Pseudo-hemorrhagic region formation in pancreatic neuroendocrine tumors is a result of blood vessel dilation followed by endothelial cell detachment

Aberrant blood vessel formation and hemorrhage may contribute to tumor progression and are potential targets in the treatment of several types of cancer. Pancreatic neuroendocrine tumors (PNETs) are highly vascularized, particularly when they are well-differentiated. However, the process of vascularization and endothelial cell detachment in PNETs is poorly understood. In the present study, 132 PNET clinical samples were examined and a special type of hemorrhagic region was observed in ~30% of the samples regardless of tumor subtype. These hemorrhagic regions were presented as blood-filled caverns with a smooth boundary and were unlined by endothelial cells. Based on the extensive endothelial cell detachment observed in the clinical samples, the formation process of these blood-filled caverns was hypothesized. Blood vessel dilation followed by detachment of endothelial cells from the surrounding tumor tissue was speculated. This was further supported using an INS-1 xenograft insulinoma model. As the formation process was distinct from the typical diffusive hemorrhage, it was named ‘pseudo-hemorrhage’. Furthermore, it was demonstrated that epithelial (E-) cadherin and β-catenin were overexpressed in tumor cells surrounding these pseudo-hemorrhagic regions. Therefore, even though no statistically significant association of pseudo-hemorrhage with clinical features (metastasis or disease recurrence) was identified, the high levels of E-cadherin and β-catenin expression may suggest that a number of features of normal islet cells are retained.