title: Immunological and viral factors associated with the response of vulval intraepithelial neoplasia to photodynamic therapy.
abstract: Topical 5-aminolevulinic acid-based photodynamic therapy (PDT) has produced complete response rates of >90% for nonmelanoma skin carcinomas, which are mostly human papillomavirus (HPV) negative. Using a similar treatment protocol, we observed a short-term response in only one third (10 of 32) of high-grade vulval intraepithelial neoplasia (VIN 2-3) lesions. Unifocal lesions were found more responsive than multifocal and pigmented lesions. Animal model studies have suggested that long-term PDT response involves an immune reaction in which CTLs play a crucial role. In this study, we have assessed: (a) HPV infection; (b) HLA expression; and (c) immune infiltrating cells in VIN biopsies from responders and nonresponders to determine whether these factors may limit response to topical 5-aminolevulinic acid-based PDT. Tissues from normal vulva (n = 9), vulval carcinoma (n = 11), and VIN (32 patients from which 19 pre- and 43 post-PDT biopsies were taken) were investigated for immune cell infiltration and HLA class I expression by immunohistochemistry and HPV infection by PCR. There was a greater likelihood of HPV positivity associated with a lack of response of VIN to PDT (P = 0.002), and VIN nonresponders were more likely to show HLA class I loss compared with responders (P = 0.030). HLA class I down-regulation was significantly greater in the carcinomas (82%, total loss) than the VIN (28%, 19%, total loss; and 9%, allele loss; P = 0.004). None of the cases with class I down-regulation responded to PDT, whereas 3 of 6 (50%) of cases that showed total class I loss subsequently developed superficial invasion. Compared with normal vulval skin, VIN lesions showed increased infiltration by CD4 (T-helper) and CD68 (macrophages) but not CD1a (Langerhans cells) or CD8 (CTLs). There was, however, a significant increase of CD8 infiltration in posttreatment VIN responders compared with nonresponders (P = 0.0001). These data clearly support the contention that high-risk HPV infection and lack of cell-mediated immunity may play a role in the observed poor response of lower genital lesions to topical PDT.
authors.affiliation: University of Manchester, Academic Department of Obstetrics and Gynaecology and Reproductive Health Care, St. Mary's Hospital, United Kingdom.
authors.forename: E S
authors.initials: ES
authors.lastname: Abdel-Hady
authors.forename: P
authors.initials: P
authors.lastname: Martin-Hirsch
authors.forename: M
authors.initials: M
authors.lastname: Duggan-Keen
authors.forename: P L
authors.initials: PL
authors.lastname: Stern
authors.forename: J V
authors.initials: JV
authors.lastname: Moore
authors.forename: G
authors.initials: G
authors.lastname: Corbitt
authors.forename: H C
authors.initials: HC
authors.lastname: Kitchener
authors.forename: I N
authors.initials: IN
authors.lastname: Hampson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006680:HLA Antigens / Q000096:biosynthesis / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use; D014412:Tumor Virus Infections / Q000150:complications; D014846:Vulvar Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*
chemical_list: D004279:DNA, Viral; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid