Chronic ulcerations following topical therapy with 5-fluorouracil for vaginal human papillomavirus-associated lesions.

Applied topically to the vagina, 5-fluorouracil (5-FU) cream is an effective therapy for human papillomavirus (HPV)-associated lesions of the vagina including condylomata acuminata and vaginal intraepithelial neoplasia. Although the acute side effects of 5-FU therapy are well recognized, long-term sequelae of intravaginal 5-FU use have not been described in detail in the literature. To assess the incidence and clinical course of 5-FU-related vaginal mucosal alterations, we studied 220 patients who underwent 5-FU therapy for HPV-associated lesions of the vagina. Eighteen women (8.2%) had epithelial ulcers 6 months after completion of the 5-FU treatment. The incidence of ulcers was higher in women who used 5-FU for longer than 10 weeks compared with those who used it for 10 weeks or less (9.6 versus 5.7%; P = .05). All but one of the mucosal defects were in the vaginal fornices and/or the periphery of the ectocervix. The ulcers were mostly singular and measured 0.5-7 cm in greatest diameter. Fourteen patients (77.8%) had symptoms related to the ulcers including a serosanguineous or watery discharge (55.6%), postcoital spotting or bleeding (44.4%), irregular bleeding unrelated to intercourse (16.7%), and pain (5.6%). Spontaneous healing of the ulcers was protracted. Office methods of therapy including estrogen creams and cauterizing agents failed to accelerate healing as compared with untreated patients. Excision of the ulcer and primary closure of the wound was curative in all four cases in which it was used. We conclude that topical 5-FU therapy may lead to troublesome chronic mucosal ulcers that tend to persist despite conservative treatment attempts.     

Human papillomavirus-associated lesions of the vagina and cervix. Treatment with a laser and topical 5-fluorouracil.

Twenty women with cervical and vaginal human papillomavirus-associated lesions were treated with CO2 laser ablation followed by eight weekly applications of 5-fluorouracil. Viral subtyping in a majority of patients and histology were obtained before and after treatment. After treatment 88% (15 of 17) had normal vaginal biopsies, and 59% (10 of 17) had normal cervical biopsies. There were no treatment failures with subtype 6/11 infection of the cervix or vagina. All the failures were with viral subtypes 16/18 and 31/35/51. The protocol was effective in treating patients with cervical and vaginal human papillomavirus-associated lesions.     

Postirradiation squamous cell carcinoma in situ of the vagina: treatment by topical 20 percent 5-fluorouracil cream.

Eight patients with squamous cell carcinoma in situ of the vagina were treated with monthly 5 day courses of 20% 5-fluorouracil cream applied to the vagina. Seven (87.5%) of the women had an initial complete response; however, three subsequently developed recurrence after the treatment was stopped. They were retreated, and two of these three patients achieved a subsequent complete response. The overall response to therapy was 75% (6/8) with six women off therapy from 1.1 to 6.9 years. Total follow-up of all patients was 3.1 to 6.9 years with no patients having developed invasive carcinoma. Because of the high success rate with no associated serous sequelae, this is believed to be a satisfactory method of therapy for women with squamous cell carcinoma in situ of the vagina occurring after pelvic irradiation.     

Topical 5-fluorouracil in the treatment of intraepithelial neoplasia of the vagina.

Twelve patients with vaginal intraepithelial neoplasia received topical therapy with 5% 5-fluorouracil cream. Six patients had carcinoma in situ, 5 had moderate dysplasia, and 1 had mild dysplasia. Five patients responded to 1 treatment course. Six patients required 2, and 1 patient required 3 courses of therapy to respond. Three patients developed recurrent vaginal intraepithelial neoplasia 11-16 months after therapy and were retreated with topical 5-fluorouracil. Vaginal irritation occurred in all patients but was limited to the duration of the treatment course.     

Resurfacing the vulva and vagina

Thirteen patients are described where split thickness skin grafts, cutaneous or myocutaneous flaps were used to cover large defects on the vulva and vagina. For defects over the pubic groin areas, the tensor fascia lata flaps are most suitable. Defects of the vulva are best covered by split thickness skin grafts or gracilis flaps, and vaginal defects by split thickness skin grafts or vulvar flaps.     

Topical 5-fluorouracil in the treatment of carcinoma in situ of the vulva.

The clinical and pathologic response of carcinoma in situ of the vulva in a 42-year-old woman treated with topical 5-fluorouracil is reported. Except for one persistent area of involvement in the anal region which required local excision, the result of treatment was excellent, with no evidence of recurrence after 2 years' followup. This important adjunct in the treatment of intra-epithelial carcinoma deserves long-range investigation.     

The use of topical 5-fluorouracil in the treatment of genital condylomas

Topical 5-FU is indicated for therapy-resistant condylomas and for extensive untreated vulvar condylomas. It may be the treatment of choice for vaginal condylomas. Applications of 5-FU once weekly to the vagina and twice weekly to the vulva for 10 weeks appear to be as effective as continued regimens but are better tolerated. Perhaps the greatest value of 5-FU lies in the periodic application for prevention of recurrences of condylomas removed by surgical methods.     

Three cases of vaginal adenosis after topical 5-fluorouracil therapy for vaginal HPV-associated lesions

Three cases of vaginal adenosis after topical 5-fluorouracil therapy for vaginal HPV-associated lesions are reported. Three patients with colposcopic, histologic and viral evidences for subclinical papillomavirus infection (in combination with low-grade vaginal intraepithelial neoplasia in of them) are treated with 5-FU. In follow-up control examinations persistent ulcerations were found without regression after applied therapy. By colposcopic and histologic examinations vaginal adenosis was proved without histories of intrautering DES exposure. After the destructive therapy the reported lesions were regressed without appearance of new lesions in follow-up control examinations. The application of 5-fluorouracil has to be used only in cases of recurrent vaginal warts and in cases of high-grade vaginal intraepithelial neoplasia with strict folow-up cytological and colposcopic control examinations.     

Lifetime changes in the vulva and vagina

The morphology and physiology of the vulva and vagina change over a lifetime. The most salient changes are linked to puberty, the menstrual cycle, pregnancy, and menopause. The cutaneous epithelia of the mons pubis, labia, and clitoris originate from the embryonic ectoderm and exhibit a keratinized, stratified structure similar to the skin at other sites. The mucosa of the vulvar vestibule, which originates from the embryonic endoderm, is non-keratinized. The vagina, derived from the embryonic mesoderm, is responsive to estrogen cycling. At birth, the vulva and vagina exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina acquire mature characteristics in a sequential fashion in response to adrenal and gonadal maturation. A trend to earlier pubertal onset has been observed in Western developed countries. In women of reproductive age, the vaginal mucosa responds to steroid hormone cycling, exhibiting maximal thickness and intracellular glycogen content at mid-cycle. Vulvar skin thickness remains unchanged but menstrual cycle-associated changes in ortho- and parakeratosis occur at the cytological level. The vulva and vagina further adapt to the needs of pregnancy and delivery. After menopause, tissue atrophy ensues. Post-menopausal changes in skin barrier function, skin hydration, and irritant susceptibility have been observed on exposed skin but not on the vulva. Nevertheless, older women with incontinence are at increased risk for developing incontinence dermatitis. A combination of factors, such as tissue atrophy, slower dissipation of excess skin hydration, shear forces associated with limited mobility, and lower tissue regeneration capacity increase the risk of morbidity from incontinence dermatitis in older women.