Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development. While minimally expressed in most normal adult tissues, FRα is frequently overexpressed in several epithelial malignancies, particularly in high-grade serous ovarian carcinoma. An immunohistochemical (IHC) evaluation of FRα expression using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is now approved as a companion diagnostic for selecting patients eligible for mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate. Clinical trials such as SORAYA and MIRASOL have demonstrated significant clinical benefit in platinum-resistant epithelial ovarian cancer patients with high FRα expression (≥75% of tumor cells with moderate to strong membrane staining). This review summarizes the biological significance of FRα in ovarian cancer progression, its predictive value for targeted therapy, and the technical aspects of IHC assessment, including scoring interpretation and pre-analytical variables. We also discuss heterogeneity in FRα expression across histological subtypes and tumor sites, as well as the impact of archival versus fresh tissue. Understanding FRα expression patterns across histologic subtypes and tissue samples is critical for optimizing clinical decision-making and expanding the role of FRα-targeted therapies in gynecologic oncology.

In locally advanced cervical cancer (LACC), definitive chemo-radiotherapy is the standard treatment, but chemo-radiotherapy followed by surgery could be an alternative choice in selected patients. We enrolled 244 patients affected by LACC and treated with CT-RT followed by surgery in order to assess the prognostic role of the histological response using the Mandard scoring system. Results: A complete pathological response (TRG 0) was observed in 118 patients (48.4%), rare residual cancer cells (TRG2) were found in 49 cases (20.1%), increased number of cancer cells but fibrosis still predominating (TRG3) in 35 cases (14.3%), and 42 (17.2%) were classified as non-responders (TRG4–5). TRG was significantly associated with both OS (p < 0.001) and PFS (p < 0.001). The survival curves highlighted two main prognostic groups: TRG1-TRG2 and TRG3-TRG4–5. Main responders (TRG1–2) showed a 92% 5-year overall survival (5y-OS) and a 75% 5-year disease free survival (5y-DFS). Minor or no responders showed a 48% 5y-OS and a 39% 5y-DFS. The two-tiered TRG was independently associated with both DFS and OS in Cox regression analysis. Conclusion. We showed that Mandard TRG is an independent prognostic factor in post-CT/RT LACC, with potential benefits in defining post-treatment adjuvant therapy.

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

Objectives: High-risk human papillomavirus (HPV) has been implicated in breast carcinogenesis, but its role remains controversial. Basal-like breast carcinomas (BLCs) share morphological and immunophenotypic features with HPV-related squamous cell cancers. This study aimed to detect HPV DNA in BLCs, perform genotyping, and evaluate p16 expression as a surrogate marker of HPV infection. Methods: A total of 36 formalin-fixed, paraffin-embedded basal-like breast carcinomas were studied. Additionally, 10 patients with high-grade (G3) invasive ductal carcinoma of no special type (NOS), of a different molecular subtype, were included as a control group. Immunohistochemistry for p16 was performed, followed by DNA PCR using L1-type specific primers for HPV genotyping in all cases, irrespective of p16 status. Ten high-grade invasive ductal carcinomas served as controls. Results: p16 overexpression was observed in 28/36 BLCs (77.8%). Overall, HPV DNA was detected in 11/36 BLCs (30.6%). Among p16-positive BLCs, HPV DNA was detected in 10 cases (35.7%): HPV45 in 4 cases, HPV16 in 4 cases, and HPV18 in 2 cases. One additional BLC that was p16-negative tested positive for HPV16. In the control group, HPV16 DNA was found in 4/5 p16-positive cases. No double infections were identified in the BLC cohort. Conclusions: High-risk HPV DNA (types 16, 18, and 45) is present in a substantial subset of p16-positive basal-like breast carcinomas, suggesting a possible pathogenetic role for the virus in these aggressive tumors, although causality remains to be established. However, p16 is not an absolute surrogate for HPV in breast tissue, and molecular confirmation is required. Further studies with E6/E7 mRNA assays are needed to confirm viral transcriptional activity.