Expression of hypoxic markers and their prognostic significance in soft tissue sarcoma

Abstract

Tumor hypoxia is significant in promoting tumor progression and resistance to therapy, and hypoxia-inducible factor 1α (HIF-1α) is essential in the adaptive response of cells to hypoxia. The aim of the present study was to investigate the expression of hypoxic markers and evaluate their prognostic significance in soft tissue sarcoma (STS). A retrospective analysis of 55 patients with STS from Pusan National University Hospital (Busan, Korea) between 1998 and 2007 was conducted, using immunohistochemistry to analyze the expression of HIF-1α, carbonic anhydrase 9 (CA9), glucose transporter-1 (GLUT1) and vascular endothelial growth factor (VEGF). The association between the overexpression of these markers and clinicopathological characteristics, including the overall survival (OS) and progression-free survival (PFS) in cases of STS, were investigated. Overexpression of HIF-1α, CA9, GLUT1 and VEGF was shown in 54.5, 32.7, 52.7 and 25.5% of tumors, respectively, and all exhibited a significant association with high French Federation of Cancer Centers (FNCLCC) grade and high American Joint Committee on Cancer (AJCC) stage. Overexpression of HIF-1α and CA9 was associated with a shorter OS and a shorter PFS. On multivariate analysis, AJCC stage and HIF-1α overexpression had independent prognostic significance. In the group receiving chemotherapy (n=27), HIF-1α overexpression was independently associated with a decreased OS. These results indicate that overexpression of HIF-1α and CA9 is associated with poor prognosis, and that HIF-1α overexpression is an independent unfavorable prognostic factor in STS.

Keywords: carbonic anhydrase 9; glucose transporter-1; hypoxia; hypoxia-inducible factor 1α; soft tissue sarcoma; vascular endothelial growth factor.

Figure 1

Immunohistochemical staining of HIF-1α, CA9, GLUT1 and VEGF in high grade soft tissue sarcoma. Representative cases are shown: (A) HIF-1α (magnification, ×200); (B) CA9 (magnification, ×200); (C) GLUT1 (magnificiation, ×200) and (D) VEGF (magnification, ×200). HIF-1α, hypoxia-inducible factor 1α; CA9, carbonic anhydrase 9; GLUT1, glucose transporter-1; VEGF, vascular endothelial growth factor.

Figure 2

Expression pattern of CA9 and GLUT1 immunostaining: (A) Perinecrotic CA9 expression in MFH (magnification, ×40); (B) diffuse CA9 expression in LMS (magnification, ×40); (C) perinecrotic GLUT1 expression in MFH (magnification, ×40) and (D) diffuse GLUT1 expression in LMS (magnification, ×40). CA9, carbonic anhydrase 9; GLUT1, glucose transporter-1; MFH, malignant fibrous histiocytoma; LMS, leiomyosarcoma.

Figure 3

Kaplan-Meier survival curves showing disease-free survival and overall survival for soft tissue sarcoma patients with HIF-1α and CA9 expression. HIF-1α, hypoxia-inducible factor 1α; CA9, carbonic anhydrase 9; FU, follow-up; DFSP, disease-fee survival period.