subgroup had significantly reduced survival compared with tumors with pathologic staining of none or only one of the markers, with 49% 5-year survival compared with 88% and 75% 5-year survival, respectively (P < .001; Fig 3).
Combined low expression of E-cadherin and high expression of P-cadherin had an estimated 5-year survival of 50%, compared with 86% and 77% 5-year survival for tumors with pathologic staining of none or only one of the markers, respectively (P < .001; Fig 3). When the endometrioid subgroup was analyzed separately, tumors with low expression of E-cadherin and high expression of P-cadherin also showed a significantly reduced survival, with estimated 5-year survival of 60%, compared with 80% and 87% estimated 5-year survival for the two other groups, respectively (P =. 009, not shown). Low-grade expression of p120ctn (SI < 3) was associated with significantly decreased survival. Even more pronounced differences were obtained by comparing tumors with total loss (SI = 0) to the positive tumors, with an estimated survival of 47% v 78%, respectively (P = .0008), but because few tumors presented with complete loss (n = 19), the lower quartile was used as cut point. All investigated variables influenced survival significantly in separate univariate analyses for the subgroup of endometrioid tumors, except for E-cadherin expression, which lost its survival influence (data not shown).
Multivariate Survival Analysis We next examined all adhesion markers in a simultaneous model, in addition to the same basic variables (Table 4). Only patients with complete information on all variables were included (n = 247). As presented in Table 4, expression of ß-catenin, P-cadherin, and p120ctn all had independent prognostic impact in addition to histologic type, FIGO grade, vascular invasion, and myometrial infiltration, whereas E-cadherin failed to obtain independent prognostic impact in this Cox model.
When FIGO stage was included, P-cadherin still remained an independent prognostic variable (hazard ratio [HR] 2.1; P = .01) together with histologic type (HR, 2.4; P = .03), FIGO grade (HR, 2.3; P = .01), vascular invasion (HR, 2.8; P = .005), myometrial infiltration (HR, 2.5;P = .01), and FIGO stage (HR, 4.2; P < .001). p120ctn expression showed a borderline significance (HR, 1.7;P = .07), whereas E-cadherin and ß-catenin had no independent prognostic impact in this model. In subset analyses of the endometrioid subgroup, including all four adhesion markers together with FIGO grade, vascular invasion, and myometrial infiltration, P-cadherin had an independent prognostic significance (HR, 2.4; P = .007), together with ß-catenin (HR, 2.1; P = .05), p120ctn (HR, 2.7; P = .003), FIGO grade (HR, 2.2; P = .01), vascular invasion (HR, 4.3; P = .001), and myometrial infiltration (HR, 2.3; P = .04), whereas E-cadherin had no independent prognostic significance (HR, 1.2; P = .4).
In this study, increased membranous expression of P-cadherin was related to a subgroup of more aggressive endometrial cancers. This phenotype was significantly associated with adverse prognostic factors, including a higher mitotic rate, vascular invasion, deep myometrial infiltration, and reduced survival as confirmed by multivariate analysis. To our knowledge, the prognostic impact of this feature has not been studied previously in endometrial carcinoma, and our findings suggest that P-cadherin might be a novel marker in these tumors, similar to results found for breast cancer.33,34 P-cadherin expression showed an independent prognostic significance in multivariate analysis, in addition to established and strong prognostic variables such as histologic type, FIGO grade, and FIGO stage. In the subgroup of endometrioid carcinomas, strong staining of P-cadherin was associated with high nuclear and histologic grade, deep myometrial infiltration, and pathologic expression of p53 protein, and still had an independent prognostic impact in multivariate analysis. These findings indicate that P-cadherin upregulation is important across the distinction between endometrioid and nonendometrioid tumors. Downregulation of E-cadherin expression with concomitant upregulation of N-cadherin or P-cadherin, termed cadherin switching, has been reported for carcinomas in the esophagus, prostate, cervix, and ovary, and has been associated with tumor progression and metastatic disease.48–51 Our results support the hypothesis that a cadherin switch also could represent an important step in tumor progression52 for endometrial carcinoma. Tumors with a low expression of E-cadherin and high expression of P-cadherin phenotype had vascular and deep myometrial invasion significantly more often as well as higher tumor cell proliferation, with significantly reduced survival, possibly related to a more invasive phenotype. These results were confirmed when the endometrioid subgroup was analyzed separately. Few studies have investigated the prognostic role of altered ß-catenin expression in endometrial carcinoma. In a small study (33 patients) by Kim et al,16 no prognostic impact was reported. However, our data showed a significant and independent association between reduced membranous ß-catenin expression and patient survival, indicating that this could be a useful prognostic marker in addition to standard variables. Studies on gastric53 and lung cancer10 have reported similar findings. Recently, Patel et al51 reported that coregulation of P-cadherin and ß-catenin could represent a critical step in the progression of ovarian cancer. In line with this, our study showed that patients who had endometrial tumors with a combination of low ß-catenin and high P-cadherin expression had a significantly worse prognosis, compared with the remaining patients. Previous studies have reported an association between nuclear expression of ß-catenin and mutations in the corresponding CTNNB1 gene,20,54–56 with a reported mutation frequency of 14% to 44%, especially in low-grade, low-stage tumors of the endometrioid subtype.19–21 Tumors lacking ß-catenin mutations might also express nuclear ß-catenin, indicating that other gene inactivating mechanisms contribute.56 Interestingly, we found that nuclear expression was detected in the endometrioid subtype only, supporting previous findings for mutations. In contrast, reduced membranous ß-catenin expression had no association to histologic type. Regarding prognosis, nuclear ß-catenin-expression had no prognostic significance in this series. The role of different patterns of ß-catenin expression in histologic subtypes of endometrial carcinoma must be clarified further. Decreased expression of E-cadherin in endometrial carcinomas has been related to dedifferentiation and deep myometrial invasion.13,14,57 Our data are in line with these observations. Weak expression was associated with a diffusely infiltrative growth pattern, supporting a role for E-cadherin in tumor cell invasion of surrounding tissues,4 similar to results shown for poorly differentiated gastric adenocarcinomas9 and lobular carcinomas of the breast.8 Decreased expression was more frequent in the nonendometrioid subtype compared with endometrioid carcinomas.17 In our study, low expression of E-cadherin influenced survival significantly in univariate analysis, and a combined low expression of E-cadherin and ß-catenin obtained even better prognostic impact than evaluation of E-cadherin alone, in line with a previous study of breast carcinoma.58 The role of altered p120ctn expression is not clarified in several human tumors. In our study, membranous expression of p120ctn was downregulated or absent in a subgroup of tumors. There was no correlation between the expression of p120ctn and E-cadherin, indicating an independent function of these molecules, similar to results found for breast carcinoma.25 Decreased or absent p120ctn was associated with significant survival differences in both univariate and multivariate analysis. Vascular invasion is a marker of aggressive tumors and is essential for the development of metastatic disease.59 In our study, altered expression of E-cadherin, ß-catenin, and P-cadherin was significantly associated with vascular involvement, indicating a relationship between decreased cell adhesion and migration of tumor cells into the vascular system. Whether this process depends on active tumor-associated angiogenesis should be studied further. A correlation between reduced E-cadherin expression and increased vascular invasion has been reported for gastric60 and breast carcinomas.61 Compared with E-cadherin, we found an even stronger relationship between decreased ß-catenin expression and vascular invasion, similar to previously published results of a lung carcinoma study.10 Our study demonstrates a highly significant relationship between immunohistochemical staining by using the TMA technique compared with regular slides, in line with previous findings.62 This method represents a tissue-conserving and efficient way to examine multiple interesting and potentially important markers within various pathways or protein families. Care should be used, however, in the interpretation of selected tumor areas, and the results need to be validated in future studies. In conclusion, our study indicates that altered expression of cell adhesion markers, among them P-cadherin and ß-catenin, is an important and frequent feature of endometrial cancer. P-cadherin expression also independently predicts decreased patient survival among the endometrioid tumors. Strong P-cadherin staining may serve as a useful and novel marker of endometrial cancer progression, possibly by indicating a more invasive phenotype. Our data also demonstrate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.
The authors indicated no potential conflicts of interest.
We thank Gerd Lillian Hallseth, Bendik Nordanger, and Randi Nygaard for excellent technical assistance.
Supported by the Research Council of Norway (grant No.143049/320), the Norwegian Cancer Society (grant No. 94070/001), Meltzer Research Foundation, and Helse Vest. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test; 
= 0.78 and 0.79 for P-cadherin and p120ctn, respectively). 
.15) were examined by log-log plot to determine how these variables could be incorporated in Cox proportional hazards regression models. Tests for interactions were carried out for the variables that were significantly related to survival in Cox regression analysis. Data were analyzed using the SPSS software package (SPSS Inc, Chicago, IL). 
