Folate Receptor Alpha Expression Across the Spectrum of Serous Tubal Lesions: An Adjunct Biomarker for Distinguishing Serous Tubal Intraepithelial Carcinoma From Serous Tubal Intraepithelial Lesions.

Abstract

Folate receptor alpha (FRα) is highly expressed in tubo-ovarian high-grade serous carcinoma (HGSC), but its expression in serous tubal intraepithelial carcinoma (STIC) and earlier tubal lesions has not been systematically characterized. We evaluated FRα expression across the spectrum of fallopian tube lesions and assessed its potential as an adjunctive diagnostic biomarker. Immunohistochemistry was performed on 408 tubal epithelial samples from 262 patients, including 52 normal fallopian tube samples, 110 secretory cell expansions (SCE), 88 secretory cell outgrowths (SCOUT), 72 serous tubal intraepithelial lesions (STIL), and 56 STICs. An additional 30 HGSCs were included for comparison. FRα expression was assessed using the percentage score ≥2+ (PS2+) system. Associations with germline BRCA status and age were evaluated. FRα expression was detectable in normal fallopian tube epithelium but usually below the high-expression threshold. In contrast, expression was increased in STIC and HGSC, with high PS2+ scores in 73.2% and 76.7% of cases, respectively. Earlier tubal lesions showed predominantly low or negative/very low expression. No significant difference in FRα expression was observed between STIC and HGSC. BRCA-mutated STIC and HGSC showed higher FRα expression than their BRCA nonmutated counterparts, whereas earlier lesions showed no such association. In normal fallopian tube epithelium, FRα expression decreased with age. These findings demonstrate that FRα upregulation is established at the STIC stage and maintained in invasive HGSC. Diffuse high-level expression is uncommon in STIL and earlier lesions, suggesting that FRα may serve as an adjunct biomarker for distinguishing STIC from morphologically overlapping lesions. When interpreted in conjunction with morphology, p53, and Ki-67, FRα may improve diagnostic confidence along the STIL-to-STIC spectrum. The early and sustained upregulation of FRα in STIC also raises interesting questions regarding the timing of FRα-targeted interventions.