Transcriptome Profiling and Network Analysis Provide Insights Into the Pathogenesis of Vulvar Lichen Sclerosus.
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SUBMITTER: Wang L
PROVIDER: S-EPMC9247155 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Vulvar lichen sclerosus (LS) is a chronic, inflammatory dermatosis that may lead to scarring of the vulva and sexual dysfunction. LS affects women of all ages and often goes unrecognized and underreported. Uncertainty continues to exist around its pathogenesis, histologic diagnosis, and treatment. However, there have been great advances in our understanding of autoimmunogenic targets in disease formation and progression. In addition, there has been recent investigation of potential non-steroid-based treatments, including platelet-rich plasma therapy and energy-based modalities such as the fractional CO2 laser, photodynamic therapy, and high intensity focused ultrasound. Refinement of surgical techniques for restoring vulvar anatomy and treating clitoral phimosis, introital stenosis, and vulvar granuloma fissuratum is leading to improved patient outcomes. This review summarizes current perspectives on the pathogenesis, symptomatology, diagnosis, and treatment for vulvar lichen sclerosus.
| S-EPMC6970240 | biostudies-literature
Project description:Vulvar lichen sclerosus (VLS) is a chronic inflammatory disorder, which affects women of all ages. The aim of this review is to focus on first-line, second-line, and maintenance therapies as well as follow-up of women with VLS. With numerous controversies, we decided to conduct a scoping review on this subject. A review protocol was developed, and the Knowledge Resource Services website was used to run a search of articles pertaining to VLS with keywords "Vulvar," "Vulval," and "Lichen Sclerosus." The search was limited to published data from the last 10 years, i.e., July 2009 onward, and researches published in English language. A total of 338 articles pertaining to VLS were obtained. Out of this, 62 were original articles related to management of VLS. Effective treatments such as high-potency topical steroids are now the standard of care and first-line treatment. Follow-up may be done every three to six months for the first two years and then at least yearly to ensure adequacy of treatment and encourage compliance. Long-term follow-up in specialist clinics is recommended for women who have persistent complaints, thickened skin, or history of neoplastic lesion. Monitoring young patients yearly is recommended as there are chances of recurrence.
| S-EPMC7995233 | biostudies-literature
Project description:BACKGROUND/AIM:Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. MATERIALS AND METHODS:DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. High-resolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. RESULTS:Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. CONCLUSION:Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.
| S-EPMC7078831 | biostudies-literature
Project description:ObjectiveTo estimate the efficacy of fractionated carbon dioxide (CO2) laser therapy for vulvar lichen sclerosus.MethodsWe conducted a prospective, double-blind, randomized, sham-controlled, trial conducted in a clinic specializing in vulvar disorders. The study participants were 40 women with active vulvar lichen sclerosus confirmed with biopsy who were abstaining from topical and systemic treatments for at least 4 weeks before enrollment. Women were randomized in a 1:1 ratio to receive either five sham laser treatments or five fractionated CO2 treatments in a 24-week period. Study participants, treating clinicians, and the evaluating pathologist were blinded. The primary endpoint was the change in the histopathology scale score between pretreatment and posttreatment biopsies. We estimated 20 per group for 80% power to detect a 40% reduction in the histopathology scale score with up to 10% attrition. A secondary endpoint was the change in the validated CSS (Clinical Scoring System for Vulvar Lichen Sclerosus).ResultsFrom November 2018 to June 2020, 40 women were randomized to participate in the trial, and 37 women (19 fractionated CO2, 18 sham) were included in an intention-to-treat (ITT) analysis. Three women were excluded from the ITT analysis because they did not have posttreatment biopsies and, therefore, a posttreatment histopathology scale score could not be obtained. There was a 0.20 reduction (improvement) in histopathology scale score from baseline in the active treatment group (95% CI -1.1, 0.80, P=.74) and a 0.1 increase from baseline in the sham treatment group (95% CI -0.90, 1.0, P=.91). The change in histopathology scale score between the active and sham arm was not statistically significant (95% CI -1.14, 1.06, P=.76).ConclusionFractionated CO2 is not an effective monotherapy treatment for vulvar lichen sclerosus.Clinical trial registrationClinicalTrials.gov, NCT03665584.Funding sourceAdditional funding for this study was supplied by El.En Group, Florence, Italy, the manufacturer of the laser used in this study. In addition, El.En Group supplied the laser used in the study.
| S-EPMC8132913 | biostudies-literature
Project description:BACKGROUND:Vulvar lichen sclerosus et atrophicus (VLSA) is a chronic inflammatory skin disease of unknown etiology that mainly affects postmenopausal and perimenopausal women. The primary clinical symptoms of VLSA are itching, burning pain, and dyspareunia that can results in decreased quality of life. Existing therapies including topical corticosteroid ointment, topical calcineurin inhibitors, estrogens, are not very effective for treatment of VLSA. OBJECTIVE:To evaluate the effectiveness and safety of 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) in the treatment of VLSA. MATERIALS AND METHODS:Ten patients with VLSA who had failed conventional treatment received ALA-PDT. 10% 5-ALA in an oil-in-water emulsion was applied to the lesions and occluded with plastic film for 3?h, when the lesions were irradiated with 100?mW/cm2, 635 ± 15?nm red light for 20?min. Treatments were repeated three times at 2-week intervals. Objective and subjective symptoms and signs of the vulvar lesions based on horizontal visual analogue scales were recorded at each treatment and 1, 3, and 6 months after the last session. The quality of life was assessed using dermatology life quality index (DLQI) questionnaire. RESULTS:All patients completed three ALA-PDT treatments and the follow-up visits. Clinical symptoms of itching disappeared completely in nine patients, one patient had itching decreased from severe to mild. All subjects showed objective improvement in lesions. The DLQI of all cases improved after treatment. The main side-effects of ALA-PDT were pain, erythema, and swelling. Side-effects were transient and tolerable. All patients reported being "satisfied" or "very satisfied" with their outcomes. CONCLUSIONS:ALA-PDT is an effective and safe approach for the treatment of VLSA.
| S-EPMC5922423 | biostudies-literature
Project description:ObjectiveTo generate a list of items through international expert consensus consisting of both symptoms and clinical signs for inclusion in an adult vulvar lichen sclerosus severity scale.MethodsThis study was carried out as a three-stage Delphi consensus exercise. After an extensive literature review, any items used to determine disease severity in previous clinical trials were compiled into a survey. The Delphi participants were recruited from the International Society for the Study of Vulvovaginal Disease most of whom were gynecologists and in practice for more than 20 years. Participants were asked to rate the importance of these items. Consensus was defined as 75% agreeing that an item was very important or essential toward determining disease severity. Participants were also asked to indicate preferred method of measurement for these items.ResultsOf approximately 400 members of the International Society for the Study of Vulvovaginal Disease, 66 participated in the study. Of the 14 symptoms presented, 7 reached consensus for inclusion. Of the 23 signs presented, 11 reached consensus for inclusion and 1 reached consensus for exclusion. Of the six architectural changes presented, all six reached consensus for inclusion. No consensus was reached regarding method of measurement for any of the symptoms and signs that reached consensus for inclusion.ConclusionInternational consensus was reached for a variety of items for use in an adult vulvar lichen sclerosus severity scale that will be further developed and tested. Ideally, this scale will be used in clinical practice and in research to allow for high-quality trials.
| S-EPMC5768225 | biostudies-literature
Project description:BACKGROUND:Vulvar lichen sclerosus (VLS) is a lymphocyte-mediated disease of unknown etiology that can cause intense itching as well stenosis, hindering the evacuation and urination. It can also limit the sex life due to severe local pruritus, pain and dyspareunia (pain during sexual intercourse). The standard treatment for this disease is the use of topical corticosteroids to reduce the clinical symptoms and to try to increase disease-free intervals. Photodynamic therapy (PDT), a treatment that associates a light radiation with a photosensitizing agent and photobiomodulation (PBM) are therapies that can promote effective immunomodulatory responses at the application site by means of photophysical and photochemical phenomena from the molecular to the systemic level, which promote their use in chronic dermatoses. The aim is to compare the effects of PDT, PBM, and topical corticosteroid in VLS evaluating clinical, histological, immunohistochemical and spectroscopic responses. METHODS:The study is prospective, randomized and controlled, in a population of 60 women with histological diagnoses of VLS. There will be 3 treatments groups: PDT, PBM and topical corticosteroid (control group), where will be allocated by randomization 20 patients in each one. The clinical course will be monitored by measuring local temperature, itching, atrophy, and the area of the lesion. Histologically, the slides will be classified and will have the ordering of collagen fibers quantified. Immunohistochemical analysis will be done using the markers IFN-?, TGF-?, CD4, CD8, IL-1, p53 and Ki-67. Finally, the spectroscopic evaluation will be done by reflectance. Descriptive and inferential statistical analyses will be conducted to compare the groups and make associations between different responses. The study is an open-label for patients with active symptomatic disease with a period of 1 year follow-up to determine the rate of recurrence in each groups. DISCUSSION:The immunological effects of PDT and PBM are described by several authors in inflammatory skin diseases, stimulating the production and organization of the associated collagen. Thus, it is reasonable to determine the efficacy and safety of these new treatments in VLS, in comparison to the control group, analyzing the recurrence time, the impact on the optical properties of the skin, and the benefit to patients. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02416531 .
| S-EPMC5550930 | biostudies-literature
Project description:Importance:Molecular alterations in lichen sclerosus-associated vulvar squamous cell carcinoma (LS-VSCC) are largely unknown. Objective:To determine whether the retinoic acid receptor ? (RAR?) tumor-suppressor gene is involved in the onset and/or progression of LS-VSCC. Design, Setting, and Participants:The case-control study, conducted at University-Hospital of Ferrara, Italy, included 20 LS-VSCC (mean [SD] age, 75 [3] years) and 20 cancer-associated vulvar LS (caVLS; mean [SD] age, 62 [11] years) formalin-fixed embedded tissue specimens, 20 cancer-free vulvar LS (cfVLS), and 20 normal skin fresh specimens from diagnostic biopsies and women surgically treated for nonmalignant skin lesions, respectively. RAR? gene expression and promoter methylation were investigated in LS-VSCC and caVLS adjacent to VSCC specimens, and in cfVLS and normal skin specimens, as controls, by RT-Q real-time polymerase chain reaction (PCR) analysis, and sequencing of PCR-amplified bisulfite-treated DNA. c-Jun expression, an RAR? pathway-related gene, was also investigated. Main Outcomes and Measures:RAR? expression, correlation with its promoter methylation and c-Jun expression, and association with onset or progression of LS-VSCC. Results:In LS-VSCC, RAR? messenger RNA was 3.4-, 3.6-, and 4.8-fold lower than in caVLS (P?=?.001), cfVLS (P?=?.005), and normal skin (P?<?.001), respectively. The RAR? mRNA levels were similar in caVLS, cfVLS, and normal skin. The RAR? promoter was hypermethylated in 18 (90%) of 20 LS-VSCC, 11 (55%) of 20 cfVLS, 10 (50%) of 20 caVLS, and 5 (25%) of 20 in the normal skin group. The degree of methylation of RAR? promoter was higher in LS-VSCC, ranging from 5 to 9 (full promoter methylation) CpGs methylated, than in caVLS (P?=?.02), cfVLS (P?=?.03), or normal skin (P?<?.001), which was up to 5 CpGs methylated. Importantly, 0 of 8 LS-VSCC with 5 to 6 CpGs methylated and 5 (63%) of 8 LS-VSCC with 7 to 8 CpGs methylated were from patients with lymph node metastasis at diagnosis, respectively, whereas there were 2 of 2 (100%) LS-VSCC samples with 9 CpG methylated from patients with lymph node metastasis at diagnosis and subsequent recurrence. In LS-VSCC c-Jun mRNA was 4.3-, 1.4-, and 2.6-fold higher than in caVLS (P?<?.001), cfVLS (P?=?.001), and normal skin (P?<?.001), respectively. The expression of c-Jun was similar in caVLS, cfVLS, and normal skin. Conclusions and Relevance:Hypermethylation-induced RAR? down-expression was associated with LS-VSCC and correlates with the upregulation of c-Jun. The degree of methylation of RAR? promoter increased with the malignancy of LS-VSCC. Therefore, RAR? gene dysregulation may play a role in progression of LS-VSCC, and RAR? promoter methylation status may be used as a prognostic marker in clinical treatment of patients with LS-VSCC.
| S-EPMC6128494 | biostudies-literature
Project description:The etiology of vulvar lichen sclerosus (LS) remains unclear; however, alterations in cutaneous and gut microbiota may be contributing to the pathogenesis of this inflammatory condition. To explore this hypothesis, we conducted a pilot case-control study, obtaining dermal swab and stool samples from prepubertal girls with vulvar LS (n = 5), girls with nonspecific vulvovaginitis (n = 5), and healthy controls (n = 3). Samples (n = 56) were subjected to total DNA extractions. Resulting DNA was purified, subjected to PCR (targeting the V3V4 region of the 16S rRNA gene), sequenced, and analyzed using QIIME, MetagenomeSeq, and DESeq2 software packages. Our findings showed that there were significant differences in the cutaneous and gut microbiotas of girls with LS compared to controls. On the skin, girls with LS had a statistically significantly higher relative abundance of Porphyromonas spp., Parvimonas spp., Peptoniphilus spp., Prevotella spp., Dialister spp., and Peptostreptococcus spp., but a lower relative abundance of Cornyebacterium compared to the control group. In the gut samples, girls with LS had a significantly higher relative abundance of Dialister spp., Clostridiales spp., Paraprevotella spp., Escherichia coli, Bifidobacterium adolescentis, and Akkermansia muciniphila, and a lower relative abundance of Roseburia faecis and Ruminococcus bromii compared to controls. These results suggest a potential association between cutaneous and gut dysbiosis and pediatric vulvar LS. Future studies involving larger samples sizes are warranted to further evaluate this association.
| S-EPMC7808574 | biostudies-literature
Project description:Lichen sclerosus (LS) is an underdiagnosed inflammatory mucocutaneous condition affecting the anogenital areas. Postmenopausal women are predominantly affected and, to a lesser extent, men, prepubertal children, and adolescents. The etiology of LS is still unknown. Hormonal status, frequent trauma and autoimmune diseases are well-known associations for LS, yet infections do not seem to be clear risk factors. LS pathogenesis involves factors such as a genetic predisposition and an immune-mediated Th1-specific IFNγ-induced phenotype. Furthermore, there is a distinct expression of tissue remodeling associated genes as well as microRNAs. Oxidative stress with lipid and DNA peroxidation provides an enabling microenvironment to autoimmunity and carcinogenesis. Circulating IgG autoantibodies against the extracellular matrix protein 1 and hemidesmosome may contribute to the progression of LS or simply represent an epiphenomenon. The typical clinical picture includes chronic whitish atrophic patches along with itching and soreness in the vulvar, perianal and penile regions. In addition to genital scarring, and sexual and urinary dysfunction, LS may also lead to squamous cell carcinoma. Disseminated extragenital LS and oral LS are also reported. The diagnosis is usually clinical; however, a skin biopsy should be performed in case of an unclear clinical picture, treatment failure or suspicion of a neoplasm. The gold-standard therapy is the long-term application of ultrapotent or potent topical corticosteroids and, alternatively, topical calcineurin inhibitors such as pimecrolimus or tacrolimus. Collectively, LS is a common dermatological disease with a so far incompletely understood pathogenesis and only limited treatment options. To foster translational research in LS, we provide here an update on its clinical features, pathogenesis, diagnosis and (emerging) treatment options.
| S-EPMC9978401 | biostudies-literature