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

Abstract

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.

Phosphorylated ezrin is located in the nucleus of the osteosarcoma cell

“…We observed that immunohistochemical detection of ezrin is not statistically associated with poor prognosis as reported for other cancer types, such as uveal malignant melanoma, 31 high-grade soft tissue tumors, 32 or recently found in osteosarcomas. 2 However, the patients with ezrin expression in primary tumors have a worse prognosis for survival.…”

Ezrin overexpression in gastrointestinal stromal tumors: an independent adverse prognosticator associated with the non-gastric location

“…[17][18][19][20][21][22] Although this adverse prognostic effect has been established in human malignant neoplasms derived from both epithelial and mesenchymal origins, exceptions to this general rule were occasionally reported, suggesting that there may be cellspecific functions for ezrin in tumor progression. [17][18][19][20][21][22] For instance, the loss of ezrin expression in serous ovarian carcinomas was shown to be associated with poor survival. 34 Moreover, unlike osteosarcomas and adult high-grade sarcomas, ezrin overexpression was recently found not predictive of clinical outcomes in synovial sarcoma.…”

“…In this regard, this 38,39 Through the modulation of diverse actin-based functions, ezrin is known as a key component of the molecular chain connecting the metastasis-associated cell surface proteins with the signal transduction network. [17][18][19][20][21][22] What remain less clear for this pathogenetic role of ezrin are the crucial elements of its various downstream effectors, which may vary among different tumor types. In the murine model of rhabdomyosarcoma, the prometastatic activity of ezrin was recently substantiated to be mediated in part through the Rho family of small G proteins, consistent with the firmly established reciprocal relationship between the ERM proteins and Rho activity.…”

“…[14][15][16] There is mounting evidence that elevated ezrin expression through transcriptional upregulation accounts for the high metastatic propensity in a variety of epithelial and mesenchymal malignancies. [17][18][19][20][21][22] Among the latter, ezrin overexpression is not only involved in the dissemination of pediatric rhabdomyosarcomas and osteosarcomas but is also highly associated with the adverse outcome in common adult soft-tissue sarcomas. 17,19,22 More intriguingly, two recent studies using cDNA expression microarrays have identified ezrin as a frequently upregulated gene in GISTs and presumptively indicated its associations with distinct RTK mutation subtypes and tumor progression, respectively.…”

“…[17][18][19][20][21][22] Among the latter, ezrin overexpression is not only involved in the dissemination of pediatric rhabdomyosarcomas and osteosarcomas but is also highly associated with the adverse outcome in common adult soft-tissue sarcomas. 17,19,22 More intriguingly, two recent studies using cDNA expression microarrays have identified ezrin as a frequently upregulated gene in GISTs and presumptively indicated its associations with distinct RTK mutation subtypes and tumor progression, respectively. 23,24 However, the status and significance of ezrin expression have never been systematically assessed in a large, well-characterized cohort of human GIST specimens.…”