Topical testosterone versus clobetasol for vulvar lichen sclerosus.

OBJECTIVE: To compare the effects of topical testosterone and clobetasol treatments on symptoms remission and recurrence rates in patients with vulvar lichen sclerosus (LS). METHODS: A retrospective review of the records showed that, of 140 patients with biopsy-proven vulvar LS, 80 were treated with applications of testosterone propionate 2% in petrolatum and 60 with clobetasol 17-propionate 0.05%. RESULTS: The response rates after 6 months were 77.5% for patients treated with testosterone and 91.7% for those treated with clobetasol (P=0.02). The recurrence rates were 20% and 6.7% in the 2 groups, respectively (P=0.02). Premenopausal patients had higher remission rates and lower recurrence rates than postmenopausal patients (P>0.05). Considering whole patients, low remission rates and high recurrence rates were observed in patients who had had a hysterectomy (P>0.05). CONCLUSION: Treatment of LS with a corticosteroid provided excellent remission rates. In this study, clobetasol 17-propionate 0.05% was superior to testosterone for both remission induction and maintenance therapy.     

Calcineurin antagonists in vulvar lichen sclerosus

Lichen sclerosus et atrophicus is a chronic inflammatory disorder that mainly affects girls of premenarchial age and women in their fifties. Besides the anogenital region, lichen sclerosus (LS) may also affect extragenital or mucosal areas. Symptoms include soreness and pruritus, but other less common symptoms are not rare. An increased activity of fibroblasts causes increased sclerosis of the affected skin. Latest studies have identified LS as a chronic inflammatory dermatosis. Auto-antibodies against the extracellular membrane protein-1 are present in up to 80% of the patients. Moreover, in the widely accepted therapy with potent corticosteroids promising results have been presented using calcineurin antagonists in the treatment of LS. An interdisciplinary management and a continued care of patients with LS will improve the clinical manifestations and quality of life.     

Topical tacrolimus in the management of lichen sclerosus

The effective management of vulval lichen sclerosus (LS) currently depends upon the use of topical steroids and emollients. There are concerns with regard to the long-term toxicity of potent steroids and therefore is a need to consider effective alternatives. Immunomodulatory macrolactams offer an alternative to steroids in the management of some other inflammatory skin disorders and it would seem reasonable therefore to assess their activity in LS. This pilot study of 16 histologically confirmed cases of LS suggests that macrolactams have a positive pharmacological effect.     

The relevance of various vulvar epithelial changes in the early detection of squamous cell carcinoma of the vulva

The objective of this study is to evaluate the possible relevance of vulvar epithelial changes as a risk factor for squamous cell carcinoma of the vulva. The data of 66 women surgically treated for squamous cell carcinoma of the vulva have been analyzed. More than 6500 slides from the resection specimens were revised with special emphasis on concurrent epithelial changes. Synchronous epithelial changes were seen in 63 patients. Thirty-nine patients had synchronous vulvar intra-epithelial neoplasia grade 1 (VIN I), 10 VIN II and 13 VIN III. Thirty-one patients had synchronous lichen sclerosus and 49 squamous cell hyperplasia. The difference between the percentage of patients with epithelial changes diagnosed preceding their carcinoma (30%) and the percentage of patients that had synchronous epithelial changes after reviewing the specimen (95%) was striking. It was concluded that more careful diagnosis, treatment and follow-up of these conditions might lead to an earlier recognition of squamous cell carcinoma of the vulva and therefore to a better prognosis.     

Residual anogenital lichen sclerosus after cancer surgery has a high risk for recurrence: a clinicopathological study of 75 women

Objectives

Despite the strong association of lichen sclerosus (LS) and vulvar squamous cell carcinoma (SCC), the role of LS as precancerous lesion is unclear and the risk for recurrent SCC in residual LS after surgery for a LS-associated SCC is unknown.

Methods

Recurrences in residual vulvar LS after complete resection of a LS-associated SCC were analyzed in 75 women. Primary SCC, recurrences and 19 biopsies obtained 1–6 months before recurrent SCC were evaluated histologically, and for presence of HPV and monoclonally rearranged T-cell receptor gamma locus (mTRG@).

Results

40/75 patients (53%; primary SCC 25pT2, 9pT1b, 6pT1a) had no recurrence for 64 months (range 10–176 months), but 35/75 women (47%; primary SCC 1pT3, 18pT2, 13pT1b, 3pT1a) developed recurrences after 42 months (range 3–156 months). Twenty-five women had 1 recurrence: 13SCC within 18 months, 1SCC after 26 months, 10SCC and 1 differentiated vulvar intraepithelial neoplasia (d-VIN) after 74 months (range 52–136 months). Ten patients suffered multiple recurrences: 3 women had 2 recurrent d-VIN, 7 patients had multiple successive de-novo SCC with lymphocytes with mTRG@ in 6 patients. Wider resections correlated with no/late recurrences. Nineteen HPV-negative biopsies before diagnosis of recurrent SCC revealed 4 classical d-VIN and 15 verrucous, atrophic or flat intraepithelial proliferations different from d-VIN.

Conclusion

With a 50% recurrence rate after cancer surgery, residual anogenital LS has a high risk for de-novo cancer. Extent of resection of LS-affected skin and activity of residual LS with lymphocytes with mTRG@ are important criteria for recurrences, which develop rapidly through a variety of HPV-negative intraepithelial lesions.     

The role of vulvar skin biopsy in the evaluation of chronic vulvar pain

Sixty-one percent of refractory vulvodynia patients evaluated in a tertiary care vulvovaginal clinic had clinically relevant dermatoses based on dermatopathologist-analyzed vulvar biopsy including: lichen sclerosus, allergic/irritant dermatitis, lichen planus, and other inflammatory or neoplastic dermatoses. Given the frequency of dermatologic disease, vulvar biopsy and analysis by a dermatopathologist are recommended in patients with vulvodynia.     

Topical calcineurin inhibitors for the treatment of vulvar dermatoses

Repeated courses of potent topical corticosteroids and maintenance therapy with moderately potent topical corticosteroids are frequently needed to treat various forms of vulvar dermatoses, which are often characterized by an abnormal proliferation or activation of T lymphocytes. Because such therapeutic regimen is associated with an increased risk of potential side effects, particularly skin atrophy, an anti-inflammatory alternative to topical corticosteroids is desirable. The two non-steroid topical calcineurin inhibitors pimecrolimus and tacrolimus are immunomodulators that block the release of inflammatory cytokines from T lymphocytes in the skin while promoting cutaneous innate host defences. They are currently approved in Europe and in the United States of America as second-line anti-inflammatory agents for the treatment of atopic dermatitis. We provide a comprehensive summary of existing case reports, series of cases, and open-label prospective studies concerning the use of topical pimecrolimus and tacrolimus for the treatment of anogenital lichen sclerosus, genital lichen planus, vulvar lichen simplex chronicus and related pruritic vulvar dermatoses (chronic vulvar pruritus and allergic contact dermatitis of the vulva). The available data suggest that both topical calcineurin inhibitors may be effective and well tolerated in these vulvar dermatoses, although topical pimecrolimus may exhibit a better long-term tolerability profile. Being devoid of steroid-related side effects, they may represent a useful second-line therapeutic option for patients who are intolerant of, or resistant to topical corticosteroids. Controlled clinical trials and comparative studies are warranted to substantiate the promising findings summarized in this review.     

Antigens of the HLA system in women with vulvar lichen sclerosus. Association with HLA-B21

The cause of vulvar lichen sclerosus (VLS) is unknown. An autoimmune origin has been suggested. The HLA system is responsible for the synthesis of major histocompatibility antigens and is considered a genetic marker of the risk of or resistance to some diseases. Recently, the association between some antigens of the HLA system and diseases of proven autoimmune origin has been reported. A possible association between antigens of the HLA system and VLS has been investigated by others, with contradictory results. Here we report the results of HLA typing in 68 women with histologically proven VLS. The following antigens were tested: A1, A2, A3, A9-11, A28, A29, A32, B5, B7, B8, B12-B18, B21, B22, B27, B35, B40, Cw1-4, Dr1-5 and Dr7. The results were compared with the frequency of HLA antigens in about 2,000 controls. Patients affected by VLS showed an increased frequency of HLA-B21 (22.06% vs. 9.56%, P less than .001), HLA-Dr5 (55.38% vs. 40.92%, P less than .025) and HLA-Dr7 (38.46% vs. 25.19%, P less than .025). After correction for the number of antigens tested (44) the difference in HLA-B21 frequency was significant at the P less than .05 level. This finding gives further support to the suggestion that an immune system disorder is involved in the origin of VLS.     

The role of angiogenesis and COX-2 expression in the evolution of vulvar lichen sclerosus to squamous cell carcinoma of the vulva

OBJECTIVES: We aimed to determine whether premalignant changes in vulvar lichen sclerosus (LS) could be identified by analysing markers of angiogenesis and the expression of the enzyme cyclooxygenase-2 (COX-2). METHODS: Eight cases of histologically diagnosed vulvar LS, which showed an evolution to carcinoma of the vulva histologically documented, were compared to 10 cases of vulvar LS, for which follow-up information was available for at least 9 years, and to 10 cases of LS adjacent to squamous cell carcinoma (SCC) of the vulva. The microvessel density (MVD), and the expression of vascular endothelial growth factor (VEGF) and of COX-2 were analysed. RESULTS: Difference of MVD between unchanged LS cases and LS cases evolving to SCC and LS adjacent to SCC cases was statistically significant (P=0.008, Wilcoxon Mann-Whitney test). Difference of VEGF and COX-2 expression between unchanged LS cases and LS cases evolving to SCC and LS adjacent to SCC cases were statistically significant (P=0.007 and P=0.01, respectively; Fisher's exact test). CONCLUSIONS: Our study addresses the possibility that immunohistochemical studies may add information to permit the identification of LS as a precursor lesion that has a greater potential to evolve into SCC. These data may identify characteristics of vulvar LS disclosing alterations that indicate the further development to cancer; therefore, it may allow the identification of a group of LS patients who need a careful follow-up and adjunctive biopsies.     

Aggressive locally recurrent vulvar cancer: review of cases presented to Massachusetts General Hospital 1990 to present

Isolated recurrences of squamous cell vulvar carcinoma treated by surgical re-excision have excellent outcomes. There is a subset of these patients who develop multiple local recurrences that are difficult to manage and have a high risk of dying from their cancers. We reviewed women presenting with vulvar cancer (200 patients) to Massachusetts General Hospital from 1990 to present and identified 12 women with aggressive, locally recurrent squamous cell carcinomas of the vulva. The identified women all had successful primary radical vulvectomy and groin node dissections with negative surgical margins (except patient 2) and lymph nodes with no lympho-vascular space invasion. Seven women had underlying lichen sclerosis. Eight had a history of vulvar intraepithelial neoplasia or persistent carcinoma in situ. Ten patients had greater than three recurrences after primary surgical therapy. One died of recurrent vulvar cancer 10 months after her initial diagnosis. Two patients died after three recurrences. The only unifying clinicopathologic factor among these women was persistent lichen sclerosis and persistent carcinoma in situ. Understanding the underlying mechanisms that predisposed these premalignant lesions to transform into carcinomas will help predict in which women these are likely to re-occur and may help determine which women require more aggressive initial treatment.     

Clobetasol propionate in the treatment of premenarchal vulvar lichen sclerosus

OBJECTIVE: To assess the effectiveness of treating premenarchal vulvar lichen sclerosus with clobetasol propionate. METHODS: A retrospective chart review was performed of girls presenting to the University of Michigan Pediatric and Adolescent Gynecology Clinic from January, 1995, to July, 2000, with premenarchal lichen sclerosus. Subjects in the study were treated with topical clobetasol propionate ointment 0.05% for 2-4 weeks, and then tapered to a less potent steroid. Information was extracted concerning age at onset, symptoms, vulvar examination, previous treatments, effectiveness of clobetasol, follow-up, and complications. The parents were contacted for a follow-up telephone survey. RESULTS: Fifteen girls averaging 5.7 years at the start of symptoms met criteria. The diagnosis of lichen sclerosus was made visually in 11 and by biopsy in four. Follow-up ranged from 2 months to 6 years. Fourteen girls had good improvement within 4-7 weeks. One girl developed a yeast superinfection and one developed transient erythema. At least 1 year of follow-up by clinic visit or telephone interview was available in 11 girls. Of these 11, two girls had no further vulvar symptoms after the initial treatment, five had one or two total flares, three reported three to eight flares per year, and one girl continues to be unresponsive to therapy. CONCLUSION: Clobetasol propionate was an effective treatment of premenarchal vulvar lichen sclerosus in this small group; however, recurrences were common and required additional steroid treatment. Furthermore, complications of treatment were infrequent, minor, and easily treatable.     

Pimecrolimus for the treatment of vulvar lichen sclerosus in a premenarchal girl

BACKGROUND: Lichen sclerosus is a chronic cutaneous disorder with a predilection for the vulva. Lichen sclerosus affects more than one in 900 girls. Superpotent corticosteroids like clobetasol propionate are the most effective treatment for vulvar lichen sclerosus. However, recurrence after stopping steroids is very high. As repeated courses of corticosteroids are frequently needed, there are concerns about potential side effects. Therefore, a treatment regimen that does not rely on corticosteroids may be beneficial. As lichen sclerosus is a T-lymphocyte mediated disorder, it has been suggested that pimecrolimus, a topical T-lymphocyte inhibitor, may be safe and effective for the treatment of lichen sclerosus in children. CASE REPORT: A 10-year-old girl with lichen sclerosus was initially treated with clobetasol. Remission was achieved, but 3 months later she had a recurrence. Subsequent treatment with clobetasol led to a breakdown of her peri-anal skin with a superimposed infection. She was then treated with pimecrolimus and remission was achieved. She has had no recurrence of active lichen sclerosus and has less burning with pimecrolimus than with clobetasol. CONCLUSION: Pimecrolimus may be an effective treatment of vulvar lichen sclerosus. Pimecrolimus has been shown to be very safe in the pediatric population for the treatment of mild to moderate eczema, without causing dermal atrophy, tachyphylaxis, striae, rebound flares, or hypothalamic-pituitary axis suppression. As the recurrence rate of active lichen sclerosus in prepubertal girls treated with topical corticosteroids is high, and the majority of prepubertal girls with lichen sclerosus continue to have disease after menarche, a treatment regimen that does not rely on corticosteroids may be beneficial.