Von Hippel-Lindau (
VHL) syndrome is an inherited
cancer syndrome in which 8-17 % of germline mutation carriers develop pancreatic
neuroendocrine tumors (
PNETs). There is limited data on prognostic markers for
PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the
tumorigenesis of
PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated
PNETs. The
protein expression of eight genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3,
VEGF, and TP53) was analyzed in
PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of
phosphatase and
tensin (PTEN),
chromogranin A (CHGA), and
alpha thalassemia/
mental retardation syndrome X-linked (ATRX) were significantly different by WHO classifications (p ≤ 0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p < 0.01) and decreased CHGA nuclear expression (p = 0.03) in malignant samples as compared to benign. Lower cytoplasmic
chromogranin B (CHGB) expression (p = 0.03) was associated with malignant
tumors and
metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p = 0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p < 0.05). Cytoplasmic expression of CC-3 was associated with higher serum
chromogranin A levels (ρ = 0.72, p = 0.02). Lastly, greater cytoplasmic expression of p53 was associated with
metastasis. Our findings suggest that altered PTEN, ATRX, CHGA, and CHGB expression are associated with aggressive
PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in
PNETs.