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Clinical Cancer Research Vol. 11, 6198-6204, September 1, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Prognostic Impact of Immunohistochemical Expression of Ezrin in Highly Malignant Soft Tissue Sarcomas

Wen-Hui Weng1, Jan Åhlén1,2,3, Kristina Åström2, Weng-Onn Lui1 and Catharina Larsson1

Authors' Affiliations: Departments of 1 Molecular Medicine, 2 Surgery, and 3 Oncology and Pathology, Karolinska University Hospital-Solna, Stockholm, Sweden

Requests for reprints: Wen-Hui Weng, Department of Molecular Medicine, Karolinska University Hospital-Solna, CMM L8:01, SE-171 76 Stockholm, Sweden. Phone: 46-8-51773616; Fax: 46-8-51776180; E-mail: Wendy.Weng{at}cmm.ki.se.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Ezrin is a cytoskeleton linker protein that is actively involved in regulating the growth and metastatic capacity of cancer cells. It has recently been reported to be involved in dissemination of pediatric soft tissue sarcoma (STS).

Experimental Design: To further evaluate the prognostic value of ezrin in STS progression, we screened 50 primary STSs of high malignancy grade using immunohistochemistry. At the initial surgery, all patients were without local or distant metastasis. The expression was then compared with the outcome during follow-up for at least 4 years or until the patients' death.

Results: Twenty-five of the 50 STSs analyzed (50%) showed ezrin immunoreactivity in the membrane and cytoplasm of the tumor cells. A significant association was shown between positive expressions of ezrin and death in disease as well as overall survival (P = 0.014 and 0.007, respectively). Similarly, ezrin expression was significantly associated with development of distant metastasis during follow-up (P = 0.031), also excluding locally recurrent disease (P = 0.049). The relative abundance of metastasis in ezrin-positive cases was observed both over time and irrespective of time. In comparison with clinical, histopathologic, and genetic characteristics of the STSs, ezrin expression was found to correlate significantly with an infiltrative growth pattern outside the tumor capsule as well as with copy number gain of chromosomal region 9cen-q22.

Conclusion: Our findings suggest that ezrin immunoreactivity could be valuable as an additional prognostic marker in highly malignant STSs and support a causative role of ezrin in STS tumor dissemination.

Soft tissue sarcomas are a heterogeneous group of rare malignant tumors originating from mesenchymal tissue (1, 2). The 5-year overall survival of soft tissue sarcoma (STS) patients is ~63% to 76% (3–5) and varies considerably depending on whether the tumor is of high or low malignancy grade (3, 6, 7). The most important clinical and histopathologic parameters indicating a poor prognosis are large tumor size, presence of necrosis, high mitotic count, intralesional surgery, and deep location (2–4). Nevertheless, because the natural course of high-grade STS cannot be reliably predicted, it remains a clinical dilemma whether some or all of these patients should receive adjuvant therapy. There is, therefore, a definite need for development of additional reliable prognostic marker(s) to the group of highly malignant tumors. At the time of initial surgery, 45% to 55% of high-grade STS patients can be expected to survive; however, if recurrent disease is diagnosed during follow-up, the chances of survival are drastically reduced. This situation illustrates the special need to predict, diagnose, and cure STS recurrences in the form of metastatic disease.

The recent identification of ezrin as a key component in the metastasis of pediatric cancers (8, 9) suggests its prometastatic function in late tumor progression and metastasis. Ezrin is a member of the ezrin-radixin-moesin cytoskeleton–associated protein family, which was first described as linkers between membrane proteins and actin filaments. Following the initial description, ezrin-radixin-moesin proteins have become implicated in several important cellular complexes and processes (10).

Ezrin is a component of cell surface structures involved in cell adhesion functions, interactions with the Rho-associated signal transduction, and the Akt-mediated apoptotic pathway (11–13). Alterations of ezrin expression can mediate many changes in the metastasis-associated cell surface signals and intracellular signaling cascade that confer the metastatic capability in tumor cells. Therefore, it is conceivable that ezrin overexpression and/or deregulation could contribute to the metastatic behaviors of tumors. Evidence from both animal models and prospective human studies show correlations between ezrin expression levels and tumor progression (8, 9, 14) consistent with a crucial role for ezrin in tumor dissemination.

Using a microarray approach, Khanna et al. (8) and Yu et al. (9) identified high ezrin expression levels specifically in highly metastatic derivatives of murine rhabdomyosarcoma and osteosarcoma cell lines. Importantly, they showed that ezrin inhibition significantly reduced the metastatic capability of cell lines in both models. Similarly, the nonmetastatic cells obtained higher metastatic capability by overexpressing wild-type ezrin (9). These data provide compelling evidence for a prometastatic function of ezrin. In line with these studies, associations between increased ezrin immunoreactivity and tumor progression have been reported in some other tumor types, including astrocytoma (15) and melanoma (14). However, data for its prognostic impact is still scarce. Whereas significant correlations between ezrin overexpression and poor clinical outcome have been revealed in osteosarcoma and uveal melanoma (8, 16), the opposite was observed in serous ovarian carcinoma (17). To further investigate the impact of ezrin expression as a prognostic marker in clinical use, we determined ezrin expression using immunohistochemical staining in primary highly malignant STSs and evaluated its expression in relation to patient outcome.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients and tumor materials. This study includes a total of 50 cases (Table 1) identified from all patients treated for a primary STS of high malignancy grade (grade 3 or 4) at the Orthopedics Clinic of the Karolinska University Hospital-Solna between 1986 and 1993 (18). All 50 patients had been retrospectively followed-up from the time of surgery for at least 4 years (mean 90 months, range 50-134 months) or until their death, whereby survival and the occurrence of metastasis and/or local recurrence was recorded. All patients had been operated on with curative intent and were without local or distant metastases at the time of the initial surgery. Moreover, none of the patients had received any preoperative or postoperative adjuvant treatment. Clinical and histopathologic details and immunohistochemical expression of Ki-67, p53, p27, Bcl-2, IGF-IR, and Factor VIII for vessel density have been previously published for cases no. 1 to 50 in ref. (18), and chromosomal copy number alterations analyzed by comparative genomic hybridization were reported in ref. (19) for cases no. 15 to 38 (Table 2).


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  		Table 1. Summary of clinical, histopathologic, and ezrin expression data of the 50 STSs studied

 

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  		Table 2. Ezrin expression in relation to frequent comparative genomic hybridization alterations and immunohistochemical staining data

 
The 50 patients include 24 men (48%) and 26 women (52%) with a mean age at diagnosis of 60 years (range 19-81 years). The primary tumors were located in the lower extremities (n = 33), in the upper extremities (n = 6), in the pelvic area (n = 6), or in the trunk or in the abdominal wall (n = 5). The histopathologic diagnoses were reevaluated by an experienced sarcoma histopathologist who was without knowledge of the clinical course (18). The classification followed established histopathologic criteria and malignancy grading was according to a four-graded scale (3, 6, 7). The material consisted of the following entities: malignant fibrous histiocytoma (n = 34), liposarcoma (n = 7), malignant peripheral nerve sheath tumor (n = 2), synovial sarcoma (n = 1), fibrosarcoma (n = 1), alveolar STS (n = 2), mesenchymoma (n = 1), angiosarcoma (n = 1), and high-grade sarcoma NOS (n = 1).

The time of distant metastasis and local recurrence were recorded separately. For patients with both local recurrence and metastasis, the date of the metastasis was used in the analysis. Patients who had no evidence of disease during follow-up were used as a reference group. Furthermore, patients who were without evidence of disease at the end of follow-up but may have had a local recurrence (three cases) or metastasis (one case) earlier was used as a reference in the survival calculation concerning death from or with disease.

Immunohistochemical analyses. Paraffin-embedded sections of 4-µm thickness were prepared from the primary tumor of all cases, dewaxed, rehydrated, and pretreated with citrate buffer (pH 6) in a microwave oven for 20 minutes. After rinsing, the endogenous peroxidase activity was blocked by treatment with 0.5% hydrogen peroxide for 30 minutes. The sections were then rinsed and incubated with blocking serum (1% bovine serum albumin) for 20 minutes. The primary mouse monoclonal antibody against ezrin (Ab-1; Neomarker, Lab Vision Corporation, CA) was applied (dilution 1:200) onto the sections overnight in a moist chamber at 4°C. A biotinylated anti-mouse IgG was used as secondary antibody and incubated for 30 minutes, followed by rinsing and incubation with avidin-biotin-peroxidase complex (Vectastain, Vector, Peterborough, United Kingdom) for another 30 minutes. The peroxidase reaction was developed using 3,3-diaminobenzidine for 6 minutes. After counterstaining with H&E, the slides were dehydrated and mounted. Paraffin sections from placenta collected after birth and normal mesenchymal tissues from liposarcoma patient were analyzed in parallel as positive and negative controls, respectively.

The immunostaining was scored for all cases by two observers in an open discussion who were without knowledge of the clinical details. First, the ezrin expression was scored as positive or negative. Negative cases included those where no tumor cells showed cytoplasmic immunoreactivity or where only single tumor cells showed immunoreactivity. All cases scored as positive showed ezrin immunoreactivity in the cytoplasm of a subset or all tumor cells. Positive cases were also evaluated concerning the proportion of positively stained cells. A semiquantitative approach was used whereby the tumors were grouped into four classes with 1% to 25%, 26% to 50%, 51% to 75%, or 76% to 100% positively stained cells. For these quantitative analyses, positive cells were only counted in areas with high proportion of tumor cell representativity, whereas areas with necrosis and/or lymphocyte infiltration were excluded to rule out an incorrectly high proportion of positively stained cells.

Statistical analyses. Associations between ezrin expression and patient outcome during follow-up (Table 1) were analyzed by the Kaplan-Meier survival test and the differences were calculated with the log-rank test. Associations between ezrin expression and recurrent disease irrespective of time were determined by {chi}2 analyses. Cox proportional hazard regression model was used for multivariate analyses.

Correlation analyses were done with Spearman rank-order test to compare ezrin expression with previously published (18, 19) clinical, histopathologic, immunohistochemical, and genetic parameters for some or all of the cases (Tables 1 and 2). All calculations were done in Statistica 6.0 software and P < 0.05 was accepted as significant.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
In this study, we evaluated the prognostic impact of ezrin immunohistochemical expression in 50 primary high-grade STSs. The clinical information is detailed for each case in Table 1. Specifically, 28 of the 34 patients who developed recurrence eventually died from the disease (82%). Furthermore, all but one of the patients who only developed metastasis eventually died from the disease (17 of 18; 94%), compared with three of the eight patients with only local recurrence (3 of 8; 38%).

Ezrin immunoreactivity in highly malignant soft tissue sarcomas. Examples of staining results for ezrin immunohistochemistry in normal and tumor tissues are shown in Fig. 1. In normal placenta used as a positive control, strong immunoreactivity was seen in the cytoplasm and cell membrane of trophoblastic cells (Fig. 1A, left). In the negative control, no immunoreactivity was seen in the normal mesenchymal cells (Fig. 1A, right). Inflammatory plasma cells present in both normal and tumor tissues generally expressed ezrin, thus constituting an internal positive control for successful immunohistochemisty (Fig. 1). Ezrin immunohistochemistry was done on 50 primary tumors from patients with high-grade STSs. As detailed in Table 1, a total of 25 STSs (50%) were classified as having positive staining, whereas the other half of cases were scored as negative. The proportion of ezrin-positive tumor cells varied from 1% to 100%, most commonly with a majority of positively stained cells (Fig. 1B). In all STS scored positive, the immunoreaction tended to be homogenous throughout the membrane and cytoplasm of tumor cells (Fig. 1B). It can also be noted that two cases scored as negative exhibited clear ezrin immunoreactivity in the nucleus only (cases no. 15 and 30), which was observed in both the tumor cells and in the normal control cells (illustrated for case no. 15 in Fig. 1C).



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  		Fig. 1. Examples of immunohistochemical staining for ezrin in control tissues (A), ezrin-positive tumors (B), and ezrin-negative tumors (C). A, positive control tissue with strong expression in trophoblastic cells of placenta from a newborn infant, and negative control tissue without immunoreactivity in normal mesenchymal cells (black arrow), together with strong expression in inflammatory cells or/and endothelial cells used as internal positive control. B, positive cytoplasmic immunoreactivity for ezrin in 76% to 100% of the tumor cells for STS case no. 16, and in 51% to 75% of the cells in STS case no. 49. C, STS case no. 41 with no immunoreactivity for ezrin in the tumor cells, together with positive immunoreactivity in inflammatory cell controls and nuclear immunoreactivity for ezrin in tumor cells of STS case no. 15.

 
Association between ezrin immunoreactivity and poor outcome during follow-up. Overall, 21 of the 50 patients were alive at the end of follow-up (42%), whereas 29 patients were dead (58%), which in all but one case was related to recurrence of the disease (Table 1). During follow-up, 26 of the 50 patients had developed metastasis (52%), 16 had been diagnosed with a local recurrence (32%), and 16 remained without any recurrent disease (32%). Twenty-eight of the 34 patients who developed recurrence eventually died from the disease (82%), whereas six were alive without any sign of disease at the end of follow-up (18%). When the ezrin expression status was compared with the development of recurrent disease and patient outcome, several significant associations were observed. These significant associations were observed for positive versus negative ezrin expression and were not influenced by the varying proportion of immunoreactive tumor cells. As illustrated in Fig 2, patients with ezrin-positive tumors were found to develop distant metastases more frequently during follow-up (metastatic disease versus no metastases, n = 50, P = 0.031), and this was still significant if patients with only local recurrence were excluded (metastasis versus disease-free survival, n = 42, P = 0.049). No association was found between ezrin expression and development of local recurrence. Furthermore, this association between ezrin expression and metastases was observed both over time and irrespective of time. Overall, 17 of the 25 ezrin-positive cases developed metastasis compared with only 9 of the 25 negative cases (P = 0.023). In multivariate analyses, ezrin expression was shown to be an independent prognostic marker for development of metastatic disease. As expected from these findings, ezrin expression was also associated with death from disease (P = 0.014) as well as with overall survival (P = 0.007). Furthermore, ezrin expression in the primary tumor was, in multivariate analysis, identified as an independent prognostic marker of poor survival (disregarding metastasis as they were not present at diagnosis but developed during follow-up).



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  		Fig. 2. Kaplan-Meier plots illustrating significant associations between positive ezrin immunoreactivity and development of metastasis versus no metastasis (A), development of metastasis versus no recurrent disease during or at the end of follow-up (B), shorter disease-related survival (death from or with disease versus no evidence of disease; C), and shorter overall survival (dead versus alive; D).

 
Correlations between ezrin immunoreactivity and tumor characteristics. Clinical and histopathologic characteristics previously determined (18) for the 50 primary STSs (Table 1) were compared with ezrin immunohistochemical expression in correlation analyses. No significant correlations were observed for the clinical parameters (sex, size, site, and depth) or for the histopathologic parameters (malignancy grade, necrosis, and mitoses). Also, no correlation was identified with previously published (18) immunohistochemical expression of Ki-67, p53, p27, Bcl-2, IGF-IR, or Factor VIII (i.e., antigens involved in the proliferation, differentiation, angiogenesis, and apoptotic processes; Table 2). However, ezrin expression was significantly correlated with infiltrative growth pattern outside the tumor capsule (R = 0.31, P = 0.03). Among genetic abnormalities previously determined by comparative genomic hybridization in a subset of the cases (19), we could observe a strong correlation between ezrin expression and copy number gain of chromosomal region 9cen-q22 (R = 0.47, P = 0.02), but not to other recurrent comparative genomic hybridization abnormalities (Table 2).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Our findings show that high ezrin expression in the primary tumor of initially metastasis-free STS patients is strongly associated with development of metastases during follow-up and consequently also with poor survival. Similarly, significant correlations between ezrin expression and malignancy as well as poor survival had been shown in several other cancer types, including astrocytoma (15), melanoma (14, 16), osteosarcoma, and rhabdomyosarcoma (8, 9). However, an adverse correlation was found in serous ovarian carcinomas (17). In addition, high ezrin expression was also noted in cancer precursor lesions of endometrial and prostate adenocarcinomas (20–22). Based on these findings, it is likely that ezrin can promote tumor metastasis in some tumor types, whereas its role in precursor lesions remains to be determined. Notably, ezrin overexpression has been revealed in all studies of high-grade sarcomas reported thus far. The available data suggest that ezrin immunoreactivity could be valuable as an additional prognostic marker in highly malignant STSs. To further assess this, the ezrin expression status was combined with other parameters of poor prognosis in the same material. Indeed, the association with metastasis was considerably stronger when ezrin expression was combined with a large tumor size or high mitotic count compared with tumor size and mitotic count alone (data not shown).

The exact mechanism by which ezrin contributes to tumor dissemination remains to be described. When ezrin and other ezrin-radixin-moesin proteins are activated, they interact with membrane proteins and the actin cytoskeleton and can thus affect processes such as migration, invasion, adhesion, and survival of the cell (23). These processes are all important for establishment and progression of cancer. In agreement with these functions of ezrin, we found a significant correlation between ezrin expression and infiltrative growth pattern of the STS.

A strong and significant correlation was also observed between ezrin expression and copy number gain of chromosomal region 9cen-q22, an alteration previously found as a late event in genetic progression of these tumors (19). However, copy number gain of the 6q25.2-26 interval encompassing the villin 2 (ezrin) gene was rarely seen and was not correlated with expression of ezrin. Similar findings were reported for prostate cancer where no amplification or deletion of villin 2 was revealed by fluorescence in situ hybridization analysis in samples with strong ezrin immunoreactivity (22). In cDNA expression array analysis of gastrointestinal stromal cell tumors, high ezrin expression has been observed on the RNA level (24). This would imply a regulatory effect, an epigenetic alteration, or an activating chromosomal mutation as underlying the increased ezrin expression.

In conclusion, we have shown a significant association between ezrin immunoreactivity in primary high-grade STSs and poor outcome in terms of survival and development of metastasis. The findings thus expand the spectra of sarcomas where ezrin is related to metastasis from specific pediatric sarcomas to also include the more frequent adult STSs. The relative abundance of metastasis in ezrin-positive cases was observed both over time and irrespective of time. This suggests that ezrin has a crucial role in the tumor dissemination and that ezrin functions are good targets for new therapy strategies.


   Acknowledgments
 
We thank Dr. See-Tong Pang, Margareta Rodensjö, and Lisa Åhnfalk for excellent suggestions on the study and on the immunohistochemical technique as well as for help with sample collection.


   Footnotes
 
Grant support: Swedish Cancer Foundation, Swedish Research Council, Cornell Foundation, Stockholm County Council, and Cancer Society in Stockholm.

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.

Received 3/10/05; revised 5/17/05; accepted 6/ 2/05.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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