Expression and Diagnostic Significance of Clinical Routine VMAT2 Immunostaining in Neuroendocrine Neoplasia: A Study of Institutional Cases

Vesicular monoamine transporter 2 (VMAT2) is an integral membrane protein that packages monoamines, including dopamine, norepinephrine, serotonin, and histamine, into synaptic vesicles. VMAT2 is normally expressed in sympathetic, enteric, and central nervous system neurons and in neuroendocrine cells. Although VMAT2 immunoreactivity was originally reported in a wide range of neuroendocrine neoplasms (NENs), its diagnostic value has been largely overlooked in recent practice due to reliance on established markers such as chromogranin A (CgA), synaptophysin (SYP), and the transcription factors ISLET1 and INSM1. To reassess the relevance of VMAT2, we evaluated its expression relative to CgA, SYP, ISLET1, and INSM1 in 60 consecutively diagnosed NENs from diverse anatomic sites and tumor grades. VMAT2 was positive in 37 of 39 (95%) well-differentiated neuroendocrine tumors (NETs; grades 1-3), in all adrenal paragangliomas (7 of 7) and in one medullary thyroid carcinoma, showing sensitivity comparable to CgA and INSM1 and slightly lower than SYP. VMAT2 was detected in 7 of 12 (58%) neuroendocrine carcinomas. Sensitivity was highest in small-intestinal and gastric NETs and more variable in pancreatic NETs. These results support VMAT2 as a robust, differentiation-linked neuroendocrine marker whose inclusion in modern immunohistochemical panels may improve diagnostic accuracy.