A comparative study of MMP-2 in vulvar neoplasms

OBJECTIVE: To investigate differences in MMP-2 protein expression in VIN, vulvar invasive carcinoma, and lichen sclerosus, we performed an immunohistochemical study in which tissue samples from individuals affected by these conditions were compared with normal vulvar tissue. METHODS: A total of 57 cases were selected, as follows: 14 cases of vulvar invasive carcinoma, 22 of vulvar intraepithelial neoplasia (6 of VIN I, 5 of VIN II, and 11 of VIN III), 9 of vulvar lichen sclerosus, and 12 samples of normal vulvar tissue. Immunohistochemistry was done with primary monoclonal antibodies against MMP-2 and quantification of the immunostaining was done by counting the number of antigen-positive stromal cells per 1000 stromal cells. RESULTS: Normal vulvar tissue had a median score of 37.99 stromal cells positive for MMP-2. The median scores for VIN I/II and lichen sclerosus were 41.98 and 46.51, respectively, with no statistical differences when compared to the normal group. Invasive cancer had a score statistically higher (160.36) than any of the other groups. CONCLUSION: Invasive vulvar carcinoma had a score statistically higher of MMP-2 than normal tissue, VIN, and lichen sclerosus.     

Vulvar lichen sclerosus: an immunologic study

OBJECTIVE: To investigate the seroimmunologic (CD3, CD4, CD8 lymphocytes, C3c and C4 complement fractions, and several autoantibodies) and immunohistochemical (T lymphocyte subpopulations, B lymphocytes, natural killer cells, macrophages, immunoglobulin [Ig] G, Ig M, and C3c complement fraction) characteristics of vulvar lichen sclerosus. METHODS: Serum samples from 68 women with histologically proven lichen sclerosus were compared with those from 53 healthy controls, and tissue samples from 14 of 68 women chosen at random were compared with those from 14 of 53 healthy controls. A scoring system was constructed to compare the number of cells in the tissue. RESULTS: Patients had significantly lower counts of circulating lymphocytes CD3 and CD4 than controls (P < .05) and a higher number of autoantibodies (P < .01). Analysis of the tissue samples confirmed a lower number of CD2 cells (two-tailed P = .002 in epidermis, .005 in dermis), CD3 cells (two-tailed P = .001 in epidermis and in dermis), CD4 cells (two-tailed P = .002 in epidermis, .011 in dermis), and CD8 cells (two-tailed P = .002 in epidermis, .051 in dermis) in subjects than in controls. Numbers of monocyte-macrophage cells were similar in the epidermis but different in the dermis (two-tailed P = .003). No natural killer CD56 cells or B lymphocytes (CD19-CD21) were detected in the affected areas. Deposits of IgG, IgM, and C3 were no greater in biopsy specimens of patients than in those of controls. CONCLUSION: Vulvar lichen sclerosus is not caused by a T cell-mediated response, and a viral origin is unlikely. The absence of CD19 and CD21 cells excludes local production of autoantibodies. Our data do not confirm an autoimmune pathogenesis for vulvar lichen sclerosus but help explain why systemic cortisone is of no benefit and justify the use of petroleum jelly to relieve pruritus.     

Role of angiogenesis in benign, premalignant and malignant vulvar lesions

OBJECTIVE: To investigate the presence of angiogenic factors in benign, premalignant and malignant vulvar lesions. STUDY DESIGN: Immunohistochemical demonstration of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in normal vulvar skin, lichen sclerosus, vulvar intraepithelial neoplasia (VIN) and vulvar cancer. RESULTS: VEGF was found in the majority of vulvar cancers but only a minority of VIN lesions. PD-ECGF was found in the majority of lesions. CONCLUSION: Demonstration of angiogenesis may suggest which preinvasive lesions will progress to invasive cancer.     

Prevalence of vulvar lichen sclerosus in a general gynecology practice

OBJECTIVE: To describe the rate of vulvar lichen sclerosus in 1 general gynecology practice. STUDY DESIGN: A database of 1,675 consecutive patients presenting in a 3-year period to a general gynecology practice was utilized to identify women with lichen sclerosus. Data included age, menopausal status, symptoms and physical examination findings. Pathology specimens were reexamined by a gynecologic pathologist to confirm the diagnosis of lichen sclerosus. RESULTS: Of the 1,675 patients, 28 (1.7%) had biopsy-proven vulvar lichen sclerosus. Nine patients been diagnosed previously, and 19 were new cases. The mean age at diagnosis was 52.6 years (SD +/- 15.9) versus 37.1 years (SD +/- 16.4) for those without lichen sclerosus (p < 0.001). Fifteen of the 28 patients (54%) were post-menopausal at the time of diagnosis. Of the 19 women with newly diagnosed lichen sclerosus, 8 (42%) were symptomatic. Of the 11 asymptomatic women, 7 (64%) had scarring of the clitoral prepuce or resorption of the labia minora. CONCLUSION: The rate of vulvar lichen sclerosus in 1 general gynecology private practice is approximately 1.7%. Clinicians must maintain a high index of suspicion to make the diagnosis, as at least one third of patients may be asymptomatic.     

The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women

Summary. Seventy-eight excised specimens of squamous cell carcinoma of the vulva were reviewed retrospectively for the presence of lichen sclerosus or vulvar intraepithelial neoplasia (VTN) at sites proximal to the tumour or more distant. Lichen sclerosus was evident in 61% and VIN alone in 31%. VIN III (differentiated) was associated with over 50% of the specimens with lichen sclerosus. HPV 16 was found in six of the 11 VIN lesions, investigated but in none of the six with lichen sclerosus.     

The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women

Seventy-eight excised specimens of squamous cell carcinoma of the vulva were reviewed retrospectively for the presence of lichen sclerosus or vulvar intraepithelial neoplasia (VIN) at sites proximal to the tumour or more distant. Lichen sclerosus was evident in 61% and VIN alone in 31%. VIN III (differentiated) was associated with over 50% of the specimens with lichen sclerosus. HPV 16 was found in six of the 11 VIN lesions, investigated but in none of the six with lichen sclerosus.     

Clinically identifying women with vulvar lichen sclerosus at increased risk of squamous cell carcinoma: a case-control study

OBJECTIVE: To identify clinical factors that might identify women with vulvar lichen sclerosus who are at increased risk of developing squamous cell cacinoma. STUDY DESIGN: A retrospective, case-control study compared 46 women presenting between 1992 and 2000 with clinical and histologic evidence of squamous cell carcinoma of the vulva arising in a background of lichen sclerosus and 213 new referrals with vulvar lichen sclerosus during the same period. RESULTS: The ages of the patients and presence of clinical hyperplasia were the only differences between the 2 groups. CONCLUSION: Women presenting with vulvar cancer arising within a background of lichen sclerosus are significantly older than women presenting with lichen sclerosus. In addition, clinical evidence of squamous hyperplasia is independently associated with vulvar carcinoma. Neither the presence nor duration of symptoms nor the loss of vulvar architecture is a useful indicator of potential cancer risk.     

Pimecrolimus for the treatment of vulvar lichen sclerosus: a report of 4 cases

BACKGROUND: Lichen sclerosus is a chronic cutaneous disorder with a predilection for the vulva. The etiology is unknown. Superpotent topical corticosteroids are the most effective treatment. Dermal atrophy, however, is a well-known complication associated with changes of lichen sclerosus superpotent topical corticosteroids. In addition, some women do not respond adequately to topical steroids. 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 a topical macrolide immunosuppressant, such as pimecrolimus, may be a safe and effective alternative treatment for lichen sclerosus. Since pimecrolimus does not affect collagen synthesis, it does not cause thinning of the dermis. CASES: Four patients with biopsy-proven lichen sclerosus were treated with 1% pimecrolimus cream twice daily. At the end of 3 months of treatment, 3 of the 4 patients reported complete resolution of their symptoms of vulvar itching and burning. Two patients had repeat vulvar biopsies at the end of treatment that showed reversal of the histologic changes of lichen sclerosus. CONCLUSION: In this small series, pimecrolimus appeared to be a safe and effective treatment of vulvar lichen sclerosus. A randomized, controlled trial comparing pimecrolimus and clobetasol propionate should be performed to determine which is the safer and more effective medication for the long-term treatment of lichen sclerosus.     

Bladder and bowel symptoms among women with vulvar disease: are they universal?

OBJECTIVE: To compare the prevalence of painful bladder syndrome, recurrent urinary tract infections, urinary leakage and irritable bowel syndrome between women with specific vulvar disorders and controls. STUDY DESIGN: Women with a primary diagnosis of vulvar intraepithelial neoplasia (dysplasia), vulvar vestibulitis (vestibulitis), contact vulvitis, atrophic vulvovaginitis, lichen simplex, lichen sclerosus and lichen planus, were compared to women presenting for annual examinations. RESULTS: As compared to controls, painful bladder syndrome was more prevalent among subjects with dysplasia, vestibulitis and contact vulvitis; a history of recurrent urinary tract infection was more prevalent among subjects with contact vulvitis; and urinary incontinence was less prevalent in subjects with lichen sclerosus. Irritable bowel syndrome was more prevalent among subjects with dysplasia, vestibulitis, lichen sclerosus, lichen planus and lichen simplex than controls. CONCLUSION: The prevalence of bladder and irritable bowel symptoms varies between vulvar disorders.     

Receptor modifications in vulvar dystrophies before and after treatment with topical hormones: comparison between the dextran-charcoal technique and immunohistochemical evaluation

PURPOSE OF INVESTIGATION: The objective of the study was first to quantify estrogen receptors (ERs) and progesterone receptors (PRs) in dystrophic vulvar tissue before and after topical hormone treatment in an attempt to evaluate whether receptor modifications occurred. Second we compared quantitative analysis with immunohistochemical staining of the vulvar specimens. METHODS: We studied 115 vulvar specimens obtained from 75 consenting women ranging from 21 to 78 years of age. Of the patients, 12 had histologically normal vulvar skin, 45 had vulvar dystrophies that were not treated by topical steroid therapy, 28 patients had vulvar dystrophies that were treated by testosterone propionate (TP) 2%, 12 patients had vulvar dystrophies that were treated by progesterone in hydroalcoholic gel and 18 patients had vulvar malignant tumors. For immunohistochemical analysis we considered 25 cases of vulvar dystrophies: 11 cases of squamous hyperplasia (SH) and 14 cases of lichen sclerosus (LS). Among these 25 cases, 15 (5 SH and 10 LS) were treated with TP 2%. RESULTS: After treatment of the vulvar dystrophies with progesterone, the positivity of ERs decreased (58.3% vs 77.8%). After treatment of the vulvar dystrophies with TP 2%, the positivity of PRs significantly decreased (14.3% vs 68.9%) whereas after treatment with progesterone the positivity of PRs increased (83.3%). The immunohistochemical study showed some differences in comparison to the quantitative study. In fact we found low basal positivity especially for PRs (16% vs 68.9% of the quantitative study). This finding was due to the use of a cutoff of at least ++ in order to increase the specificity. After treatment with TP 2%, we observed an increase of immunohistochemical positivity for ERs even in cases that were negative before treatment and a lack of PRs even in cases that were positive before treatment. CONCLUSIONS: These data demonstrate the efficacy of androgen therapy with TP 2% in vulvar dystrophies with increased trophism due to the increase of ERs.     

Specific serologic response to genital human papillomavirus types in patients with vulvar precancerous and cancerous lesions

OBJECTIVE: Antibodies to human papillomavirus are indicative for previous human papillomavirus exposure. Human papillomavirus antibody reactivities to vulvar precancerous lesions were reported poorly, and the role of human papillomavirus in some of these lesions is still unclear. STUDY DESIGN: In a direct enzyme-linked immunosorbent assay, serum samples from 126 healthy control subjects, 97 women with lichen sclerosus with or without squamous hyperplasia, 78 women with vulvar intraepithelial neoplasia, and 16 women with verrucous carcinoma were examined for immunoglobulin G and A antibodies to L1 virus-like particles of genital human papillomavirus types 6, 11, 16, 18, and 31, cutaneous human papillomavirus type 8, bovine papilloma virus, and cottontail rabbit papilloma virus. RESULTS: In lichen sclerosus/squamous hyperplasia with atypia immunoglobulin G and A, antibody positivity rates to high-risk human papillomavirus virus-like particle types 16, 18, and 31 were significantly higher than in the control group and the lichen sclerosus/squamous hyperplasia group without atypia. In patients with vulvar intraepithelial neoplasia I, increased immunoglobulin G antibody prevalences with both high-risk and low-risk human papillomavirus-virus-like particles were detected; whereas in patients with vulvar intraepithelial neoplasia II/III, this was observed only with the human papillomavirus types 16, 18, and 31. When only reactivities with 2 genital human papillomavirus types were compared, percentages of positives to only 1 of these 2 types ranged between 43% and 82%, with regard to all respective positives. CONCLUSION: Our data support the role of high-risk human papillomavirus types, mainly human papillomavirus-16, in the pathogenesis of different vulvar lesions with atypia. Serologically, there are no indications that lichen sclerosus/squamous hyperplasia without atypia is associated with human papillomavirus, but high-risk human papillomavirus in lichen sclerosus/squamous hyperplasia with atypia could play a role in carcinogenesis. High antibody specificity was clearly demonstrated among 5 genital, 1 cutaneous human, and 2 animal papillomavirus types.     

Treatment of lichen sclerosus with topical dihydrotestosterone

Lichen sclerosus typically affects the vulva of postmenopausal women. Because serum levels of dihydrotestosterone are low in women with vulvar lichen sclerosus and because dihydrotestosterone is an effector androgen in vulvar skin, this double-blind cross-over study assessed five women with vulvar lichen sclerosus to determine the response to treatment with dihydrotestosterone. Objective gross and microscopic improvement in lichen sclerosus accompanied sustained treatment with topical dihydrotestosterone, but not with vehicle alone. However, there was no change in symptoms (itching and dyspareunia) in these women, although dihydrotestosterone did improve some of the features of vulvar lichen sclerosus and may represent a new treatment for this disease.     

Childhood anogenital lichen sclerosus. A case report

Childhood lichen sclerosus is a rare disorder. A 4-year-old girl with chronic vulvar pruritus who was initially suspected to be the victim of child abuse was treated. Vulvar biopsy was performed, confirming the diagnosis of lichen sclerosus. The child was treated with 2% progesterone cream, with complete resolution of her pruritic symptoms and signs of traumatic injury to the vulvar skin. The basic condition, lichen sclerosus, has persisted.     

Involucrin expression in vulvar lesions

Involucrin, a precursor of the envelope protein present in human stratum corneum, may be used as a histologic marker. Involucrin expression was studied in biopsy specimens from different types of vulvar lesions. In general, the pattern of staining for involucrin has been the one described for similar pathologies of the integument in other bodily areas. However, an unexpected pattern was noted in lichen sclerosus of the vulva.     

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.     

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.     

Increased osteopontin expression is associated with progression from vulvar precancerous lesions to vulvar squamous cell carcinoma

Purpose

Vulvar squamous cell carcinoma (VSCC) contributes to about 3–5 % of all gynecological cancers. Vulvar intraepithelial neoplasia (VIN) and vulvar lichen sclerosus (VLS) are regarded as precancerous lesions. Early detection and treatment of precancerous lesions may prevent development of VSCC. Osteopontin (OPN) has been shown to be involved in many physiological and pathological processes, such as tumor progression, by promoting cancer cell invasion and metastasis. As a result of these findings, OPN has been described as a potential marker for tumor progression in some malignancies. In this study, we investigated the expression of OPN in vulvar tissue specimens and compared its expression between different histopathological grades.

Methods

In the present study, the expression patterns of OPN in 80 paraffin-embedded tissue specimens, including 25 VSCC samples, 21 VIN lesions and 21 VLS, in addition to 13 normal vulvar samples, were examined by the immunohistochemical method and chromogenic in situ hybridization.

Results

The intensity of OPN expression steadily increased according to the pathological grades. In addition, OPN staining was found in the extracellular matrix in VSCC.

Conclusions

Expression levels of OPN increased from VLS and VIN to VSCC, and steadily increased with the pathological stage of VSCC. Our results suggest that OPN may be associated with the progression of VSCC.     

Adolescent Vulvar Angiokeratoma Associated with Lichen Sclerosus

BackgroundWe present an adolescent with multiple vulvar angiokeratomas within a background of lichen sclerosus.CaseA 13-year-old girl presented with vulvar pruritus and wart-like vulvar lesions. Four lesions were resected because of discomfort and uncertainty of the diagnosis. Pathology revealed angiokeratomas with chronic inflammation suggestive of lichen sclerosus. Postoperatively, pruritus continued in the largest excised lesion, which was associated with lichen sclerosus, and symptoms were treated successfully with topical steroids.Summary and ConclusionVulvar angiokeratomas are asymptomatic red papular lesions and are rare in the female adolescent population. In this case, the pathology revealed the rare co-occurrence of angiokeratomas and lichen sclerosus. Biopsies of vulvar vascular lesions in symptomatic adolescents are recommended. Vulvar angiokeratomas might manifest rare genetic disease in otherwise asymptomatic female patients and warrant further follow-up.     

Predicting postoperative voiding efficiency after operation for incontinence and prolapse

OBJECTIVE: The objective of this study is to assess the usefulness of perineoplasty for introital stenosis related to vulvar lichen sclerosus. STUDY DESIGN: The records of 64 patients who underwent perineoplasty for this indication were reviewed retrospectively. The median age of patients was 49 years, and the median duration of lichen sclerosus was 60 months. Ninety percent of patients complained of dyspareunia. Patient satisfaction with the outcome was assessed by means of a questionnaire. Persistence of dyspareunia and impaired quality of sexual intercourse were considered as treatment failure. Risk factors of failure that were evaluated included duration of lichen sclerosus, age, previous topical steroid therapy, previous perineotomy, time since surgery, and histologic stage. Statistical analysis was performed by use of Fisher exact test. RESULTS: Of the 64 patients, 12 were lost to follow-up and 2 patients did not respond to the questionnaire. Perineoplasty improved dyspareunia in 45 of the 50 patients (90%) and quality of sexual intercourse in 43 of 50 patients (86%). None of the risk factors evaluated were associated with failure of perineoplasty. CONCLUSION: Perineoplasty provides good functional results for women with introital stenosis related to vulvar lichen sclerosus.