The risk of vulvar squamous cell carcinoma (VSCC) in patients with high‐grade vulvar intraepithelial neoplasia (VIN) is considered lower in high‐grade squamous intraepithelial lesion (HSIL) compared ...to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high‐grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high‐grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high‐grade VIN between 1991 and 2011. Between 1991‐1995 and 2006‐2011, the ESR of HSIL increased from 2.39 (per 100 000 woman‐years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10‐year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval CI 1.3‐7.1), 2.3 (95% CI 1.5‐3.4) and 3.1 (95% CI 1.8‐5.3), respectively. The incidence of high‐grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.
What's new?
High‐grade squamous intraepithelial lesions (HSILs) and differentiated vulvar intraepithelial neoplasia (dVIN) are established risk factors for vulvar squamous cell carcinoma. Lesions classified as dVIN are less common than HSILs but potentially more aggressive. Our study, based on investigation of more than 1100 patients diagnosed with high‐grade VIN between 1991 and 2011, demonstrates a rising incidence of both HSIL and dVIN. Ten‐year cumulative risk of vulvar cancer was significantly greater for dVIN than HSIL. The findings highlight the importance of timely identification and classification of dVIN precancerous lesions and a potential need for risk stratification to prevent overtreatment in HSIL patients.
The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)‐associated and HPV‐independent squamous neoplasia with a varying cancer risk. Our study aimed to ...validate the accuracy of previously identified DNA methylation markers for detection of such high‐grade vulvar intraepithelial neoplasia (VIN). A large clinical series of 751 vulvar lesions, originally diagnosed as high‐grade VIN, were reassessed and categorized into HPV‐associated or HPV‐independent vulvar disease categories. Together with 113 healthy vulvar controls, all samples were tested for 12 methylation markers with quantitative multiplex methylation‐specific PCR (qMSP). Performance of individual markers and selection of an optimal marker panel for detection of high‐grade VIN was determined by logistic regression analysis. SST was the best‐performing individual marker (AUC 0.90), detecting 80% of high‐grade VIN cases, with excellent detection of HPV‐independent VIN (95%), known to have the highest cancer risk. Merely 2% of controls tested methylation positive for SST. Selection of a marker panel, including ZNF582, SST and miR124‐2, resulted in a comparably high accuracy for detection of high‐grade VIN (AUC 0.89). In conclusion, we clinically validated the accuracy of 12 DNA methylation markers for detection of high‐grade VIN. SST, as a sole marker or in a panel, provides an optimal diagnostic tool to distinguish high‐grade VIN in need of treatment, particularly HPV‐independent VIN, from low‐grade or reactive vulvar lesions. These findings warrant further prognostic validation of methylation biomarkers for cancer risk stratification of patients with VIN.
What's new?
Only a minority of vulvar intraepithelial neoplasia progress to cancer, and objective molecular biomarkers that reflect the cancer risk in patients are currently needed. Our study on more than 800 specimens validates the accuracy of 12 previously identified DNA methylation markers for detection of high‐grade vulvar intraepithelial neoplasia. SST, as a sole marker or in a panel, provides an optimal diagnostic tool to distinguish high‐grade vulvar intraepithelial neoplasia in need of treatment from low‐grade or reactive vulvar lesions. Identification of vulvar lesions with a high cancer risk by methylation markers can contribute to personalized patient management and prevent mutilating overtreatment.
Current clinical and histological classifications are unable to determine the risk of vulvar squamous cell carcinoma (VSCC) in high‐grade vulvar intraepithelial neoplasia (VIN), making prognostic ...biomarkers highly needed. We studied host‐cell DNA methylation markers in high‐grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN) without VSCC, in HSIL and dVIN adjacent to VSCC and in human papillomavirus (HPV) positive and negative VSCC, relative to control vulvar tissues. A series of 192 formalin‐fixed paraffin‐embedded vulvar samples, including VSCC (n = 58), VIN adjacent to VSCC (n = 30), VIN without VSCC during follow‐up (n = 41) and normal vulvar tissues (n = 63), were tested for 12 DNA methylation markers with quantitative multiplex methylation‐specific PCR (qMSP). HPV status was determined by p16INK4A immunohistochemistry and high‐risk HPV PCR analysis. Logistic regression analyses were used to determine methylation patterns and methylation marker performance for VIN and VSCC detection. Methylation markers showed significantly higher methylation levels with increasing severity of disease. VIN adjacent to VSCC showed a similar methylation‐high pattern as VSCC, while VIN without VSCC displayed a heterogeneous methylation pattern. Vulvar carcinogenesis is associated with increased DNA methylation. Higher DNA methylation levels in VIN seem to reflect higher cancer risk, emphasizing the high potential of DNA methylation biomarkers in the diagnostic workup of VIN. As a next step, longitudinal studies are needed to verify the prognostic value of methylation biomarkers as a clinical tool for stratification of cancer risk in women with VIN.
What's new?
In high‐grade vulvar intra‐epithelial neoplasia (VIN), existing clinicopathological classifications lack accuracy in predicting cancer risk, resulting in a need for objective prognostic biomarkers. Here, 12 DNA methylation markers were investigated for prognostic capability in a series of high‐grade squamous intraepithelial lesion, differentiated VIN, and vulvar carcinomas. For all 12 methylation markers, as disease severity increased, methylation levels also increased. Methylation patterns were more heterogeneous for VIN without vulvar squamous cell carcinoma. The results link elevated DNA methylation levels with increased VIN cancer risk and indicate that methylation biomarkers are promising diagnostic tools for cancer risk stratification in VIN.
Human papillomavirus (HPV)-induced vulvar high-grade squamous intraepithelial lesions (vHSIL), formerly known as usual-type vulvar intraepithelial neoplasia (VIN), has a cancer risk of approximately ...10% and treatment is aimed at relieving symptoms and preventing progression towards cancer.1 New therapeutic options have emerged to provide alternative non-surgical management strategies, including immune-response modulators, anti-viral agents, photodynamic therapy, and prophylactic HPV vaccination.2 The most widely used immunotherapeutic approach is topical imiquimod, a toll-like receptor 7 (TLR-7) agonist. Activating TLR-7 triggers both an innate and acquired immune response by synthesis of various proinflammatory chemokines and cytokines, including interferon γ, interleukin-12 and tumour necrosis factor α.3 Several randomised controlled trials have previously shown efficacy and safety of topical imiquimod for treatment of vHSIL, comparing imiquimod with placebo or cidofovir, a potent anti-viral gel.4–6 Complete response rates after 6–12 months range from 35% to 81%, resulting in the advice, also in international guidelines, to consider imiquimod as first-choice treatment of vHSIL.2,7 Thus far, studies comparing topical imiquimod to surgical intervention have been scarce. A recent study has shown that complete clinical response to imiquimod is associated with coordinated influx of type 1 CD4 and CD8 T cells and CD14 inflammatory myeloid cells.13 Patients without such a pre-existent and coordinated immune microenvironment might show resistance to therapy. ...discovery of biomarkers to predict response is needed, using multiparameter methods such as spatial transcriptomics and imaging mass cytometry.
In patients with high-grade squamous intraepithelial lesion (HSIL) of the vulva, the presence of multiple lesions, called multifocal HSIL, is common. The aim of this exploratory study was to ...investigate biomarker expression profiles in multifocal HSIL. In total, 27 lesions from 12 patients with high-risk human papillomavirus (HPV)-positive multifocal HSIL were tested for HPV genotype, expression of p16INK4a and Ki-67, and DNA methylation of six genes. HPV16 was found most commonly in 21 (77.8%) HSILs. In two (16.4%) patients, HPV genotype differed between the lesions. All lesions demonstrated diffuse p16INK4a staining, of which three (11.1%) were combined with patchy staining. One patient (8.3%) demonstrated markedly different DNA methylation levels between lesions. Generally, heterogeneity in methylation profiles was observed between different patients, even when other biomarkers showed similar expression. In conclusion, this study is the first to demonstrate heterogeneity of individual lesions in patients with multifocal HSIL. The studied biomarkers have the potential to refine prognostic and predictive diagnostics. Future prospective, longitudinal studies are needed to further explore the potential of a biomarker profile for management of patients with multifocal HSIL.
There has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing ...salpingo-oophorectomy (RRSO).
In this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy–Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data.
Twenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = −0.40 and p < 0.001, ES = −0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT-users and the GS-group on any of the outcomes.
Our results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO.
•HRT after RRSO has beneficial effects on menopausal symptoms.•HRT minimises hot flashes and sexual problems in premenopausal women.•Menopause-related complaints return to pre-RRSO levels when using HRT.•HRT-non-users experience an increase in overall endocrine symptoms.•HRT-use should be a shared decision between clinician and patient.
Vulvar lichen sclerosus and lichen planus are T-cell–mediated chronic skin disorders. Although autoimmunity has been suggested, the exact pathogenesis of these disorders is still unknown. Therefore, ...the aim of the current study was to investigate the molecular and immunological mechanisms critical to the pathogenesis of vulvar lichen sclerosus and lichen planus. By using gene expression profiling and real-time RT-PCR experiments, we demonstrated a significantly increased expression of the pro-inflammatory cytokines (IFNγ, CXCR3, CXCL9, CXCL10, CXCL11, CCR5, CCL4, and CCL5) specific for a Th1 IFNγ-induced immune response. In addition, BIC/microRNA-155 (miR-155)—a microRNA involved in regulation of the immune response—was significantly upregulated in lichen sclerosus and lichen planus (9.5- and 17.7-fold change, respectively). Immunohistochemistry showed a significant T-cell response, with pronounced dermal infiltrates of CD4+, CD8+, and FOXP3+ cells. In conclusion, these data demonstrate an autoimmune phenotype in vulvar lichen sclerosus and lichen planus, characterized by increased levels of Th1-specific cytokines, a dense T-cell infiltrate, and enhanced BIC/miR-155 expression.
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