Vulvar Squamous Cell Carcinoma Research Articles

Prognostic and clinicopathological significance of survivin in gynecological cancer

Survivin belongs to the inhibitor of apoptosis protein (IAP) family and is encoded by the baculoviral inhibitor of apoptosis repeat-containing, or BIRC5, gene. It is preferentially expressed in cancers with functional complexity in cell signaling cascades such as extracellular signal-regulated kinases (ERK), mitogen-activated protein kinases (MAPK), heat shock protein-90 (HSP90), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), and others. Survivin plays a role in cell division and cell death, properties that have attracted a large body of research to decipher its therapeutic and prognostic significance in cancer. Survivin has tumor-promoting effects in endometrial (EC) and ovarian (OC) cancers, and its upregulation in endometrial cancer has been associated with poor overall survival (OS). While survivin protein is abundantly expressed in OC, it is barely detectable in normal ovarian tissue or benign ovarian tumors. Survivin expression is also a marker for cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus, and a predictor of viral clearance and prognosis in uterine cervical cancer (UCC). Furthermore, nuclear survivin expression is very low in normal vulvar squamous epithelium and increases to become abundant in vulvar invasive squamous cell carcinoma (ISCC), conferring resistance to apoptosis in vulvar carcinogenesis. In this review, we discuss in detail the impact of survivin signaling on gynecological cancers and provide insight on its therapeutic and diagnostic potential, existing research gaps, and areas for future research.

Vulvar squamous cell carcinoma: The role of p53 and p16 immunohistochemistry

Vulvar squamous cell carcinomas (SCC) represent a heterogeneous group of patients with implications for prognosis and response to treatment. Human papillomavirus (HPV)-associated SCC is characterised by p16 positivity, whereas non-HPV SCC often shows aberrant p53 expression. We conducted a retrospective analysis involving 148 patients with vulvar SCC from two Gynecologic Oncology units from Sydney, Australia. Patients’ demographics, tumor characteristics, types of treatment and survival were analyzed and compared to p16 and p53 immunohistochemistry status. The p16-positive group was younger and included a higher prevalence of smokers, while the p53-positive group demonstrated greater comorbidity indices and was associated with tumor features that are independently related to poor prognosis. Compared to p16-positive patients our study has shown significantly higher recurrence rates and lower overall survival in the p53-positive group. Our findings support existing literature, emphasizing the prognostic significance of p16 and p53 in vulvar SCC. Despite the retrospective nature and variations in immunohistochemistry reporting, our study provides valuable insights into patient outcomes, particularly in a demographically diverse population. Future research, like the STRIVE trial, may determine if implementation of p16 and p53 stratified management algorithm will improve outcomes for women with vulvar SCC (McAlpine, 2024).

Impact of age on surgical excision margins for vulvar squamous cell carcinomas: A multicenter study by the francogyn group

IntroductionVulvar cancer is a rare cancer, it most often affects older women, with tumours of more advanced size and stage than in younger patients. The first-line treatment for vulvar cancer is surgery. Current European and American guidelines recommend negative histological margins. As tumor size is greater in older patients, the aim of this study was to assess the impact of patient age on surgical excision margins in squamous cell carcinomas of the vulva. Material and methodThis was a retrospective multicenter observational study. A descriptive analysis of the population was performed and a univariate analysis was performed according to patient age. Survival data were plotted using the Kaplan-Meier method and compared using a log rank test. Survival was analyzed using a Cox model to calculate the Hazard Ratio. ResultsAmong the 547 patients included, there were 206 patients <65 years and 341 ≥ 65 years, including 135 ≥ 80 years. Median postoperative histological lesion size and interquartile range was greater in patients ≥65 years (30 mm [18–45] versus 26 mm [14–34], p < 0.001). Patients ≥65 years of age more often benefited from radical total vulvectomy (n = 103 (28.8 %) versus n = 44 (20.4 %), p = 0.03). However, negative surgical excision margins were identical between the 2 groups (n = 180 (87.4 %) versus n = 286 (83.9 %), p = 0.21). Revision surgery was performed more frequently in patients <65 years. Recurrence-free survival was better in patients aged <65 years (HR = 0.60; CI95 % (0.45–0.82), p = 0.001). ConclusionDespite larger tumour size, age is not a factor influencing the achievement of negative excision margins in squamous cell carcinomas of the vulva, at the cost of more radical surgery.

Comparison of different histomorphological grading systems in vulvar squamous cell carcinoma.

Histopathological biomarkers of carcinomas and their prognostic relevance, such as Broder's grading system (based on the total number of undifferentiated cells) or Bryne's grading system (rating morphological features at the tumor invasive front), have been repeatedly and successfully put to test. Since most studies focus on head and neck cancers or oral carcinomas, for squamous cell carcinoma of the vulva, no standardized and agreed on pathological tumor grading system, yielding prognostic significance, could be determined so far. To determine prognostic associations of different grading systems with regard to groin lymph node metastasis, 73 cases of vulvar carcinomas (VC) were re-examined within our study and Broder's and Bryne's grading system individually performed. To sub-classify between HPV-associated or HPV-independent VC, immunohistochemical p16 stainings were performed. Statistical relationships were evaluated using Spearman correlation and logistic regression analysis, validation was achieved by employment of the likelihood ratio test (LRT) and assessment of ROC curves/AUC values. Within our cohort, Broder's grade I (40≈55%) and Bryne's grade II (48≈66%) were the most frequently assigned histological gradings. We determined a positive correlation of Bryne's grading with the extent of lymph node involvement in HPV-associated tumors and demonstrated the feasibility of Bryne's grading to predict the presence of carcinoma cells within groin lymph nodes (LRT p = 0.0066; AUC value≈0.91) in this cohort. On the other hand, our data suggest that especially HPV-independent tumors may not sufficiently be characterized by current standardly performed grading approaches. Since only Bryne's grading system correlated positively with lymph node involvement in HPV-associated squamous cell carcinoma of the vulva, we propose to include it by name next to the distinct tumor entity on the histopathological report, allowing not only the interpretation of its prognostic relevance but also future research attempts.

Precancerous Lesions of HPV-independent Vulvar Squamous Cell Carcinoma: Clinicopathologic Consideration of an Evolving Spectrum.

HPV-independent squamous cell carcinomas of the vulva comprise the majority of vulvar cancers, but their putative precancers represent only a small proportion of the vulvar squamous intraepithelial lesions that are encountered in routine practice. The precancerous lesions of HPV-independent vulvar squamous cell carcinoma encompass a spectrum of lesions that, collectively, may pose significant diagnostic challenges. Included in this spectrum are differentiated vulvar intraepithelial neoplasia [dVIN], the prototypical lesion of the group, which is characterized by a high propensity for progression, a relatively short duration to progression, frequent association with lichen sclerosus, and according to our review of the recent literature, TP53/p53 aberration in 50% to 95% (mean 77.4%) of cases. Regarding the latter, some authors consider TP53/p53 aberration to be a diagnostic requirement for dVIN, although this is controversial, as discussed further herein. Also included in the spectrum of lesions that are considered in this review are possibly related HPV-independent, p53-wild type lesions that have historically been reported as "vulvar acanthosis with altered differentiation" (VAAD), "differentiated exophytic vulvar intraepithelial lesion" (DEVIL), "verruciform lichen simplex chronicus" (vLSC), and which more recently, have collectively been described as "verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN)" or "vulvar aberrant maturation (VAM)." In this review, we perform a comprehensive clinicopathologic review of putative precancerous lesions of HPV-independent squamous cell carcinomas of the vulva, with an emphasis on recent developments in terminology, practical diagnostic issues, biomarkers, and pathogenesis.

Advances in Vulvar Cancer Biology and Management.

Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC. We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC. Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV-) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV-/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design. Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.

9185 Pembrolizumab-Induced New-Onset Type 1 Diabetes Mellitus: A Case Report

Abstract Disclosure: D. Teng: None. T.L. Connelly: None. M. Ahmad: None. R. Saeed: None. Introduction: Immune checkpoint inhibitors are becoming essential in the treatment of various cancers. Pembrolizumab is a monoclonal antibody that binds PD-1 receptors, thereby enabling an anti-tumor response by preventing T-cell suppression. Common side effects associated with pembrolizumab include thyroid disorders, hepatitis, pneumonitis, and acute kidney injury, among others. We describe an interesting case of a woman presenting with diabetic ketoacidosis (DKA) in the setting of pembrolizumab-associated new-onset type 1 diabetes mellitus, which was reported at 0.1% during initial clinical trials but is now being increasingly recognized as a complication of immune checkpoint therapy. Case Description: The patient is a 70-year-old female with past medical history notable for stage IIIA vulvar squamous cell carcinoma initially diagnosed and treated in 2017, with recurrence in 2022 and in 2023, at which point pembrolizumab therapy was initiated. Approximately one month after her first dose, the patient presented to the emergency department with palpitations, nausea, non-bloody vomiting, polydipsia, and non-bloody diarrhea. On arrival, the patient’s vital signs were as follows: 97.2 °F, BP 128/74 mmHg, heart rate 80 bpm, respiratory rate 18 per minute, and SpO2 100% on room air. No acute findings were noted on physical exam. Initial blood work was notable for: pH 7.146, lactate 2.4 mmol/L, bicarbonate 8 mmol/L, anion gap 37 mmol/L, creatinine 1.59 mg/dL, glucose 563 mg/dL, C-peptide 0.16 ng/mL, HbA1c 6.9%, and WBC 18.8 B/L with neutrophilic predominance. Urinalysis was notable for 4+ glucose and 4+ ketones. The patient was admitted to the progressive care unit and DKA protocol was initiated including the administration of IV fluids, insulin infusion, and electrolyte replacement. Additional blood work was unrevealing, including insulin autoantibodies &amp;lt;0.4 U/mL, negative islet cell IgG cytoplasmic autoantibodies, and negative anti-GAD65 antibodies. The patient was eventually discharged with outpatient Endocrinology follow-up. Discussion: Immunotherapy is quickly redefining the standard of care in the treatment of several types of malignancies through the leveraging of the body’s immune defense apparatus. Pembrolizumab prevents the deactivation of T-cells via the PD-1/PD-L1 pathway. Unfortunately, this also predisposes non-cancerous cells to autoimmune destruction by these T-cells. It is proposed that such is the mechanism by which pancreatic beta islet cells are destroyed in the setting of pembrolizumab use, thereby resulting in a rapid reduction in insulin production capability. New-onset type 1 diabetes complicated by DKA is potentially life-threatening, and so we believe this case highlights the need for both pre-treatment counseling as well as follow-up screening following initiation of pembrolizumab therapy. Presentation: 6/2/2024

MO52-6 Results of treatment for FIGO stage I-II vulvar squamous cell carcinoma at Viet Nam National Cancer Hospital

MO52-6 Results of treatment for FIGO stage I-II vulvar squamous cell carcinoma at Viet Nam National Cancer Hospital

Typing of Vulvar Squamous Cell Carcinoma: Why it is Important?

The classification of vulvar squamous cell carcinoma (VSCC), as in endometrial cancer, has shifted from the histology-based descriptors toward molecular-based identifiers. Recently, it has been reported that there are 3 genetically distinct and clinically significant subtypes of VSCC: HPV-associated VSCC, HPV-independent/p53 wild-type VSCC, and HPV-independent/p53-mutated VSCC. Each group has different prognostic implications as well as response to treatment, thus reinforcing the need for this 3-tier molecular classification. This molecular subtyping can easily be done on vulvar biopsies using p16 and p53 immunohistochemistry stains to further improve risk prediction and individualized treatment decisions, leading to better patient outcomes.

Sentinel lymph node biopsy for early stage vulvar squamous cell carcinoma

Background Patients with regional lymph node involvement from squamous cell carcinoma (SCC) of the vulva have a 48% 5-year relative survival. Recently, sentinel lymph node (SLN) biopsy has become a viable alternative to inguinofemoral lymphadenectomy. We sought to identify risk factors for predicting a positive SLN in patients with vulvar SCC. Methods A retrospective review of 29 patients with vulvar SCC was performed from 2016 to 2021 at a tertiary care center. Clinicopathologic data were collected in addition to SLN status, including number of lymph nodes removed. Results The average depth of invasion was 7.9 mm, average tumor size was 1.8 cm, 3 of 23 patients had perineural invasion, and 4 of 23 patients had lymphovascular invasion. One patient who did not map on lymphoscintigraphy and five patients with recurrent vulvar SCC were excluded from final analysis. The average number of SLNs removed was two. One patient had a positive SLN: the depth of invasion was 17 mm, tumor size was 5.1 cm, and lymphovascular invasion was present. Conclusions Most patients with early stage vulvar SCC had a negative SLN biopsy. Further study is needed to determine the patient subset that could avoid SLN biopsy altogether.

D2-40 and CK17 Immunohistochemistry as a Diagnostic Adjunct for HPV-Independent Squamous Lesions in the Vulva and Their Role in Defining Atypical Lichen Sclerosus.

Vulvar lichen sclerosus (LS) is a common, chronic inflammatory disorder with a subset of cases progressing to differentiated vulvar intraepithelial neoplasia (dVIN) and/or squamous cell carcinoma (SCC). Histopathologic diagnosis of LS and dVIN can be challenging, and it is difficult to predict the subset of LS cases that progress. Immunohistochemistry (IHC) may be a useful diagnostic aid in this setting. CK17 has been shown to be overexpressed in invasive SCC and dVIN, and less commonly in LS. Similar to CK17, D2-40 has been correlated with cutaneous SCC prognosis but has not been evaluated in vulvar lesions. We identified a total of 13 patients with HPV-independent vulvar SCC that had precursor LS or dVIN. CK17 and D2-40 IHC stain intensity and pattern was scored in foci of LS, dVIN, and SCC. An increase in basal layer D2-40 expression was observed with progression from LS to dVIN with strong and diffuse staining in SCC. CK17 maintained similar stain intensity among squamous lesions, but displayed different patterns of staining, with superficial staining in LS, suprabasal staining in dVIN, and diffuse staining in SCC. A subset of LS cases displayed an intermediate (suprabasal) CK17 IHC profile, wild-type p53 expression, and cytomorphologic and architectural features intermediate between LS and dVIN; we defined such cases as "atypical LS." We found that a panel of D2-40/CK17 can serve as a diagnostic adjunct to differentiate LS, dVIN, and invasive SCC. Additional studies with larger patient cohorts are needed to validate these findings and determine their prognostic significance.

Prevalence and indicators of cure of Italian women with vulvar squamous cell carcinoma: A population-based study

ObjectiveFive-year net survival and conditional survival from vulvar squamous cell carcinoma (VSCC) patients in Italy have shown no progress during the past three decades. This study aims to estimate the complete prevalence and multiple indicators of cure. MethodsObserved prevalence was estimated using 31 Italian cancer registries covering 47 % of Italian women. A subset of 22 cancer registries was used to estimate model-based long-term survival and indicators of cure, i.e., complete prevalence, cure fraction (CF), time to cure (TTC), proportion of ‘already cured' patients, and cure prevalence. ResultsIn 2018, VSCC patients alive in Italy (complete prevalence) were 6620 or 22 per 100,000 women. The cure fraction (the proportion of newly diagnosed patients who will not die of VSCC) did not change between 2000 and 2010 both for all patients (32 %) and in each age group. The time to cure (5-year conditional net survival >95 %) was 11 years for patients aged ≥44 years, but excess mortality remained for >15 years in the other age groups. This led to a negligible (5 %) proportion of ‘already cured’ patients (living longer than time to cure). The proportion of patients alive <2 years (21 %) was the same as that of patients surviving ≥15 years. The cure prevalence (patients who will not die of VSCC) was 64 %. A considerable proportion of patients will not be cured even among those who survived ≥5 years. ConclusionThere is an urgent need to reshape the current vulvar care model in Italy.

Investigating racial and ethnic disparities in vulvar squamous cell carcinoma: A retrospective cohort analysis of the Surveillance, Epidemiology, and End Results database

Investigating racial and ethnic disparities in vulvar squamous cell carcinoma: A retrospective cohort analysis of the Surveillance, Epidemiology, and End Results database

The Vertical Profunda Artery Perforator Flap for Perineal Reconstruction.

Colorectal cancer is a significant cause of cancer-related death in the United States with abdominoperineal resection (APR) remaining a necessary procedure for many patients. The resultant defects of this radical operation are complex and characterized by significant tissue voids. Pedicled vertical profunda artery perforator flaps (vPAP) can be used to obliterate these defects in patients receiving minimally invasive APR or when the abdominal donor site is unavailable. After receiving local institutional review board approval, a single center, retrospective cohort study from January 2020 to December 2021 was performed assessing pedicled vPAP flap reconstruction of APR defects. Age, sex, body mass index, primary diagnosis, comorbidities, concomitant oncologic procedures, radiation, timing, incorporation of gracilis flaps, follow-up, and complications were compared. Ten patients (70% male) with an average age of 56.2 years and BMI of 27.6 were included in the study. Rectal adenocarcinoma (50%) was the most common indication for APR, followed by rectal squamous cell carcinoma (30%), vulvar squamous cell carcinoma (10%), and Crohn disease (10%). Eighty percent of the patients received radiation, and 70% of reconstructions were delayed after the initial resection. The average length of clinical follow-up was 26.1 months. Concerning major complications, 2 patients were required to return to the operating room due to venous congestion (20%), and 2 patients suffered partial flap failure (20%). Minor complications were perineal dehiscence (50%), abscess requiring percutaneous drainage by interventional radiology (30%), and infection requiring antibiotics (20%). Twenty percent of patients developed fistulas requiring surgical excision. There were no instances of donor site dehiscence, and there was no complete flap loss, indicating successful reconstruction in all included cases. vPAP flaps are a reliable method to reconstruct perineal defects with less donor-site morbidity than previous reconstructive options. vPAP flaps should be considered in the setting of delayed reconstruction, minimally invasive APRs, and when the abdominal donor site is unavailable.

Vulvar Squamous Cell Carcinoma Guidelines May Benefit From Consideration of Tissue-Sparing Techniques as Treatment Options.

Vulvar Squamous Cell Carcinoma Guidelines May Benefit From Consideration of Tissue-Sparing Techniques as Treatment Options.

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.

Confusing Histopathological Features and HPV Testing Results in Vulvar Squamous Cell Carcinoma Arising in a Young Woman: A Case Solved Using Next-Generation Sequencing

Confusing Histopathological Features and HPV Testing Results in Vulvar Squamous Cell Carcinoma Arising in a Young Woman: A Case Solved Using Next-Generation Sequencing

Biopsy-verified vulvar lichen sclerosus and the risk of non-vulvar cancer: A nationwide cohort study.

Vulvar lichen sclerosus (VLS) is a chronic inflammatory mucocutaneous disease known to be associated with human papillomavirus-independent vulvar squamous cell carcinoma. Evidence on the association with other types of cancer, however, is sparce. We conducted a large nationwide cohort study examining the incidence of non-vulvar cancers among women with biopsy-verified VLS compared with the general female population. By using the nationwide Pathology Registry, we identified all women in Denmark with a biopsy-verified VLS diagnosis during 1978-2019 (n = 16,921). The cohort was followed up in the Danish Cancer Registry until 2022 for a subsequent non-vulvar cancer diagnosis. Standardized incidence ratios (SIRs) were computed with 95% confidence intervals (CIs) as relative risk estimates of all specific non-vulvar cancer sites. Compared with general female population rates, women with biopsy-verified VLS had decreased rates of several non-vulvar cancers, including HPV-related cancers (combined estimate: SIR = 0.5; 95% CI: 0.3-0.7), and lung (SIR = 0.6; 95% CI: 0.5-0.7), liver (SIR = 0.5; 95% CI: 0.2-0.9), and thyroid cancer (SIR = 0.5; 95% CI: 0.3-0.9). The decreased SIRs tended to sustain throughout the follow-up period following the VLS diagnosis. This large nationwide cohort study shows that women with biopsy-verified VLS may have a long-term reduced risk of developing HPV-related (cervical, vaginal, oropharyngeal, and anal) and smoking-associated cancers (lung, liver, and cervical) as well as thyroid cancer. Future studies focusing on the mechanisms behind the decreased cancer risk are needed.

Monocyte infiltration is an independent positive prognostic biomarker in vulvar squamous cell carcinoma

BackgroundVulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment.MethodsA total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan–Meier analyses).ResultsHealthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADR−CD11c−CD14+CD68−CD163−CD33−) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001).ConclusionA hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.

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% vs 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 vs 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% vs 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.