Blood-Brain Barrier Alterations and Edema Formation in Different Brain Mass Lesions

Abstract

Differential diagnosis of brain lesion pathologies is complex, but it is nevertheless crucial for appropriate clinical management. Advanced imaging methods, including diffusion-weighted imaging and apparent diffusion coefficient, can help discriminate between brain mass lesions such as glioblastoma, brain metastasis, brain abscesses as well as brain lymphomas. These pathologies are characterized by blood-brain barrier alterations and have been extensively studied. However, the changes in the blood-brain barrier that are observed around brain pathologies and that contribute to the development of vasogenic brain edema are not well described. Some infiltrative brain pathologies such as glioblastoma are characterized by glioma cell infiltration in the brain tissue around the tumor mass and thus affect the nature of the vasogenic edema. Interestingly, a common feature of primary and secondary brain tumors or tumor-like brain lesions characterized by vasogenic brain edema is the formation of various molecules that lead to alterations of tight junctions and result in blood-brain barrier damage. The resulting vasogenic edema, especially blood-brain barrier disruption, can be visualized using advanced magnetic resonance imaging techniques, such as diffusion-weighted imaging and apparent diffusion coefficient. This review presents a comprehensive overview of blood-brain barrier changes contributing to the development of vasogenic brain edema around glioblastoma, brain metastases, lymphomas, and abscesses.

Keywords: blood-brain barrier; brain abscess; brain edema; brain lymphoma; brain metastasis; glioblastoma multiforme.

FIGURE 1

GBM microvasculature. Different microvasculature types detected in GBM, including vascular clusters, glomeruloid vascular proliferations, vascular garlands, and vascular mimicry. Vascular mimicry, unlike other microvascular types, shows a lumen lined by tumor cells.

FIGURE 2

Vascular morphology. Microvascular proliferations at the invasive edge of GBM—(A) glomeruloid vascular proliferation (white arrow) and vascular garlands (black arrows). (B) CD31 expression in a vascular garland seen by immunohistochemistry. (C) Metastasis of clear cell renal cell carcinoma to the brain seen on the right side surrounded by microvascular proliferation (arrow). (D) Pulmonary non-mucinous adenocarcinoma metastatic to the brain (bottom left corner) surrounded by multiple glomeruloid microvascular proliferations (arrows). (E) Perivascular infiltration of the PCNSL intermingled with reactive lymphocytes forming vascular cuffs. (F) Reticulin-specific stain highlights the complex reticulin web encompassing the tumor cell caused by neoplastic lymphoid cells penetrating through the vascular wall. (G) Vessels in acute abscess in the brain with leukostasis and neutrophil transmigration across the BBB. H, vessels in chronic abscess display reactive pericytes prominently (white arrows), and no microvascular proliferations are seen. Panels (A–D) magnification 100x, panels (E–H) magnification 400x.

FIGURE 3

Disruption of the blood-brain barrier in glioblastoma. GBM cells infiltrate the perivascular space with subsequent astrocytic end-feet displacement. Tumor, stromal, and immune cells occupy a specific tumor niche with a diverse proteomic profile but most importantly show upregulated VEGF and TGF-ß. VEGF binds to its receptor on endothelial cells leading to increased transendothelial permeability and downregulation of specific TJs (e.g., claudin-5, occludin, and ZO-1) and subsequent increased paracellular influx. Matrix metalloproteinases, most importantly MMP-9, that are secreted by tumor cells contribute to the disruption of the basal membrane by cleaving the ECM. Inset shows a more detailed view of the transcellular and paracellular movements across the BBB. The endothelium forms the inner layer of the BBB. GBM promotes a “leaky” phenotype in endothelial cells with increased transcellular transport and endothelial fenestrations. Additionally, down-regulation of TJs leads to increased paracellular transport with subsequent edema formation.

FIGURE 4

Disruption of the peritumoral blood-brain barrier in brain metastasis. Expression of VEGF and SH/VEGF by metastatic cells leads to alteration in TJ proteins such as occludin, claudin-1, and claudin-5 resulting in increased paracellular water influx. In addition to metastatic cells, tumor-infiltrating lymphocytes contribute to the production of VEGF as well as some cytokines including IL-2. Degradation of TJ proteins and the basal membrane is also potentiated by increased expression of matrix metalloproteinases such as MMP-2 and MMP-9. Activation of metalloproteinases is induced by overexpression of ET-1, which leads to up-regulation of ROS and eNOS. Increased expression of AQP4, a part of the glymphatic system on astrocytic endfeet around metastatic lesions, contributes to the development of vasogenic edema by the accumulation of CSF into the brain interstitium.

FIGURE 5

Development of primary CNS lymphoma. Progression of PCNSL (clockwise from top). Initially, neoplastic lymphoid cells accumulate within the vascular wall of arteries and venules fragmenting the reticular fiber network. The outer vascular layer with the glial end-feet maintains an impermeable barrier preventing tumor cells from infiltrating the brain tissue. Later, tumor cells fragment the outer layer and infiltrate brain tissue, where multiple reactive astrocytes can be detected. Endothelial cells undergo regressive as well as reparative changes throughout, leading to disruption of the endothelial lining.

FIGURE 6

Molecular and cellular changes in the blood-brain barrier around brain abscess. Bacteria and other microorganisms in brain abscess release PAMPs that are recognized by TLR2 on astrocytes and microglia. Activation of TLR2 receptors leads to increased expression of various cytokines and chemokines, including TNF-α, IL-1β, IL-12, and MIP-2. These pro-inflammatory molecules increase the expression of adhesion molecules such as ICAM-1 and VCAM-1 that interact with integrins (LFA-1 and VLA-4) on immune cells and thus potentiate the transfer of leukocytes across the BBB. The pro-inflammatory molecules, as well as ROS, lead to increased expression and activation of matrix metalloproteinases resulting in disruption of TJ proteins. The formation of ROS is potentiated by metal ions, mainly potassium, zinc, and copper, that are released from the abscess. Moreover, decreased expression of TJ proteins such as claudin-5 and occludin is also potentiated by increased expression of VEGF from reactive astrocytes.