Utilizing Digital Pathology to Quantify Stromal Caveolin-1 Expression in Malignant and Benign Ovarian Tumors: Associations with Clinicopathological Parameters and Clinical Outcomes

Loss of stromal caveolin-1 (Cav-1) is a biomarker of a cancer-associated fibroblast (CAF) phenotype and is related to progression, metastasis, and poor outcomes in several cancers. The objective of this study was to evaluate the clinical significance of Cav-1 expression in invasive epithelial ovarian cancer (OvCa). Epithelial and stromal Cav-1 expression were quantified in serous OvCa and benign ovarian tissue in two, independent cohorts – one quantified expression using immunohistochemistry (IHC) and the other using multiplex immunofluorescence (IF) with digital image analysis designed to target CAF-specific expression. Cav-1 expression was significantly downregulated in OvCa stroma compared to non-neoplastic stroma using both the IHC (p=0.002) and IF (p=1.8×10 -13 ) assays. OvCa stroma showed Cav-1 downregulation compared to tumor epithelium with IHC (p=1.2×10 -24 ). Conversely, Cav-1 expression was higher in OvCa stroma compared to tumor epithelium with IF (p=0.002). There was moderate correlation between IHC and IF methods for stromal Cav-1 expression ( r 2 = 0.69, p=0.006) whereas there was no correlation for epithelial expression ( r 2 =0.006, p=0.98). Irrespective of the staining assay, neither response to therapy or overall survival correlated with the expression level of Cav-1 in the stroma or tumor epithelium. Our findings demonstrate a loss of stromal Cav-1 expression in ovarian serous carcinomas. Studies are needed to replicate these findings and explore therapeutic implications, particularly for immunotherapy response.