RESEARCH ARTICLE: Intravascular Thrombosis in Central Nervous System Malignancies: A Potential Role in Astrocytoma Progression to Glioblastoma

Abstract

The presence of necrosis within a diffuse glioma is a powerful predictor of poor prognosis, yet little is known of its origins. Intravascular thrombosis is a frequent finding in glioblastoma [GBM; World Health Organization (WHO) grade IV] specimens and could potentially be involved in astrocytoma progression to GBM or represent a surrogate marker of GBM histology. We investigated whether intravascular thrombosis was more frequent or prominent in GBM than other central nervous system (CNS) malignancies and considered its prognostic significance in anaplastic astrocytoma (AA; WHO grade III), which lacks necrosis. Histologic sections were examined for thrombosis, necrosis and microvascular hyperplasia from each of 297 CNS tumors, including 103 GBMs, 46 AAs, 20 diffuse astrocytoma (DAs; WHO grade II), eight anaplastic oligodendrogliomas (AOs; WHO grade III), 20 oligodendrogliomas (ODs; WHO grade II), 49 metastatic carcinomas (METs), 31 primary central nervous system lymphomas (PCNSLs) and 20 medulloblastomas (MBs). Among newly diagnosed tumors, thrombosis was present in 92% of GBM resections, significantly greater than other types of CNS malignancies. Of tumors with thrombosis, GBMs had a higher frequency of affected vessels than AAs, DAs, AOs, ODs and MBs, but had a frequency similar to METs and PCNSLs. The sensitivity of thrombosis for the diagnosis of GBM in this set of tumors was 92% and the specificity was 91%. Intravascular thrombosis was uncommon in AAs and was only noted in stereotactic biopsies. This subset of patients had shorter survivals than those AAs without thrombosis. Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior.

Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model

“…The mechanisms responsible for this abrupt onset of rapid growth are still being defined but are likely associated with the development of necrosis and intense angiogenesis, which are two A B defining features of GBM histology and powerful predictors of poor prognosis (15,34). Almost all GBM specimens show microscopic intravascular thrombosis within tissue specimens and this event has been documented as an additional distinguishing pathological feature of GBM compared with lower grade astrocytoma (35). Furthermore, necrosis and subsequent hypoxia-induced angiogenesis may be initiated or propagated by intravascular thrombosis.…”

Identification of blood protein biomarkers that aid in the clinical assessment of patients with malignant glioma

“…Neuronal and glioma-derived SCF can induce angiogenesis within the brain (28). Factor VII is a central protein in the blood coagulation cascade, and thrombosis frequently found in GBM (29). Expression of tissue factor, the cell surface receptor for factor VII, correlates with histologic grade of human glioma malignancy and vascularity (30).…”

Hypoxia Helps Glioma to Fight Therapy

“…These densely packed tumour cells surrounding a necrotic area are not a result of hyper-proliferation or resistance to apoptosis, but represent hypoxic astrocytoma cells with enhanced MMP-2 and MMP-9 activity and a low proliferation rate, which have migrated away from a hypoxic/anoxic focus triggered by intravascular thrombosis [17,18]. In a large histological analysis intravascular thrombosis was found in 92% of all primary resections of GBMs (88 cases), whereas it was uncommon in anaplastic astrocytomas (grade III) [19]. One of the strongest pro-thrombotic proteins is tissue factor, which is highly upregulated in malignant astrocytomas and its expression is correlated with tumour grade [20][21][22].…”