PROX1 expression in gastric cancer: from hypothesis to evidence

PROX1 is involved in cancer development and progression as both a tumor suppressor and oncogene. Immunohistochemical (IHC) PROX1 nuclear expression is a widely accepted pattern. Scattered data reported PROX1 IHC cytoplasmic expression in different tumors, including gastric cancer but it is not clear if this holds true.

Evaluation of the cytoplasmic expression of PROX1 in normal gastric mucosa and gastric cancer was performed by IHC followed by RNAscope, an in situ hybridization-based method for detecting PROX1 mRNA amplification on paraffin-embedded samples and to evaluate its clinical impact.

Twenty five out of 48 cases of gastric cancer showed PROX1 nuclear and cytoplasmic immunohistochemical expression. Twelve out of these 20 cases positive for PROX1 on IHC (54.5%) had PROX1 mRNA gene amplification. The overlapping of PROX1 cytoplasmic expression assessed by immunohistochemistry and cytoplasmic RNAscope amplification was statistically significant (p=0.031). PROX1 mRNA gene amplification correlated with tumor grade (p=0.05) and regional lymph node metastasis as well (p=0.033). No significant correlation was obtained between PROX1 and histopathology, tumor size or distal metastasis.

A significant correlation was found between IHC and RNAscope PROX1 expression in the cytoplasm of normal and gastric cancer cells. This strongly supports its validation as a true expression on immunohistochemistry. A strong correlation between PROX1 mRNA amplification and regional lymph node metastasis supports its implications in cancer spreading and metastasis and sustains its utility, not only as a lymphatic marker, but also as a potential tumor marker in various tumor types, including gastric cancer.