The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles

Abstract

The cell type and localization of vascular endothelial growth factor (VEGF)-producing cells in human radiation necrosis (RN) are investigated from a histopathological and immunohistochemical standpoint using clinical specimens. Eighteen surgical specimens of symptomatic RN in the brain were retrospectively reviewed. These cases included different original histological tumor types and were treated with different radiation modalities. Histological analyses were performed using hematoxylin and eosin (H&E) staining, and anti-VEGF and anti-hypoxia-inducible factor (HIF)-1α immunohistochemistry. H&E staining showed marked angiogenesis and reactive astrocytosis at the perinecrotic area. The most prominent vasculature in this area was identified as telangiectasis. Immunohistochemistry indicated that HIF-1α was expressed predominantly in the perinecrotic area and that a large majority of VEGF-expressing cells were reactive astrocytes intensively distributed in this area. VEGF produced by the reactive astrocytes localized mainly in the perinecrotic area might be a major cause of both angiogenesis and the subsequent perilesional edema typically found in RN of the brain. The benefits of anti-VEGF antibody (bevacizumab) treatment in RN may be that VEGF secretion from the perinecrotic tissue is inhibited and that surgery would remove this tissue; both of these benefits result in effective reduction of edema associated with RN.

Single dose bevacizumab as treatment for symptomatic, corticosteroid-refractory pseudoprogression after chemoradiation therapy for newly diagnosed glioblastoma: A case report

“…There is no obvious histological difference between RN and pseudoprogression, with necrosis being the central feature of both [21,22]. In addition, RN is also characterized by marked enhancement in the tumor bed but without actual tumor, like pseudoprogression.…”

“…In contrast, RN often shows severe symptoms and occurs at least 6 months following radiotherapy, can be long lasting, and improves only with intensive therapy such as surgery or bevacizumab administration [23,24]. Human surgical specimens of RN have been shown to exhibit overproduction of VEGF in reactive astrocytes in the perinecrotic area, resulting in leaky angiogenesis with perifocal edema [22]. Bevacizumab would serve to neutralize this overproduced VEGF and subsequently reduce the associated edema [19,20].…”

Laser Interstitial Thermal Therapy for Radiation Necrosis/Adverse Inflammatory Responses to SRS - Case Report and Literature Review

“…The resulting edema promotes perilesional hypoxia, driving HIF-1α expression [35] and stimulating a VEGF feedback loop, perpetuating a cycle of edema. Surgical resection of the perinecrotic contrast-enhancing zone in AIRS has been shown to often result in radiographic and clinical improvement [36]; in the case of LITT, the goal of treatment is transformation of the perinecrotic zone into an area of inactive, factor-depleted coagulative necrosis [33].…”

“…The resulting edema promotes perilesional hypoxia, driving HIF-1α expression [35] and stimulating a VEGF feedback loop, perpetuating a cycle of edema. Surgical resection of the perinecrotic contrast-enhancing zone in AIRS has been shown to often result in radiographic and clinical improvement [36]; in the case of LITT, the goal of treatment is transformation of the perinecrotic zone into an area of inactive, factor-depleted coagulative necrosis [33].In this case, surgical extirpation would have alleviated the mass effect directly, with the additional benefit of offering a histologic diagnosis. However, the lesion was in the superior frontal gyrus, within the supplemental motor area and abutting motor cortex; the associated edema can be seen infiltrating hand motor cortex (Fig.…”

The Role of Bevacizumab in the Management of Head and Neck Squamous Cell Carcinoma Patients

“…Although classically characterized as an angiogenic factor, VEGF also potentiates capillary permeability [8]. Nonoguchi et al showed overexpression of VEGF in resected radiation necrosis lesions [9]. Furthermore, degree of radiation injury has been correlated with amount of VEGF expression [10].…”