Lichen Sclerosus Patients Research Articles

Management of Lichen Sclerosus With Triamcinolone Ointment

To determine whether topical triamcinolone ointment effectively reduces patient's symptoms for the management of lichen sclerosus (LS). A retrospective chart review of LS patients seen during 2004 to 2008 in the Saint Louis University Vulvar Clinic was conducted. Inclusion criteria were biopsy-confirmed LS and age 18 years and older. Data were collected at the initial visit and at 6 to 10 weeks, 3 months, and 6 months of follow-up. Effectiveness was assessed using symptom scores on a Likert scale. Data were analyzed using either paired t tests or nonparametric Wilcoxon signed rank tests using a p value less than.05 to denote statistical significance. Of 41 women, 34 met inclusion criteria. Vulvar pruritus was the most frequently reported vulvar symptom, occurring in 32 (94.1%) of 34 women. Dyspareunia, vulvar burning, and vulvar pain were reported in 17 (54.8%) of 31, 22 (64.7%) of 34, and in 13 (38.2%) of 34 women, respectively. Statistically significant reductions in mean symptom scores between the initial and the 6- to 10-week follow-up visits were found for dyspareunia, vulvar burning, vulvar pruritus, and pain (p values < .05 to < .001) and at 3-month follow-up visits for dyspareunia, vulvar burning, and vulvar pruritus (p < .05). Complete symptom relief was reported for 8 (47.1%) of 17 women with dyspareunia, 19 (86.4%) of 22 women with vulvar burning, 23 (71.9%) of 32 women with vulvar pruritus, and 12 (92.3%) of 13 women with vulvar pain. Topical triamcinolone ointment is an effective treatment for the management of LS based on the significant reduction of patient symptom scores. Inherent risks with long-term use of high-potency corticosteroids should prompt all practitioners to consider triamcinolone ointment as a safer long-term treatment for patients with LS.

Differential expression of connective tissue growth factor and extracellular matrix proteins in lichen sclerosus

The histopathology of lichen sclerosus (LS) suggests abnormalities in extracellular matrix (ECM) composition. We aimed to investigate the expression pattern of ECM proteins and related growths factors and Smad signal transducers in LS as compared with healthy skin. To assess the expression of decorin, biglycan, versican, perlecan, fibronectin, dermatopontin, extracellular matrix protein 1 (ECM-1), matrix metalloproteinase 1, tissue inhibitor of metalloproteinase 1, connective tissue growth factor (CTGF), transforming growth factor β1, and Smad-3 protein, real-time RT-PCR and immunohistochemistry were performed on skin specimens obtained from the genital region of healthy subjects (n = 10) as well as LS patients (n = 26). Median mRNA as well as mean protein expression of biglycan, versican, fibronectin, and ECM-1 was significantly higher in LS when compared with healthy controls. Both mRNA and protein CTGF expression observed in LS was significantly higher than in controls. CTGF mRNA expression significantly correlated with mRNA expression of biglycan, versican and fibronectin. Expression of ECM proteins (e.g. proteoglycans, ECM-1) and CTGF is altered in LS. TGF-ß/Smad-3 independent up-regulation of CTGF may induce accumulation of ECM proteins and maintain fibrosis in chronic LS.

978 PENILE CANCER BIOMARKERS IN MEN WITH LICHEN SCLEROSUS

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease1 Apr 2011978 PENILE CANCER BIOMARKERS IN MEN WITH LICHEN SCLEROSUS Joshua Meeks, Tao Qi, Shreenath Bishu, chris gonzalez, and Ximing Yang Joshua MeeksJoshua Meeks Chicago, IL More articles by this author , Tao QiTao Qi Chicago, IL More articles by this author , Shreenath BishuShreenath Bishu Chicago, IL More articles by this author , chris gonzalezchris gonzalez Chicago, IL More articles by this author , and Ximing YangXiming Yang Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.989AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lichen sclerosus (LS) is an inflammatory disorder that affects the genital skin and urethra of men. Rare cases of LS can undergo malignant transformation and result in penile carcinoma. The relationship between LS and squamous cell cancer (SCCA) of the penis remain unclear and LS may be a premalignant state. In order to evaluate if LS is associated with cytological changes that occur in SCCA of the penis, we performed immunohistochemical analysis of tissues from men with LS. METHODS Tissue from men that underwent urethroplasty, penile biopsy or circumcision were subjected to immunohistochemistry specific for the tumor suppressors p53, p16, and the proliferative marker Ki67. Immunostains were semiquantitated and compared to those of penile squamous cell carcinoma by genitourinary pathologists. RESULTS A total of 38 men had a histological diagnosis of LS. Urethral strictures were found in 12 of 38 cases (32%). Chronic non-specific inflammation was found in 26/38 (68%) cases, while the remaining 32% demonstrated sclerotic fibrosis. Nuclear overexpression of p53, a tumor suppressor gene upregulated in cancer, was found in only 10(26%) of LS tissues. The cell-cycle regulating tumor suppressor p16, a target of the human papilloma virus oncoprotein E7, was upregulated at low levels in 27 patients (71%) and high levels in 5(13%). In addition to the high level of p53 and p16 immunoreactivitiy, penile SCCA demonstrated a high level of cellular proliferation by high Ki67 reactivity. Tissue from LS patients had relatively little proliferative activity with 23 patients demonstrating weak or focal staining (60%) and only 5 (13%) expressing strong nuclear Ki67 staining. CONCLUSIONS Based on histologic and immunohistochemical profiles, LS can be divided into two groups that may represent early (inflammatory) and late (sclerosing) phases of the disease or different risk groups for penile cancer development. A subset of patients in the inflammatory group shared similarities to penile squamous cell carcinoma by immunostaining, while the majority of LS showed low proliferative activity and negativity for p53 and p16, which does not suggesting a pre-malignant lesion. These markers may be useful in patients with LS for evaluation of their risks for developing squamous cell carcinoma. Future prospective studies are needed to determine the predictive value of these biomarkers in men with LS. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e394 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Meeks Chicago, IL More articles by this author Tao Qi Chicago, IL More articles by this author Shreenath Bishu Chicago, IL More articles by this author chris gonzalez Chicago, IL More articles by this author Ximing Yang Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cell cycle regulation and proliferation in lichen sclerosus

IntroductionGenital lichen sclerosus (LS) is considered a potential precursor lesion of squamous cell carcinoma. We aimed to investigate the expression pattern of cell cycle regulators, tumour suppressor proteins and proliferation markers in genital LS as compared to extragenital LS (ELS) and healthy controls (HC). MethodsIn order to assess the expression of minichromosome maintenance protein 3 (MCM3), MCM7, Ki-67, cyclin D1, cyclin E, p16, p21, and p53, immunohistochemistry and immunofluorescence were performed on skin specimens obtained from the genital region of LS patients (short-standing LS, n=19; long-standing LS, n=15), patients with ELS (n=10), and HC (n=8). ResultsMedian protein expression of MCM3 and Ki-67 was significantly higher in LS when compared to ELS and HC. In patients with long-standing LS, the expression profiles of MCM3 and Ki-67 significantly correlated. Moreover, long-standing LS lesions showed significantly increased expression of p53 when compared to short-standing LS, ELS, and HS. Immunoreactivity of MCM7, p16, p21, cyclin D1 and cyclin E did not significantly differ between the groups. ConclusionsTumour suppressor proteins such as p53 are significantly overexpressed in genital LS when compared to extragenital disease and healthy skin. The significant p53 overexpression, particularly in long-standing genital lesions, may reflect the increased risk of malignant transformation and/or oxidative stress associated with LS. Moreover, we have demonstrated that proliferation markers such as Ki-67 and MCM3 are significantly up-regulated in genital LS as compared to controls. With regard to cell cycle regulation and proliferation rates, ELS significantly differs from its genital counterpart.

Lichen Sclerosus

To compare the treatment and follow-up of patients with lichen sclerosus (LS) at the departments of Gynaecology and Dermatology at the Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, to evaluate the need for a multidisciplinary vulvar clinic. Treatment and follow-up data of all women with histologically proven (between January 1995 and January 2001) anogenital LS visiting the outpatient clinics of the departments of Obstetrics & Gynaecology and Dermatology were collected (last date of follow-up: January 2008). Eighty-four patients with LS were included in this study, 10 patients (12%) of which were treated by both specialties. At the Gynaecology department, LS patients more often received surgical treatment, topical estrogens, and lidocaine ointment, whereas at the Dermatology department, local class 2/3 corticosteroids were more often prescribed. Follow-up frequencies were similar in both specialties and took place at 3 to 4 visits in the first year and at least once a year afterward. One patient developed vulvar squamous cell carcinoma. This patient had withdrawn from follow-up and had her condition diagnosed with carcinoma 74 months after the LS had been diagnosed. Although no hospital guidelines existed, management of patients with LS agreed with current recommendations in the literature, although differences in secondary and supportive therapy existed owing to differences in expertise. The relatively high percentage of patients treated by both specialties with a high frequency of visits emphasizes the need for a multidisciplinary clinic for vulvar disease.

849 ROLE OF TESTOSTERONE IN THE PATHOGENESIS AND TREATMENT OF LICHEN SCLEROSUS

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease III1 Apr 2010849 ROLE OF TESTOSTERONE IN THE PATHOGENESIS AND TREATMENT OF LICHEN SCLEROSUS Joshua Meeks, Tao Qi, John Cashy, Ximing Yang, and Chris Gonzalez Joshua MeeksJoshua Meeks More articles by this author , Tao QiTao Qi More articles by this author , John CashyJohn Cashy More articles by this author , Ximing YangXiming Yang More articles by this author , and Chris GonzalezChris Gonzalez More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2351AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lichen sclerosus (LS) is an inflammatory disorder that affects the urethra of men and genital skin of both men and women. Testosterone cream has been used to treat vulvar lichen sclerosus but the role of hormonal deficiency and testosterone application in the treatment of LS remains undescribed. The goal of our study was to determine the frequency of hypogonadism in men with LS and quantify the expression of the androgen receptor in tissue from men with LS. METHODS From the Northwestern University Enterprise Data Warehouse, a database of over 2 million patients cared for at Northwestern University from 1986 to 2009, men with pathologically identified LS were identified. As a control population, a cohort of control men matched 5:1 by both age and race were identified from the men who presented to our urology department for any treatment. A diagnosis of hypogonadism was identified by ICD9 code and medications used to treat hypogonadism were selected from a list of medications prescribed by physicians. Immunohistochemistical analysis was performed on formalin-fixed and paraffin embedded tissue sections of men with LS using standard protocols and immunoreactivity for the androgen receptor (AR) was determined by a urological pathologist. RESULTS A total of 97 men were identified to have biopsy proven LS and this cohort was compared to 485 men without LS as a control population. Of men with LS 3(3%) had a diagnosis of hypogonadism as compared to 62 men (12.8%) in the control population (p=0.006). There were no men with LS receiving testosterone supplementation for hypogonadism as compared to 12 men (2.5%) of the control population (p=0.11). Immunohistochemical analysis of 31 specimens for AR expression was performed to determine if tissues affected by LS could benefit from treatment with testosterone application. Weak (focal) or cytoplasmic expression of the AR was found in 9 (29%) men, while strong nuclear positive expression was identified in only 7 (22%). CONCLUSIONS Men with LS rarely have an associated diagnosis of hypogonadism and none have undergone testosterone supplementation at our institution. Importantly, immunohistochemical analysis of LS affected tissue did not demonstrate androgen receptor expression in the majority of specimens from men with LS. This suggests that local testosterone application would have benefit in only a subset of LS patients. Chicago, IL© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e331 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Meeks More articles by this author Tao Qi More articles by this author John Cashy More articles by this author Ximing Yang More articles by this author Chris Gonzalez More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

T cells reactive with the NC16A domain of BP180 are present in vulval lichen sclerosus and lichen planus

Lichen sclerosus (LS) is a chronic inflammatory skin condition. The recent demonstration of circulating autoantibodies to extracellular matrix protein 1 and to basement membrane zone (BMZ) components, chiefly BP180, suggests that autoimmunity to these components might contribute to pathogenesis. However, there is no binding of autoantibodies in vivo and as LS is characterized by a lymphocytic infiltrate, it seems likely that LS is mediated, in part, by antigen-specific lymphocytes. Similar mechanisms may apply to vulval lichen planus (LP), an interface dermatitis, with clinical and immunological overlap with LS. This study aims to test the hypothesis that T cells reactive with the NC16A domain of BP180 are present in the peripheral blood of patients with vulval LS and LP. Isolated peripheral blood mononuclear cells from 14 patients with vulval LS, 5 with vulval LP and 4 healthy controls were grown in vitro. We examined for immunogenicity of overlapping peptides spanning the NC16A domain of BP180 using interferon-gamma enzyme-linked immunospot assay (ELIspot) on the cultured T-cell lines. BMZ antibodies were assayed, HLA type determined and clinical parameters noted. Significant interferon-gamma production was observed in response to the NC16A peptides in 6 of the 14 vulval LS and 2 of the 5 LP patients, but not in the control subjects. There was an associated autoantibody response to BP180 in 3 LS and 1 LP patient with T-cell responses. These data suggest that in some vulval LS and LP patients, NC16A domain-specific T cells circulate at sufficiently high frequency to be detectable in vitro and show rapid effector function. There was no association with HLA type or clinical parameters. We have demonstrated that in > 40% of our vulval LS and LP patients, the NC16A domain of BP180 is a target for circulating T cells, and in vulval LS and LP there are associated autoantibodies to BP180.

High Prevalence of Concomitant Anogenital Lichen Sclerosus and Extragenital Psoriasis in Adult Women

To analyze the prevalence of lichen sclerosus and psoriasis in gynecologic patients. The prevalence of lichen sclerosus and psoriasis individually, as well as the prevalence of both diseases in the same patient, was evaluated among 2,800 women attending a primary care gynecology practice for annual routine gynecologic examinations. The incidence of lichen sclerosus (new diagnosis of lichen sclerosus per year/population at risk) was calculated for the last 5 years. Two hundred (7.1%) women had a biopsy-proven anogenital lichen sclerosus, and 57 women (2%) had an extragenital psoriasis vulgaris. Fifteen women had both diseases (0.5%). The prevalence of psoriasis in lichen sclerosus patients was 7.5% (15 of 200; 95% confidence interval 4.3-12.1%) compared with 1.6% (42 of 2,600) in the non-lichen sclerosus patient group. Lichen sclerosus was diagnosed in 13 of 15 psoriasis patients at an average of 19.5 years after the diagnosis of psoriasis at the age of 48 years (range 30-70 years). The incidence rates of lichen sclerosus for the last 5 years were 0.5% in 2002, 0.7% in 2003 and 2004, 1.9% in 2005, and 1.8% in 2006. The prevalence of psoriasis in lichen sclerosus patients (7.5%) is higher than in the general population and among the non-lichen sclerosus patients in this practice (1.6%). This association may result from a similar immune dysregulation in these women. II.

Safety and Tolerability of Adjuvant Topical Tacrolimus Treatment in Boys with Lichen Sclerosus: A Prospective Phase 2 Study

BackgroundManagement of lichen sclerosus (LS) in boys is still controversial. Although in most cases only the prepuce is affected, meatal and urethral involvement may require major surgical reconstruction with substantial morbidity. ObjectiveBecause the frequency of such complicated courses is still unclear, an adjuvant postoperative treatment is highly desirable. Therefore, we addressed safety and tolerability of tacrolimus 0.1% ointment in the postoperative period. Design, Setting, and ParticipantsAmong 222 penile surgeries, in 25 cases LS was confirmed histologically and 20 of those patients participated in the adjuvant treatment study. Moreover, 18 patients of the same cohort showed a lichenoid inflammatory reaction pattern suggestive of early but not fully established LS. Interventions and MeasurementsSubsequent to the operation and after explicit information about off-label use, parents applied tacrolimus 0.1% ointment twice daily to the glans and the meatus for 3 wk in cases of proven LS. The 18 patients with possible early LS were followed up only without any treatment. Clinical follow-up was performed up to 13 mo (median). Results and LimitationsAll 20 LS patients completed the topical treatment without any relevant side-effects. Two relapses occurred in the treatment group and were clinically cured with an additional 3-wk cycle of topical tacrolimus 0.1% ointment. None of the 18 early LS cases progressed to full-scale LS. ConclusionsThis is the first study showing that tacrolimus 0.1% ointment applied immediately after surgery of fully established LS is a tolerable and most probably safe adjuvant novel treatment option. Because the therapy led to disease control in all treated individuals for >1 yr (median), this study establishes the groundwork for future trials with expanded treatment and follow-up periods to verify the true clinical benefit of tacrolimus in patients after LS surgery. Lichenoid tissue reactions suggestive of early LS seem to require no adjuvant treatment.

Early onset vulvar Lichen Sclerosus in premenopausal women and oral contraceptives

Objective For vulvar Lichen sclerosus (LS) immunological factors, genetic predisposition, and decreased 5 alpha-reductase activity have been discussed as aetiological factors. During the last decade an increase of LS in young women has been suspected. Aim of this study was to evaluate data of premenopausal women with early onset LS to find potential risk factors focussing on the use of oral contraceptives. Study design We retrospectively analyzed the data of 40 premenopausal patients with early onset LS regarding use of oral contraceptives (OCPs), and first occurrence of LS. To compare these data in a case-control study we analyzed a matched control group of 110 healthy women. Results All our LS patients were using OCPs compared to 73 women (66.4%) in the control group. OCPs with anti-androgenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone) were used by 28 (70%) of the LS patients and by 35 (47.9%) of the 73 women using OCPs in the control group. Thus, the odds ratio for early onset LS for women using anti-androgenic OCPs was 2.53 (95% CI: 1.12–5.75). Conclusion Our data suggest that disturbance of the androgen dependent growth of the vulvar skin by OCPs and especially by OCPs with anti-androgenic properties might trigger the early onset of LS in a subgroup of susceptible young women.

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.

A clinical study of vulval lichen sclerosus at a tertiary care hospital in South India

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that causes substantial discomfort and morbidity, most commonly in adult women. The objective of our study is to study the pattern of vulval LS and to correlate LS with various clinical parameters. The study included 26 female patients with vulval LS presenting over a period of 22 months, starting from September 2005 to June 2007. Demographic characteristics and clinical findings were recorded. The mean age of LS patients was 44 years (range 3-65 years). Lichen sclerosus was most commonly observed in postmenopausal women (18, 69.2%), followed by women in reproductive age group (5, 19.23%), and prepubertal girls (3, 11.5%). All patients presented with ivory white atrophic plaque. Surface of the plaque showed telangiectasia in one patient; both erosions and fissuring in two patients, ­erosions in four patients, fissuring in two patients, and wrinkling in all patients. Introitus was stenosed in five (19.2%) patients, out of which three (11.5%) patients also had perianal involvement leading to figure of 8 appearance. Three patients had atrophy of labia minora and clitoris to an extent that labia minora appeared merged with labia majora and clitoris was buried. This study highlights the importance of diagnosing LS as it is associated with considerable morbidity.

The Association Between HLA DR, DQ Antigens, and Vulval Lichen Sclerosus in the UK: HLA DRB1*12 and its Associated DRB1*12/DQB1*0301/04/09/010 Haplotype Confers Susceptibility to Vulval Lichen Sclerosus, and HLA DRB1*0301/04 and its Associated DRB1*0301/04/DQB1*0201/02/03 Haplotype Protects from Vulval Lichen Sclerosus

Lichen sclerosus (LS) is considered to have an immunogenetic background. Several small studies, using serological typing, have reported that HLA-DR11, DR12, and DQ7 were increased in LS, with DR17 less frequent. This study aimed to validate and detect new HLA-DR and DQ associations with LS in females and its characteristic clinical parameters. The cases, 187 female LS patients, and 354 healthy controls were all UK North Europeans. PCR-sequence specific primers method was applied to genotype the HLA-DR, DQ polymorphisms that correspond to 17 serologically defined DR and seven DQ antigens. Statistical analysis was performed with two-tailed Fisher's exact test with Bonferroni adjustment (p value after Bonferrroni adjustment, Pc). We found increased frequency of DRB1*12 (DR12) (11.2%vs 2.5%, pc < 0.01) and the haplotype DRB1*12/DQB1*0301/04/09/010 (11.2%vs 2.5%, p < 0.001, pc < 0.05), and a lower frequency of DRB1*0301/04 (DR17) (11.8%vs 25.8%, pc < 0.01) and the haplotype DRB1*03/DQB1*02DRB1*0301/DQB1*0201/02/03 (11.2%vs 24.6%, pc < 0.0001) in patients compared with controls. HLA DR and DQ antigens were not associated with time of onset of disease, site of involvement, structural changes of genitals, and response to treatment with potent topical steroids. In conclusion, HLA-DR and DQ antigens or their haplotypes appear to be involved in both susceptibility to and protection from LS.

Association of penile lichen sclerosus and oncogenic human papillomavirus infection

Data on the prevalence of human papillomavirus (HPV) infection in patients with penile lichen sclerosus (LS) are scant and controversial. To investigate the prevalence of HPV infections in patients with penile LS. HPV infection was assessed by polymerase chain reaction (PCR) in paraffin-embedded penile biopsies obtained from the glans or inner foreskin of 46 adult patients with penile LS, and in brush cytology smears of penile healthy mucosa from an equal number of randomly selected control males matched for age. Statistical evaluation was performed using conditional logistic regression analysis. PCR disclosed the presence of HPV infection in 17.4% of LS patients (HPV 16, six cases; HPV 18, one case; HPV 45, one case). Amongst the controls, HPV infection occurred in 8.7% of patients (HPV 16, two cases; HPV 53, one case; HPV 70, one case). Statistical regression analysis confirmed that the rate of HPV infection was higher amongst patients with genital LS than amongst healthy controls [odds ratio (OR), 2.55; 95% confidence interval (CI), 0.73-8.89]. Infection with oncogenic "high-risk" HPV types in patients with genital LS may enhance the risk of penile cancer arising on LS.

Characterization of IgG autoantibodies to extracellular matrix protein 1 in lichen sclerosus.

Although the precise aetiology of lichen sclerosus is unknown, evidence for an autoimmune basis to the disorder is emerging. Indeed, circulating IgG autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been demonstrated in the sera of about 75% of affected individuals. To assess this humoral immune response further, immunoblotting was performed using bacterial recombinant proteins spanning different domains of the ECM1 protein. The aim was to identify autoantibody-reactive sites recognized by 90 lichen sclerosus sera. The subclass distribution of anti-ECM1 IgG autoantibodies was also determined in 54 lichen sclerosus sera. Immunoblotting showed that the IgG autoantibodies from lichen sclerosus patients recognize multiple antigenic reactive sites on the ECM1 protein within both the amino terminus (50/90, 55.6%) and the protein loop cysteine-rich repeat domains (54/90, 60%), although few sera (7/90, 7.8%) had antibodies to the carboxyl terminus of ECM1. IgG subclass analysis revealed that the anti-ECM1 autoantibodies belong predominantly to the IgG(2) subclass (48/54, 88.9%), either IgG(2) alone (28/54, 51.9%) or in combination with one or more other IgG subclasses. No correlation was found between the site(s) of the ECM1 epitopes or the anti-ECM1 IgG profile and any specific clinical parameters. Nevertheless, characterization of anti-ECM1 antibodies does provide further insight into humoral immune responses and understanding disease mechanisms in lichen sclerosus.

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus.

Lichen sclerosus is a common, acquired chronic inflammatory skin disease of unknown etiology, although circulating autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been detected in most patients' sera. We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed an ELISA system for serologic diagnosis, and assessed clinicopathological correlation between ELISA titer and disease. Epitope-mapping studies revealed that lichen sclerosus sera most frequently recognized the distal second tandem repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody reactivity against this immunodominant epitope in 413 individuals (95 subjects with lichen sclerosus, 161 normal control subjects, and 157 subjects with other autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity. It was also highly specific (93.7%) in discriminating between lichen sclerosus and other disease/control sera. Higher anti-ECM1 titers also correlated with more longstanding and refractory disease and cases complicated by squamous cell carcinoma. Furthermore, passive transfer of affinity-purified patient IgG reproduced some histologic and immunopathologic features of lichen sclerosus skin. This new ELISA is valuable for the accurate detection and quantification of anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in patients with lichen sclerosus.

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

Lichen sclerosus is a common, acquired chronic inflammatory skin disease of unknown etiology, although circulating autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been detected in most patients’ sera. We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed an ELISA system for serologic diagnosis, and assessed clinicopathological correlation between ELISA titer and disease. Epitope-mapping studies revealed that lichen sclerosus sera most frequently recognized the distal second tandem repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody reactivity against this immunodominant epitope in 413 individuals (95 subjects with lichen sclerosus, 161 normal control subjects, and 157 subjects with other autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity. It was also highly specific (93.7%) in discriminating between lichen sclerosus and other disease/control sera. Higher anti-ECM1 titers also correlated with more longstanding and refractory disease and cases complicated by squamous cell carcinoma. Furthermore, passive transfer of affinity-purified patient IgG reproduced some histologic and immunopathologic features of lichen sclerosus skin. This new ELISA is valuable for the accurate detection and quantification of anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in patients with lichen sclerosus.

Lichen Sclerosus in 68 Patients With Squamous Cell Carcinoma of the Penis

Lichen sclerosus, an unusual chronic mucocutaneous condition of the penis, has been found in association with invasive penile cancer, and squamous cell carcinoma has been reported in patients with longstanding lichen sclerosus. The aim of this study was to determine the anatomic distribution and prevalence of lichen sclerosus in patients with squamous cell carcinoma of the penis and to search for a correlation with special types of carcinomas. Clinical and pathologic data from 207 penectomy and circumcision specimens with squamous cell carcinomas and giant condylomas were evaluated, and 68 patients with lichen sclerosus were identified. Mean age was 61 years. The preferential anatomic site of lichen sclerosus was the foreskin, but other sites (glans and coronal sulcus) including urethra were also involved. Grossly, the lesions showed white-gray smooth or irregular patches and plaques adjacent to invasive cancers. Microscopically, the lesion was stromal-epithelial with atrophic and hyperplastic epithelium and edematous or densely eosinophilic hyalinized lamina propria. A variable band of lymphocytic infiltration beneath the sclerosis was noted. Lichen sclerosus were preferentially associated with non-human papillomavirus variants of squamous cell carcinoma. When lichen sclerosus was associated with malignancy, it often showed, in addition to the hyperplastic epithelium, a low-grade squamous intraepithelial lesion. These findings suggest that lichen sclerosus may represent preneoplastic condition for at least some types of penile cancers, in particular those not related to human papillomavirus.

High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis.

There is a well-documented association between lichen sclerosus (LS) and vulval carcinoma in women; however, until recently, there have only been anecdotal reports of penile squamous cell carcinoma (SCC) occurring in men with LS. The incidence of penile carcinoma occurring on a background of LS remains uncertain, and we wished to examine this possible association further. To address this, all the cases (n = 20) of penile SCC held on our pathology database (4 years) were examined. Histology was reviewed, blind to the clinical picture, for evidence of LS, applying strict histological criteria. Subsequently, clinical notes were reviewed for history of LS before the SCC presented, and history of previous circumcision, treatments, node involvement, metastases and death. In eight cases, evidence of LS was found in the excision specimen. Seven of these had well-differentiated SCC. In the 12 cases with no evidence of LS, only three were well differentiated. With case note review, seven had a history of LS (four with histological LS), sometimes preceding the SCC by 10 years. These all had well-differentiated SCC. Ten of the 20 patients are dead, seven from metastatic disease. Four deaths occurred in the 'well-differentiated LS' group, but only one from penile SCC metastatic disease. There appears to be a definite association between SCC of the penis and the presence of LS, similar to that reported between LS and vulval SCC in women. Of the 20 patients with penile SCC studied, 11 had a clinical history and/or histological evidence of LS. However, clinical presentation of the LS or need for circumcision may precede the SCC by many years. As follow-up is impractical, counselling at the time of diagnosis is very important, and it is essential that medical practitioners are aware of this association so that the subsequent risk from SCC is reduced.

Alterations in Distribution of Tenascin, Fibronectin and Fibrinogen in Vulval Lichen sclerosus

Background: The pathophysiology of lichen sclerosus remains uncertain. The clinical features, including increased fragility and scarring, and the histology suggest that significant reorganisation of the extracellular matrix is occurring. Tenascin, fibrinogen and fibronectin are extracellular matrix components that play a significant role in tissue remodelling, for example during wound repair. Aim: To examine the distribution of tenascin, fibrinogen and fibronectin in vulval lichen sclerosus. Materials and Methods: Immunohistochemical staining was performed to study the distribution of tenascin, fibronectin and fibrinogen in 16 specimens of untreated vulval lichen sclerosus and 1 specimen of extragenital lichen sclerosus. Haematoxylin and eosin staining of the specimens was also performed to identify the position of the pale staining homogenous zone/zone of sclerosis and the inflammatory infiltrate below this. The control tissues studied included biopsies taken from the uninvolved thigh of 13 of the lichen sclerosus patients and 6 samples of normal vulva tissue obtained during gynaecological procedures from women of similar age to the lichen sclerosus women. Results: All the lichen sclerosus specimens demonstrated increased immunostaining of tenascin in the upper dermis and comparing this with the haematoxylin and eosin staining this corresponded to the zone of sclerosis with relatively little tenascin staining associated with the inflammatory band. In 14 out of the 16 vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen fibrinogen immunostaining was increased in the upper dermis which corresponded – in haematoxylin and eosin staining – to the zone of sclerosis. There was also slightly increased fibrinogen staining in the mid dermis which corresponded to the inflammatory band. Fibronectin staining was reduced in the upper dermis of 12 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen which corresponded to the zone of sclerosis. However, in 14 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen, fibronectin was slightly increased in the mid and deeper dermis which corresponded to the zone of inflammatory cells and the area below this. There was also increased fibronectin staining around blood vessel walls both in the mid dermis and within the zone of sclerosis. Conclusion: The distribution of tenascin, fibrinogen and fibronectin is altered in lichen sclerosus and the alteration in these extracellular matrix components may be relevant to the initiation of scarring in lichen sclerosus and the associated increased skin fragility.