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Abstract
Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been examined for PitNETs. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is strongly associated with the tumor immune microenvironment. In the present study, these molecular and histopathological characteristics were examined in invasive non-functional PitNETs (NF-PitNETs). Twenty-seven patients with newly diagnosed NF-PitNETs (with CS invasion: 17, without CS invasion: 10) were analyzed by immunohistochemistry for VEGF-A/VEGFR1 and 2, hypoxia-inducible Factor (HIF), tumor-infiltrating lymphocytes, immunosuppressive cells including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and immune checkpoint molecules. Previously validated tumor proliferation markers including mitotic count, Ki-67 index, and p53 were also analyzed for their expressions in NF-PitNETs. VEGF-A and VEGFR1 were expressed on not only vascular endothelial cells, but also on tumor cells. The expressions of VEGF-A and VEGFR1 were significantly higher in NF-PitNETs with CS invasion. The number of TAMs and the expression of PD-L1 were also significantly higher in NF-PitNETs with CS invasion than in NF-PitNETs without CS invasion. The high expression of VEGF-A and VEGFR1 and associated immunosuppressive microenvironment were observed in NF-PitNETs with CS invasion, suggesting that a novel targeted therapy can be applied.
Highlights
Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that arise from the pituitary gland [1]
After tissue sections were deparaffinized and rehydrated, antigen retrieval was performed in citrate buffer (Ki-67, p53, VEGFR1, CD34, Foxp3, CD163, CD3, CD4, and programmed cell death-1 (PD-1)), or in Tris buffer using microwave irradiation or autoclave (HIF-1α and programmed cell death ligand-1 (PD-L1))
Our data suggested that vascular endothelial growth factor (VEGF)-A/VEGFR1 expressions could be associated with cavernous sinus (CS) invasion
Summary
Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that arise from the pituitary gland [1]. The development of transnasal endoscopic surgery has improved the surgical outcomes in patients with PitNETs. PitNETs often invade into the surrounding cavernous sinus (CS), making them difficult to remove entirely. Radiation therapy including gamma knife is performed for residual tumors [2], it is onerous to protect essential structures including the optic nerve and internal carotid artery around the sella turcica. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is a potent activator of angiogenesis that is known to correlate with disease progression and hemorrhage in PitNETs [3,4]. The difference in the status of VEGF/VEGFR signaling remains controversial. Niveiro et al [3] demonstrated that the lowest protein level of VEGF-A was detected in prolactin-secreting
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