Navigating the blood-brain barrier to blood-brain tumor barrier transition: microvascular P-glycoprotein and CD146 potentially contribute to glioma grading.

Background: Adult-type diffuse gliomas are highly vascular malignant tumors of the central nervous system (CNS), classified according to the 2021 WHO CNS criteria. Their neovasculature arises through both angiogenesis and vascular co-option, generating heterogeneous microvascular patterns, often associated with microvascular proliferations (MVPs). The transition from an intact blood-brain barrier (BBB) to a dysfunctional blood-brain tumor barrier (BBTB) involves progressive disruption of the neurovascular unit (NVU), yet the phenotypic identity of tumor-associated endothelial cells (ECs) remains poorly characterized.

Methods: We investigated the endothelial phenotype in 22 adult-type diffuse gliomas (glioblastoma, astrocytoma grade 4 and 3, oligodendroglioma grade 3 and 2) by immunohistochemical analysis of two EC markers: P-glycoprotein (P-gp), a transporter associated with mature BBB phenotype, and CD146, an adhesion molecule linked to immature, mesenchymal-like ECs. Expression was assessed in the vascular endothelium, perivascular, and extravascular compartments using both qualitative evaluation and morphometric quantification on digital slides.

Results: Our findings revealed heterogeneous expression patterns of P-gp and CD146 among glioma subtypes. P-gp expression decreased progressively from oligodendrogliomas to glioblastomas, in line with increasing vascular dedifferentiation. Conversely, CD146 expression was higher in high-grade tumors, particularly in proliferating vessels and perivascular regions. These opposing trends reflected a gradual phenotypic shift from BBB-like to BBTB-like microvasculature, correlating with tumor histotype and grade.

Conclusion: P-gp and CD146 represent complementary markers of endothelial identity in gliomas and may serve as histopathological indicators of BBB integrity and tumor vascular remodeling. Their combined evaluation offers a novel insight into the BBB-BBTB transition and may support microvascular phenotyping as an adjunct criterion for glioma grading.