Vulvar Intraepithelial Neoplasia: New concepts and strategy

Vulvar intraepithelial neoplasia (VIN) is a rare condition which can develop into an invasive carcinoma. This skin-disease affects mainly young women, and causes many severe and long-lasting symptoms such as pruritus, vulvodynia and psychosexual dysfunction. Over 80% of VIN-affected women present with multifocal vulvar disease, and often neoplastic changes can be found in the entire lower genital tract. Clinically, it is important to distinguish unifocal from multifocal lesions, since unifocal VIN tends to progress to invasive carcinoma ten times more often than multifocal VIN doe

Imiquimod in the treatment of multifocal vulvar intraepithelial neoplasia 2/3. Results of a pilot study

To investigate the efficacy of topical treatment with imiquimod 5% cream, an immune response modifier, in patients with vulvar intraepithelial neoplasia (VIN) 2/3. Fifteen women (aged 35-51) with histologically proven multifocal VIN 2/3 without invasion, were entered into a prospective, observational, pilot study. Imiquimod 5% cream was applied by the patient to the vulvar lesions one to three times a week at night. Clinical response was analyzed by macroscopic examination and categorized as complete (CR) or partial (PR). Four patients achieved CR (27%) and nine patients, PR (60%) after 6-34 weeks of treatment. Two patients discontinued medication. CR was reached after 6, 7, 11 and 30 weeks of treatment. This pilot study showed the potential beneficial effect of imiquimod 5% cream in multifocal VIN 2/3. In contrast to current surgical treatment, imiquimod focuses on the cause of VIN and preserves the anatomy and function of the vulva. Therefore, imiquimod may prove to be the treatment of choice in multifocal, high grade VI

Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients

To establish the true natural history of VIN III from literature data. In a systematic review, data of women with VIN III indexed in several computer databases were pooled. The effect of treatment was correlated with recurrences and progression of VIN III. Ninety-seven articles met the inclusion criteria. Data of 3322 patients were available. The mean age at diagnosis of VIN III was 46. This decreased over time, although not significantly (P = 0.08). Recurrences were seen as often after local excision as after vulvectomy. The percentage of recurrences was lower, but not absent, after free surgical margins than after involved surgical margins (P < 0.001). 6.5% of the 3322 patients progressed to an invasive vulvar carcinoma. Occult carcinomas were diagnosed in 3.2% of patients and 3.3% carcinomas were diagnosed during follow-up. The mean age at diagnosis of invasive vulvar carcinoma was 52 years. Nine percent of 88 untreated patients progressed in 12 to 96 months to invasive vulvar carcinoma. Only 1.2% of the 3322 patients showed complete regression, mostly during the first 10 months after diagnosis, 41% of which was related to pregnancy. Evidence exists that VIN III may progress to invasive vulvar carcinoma. However, the available literature suggests that the progression rate to invasive vulvar carcinoma is low. The incidence of invasion as found in this systematic review is probably even too high, because overreporting of (micro)invasive cases cannot be excluded. Only a prospective registration using a standardized pathology examination will provide information about the real natural history of VIN II

Disturbed patterns of immunocompetent cells in usual-type vulvar intraepithelial neoplasia

Genital infection with human papillomavirus (HPV) is usually transient, as the immune system is capable of eliminating the virus. When immunity "fails" and the infection persists, vulvar intraepithelial neoplasia (VIN) may develop. In this study, we examined the distribution of inflammatory cells in 51 patients with HPV-associated usual-type VIN and in 19 healthy controls. Frozen vulvar tissue samples were tested for the presence of HPV-DNA, and immunohistochemical staining for the markers CD1a, CD207, CD208, CD123/CD11c, CD94, CD4, CD8, and CD25/HLA-DR was performed. Cells were counted in both the epidermis and dermis over at least 2 mm of basal membrane length. In the epidermis of VIN patients, CD1a(+) and CD207(+) (Langerin) dendritic cells (DC) and CD8(+) T cells were significantly lower than in controls, whereas the number of CD123(+)/CD11c(-) plasmacytoid DCs (pDC) was significantly increased. No significant changes were observed for CD208(+) DCs, CD94(+) natural killer (NK) cells, CD4(+) T cells, and CD25(+)/HLA-DR+ regulatory T cells. In the dermis of VIN patients, elevated numbers of CD208(+), CD123(+)/CD11c(-), CD94(+), CD4(+), CD8(+), and CD25(+)/HLA-DR+ cells were observed when compared with healthy controls. The numbers of CD1a(+) and CD207(+) DCs were not different between groups. In summary, high-risk HPV-related usual-type VIN lesions are characterized by an immunosuppressive state in the epidermis, showing a reduction of immature myeloid DCs (mDC) and CD8(+) T cells. In the dermis, inflammatory activation is reflected by the influx of mature mDCs and pDCs, NK cells, and T cells, suggesting that the cellular immune response on viral HPV infection occurs in the dermis of VIN patients

Nonsteroidal anti-inflammatory drugs do not interfere with imiquimod treatment for usual type vulvar intraepithelial neoplasia

Imiquimod has been shown to be an effective treatment for usual type vulvar intraepithelial neoplasia (uVIN). Since local inflammation and burning are common side effects, patients often use nonsteroidal anti-inflammatory drugs (NSAIDs). Our study investigated whether NSAID-use, which has been documented to inhibit the cell-mediated immune response, interferes with the outcome of imiquimod treatment. Monocyte-derived dendritic cells (moDCs) and Langerhans cells (moLCs) were cultured in the presence of NSAIDs. The expression of relevant surface markers (CD80, CD86, CD40, HLA-DR, CCR6 and CCR7), stimulatory function, and cytokine production were evaluated. Furthermore, we analyzed in uVIN patients whether frequent NSAID-use had an effect on the clinical response and on immunocompetent cell counts before and after imiquimod treatment. Although an effect was observed on the expression of moDC and moLC maturation markers, NSAIDs did not affect the ability of moDCs and moLCs to stimulate allogeneic T-cell proliferation, or the production of cytokines in an allogeneic T-cell stimulation assay. In agreement with this, in uVIN patients treated with imiquimod, no interference of frequent NSAID-use with clinical outcome was observed. However, we did notice that high CD1a(+) and CD207(+) cell counts in frequent NSAID-users before treatment seemed to predict a favourable response to imiquimod treatment. Our data indicate that NSAID-use does not seem to interfere with moDC and moLC function and does not interfere with immunomodulatory properties of imiquimod in uVIN patients. Therefore, NSAIDs can safely be used to reduce imiquimod side effects in uVIN patients during treatment