Pheochromocytomas with Aggressive Histopathological Features Have Reduced Apelin and Increased VEGF Expression: Diagnostic and Prognostic Implications

Background: Pheochromocytoma is a highly vascular neuroendocrine tumor with variable biological behavior. Reliable biomarkers reflecting tumor aggressiveness remain limited. This study evaluated apelin and vascular endothelial growth factor (VEGF) expression in pheochromocytoma and their associations with histopathological prognostic parameters. Methods: This retrospective single-center study included 20 pheochromocytoma patients and 18 normal adrenal medulla controls. Apelin and VEGF expression were evaluated immunohistochemically using the immunoreactivity score (IRS). Associations between IRS values and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score, Ki-67 index, tumor size, clinicopathological characteristics, and individual PASS components were analyzed. Results: Apelin IRS was significantly lower in pheochromocytoma than in normal adrenal medulla (median 0 vs. 4, p = 0.001), whereas VEGF IRS was significantly higher (median 6 vs. 2, p < 0.001). Tumors with PASS ≥ 4 had significantly lower apelin IRS than those with PASS < 4 (p = 0.001). Apelin IRS was inversely correlated with PASS (r = −0.874, p < 0.001), GAPP score (r = −0.618, p = 0.004), and Ki-67 (r = −0.560, p = 0.010). Lower apelin expression was also associated with diffuse growth pattern, central/confluent necrosis, and tumor cell spindling. VEGF IRS showed no significant association with PASS, GAPP score, Ki-67, tumor size, or individual PASS components. Conclusions: Reduced apelin immunoreactivity was associated with unfavorable histopathological features in pheochromocytoma, whereas increased VEGF immunoreactivity was not associated with the evaluated histopathological risk parameters. These exploratory findings suggest that apelin may be a candidate tissue marker; however, its clinical and prognostic relevance requires further investigation in larger multicenter studies.