GLUT-1 expression in mesenchymal tumors: an immunohistochemical study of 247 soft tissue and bone neoplasms

Summary

GLUT-1, an erythrocyte-type glucose transporter protein expressed in juvenile hemangiomas, has recently been shown to be a sensitive marker of perineurial cells and their tumors in a small number of cases. However, GLUT-1 expression has not been systematically examined in other mesenchymal neoplasms. Prompted by a recent report of GLUT-1 expression in epithelioid sarcoma, a tumor not generally felt to show perineurial differentiation, we examined GLUT-1 expression in a wide variety of mesenchymal tumors. Sections from 247 mesenchymal tumors of a variety of histologic subtypes were retrieved from our archives and immunostained for GLUT-1 using heat-induced epitope retrieval and the DAKO ADVANCE detection system (DAKO, Carpinteria, CA). Scoring was as follows: negative (<5% of cells), 1+ (5%-25% of cells), 2+ (25%-50% of cells), and 3+ (>50% of cells). All benign nerve sheath tumors showed a peripheral rim of positive normal perineurial cells, with 2 neurofibromas and 3 schwannomas showing more extensive staining. Three of 4 perineuriomas showed strong GLUT-1 expression. All juvenile hemangiomas were GLUT-1 positive. GLUT-1 expression was also seen in a wide variety of benign and malignant mesenchymal tumors. However, GLUT-1 expression was absent in nonjuvenile hemangioma endothelial tumors and in almost all low-grade lesions that enter the histologic differential diagnosis of perineurial tumors, including low-grade fibromyxoid sarcoma, dermatofibrosarcoma protuberans, and myxofibrosarcoma. We conclude that GLUT-1 expression in mesenchymal tumors is by no means specific for perineurial differentiation, but may instead represent upregulation of this protein within hypoxic zones, secondary to upstream activation of proteins such as hypoxia-inducible factor 1-α.

Introduction

GLUT-1 is an erythrocyte-type glucose transporter protein and a member of the facilitative cell-surface glucose transporter family which includes 5 other isoforms [1]. It was originally purified from human erythrocyte membranes [2] and has been subsequently identified in the brain capillary endothelium, where it plays a critical role in the transport of glucose across the blood-brain barrier [3]. In addition to its role as a glucose transporter, GLUT-1 is also known to play an important role in the cellular response to hypoxia, as a downstream target of hypoxia-inducible factor 1-α (HIF1-α) [4]. Constitutive GLUT-1 expression has been documented in a variety of normal cell types, including placental trophoblast and perineurial cells [5], [6]. Upregulation of GLUT-1 expression, presumably due to enhanced glycolytic metabolism, has recently been shown to be a relatively common feature in various carcinomas [7].

In mesenchymal neoplasms, expression of GLUT-1 has been shown to be a constant feature of juvenile capillary hemangiomas, where its expression is useful in the discrimination of such tumors from various mimics, such as vascular malformations and kaposiform hemangioendothelioma [8], [9], [10], [11]. GLUT-1 expression has also been noted in a subset of soft tissue perineuriomas, consistent with its expression in normal perineurium [12], [13], [14]. Most recently, Smith et al [15] have documented GLUT-1 expression in a small number of epithelioid sarcomas and have suggested that this observation supports the concept of perineurial differentiation in this otherwise enigmatic sarcoma.

We undertook a large, retrospective study of GLUT-1 expression in a broad variety of mesenchymal tumors with the goal of better establishing the range of GLUT-1 expression in mesenchymal tumors.