Biopsy-verified vulvar lichen sclerosus: Incidence trends 1997-2022 and increased risk of vulvar squamous precancer and squamous cell carcinoma.

Population-based data on the epidemiology of vulvar lichen sclerosus (LS) are sparse and only few prospective studies have investigated the malignant potential of the disease. We used the nationwide Danish Pathology Registry to first assess the incidence of biopsy-verified vulvar LS in the period 1997-2022 and second to examine the incidence of vulvar high-grade squamous precancer and squamous cell carcinoma (SCC) in women with biopsy-verified vulvar LS (1978-2019) compared with that expected in the general female population. For the latter aim, we computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). During our study period, the age-standardized incidence rate of vulvar LS increased from 5.0 (1997-1998) to 35.7 (2021-2022) per 100,000 person-years. Compared with the general female population, women with biopsy-verified vulvar LS had significantly increased rates of vulvar high-grade squamous precancer (SIR = 8.5; 95% CI: 7.2-10.0) and SCC (SIR = 16.2; 95% CI: 14.2-18.4). The SIRs of vulvar high-grade squamous precancer and SCC did not vary substantially according to length of follow-up. This nationwide and population-based study shows a 7-fold increase in the incidence of biopsy-verified vulvar LS since 1997. Data also show that women with biopsy-verified vulvar LS have 8.5 and 16 times higher than expected incidence of vulvar high-grade squamous precancer and SCC, respectively. The substantially increased incidence of vulvar high-grade squamous precancer and SCC following LS is important in relation to the clinical management and follow-up of LS patients.

The risk of vaginal, vulvar and anal precancer and cancer according to high-risk HPV status in cervical cytology samples.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.

Whole-Exome Sequencing of Vulvar Squamous Cell Carcinomas Reveals an Impaired Prognosis in Patients With TP53 Mutations and Concurrent CCND1 Gains.

Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor (human papillomavirus [HPV]-associated [HPV-A], HPV-independent [HPV-I] with TP53 mutation [HPV-I/TP53mut], and HPV-I with wild-type TP53 [HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities.Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for International Federation of Gynecology and Obstetrics stage, revealed that TP53 mutation, CCND1 gain, and the combination of the 2 alterations were strongly associated with impaired recurrence-free survival (hazard ratio, 4.4; P < .001) and disease-specific survival (hazard ratio, 6.1; P = .002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.

DNA Methylation and P53 Immunohistochemistry as Prognostic Biomarkers for Vulvar Lichen Sclerosus.

Vulvar lichen sclerosus (LS) is an inflammatory dermatosis that can progress to human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (HPVi VIN) and vulvar squamous cell carcinoma (VSCC). Although LS has a much lower cancer risk compared with HPVi VIN (5% versus 50%, respectively), its incidence is significantly higher. Therefore, there is a clinical need to identify LS patients with an increased cancer risk. Our objective was to study the value of DNA methylation and p53 immunohistochemistry (IHC) as prognostic biomarkers for progression to cancer in patients with LS. Vulvar tissues from 236 patients were selected, including 75 LS and 68 HPVi VIN, both with and without cancer development, 32 VSCC, and 61 healthy vulvar controls. Samples were subjected to p53 IHC and DNA methylation analysis of a 3-gene marker panel containing ZNF582, SST, and miR124-2. Methylation levels and p53 IHC status (mutant or wild-type) were assessed and compared among all disease categories. Odds ratios were determined to identify whether the biomarkers were associated with progression to cancer in patients with LS. The highest methylation levels were found in HPVi VIN and VSCC, followed by LS and healthy vulvar controls. The largest heterogeneity in methylation levels was observed in LS cases. In fact, the 3-marker panel tested positive in 70% of LS, which progressed to VSCC versus only 17% of LS in patients without cancer development (P = .002). Also, mutant p53 IHC was observed more frequently in LS with progression to VSCC compared with nonprogressive LS cases (42% versus 3%, respectively, P = .001). Multivariable analysis identified a mutant p53 status as the only independent risk factor for cancer development in LS (odds ratio: 34.0, 95% CI: 1.4-807.4). In conclusion, DNA methylation testing and p53 IHC show strong potential as prognostic biomarkers for the identification of LS patients at high risk of progression to cancer.

PD-L1 expression in vulvar cancer: a systematic review and meta-analysis.

Programmed cell death ligand-1 (PD-L1) expression in cancer may predict clinical response to immunotherapeutic treatment with PD-1/PD-L1 inhibitors. Within the vulvar cancer field, PD-L1 expression has only been assessed by a few studies. We conducted a meta-analysis to examine the prevalence of PD-L1 positivity in vulvar cancer. PubMed, Embase, and Cochrane were searched for articles reporting on PD-L1 expression in vulvar cancer. Study selection and data extraction were performed independently by two authors. We extracted data on PD-L1 prevalence in vulvar cancer according to combined positive score (CPS) and tumour proportion score (TPS). Cutoff values for positivity were ≥1 or ≥10 for CPS and ≥1% and ≥5% for TPS. Random-effects models were used to estimate pooled PD-L1 prevalence, with 95% confidence intervals (CIs). Tests of between-study heterogeneity were evaluated by the I2 statistics. Sources of heterogeneity were explored by subgroup analyses and meta-regression. In total, 19 studies were included. Pooled PD-L1 prevalence in vulvar cancer was 83.4% (95% CI: 70.8-91.3; I2 = 80.0) and 53.9% (95% CI: 37.4-69.6; I2 = 93.0) according to CPS and TPS, respectively. Based on TPS, human papillomavirus (HPV)-associated vulvar squamous cell carcinomas (SCC) showed a lower PD-L1 prevalence (39.9%; 95% CI: 13.3-74.2) compared with HPV-independent SCC (62.6%; 95% CI: 33.7-84.6), but meta-regression showed no significant variation in PD-L1 prevalence by HPV status. PD-L1 prevalence was similar in advanced (44.9%; 95% CI: 29.8-61.1) and localized vulvar cancer (56.7%; 95% CI: 18.9-76.7). In conclusion, PD-L1 expression in vulvar cancer is frequent but between-study heterogeneity was high. Based on a subgroup of heterogenous studies, we found no strong variation in PD-L1 prevalence according to HPV status and stage.

Diagnosis of verruciform acanthotic vulvar intra-epithelial neoplasia (vaVIN) using CK17, SOX2 and GATA3 immunohistochemistry.

AIMS: Verruciform acanthotic vulvar intra-epithelial neoplasia (vaVIN) is an HPV-independent, p53 wild-type lesion with distinct morphology and documented risk of recurrence and cancer progression. vaVIN is rare, and prospective distinction from non-neoplastic hyperplastic lesions can be difficult. CK17, SOX2 and GATA3 immunohistochemistry has emerging value in the diagnosis of HPV-independent lesions, particularly differentiated VIN. We aimed to test the combined value of these markers in the diagnosis of vaVIN versus its non-neoplastic differentials in the vulva. METHODS AND RESULTS: CK17, SOX2 and GATA3 immunohistochemistry was evaluated on 16 vaVINs and 34 mimickers (verruciform xanthoma, lichen simplex chronicus, lichen sclerosus, psoriasis, pseudo-epitheliomatous hyperplasia). CK17 was scored as 3+ = full-thickness, 2+ = partial-thickness, 1+ = patchy, 0 = absent; SOX2 as 3+ = strong staining ≥ 10% cells, 2+ = moderate, 1 + =weak, 0 = staining in < 10% cells; and GATA3 as pattern 0 = loss in < 25% basal cells, 1 = loss in 25-75% basal cells, 2 = loss in > 75% basal cells. For analysis, results were recorded as positive (CK17 = 3+, SOX2 = 3+, GATA3 = patterns 1/2) or negative (CK17 = 2+/1+/0, SOX2 = 2+/1+/0, GATA3 = pattern 0). CK17, SOX2 and GATA3 positivity was documented in 81, 75 and 58% vaVINs, respectively, versus 32, 17 and 22% of non-neoplastic mimickers, respectively; ≥ 2 marker positivity conferred 83 sensitivity, 88 specificity and 86% accuracy in vaVIN diagnosis. Compared to vaVIN, SOX2 and GATA3 were differentially expressed in lichen sclerosus, lichen simplex chronicus and pseudo-epitheliomatous hyperplasia, whereas CK17 was differentially expressed in verruciform xanthoma and adjacent normal mucosa. CONCLUSIONS: CK17, SOX2 and GATA3 can be useful in the diagnosis of vaVIN and its distinction from hyperplastic non-neoplastic vulvar lesions. Although CK17 has higher sensitivity, SOX2 and GATA3 are more specific, and the combination of all markers shows optimal diagnostic accuracy.

Incidence of postoperative venous thromboembolism in patients with vulvar carcinoma undergoing vulvectomy with or without lymphadenectomy.

OBJECTIVES: The incidence of venous thromboembolism (VTE) following radical surgery for vulvar carcinoma remains poorly characterized, and recommendations for postoperative chemoprophylaxis are varied. Our objective was to assess the incidence of postoperative VTE in patients undergoing surgery for vulvar carcinoma and to determine if VTE incidence differs by radical vulvectomy with or without lymph node assessment. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients with a diagnosis of vulvar cancer undergoing radical vulvectomy with or without lymph node assessment from 2012 to 2020. Clinical characteristics and 30-day incidence of VTE as well as other postoperative outcomes were abstracted. Variables were compared using Chi-square test and Fischer's exact test, as well as Kruskal-Wallis and Wilcoxon rank sum tests where appropriate. RESULTS: A total of 1672 patients underwent radical vulvectomy for vulvar carcinoma. 11 patients (0.7%) experienced postoperative VTE within 30 days of surgery. The incidence of VTE was similar when radical vulvectomy was performed alone or with lymph node dissection by any method (p = 0.116). Longer operative times (p = 0.033) and greater postoperative length of stay (p = 0.001) were associated with increased risk of postoperative VTE. CONCLUSIONS: The incidence of postoperative VTE is low in patients undergoing radical vulvar surgery in this national cohort. Inguinofemoral lymph node dissection by any method does not appear to be a risk factor for VTE when compared to radical vulvectomy alone. Further research is needed to determine if extended VTE prophylaxis is beneficial in this population.

Clinical outcomes with utilization of high-potency topical steroids in patients with lichen sclerosus-associated vulvar cancer.

OBJECTIVES: To evaluate the impact of high-potency topical steroid use on risk of recurrence of lichen sclerosus-associated vulvar cancer. METHODS: This is a retrospective cohort study evaluating patients with lichen sclerosus (LS)- associated vulvar squamous cell cancer (VSCC). Demographic and clinical outcome data were compared between two comparison groups: patients who received steroids, mainly clobetasol, and patients who did not receive steroids following treatment of LS-related vulvar cancer. Categorical variables were compared using Fisher's exact test or chi-square test. Continuous variables were compared using a two-sided student's t-test. Time to recurrence (TTR) and overall survival (OS) were analyzed using Kaplan-Meier survival plot and compared using Mantel-Cox log rank test. Cox proportional hazard regression models were conducted to generate hazard ratios for both TTR and OS. A p value of <0.05 was considered statistically significant. RESULTS: A total of 49 patients were included, with 36 patients receiving steroid treatment and 13 patients in the expectant management group. The median age of diagnosis was 68. The average BMI was 31.7 +/- 7.0. The median length of follow up was 41 months. The majority of patients were diagnosed with stage I VSCC. There was no difference in demographics or oncologic management of vulvar cancer between the two cohorts. Overall recurrence was decreased among patients who received steroid treatment when compared to patients who did not, 12 patients (33.3%) versus 9 patients (69.2%) respectively (p = 0.048). CONCLUSIONS: High-potency topical steroid use following treatment of lichen sclerosus-associated vulvar squamous cell carcinoma is associated with decreased risk of recurrence and prolonged median time to recurrence.

Superparamagnetic iron oxide (SPIO) for sentinel lymph node detection in vulvar cancer.

OBJECTIVES: Sentinel lymph node (SLN) detection with superparamagnetic iron oxide (SPIO) nanoparticles has been widely studied and standardized for breast and prostate cancer, but there is scarce evidence concerning its use in vulvar cancer. The objective of this study was to compare SLN detection using a SPIO tracer injected at the time of the surgery detected by a magnetometer, with the standard procedure of using a technetium 99 radioisotope (Tc99) detected by a gamma probe, in patients with vulvar cancer. METHODS: The SPIO vulvar cancer study was a single-center prospective interventional non-inferiority study of SPIO compared to Tc99, conducted between 2016 and 2021 in patients who met the GROINSS-V study inclusion criteria for selective sentinel lymph node dissection in vulvar cancer. RESULTS: We included 18 patients and a total of 41 SLNs. The level of agreement between tracers was 92.7% (80.6%-97.4%), corresponding to 38 out of 41 SLNs, which confirms the non-inferiority of SPIO compared to Tc99. The SLN detection rate per groin was 96.3 (81.7%-99.3) using Tc99 and 100% (87.5%-100%) using SPIO. Both tracers had a detection rate of 100% for positive lymph nodes. CONCLUSIONS: The use of SPIO as a tracer for detecting SLNs in patients with vulvar cancer has shown to be non-inferior to that of the standard radiotracer, with the advantages of not requiring nuclear medicine and being able to inject it at the time of surgery after induction of anesthesia.

High concordance of molecular subtyping between pre-surgical biopsy and surgical resection specimen (matched-pair analysis) in patients with vulvar squamous cell carcinoma using p16- and p53-immunostaining.

OBJECTIVE: Vulvar squamous cell carcinoma (VSCC) can be stratified into three molecular subtypes based on the immunoexpression of p16 and p53: HPV-independent p53-abnormal (p53abn) (most common, biologically aggressive), HPV-associated, with p16-overexpression (second most common, prognostically more favourable) and more recently recognised HPV-independent p53-wildtype (p53wt) (rarest subtype, prognostically intermediate). Our aim was to determine whether molecular subtypes can be reliably identified in pre-operative biopsies and whether these correspond to the subsequent vulvectomy specimen. METHODS: Matched-paired pre-surgical biopsies and subsequent resection specimen of 57 patients with VSCC were analysed for the immunohistochemical expression of p16 and p53 by performing a three-tiered molecular subtyping to test the accuracy rate. RESULTS: Most cases 36/57 (63.2%) belonged to the HPV-independent (p53-abn) molecular subtype, followed by HPV-associated 17/57 (29.8%) and HPV-independent (p53wt) 4/57 (7.0%). The overall accuracy rate on biopsy was 91.2% (52/57): 97.3% for p53-abnormal, 94.1% for p16-overexpression and 50% for p16-neg/p53-wt VSCC. Incorrect interpretation of immunohistochemical p53 staining pattern was the reason for discordant results in molecular subtyping in all five cases. In one case there was an underestimation of p53 pattern (wildtype instead of abnormal/aberrant) and in one case an overestimation of the p53 staining pattern (abnormal/aberrant instead of wildtype). In 3/5 there was a "double positive" staining result (p16 overexpression and abnormal/aberrant p53 staining pattern). In that cases additional molecular workup is required for correct molecular subtyping, resulting in an overall need for molecular examination of 3/57 (3.5%). CONCLUSIONS: Compared to the final resections specimen, the three-tiered molecular classification of VSCC can be determined on pre-surgical biopsies with a high accuracy rate. This enables more precise surgical planning, prediction of the response to (chemo) radiation, selection of targeted therapies and planning of the optimal follow-up strategy for patients in the age of personalised medicine.

The emerging and challenging role of PD-L1 in patients with gynecological cancers: An updating review with clinico-pathological considerations.

Over recent years, there has been significant progress in the development of immunotherapeutic molecules designed to block the PD-1/PD-L1 axis. These molecules have demonstrated their ability to enhance the immune response by prompting T cells to identify and suppress neoplastic cells. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in gynecological malignancies is extremely variable based on tumor stage and molecular subtypes. As a result, a class of monoclonal antibodies targeting the PD-1 receptor and PD-L1, known as immune checkpoint inhibitors, has found successful application in clinical settings. In clinical practice, the standard method for identifying suitable candidates for immune checkpoint inhibitor therapy involves immunohistochemical assessment of PD-L1 expression in neoplastic tissues. The most commonly used PD-L1 assays in clinical trials are SP142, 28-8, 22C3, and SP263, each of which has been rigorously validated on specific platforms. Gynecologic cancers encompass a wide spectrum of malignancies originating from the ovaries, uterus, cervix, and vulva. These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting.

Lower incidence of vaginal cancer after cervical human papillomavirus screening - long-term follow-up of Finnish randomized screening trial.

OBJECTIVE: Around 70% of vaginal cancers and 40-50% of vulvar cancers are attributable to human papillomavirus (HPV). Globally the burden of these diseases is estimated to grow due to the increasing HPV prevalence and rapidly aging global population. We aimed to examine if HPV screening for cervical cancer has an additional beneficial effect in preventing vaginal and vulvar cancers. To assess this, we used long-term follow-up data from the Finnish randomized HPV screening trial. METHODS: Between 2003 and 2008, over 236,000 women were individually randomized (1:1) to primary HPV or cytology screening in Southern Finland. We followed this cohort up to the year 2020. To compare the study arms, we calculated site-specific and pooled incidence rate ratios (IRRs) and mortality rate ratios (MRRs) for vaginal and vulvar cancers using Poisson regression. RESULTS: During 3,5 million person-years of follow-up, the IRR for vaginal cancer in the HPV arm compared to the cytology arm was 0.40 (95% CI 0.17-0.88) and the corresponding MRR was 0.74 (95% 0.21-2.24). The corresponding IRR for vulvar cancer was 0.73 (95% 0.50-1.08) and the MRR was 0.64 (95% 0.23-1.62). The pooled IRR was 0.67 (95% 0.47 ̶ 0.95) and MRR 0.67 (95% 0.31 ̶ 1.37). CONCLUSION: We found lower incidence of vaginal cancers with HPV screening compared to cytology screening. To validate our results, we recommend analyzing data on vaginal and vulvar cancers also from other HPV screening studies.

Sentinel Lymph Node Evaluation in Early-Stage Vulvar Cancer.

OPINION STATEMENT: Sentinel lymph node mapping (SLNM) and dissection (SLND) should be used as an alternative to full inguinofemoral lymph node dissection (IFLND) in select patients with early-stage vulvar cancer. IFLND is associated with high postoperative complications such as wound breakdown, lymphedema, lymphocyst formation, and infection. SLND in select patients offers a safe, effective, and less morbid alternative. Candidates for SLND include patients with a unifocal vulvar tumor less than four centimeters, clinically negative lymph nodes, and no prior inguinofemoral surgeries. SLND should ideally be performed by a high-volume SLN surgeon. Most commonly, SLND is performed using both radiocolloid lymphoscintigraphy (e.g., Technetium-99) and a visual tracer such as blue dye; however, near infrared imaging with indocyanine green injection is becoming more widely adopted. Further prospective studies are needed to examine the safety and efficacy of various techniques for SLND. SLND has been demonstrated to be cost-effective, especially when including perioperative complications. Further studies are needed to demonstrate quality of life differences between IFLND and SLND.

Time trends in human papillomavirus prevalence and genotype distribution in vulvar carcinoma in Norway.

INTRODUCTION: Approximately 25%-43% of all vulvar carcinomas are associated with human papillomavirus (HPV). In many countries, vulvar carcinoma incidence rates are increasing, possibly due to greater HPV exposure. However, studies exploring changes in HPV prevalence and genotype distribution in vulvar carcinoma over time are scarce. Our aim was to evaluate time trends in HPV prevalence and genotype distribution in vulvar squamous cell carcinoma in an unselected, nationwide sample of Norwegian women. Further, we explored clinical and histopathological aspects in relation to HPV status and investigated whether HPV status was associated with survival. MATERIAL AND METHODS: All vulvar squamous cell carcinoma cases from 1970-1975 and 2000-2005 were extracted from the Cancer Registry of Norway and corresponding tissue blocks were retrieved. After detailed histology review, HPV testing was conducted using real-time TaqMan PCR. Overall survival rates were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was performed to estimate hazard ratios adjusted for age at diagnosis, stage and diagnostic period. RESULTS: Histological review was performed on 352 vulvar squamous cell carcinoma cases. We were able to obtain valid HPV analysis results for 282 cases, Overall, 29.8% (95% CI 24.5%-35.5%) of cases were high-risk HPV (hrHPV)-positive. When comparing the two periods, we found that the percentage of hrHPV-positive tumors increased significantly from 23% (95% CI 16.0%-31.4%) in 1970-1975 to 35.3% (95% CI 27.8%-43.3%) in 2000-2005 (P = 0.025). The predominant genotypes were HPV 16 (73%), HPV 33 (21%), and HPV 18 (6%), with similar distributions in both periods. In the more recent cohort, several additional genotypes were detected: HPV 6, 11, 39, 45, 52, 58 and 66 were found in smaller percentages, ranging from 1.8% to 3.6%. In univariate analysis, patients with HPV-positive tumors showed improved overall survival compared with patients with HPV-negative tumors (hazard ratio [HR] 0.65, 95% CI 0.48-0.86). CONCLUSIONS: The prevalence of HPV in vulvar squamous cell carcinomas in Norway was significantly higher in 2000-2005 than in 1970-1975. The three predominant genotypes were HPV 16, 33 and 18 in both time periods. However, several other HPV genotypes have emerged over the last decades. HPV-positivity was associated with better overall survival.

Anxiety and depression among women with newly diagnosed vulvar cancer - A nationwide longitudinal study.

INTRODUCTION: Our objective was to investigate the trajectories of anxiety, depression, emotional and social functioning in women with newly diagnosed vulvar cancer from the time of diagnosis to 12 months after treatment. A further aim was to identify risk factors for high levels of anxiety. MATERIAL AND METHODS: PROVE (PROspective Vulvar Cancer Evaluation) is a nationwide longitudinal cohort study investigating quality of life in women with newly diagnosed vulvar cancer by the following validated patient-reported outcome measures at diagnosis, and 3 and 12 months after treatment: The Hospital Anxiety and Depression Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Vulvar module VU34. Mean scores, changes over time and associations were analyzed by generalized estimated equations and log-linear regression models, adjusted for possible confounders. RESULTS: Between 2019 and 2021, 105 (69%) women completed the questionnaires at all three time points. At diagnosis, 42% of the women reported elevated anxiety levels, decreasing significantly to 30% during the first 12 months. Insomnia, persisting vulvar symptoms and high information needs were significantly associated with a high level of anxiety (relative risk [RR] 2.1, 95% CI 1.2-3.7 for insomnia; RR 2.8, 95% CI 1.7-4.6 for vulvar symptoms, RR 2.7, 95% CI 1.5-4.9 for information needs). We found a trend towards a higher level of anxiety in younger women (<65 years: RR 1.5, 95% CI 1.0-2.5). Participants reported a low and stable prevalence of depression (14%) and high social functioning throughout the study period. CONCLUSIONS: Women with newly diagnosed vulvar cancer report a high level of anxiety at diagnosis. Despite a significant improvement, anxiety remains widely prevalent during the first year of follow-up. Targeting insomnia, vulvar symptoms and unmet needs may decrease anxiety during surveillance.

Differentiated vulvar intraepithelial neoplasia long-term follow up and prognostic factors: An analysis of a large historical cohort.

INTRODUCTION: Differentiated vulvar intraepithelial neoplasia (dVIN) is a high-risk preinvasive vulvar lesion and precursor of human papillomavirus-independent vulvar squamous cell carcinoma (VSCC). Due to its rarity, literature data on its malignant potential are scant. The aim of the study is to assess the risk of developing VSCC in patients surgically treated for dVIN not associated with VSCC (solitary dVIN) and the risk of VSCC recurrence in patients treated for dVIN associated with VSCC (dVIN-VSCC) at first diagnosis. MATERIAL AND METHODS: A historical cohort study was performed in a northern Italy referral center for vulvar neoplasms. All consecutive women surgically treated for histologically confirmed dVIN from 1994 to 2021 were collected. Primary outcome was cancer risk or recurrent cancer risk, secondary outcomes were risk factors associated with VSCC development or recurrence. Kaplan-Meier method and log-rank test were used to estimate cancer risk or recurrent cancer risk differences and uni- and multivariate Cox regression analyses to identify risk factors associated with VSCC development in solitary dVIN and recurrence of dVIN-VSCC. RESULTS: Seventy-six patients with dVIN at preoperative biopsy were included: at excisional specimens 44 were solitary dVIN and 32 were dVIN-VSCC. The absolute risk of VSCC development after solitary dVIN treatment was 43.2% with median time to to VSCC diagnosis of 25.4 months (range 3.5-128.0 months). VSCC recurrence absolute risk in treated dVIN-VSCC patients was 31.3% with median time to VSCC recurrence of 52.9 months (range 6.5-94.8 months). At uni- and multivariate regression analyses, only compliant topical ultrapotent corticosteroid treatment after solitary dVIN excision showed an ability to prevent VSCC development. No protective effect by corticosteroid treatment was shown for VSCC recurrence in dVIN-VSCC patients. Smoking was associated with higher cancer recurrence risk in dVIN-VSCC patients on both uni- and multivariate regression analyses. CONCLUSIONS: Patients with dVIN have a high risk of developing both primary and recurring VSCC. Early recognition, long-term follow up, and compliant ultrapotent topical corticosteroid treatment are recommended.

Gynecological cancer during pregnancy-From a gyne-oncological perspective.

Gynecological cancer diagnosed during pregnancy requires accurate diagnosis and staging to determine optimal treatment based on gestational age. Cervical and ovarian cancers are the most common and multidisciplinary team collaboration is pivotal. Magnetic resonance imaging and ultrasound can be used without causing fetal harm. In cervical cancer, early-stage treatments can often be delayed until fetal lung maturation and cesarean section is recommended if disease prevails, in combination with a simple/radical hysterectomy and lymphadenectomy. Chemoradiotherapy, the recommended treatment for advanced stages, is not compatible with pregnancy preservation. Most gestational ovarian cancers are diagnosed at an early stage and consist of nonepithelial cancers or borderline tumors. Removal of the affected adnexa during pregnancy is often necessary for diagnosis, though staging can be performed after delivery. In selected cases of advanced cervical and ovarian cancers, neoadjuvant chemotherapy may be an option to allow gestational advancement but only after thorough multidisciplinary discussions and counseling.

Definitive chemoradiation in vulvar squamous cell carcinoma: outcome and toxicity from an observational multicenter Italian study on vulvar cancer (OLDLADY 1.1).

BACKGROUND: Vulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT. METHODS: The primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale. RESULTS: Retrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010-November 2021). Median age at diagnosis was 72 years (range 32-89). With a median follow-up of 19 months (range 1-114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1-53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded. CONCLUSION: In the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management.

Genetics and beyond: Precision Medicine Real-World Data for Patients with Cervical, Vaginal or Vulvar Cancer in a Tertiary Cancer Center.

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.

Surgical treatment of recurrent gynecological malignancies.

OBJECTIVE: A comprehensive overview of surgical treatment of recurrent gynecological malignancies. Recurrent breast malignancies are not included in this review. METHODOLOGY: A review providing overview of surgical treatment options for recurrent malignancies of adnexa of the uterus (ovary, fallopian tube), uterine corpus, uterine cervix, and carcinoma of the vagina and vulva. CONCLUSION: Optimal surgical treatment for patients with recurrent cancer is based on multidisciplinary approach with stratification according to individual prognostic markers. These include patient's performance status, outcome of primary surgery, current extent of recurrence, and histopathological, molecular, and biochemical characteristics. Decision about choice of treatment should be individually discussed and evaluated by the multidisciplinary oncogynecological commission board.