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PRAME Expression in HPV-associated and Differentiated Vulvar Intraepithelial Neoplasia-associated Vulvar Squamous
Eyas Alzayadneh1, Sarah E Gradecki2, Landon K Hobbs3
1Department of Pathology, University of Virginia, Charlottesville, Virginia.
Abstract:
Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry was initially used diagnostically in melanoma but is increasingly evaluated across malignancies for diagnostic, prognostic, and therapeutic purposes. PRAME protein acts as a dominant repressor of retinoic acid signaling and may help stratify patients for retinoic acid-based therapy. Multiple PRAME-targeted immunotherapy trials are ongoing, supported by its selective tumor expression. Vulvar intraepithelial neoplasia (VIN) is an appealing setting for PRAME assessment because lesions are often multifocal or extensive, and treatment by excision can be disfiguring. Immunotherapy is also of rising interest in advanced vulvar squamous cell carcinoma (VSCC). We aimed to evaluate PRAME expression in HPV-associated and differentiated vulvar intraepithelial neoplasia (dVIN)-associated squamous lesions of the vulva. Full tissue sections from 106 vulvar squamous neoplasms (31 HSIL, 29 VSCC arising in HSIL, 20 dVIN, 26 VSCC arising in dVIN) were stained with PRAME antibody. Expression was recorded as the percentage of positive tumor cells, with intensity (0-3+) and staining localization documented, and an H-score was subsequently calculated. Groups were compared using the Wilcoxon rank-sum or Kruskal-Wallis tests. Most VSCCs (78%) expressed PRAME, with significantly higher expression in dVIN-associated lesions (P=0.006). Subgroup analysis showed the highest PRAME expression in dVIN-associated VSCC and the lowest in HSIL (P<0.00001). These findings suggest that distinct biological drivers of HPV-associated and dVIN-associated vulvar neoplasia contribute to differential PRAME expression. The strongest expression in dVIN-associated VSCC highlights a possible link between aggressive tumor behavior and PRAME. dVIN-associated lesions may therefore represent promising candidates for PRAME-targeted therapy.
Insights
Preferentially expressed antigen in melanoma (PRAME) is found in vulvar squamous lesions. Higher PRAME expression in differentiated vulvar intraepithelial neoplasia (dVIN)-associated cancers suggests potential for targeted therapies.
Area of Science:
- Gynecologic Oncology
- Immunohistochemistry
- Molecular Pathology
Background:
- Preferentially expressed antigen in melanoma (PRAME) is a protein repressor of retinoic acid signaling with potential in cancer diagnostics and therapy.
- PRAME's selective tumor expression and role in immunotherapy trials make it a target of interest across malignancies.
- Vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC) are conditions where PRAME assessment could inform treatment, especially given the disfigurement from extensive lesions.
Purpose of the Study:
- To evaluate PRAME expression in human papillomavirus (HPV)-associated and differentiated vulvar intraepithelial neoplasia (dVIN)-associated squamous lesions.
- To determine if PRAME expression levels differ between HPV-associated and dVIN-associated vulvar neoplasms.
- To explore the potential of PRAME as a biomarker and therapeutic target in vulvar cancer.
Main Methods:
- Immunohistochemistry was used to stain PRAME in 106 vulvar squamous neoplasms, including HSIL, VSCC arising in HSIL, dVIN, and VSCC arising in dVIN.
- PRAME expression was quantified by the percentage of positive tumor cells, staining intensity (0-3+), and localization, with an H-score calculated.
- Statistical analysis using Wilcoxon rank-sum or Kruskal-Wallis tests compared PRAME expression across different lesion types.
Main Results:
- PRAME was expressed in most VSCCs (78%), with significantly higher expression observed in dVIN-associated lesions compared to HPV-associated lesions (P=0.006).
- The highest PRAME expression was found in dVIN-associated VSCC, while the lowest expression was observed in HSIL (P<0.00001).
- Distinct biological drivers in HPV-associated and dVIN-associated vulvar neoplasia appear to influence differential PRAME expression.
Conclusions:
- Differential PRAME expression in vulvar squamous lesions correlates with distinct etiological pathways (HPV vs. dVIN).
- The strong PRAME expression in dVIN-associated VSCC suggests a link to aggressive tumor behavior and highlights its potential as a therapeutic target.
- dVIN-associated vulvar lesions show promise for PRAME-targeted therapies, potentially offering new treatment avenues for advanced vulvar cancer.
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