title: Imiquimod-induced clearance of HPV is associated with normalization of immune cell counts in usual type vulvar intraepithelial neoplasia.
abstract: Recently, we reported on the efficacy of imiquimod for treatment of usual type vulvar intraepithelial neoplasia (uVIN). A histologic regression of uVIN to normal tissue was observed in 58% of patients. As success of treatment is related to clearance of high-risk human papilloma virus (HPV), the aim of our study was to assess differences in immune cell counts and in the expression of p16(INK4a) in VIN tissue before and after imiquimod treatment, in relation to HPV clearance and clinical response. Vulvar tissue samples taken prior to imiquimod treatment and 4 weeks after treatment were tested for the presence of HPV. Previously determined immune cell counts (CD1a, CD207, CD208, CD123/CD11c, CD94, CD4, CD8 and CD25/HLA-DR) in epidermis and dermis of 25 VIN patients and 19 healthy controls were completed with the counts for CD14 and CD68. The expression of p16(INK4a) was investigated by immunohistochemistry in 15 patients. Before imiquimod treatment, both HPV cleared and HPV noncleared patients showed mainly in the dermis significantly upregulated immune cell counts compared to healthy controls. However, in patients that cleared HPV and showed histologic regression already 4 weeks after imiquimod treatment, immune cell counts and p16(INK4a) expression were normalized. In conclusion, our data indicate that imiquimod-induced clearance of HPV results in normalization of counts for certain immune cells and is strongly correlated with histologic regression of the disease.
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, The Netherlands. a.terlou@erasmusmc.nl
authors.forename: Annelinde
authors.initials: A
authors.lastname: Terlou
authors.forename: Manon
authors.initials: M
authors.lastname: van Seters
authors.forename: Alex
authors.initials: A
authors.lastname: Kleinjan
authors.forename: Claudia
authors.initials: C
authors.lastname: Heijmans-Antonissen
authors.forename: Lindy A M
authors.initials: LA
authors.lastname: Santegoets
authors.forename: Ilse
authors.initials: I
authors.lastname: Beckmann
authors.forename: Marc
authors.initials: M
authors.lastname: van Beurden
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Helmerhorst
authors.forename: Leen J
authors.initials: LJ
authors.lastname: Blok
mesh_terms: D000328:Adult; D000634:Aminoquinolines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007124:Immunoenzyme Techniques; D018655:Lymphocyte Count; D008875:Middle Aged; D027383:Papillomaviridae / Q000187:drug effects*; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D014846:Vulvar Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D000077271:Imiquimod