Vulvar Squamous Cell Carcinoma Research Articles

A Mimicker of Differentiated Vulvar Intraepithelial Neoplasia: Reactive Atypia From Noncompliance With Lichen Sclerosus Therapy.

Differentiated vulvar intraepithelial neoplasia (d-VIN) is an HPV-independent precursor to vulvar squamous cell carcinoma. The histology of d-VIN lesions is difficult to differentiate from that of non-neoplastic epithelial disorders, especially lichen sclerosus (LS). The authors present a case of LS, where relying on histopathology alone could have led to misdiagnosis. The patient was a 17-year-old female patient with clinical features of vulvar dermatitis and LS for 2 years. She was counseled to apply clobetasol 0.05% to the affected area daily but reported no improvement after 6 months. A biopsy of the right labia majora revealed histologic findings typical of d-VIN and near-contiguous p53 expression. These features are characteristic of d-VIN. However, d-VIN is exceedingly rare in young patients. The case was reviewed by 6 dermatopathologists and gynecologic pathologists, who observed that the degree of inflammation would be unusual postclobetasol therapy and could be due to noncompliance. A review of the patient's chart revealed that she "does not always remember to apply" clobetasol. The patient's clinician confirmed that there were compliance issues, and the follow-up biopsy was negative for d-VIN. The case was signed out as LS, with a note describing the above, and to rebiopsy if concern persisted. The authors conjecture that inflammatory infiltrates in the biopsied area caused reactive atypia due to lack of adherence to treatment. Although the patient's age helped rule out d-VIN, similar cases in elderly patients may be occurring. Pathologists must be aware that reactive forms of untreated LS can mimic d-VIN, to avoid misdiagnosis.

Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279.

To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

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.

Abstract 6454: Genomic characterization of vulvar squamous cell carcinoma

Abstract Introduction: Understanding the molecular underpinnings of vulvar squamous cell carcinoma (vSCC) has strong potential for clinical impact, given the unmet need for this rare cancer. vSCCs have two main etiologies, including human papillomavirus (HPV) infection or skin conditions such as lichen sclerosis. Clinically, few treatment options with limited efficacy are available for recurrent vSCCs and large whole transcriptome disease subtyping studies are limited due to the rarity of this cancer type. Here, we present a whole transcriptome subtyping study of 244 vSCC clinical samples with DNA genomic profiling. Furthermore, we compared vSCCs to other SCC disease subtypes (pan-SCC), including lung, esophageal, skin, urothelial, anal, and head and neck (HN). Our goal was to gain novel insights into the molecular landscape of vSCCs to inform new routes of therapy. Methods: Deidentified records of SCC patients were selected from the Tempus clinico-genomic database. The vSCC cohort was predominantly composed of, but not exclusively, naive or pre-treatment primary tissue. The pan-SCC cohort was limited to randomly sampled primary pre-treatment female samples with paired RNA and DNA sequencing. To perform vSCC subtyping, we used bulk RNA-seq and clustered the samples using FastPG-CC, an internally developed consensus-clustering extension of FastPG, a graph-based parallelized clustering tool. We next performed differential expression, pathway analysis, and cell type abundance estimation. Results: Unbiased gene expression clustering analysis identified three vSCCs clusters; an HPV+ cluster (HPV+, 32% of vSCC samples), HPV- cluster (HPV-, 33%), and an intermediate cluster which contained both HPV+ and HPV- samples (Mix, 35%). The HPV- cluster was enriched for TP53 and TERT promoter mutations, EMT and tumor microenvironment gene expression-derived pathways, and was most similar to HPV- oral HN tumors. The HPV+ cluster was enriched with PIK3CA mutations, cell cycle gene expression and was most similar to other HPV+ SCC samples, including cervical, anal, and HN. The Mix cluster was enriched for neutrophils, fatty acid metabolism and was most similar to skin SCC. Conclusions: We performed a multi-modal molecular subtyping analysis on a large cohort of vSCCs and identified three molecular subtypes, which enabled us to identify heterogeneity within vSCC, and observe that a subset of vSCCs share features with SCC tumor types for which there are emerging therapy options. Thus, this approach identifies a subset vSCCs that may be responsive to existing SCC therapeutics. Citation Format: Sara R. Selitsky, Tasha Thong, Kimberley Roche, Justin Guinney, Praveen Sethupathy, Catherine Igartua. Genomic characterization of vulvar squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6454.

Update on the Sentinel Node Procedure in Vulvar Cancer.

Early-stage vulvar cancer is managed by a local excision of the primary tumor and, if indicated, a sentinel node (SN) biopsy to assess the need for further groin treatment. With the SN procedure, many patients can be treated less radically and will experience less complications and morbidity compared with an inguinofemoral lymphadenectomy (IFL). Still, the SN procedure can be further optimized. Different tracers for detecting the SN are being investigated, aiming to optimize detection rates and decrease the burden of the procedure and short-term complications. Until now, no standardized protocols exist for the pathologic workup of the SN, possibly leading to discrepancies in detection of metastases between institutes using different methods. New techniques, such as one-step nucleic amplification, seem to have potential in accurately detecting metastases in other cancers, but have not yet been investigated in vulvar squamous cell carcinoma (VSCC). Furthermore, several studies have investigated the possibility to broaden the indications for the SN procedure, such as its use in recurrent disease, larger tumors, or multifocal tumors. Although these studies show encouraging results, cohorts are small and further studies are needed. Prospective studies are currently investigating these subgroups. Lastly, several studies investigated optimization of groin treatment of patients with a metastatic SN. Inguinofemoral radiotherapy is a good alternative to IFL in patients with micrometastases in the SN, with comparable efficacy and less treatment-related morbidity. Reduction of the radicality of groin treatment is also possible in other ways, such as omitting contralateral IFL in patients with lateralized tumors and a unilateral metastatic SN. In conclusion, the SN procedure is an established procedure in early-stage VSCC, although optimization of the technique, pathologic workup, indications, and treatment in the setting of metastatic disease are the subject of ongoing research.

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.

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

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. 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. 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. 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.

PD-L1 Expression in HPV-associated Versus HPV-independent Invasive Vulvar Squamous Cell Carcinoma.

Two etiological pathways have been implicated in the pathogenesis of vulvar squamous cell carcinoma (VSCC): a high-risk human papillomavirus (HPV)-associated route and an HPV-independent pathway characterized by TP53 mutations. Programmed cell death ligand 1 (PD-L1) has become increasingly useful in predicting the response to checkpoint inhibitor therapy in squamous cell carcinomas at various anatomical sites. This study aimed to assess the association between PD-L1 expression and the VSCC subtype to evaluate the utility of PD-L1 in prognostication and therapeutic selection based on HPV status. PD-L1 status was assessed using 3 separate metrics for the extent of PD-L1 staining in various cell types: immune cell score, tumor proportion score (TPS), and combined positive score. The study group consisted of 25 HPV-associated and 28 HPV-independent VSCCs. PD-L1 expression was positive in the majority of VSCCs according to all 3 scoring metrics (84.9% by immune cell score, 77.3% by TPS, and 90.6% by combined positive score). PD-L1 expression was observed in the majority of cases in both groups (60%-96.4%). PD-L1 expression using the TPS method was greater in HPV-independent tumors than in HPV-associated tumors (P = 0.004), and high PD-L1 expression was also more common in the HPV-independent subtype (P = 0.016 using the TPS method and P = 0.013 using the combined positive score method). Our findings contribute to the growing evidence that PD-L1 is expressed in the majority of invasive VSCCs, and thus may serve as an attractive therapeutic target. PD-L1 expression is higher in HPV-independent tumors, suggesting that this subtype may be more responsive to PD-L1 inhibitor therapy.

Survival nomograms for vulvar squamous cell carcinoma based on the SEER database and a Chinese external validation cohort.

The aim of study was to construct a nomogram to effectively predict the overall survival (OS) and cancer-specific survival (CSS) for patients with vulvar squamous cell carcinoma (VSCC). The training cohort consisted of 5405 patients with VSCC, extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Eighty-four patients with VSCC were selected from the disease database of the Shengjing Hospital of China Medical University from 2014 to 2020, and enrolled as the external validation cohort. Significant independent prognostic factors were identified using Cox regression analysis and used to develop nomograms to predict 1-, 3-, and 5-year OS and CSS in patients with VSCC. The nomogram predicting OS was developed based on tumor size, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, regional lymph node involvement, distant metastases, surgery, chemotherapy, age, and race. The nomogram for CSS was constructed using the similar factors, excluding race but including marital status. The nomogram for 1-, 3-, and 5-year OS demonstrated robust performance with receiver operating characteristic curves (AUCs) exceeding 80% (0.86, 0.84, and 0.82), outperforming the FIGO staging alone (0.77, 0.75, and 0.72). Similarly, for CSS, our nomograms achieved larger AUCs of 0.89, 0.88, and 0.86 compared with FIGO staging alone (0.81, 0.79, and 0.78). The nomograms more accurately predict prognosis than simple FIGO staging. Moreover, the nomograms developed in this study provide a convenient, operable, and reliable tool for individual assessment and clinical decision-making for patients with VSCC.

The prognostic significance of primary tumor site in vulvar cancer: a population-based cohort study.

To investigate the association of primary tumor site with prognosis in vulvar cancer, stratified by vulvar squamous cell carcinoma (SCC) and non-SCC histological types. This population-based retrospective study enrolled patients with vulvar cancer from the Surveillance, Epidemiology, and End Results database between January 2000 and December 2018. The primary outcome was cancer-specific survival (CSS). The prognostic difference between labium majus, labium minus and clitoris groups was investigated using Kaplan-Meier analyses and Cox proportional hazards regression analyses. A total of 3,465 eligible patients with vulvar cancer were included with a mean age of 54.5 years. Among the 1,076 (31.1%) patients with non-SCC, the multivariate Cox regression analyses showed that labium minus-sited disease (hazard ratio [HR]=1.85; 95% confidence interval [CI]=1.27-2.71; p=0.001) and clitoris-sited disease (HR=2.37; 95% CI=1.47-3.85; p<0.001) were significantly associated with worse CSS, compared with labium majus-sited disease. However, among the 2,389 (68.9%) patients with SCC, no significant association of primary tumor site with CSS was found (p>0.05). Kaplan-Meier analyses also showed that the primary tumor site had a significant prognostic effect in vulvar non-SCC (p<0.001) but not in vulvar SCC (p=0.330). Among vulvar non-SCC, patients with labium minus-sited disease had a significantly worse prognosis than those with labium majus-sited disease, and a significantly better prognosis than those with clitoris-sited disease. Gynecologic oncologists should consider the prognostic effect of primary tumor site in vulvar non-SCC, and make optimal, personalized treatment and surveillance strategies based on different primary tumor sites.

Prevalence of prescribing topical corticosteroids to patients with lichen sclerosus following surgery for vulvar cancer: a survey among gynaecologic oncologists in The Netherlands

Background Vulvar lichen sclerosus (LS) is a chronic inflammatory dermatosis which can progress to precursor lesion differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar squamous cell carcinoma (VSCC). The risk of developing recurrent vulvar cancer following LS-associated VSCC is high. Evidence suggests that treatment of LS with topical corticosteroids (TCS) can prevent progression to dVIN, VSCC and recurrences. However, current guidelines do not give any recommendation on the management of LS following surgery for VSCC. The aim of this study was to conduct a survey among all registered gynaecologic oncologists (GOs) in the Netherlands to evaluate the current management of LS patients without a history of VSCC (LSnoVSCC) and patients with LS following surgery for VSCC (LSVSCC). Methods An online survey was distributed to all registered GOs in the Netherlands. Primary outcome measures were the frequency, type and duration of TCS treatment prescribed for LSnoVSCC and LSVSCC patients, separately. As a secondary outcome measure, reasons for treating or not treating patients with LSnoVSCC and LSVSCC with TCS were analysed. Results Forty-four GOs completed the survey, resulting in a response rate of 75%. TCS were prescribed more often to patients with LSnoVSCC as compared to patients with LSVSCC (86% versus 52%, respectively, p < 0.001). If treatment was initiated, ultra-potent (class IV) TCS were most commonly prescribed for an indefinite period of time for both patient groups. The most reported reason for treating patients in both groups with TCS was symptoms, followed by clinical aspects of the lesion and prevention of progression to dVIN and VSCC. Conclusion The majority of GOs who participated in our study endorse the utilisation of long-term ultra-potent TCS therapy in both patients with LSnoVSCC and LSVSCC. Nevertheless, Dutch GOs are currently prescribing TCS more frequently to patients with LSnoVSCC than to patients with LSVSCC.

The diagnosis and management of vulval intraepithelial neoplasia

Key content High‐risk human papilloma virus (HPV)‐associated vulval high‐grade squamous intraepithelial lesions and HPV‐independent differentiated vulval intraepithelial lesions represent distinct disease processes with different risks of progression to vulval squamous cell carcinoma. First‐line medical management is appropriate for women with biopsy‐confirmed vulval high‐grade squamous intraepithelial lesions who have been adequately counselled on the risk of occult invasive disease. Topical treatment should be undertaken in the context of a specialist clinic because it is not suitable for all patients. Surgical management is needed for differentiated vulval intraepithelial neoplasia. Learning objectives To understand the clinical, histological, and pathological classification of squamous intraepithelial lesions and diagnostic challenges. To be able to contribute to the multidisciplinary investigation and diagnosis of squamous intraepithelial lesions. To understand the basis for patient‐centred counselling on the investigation, diagnosis and treatment of suspected squamous intraepithelial lesions. Ethical issues Treatment must be tailored towards the patient's appreciation of risk and benefit, informed by the clinical and pathological features of the disease.

Genomic characterization of vulvar squamous cell carcinoma reveals differential gene expression based on clinical outcome

ObjectiveThe greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. MethodsFrom 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumors from 21 patients were subjected to whole exome sequencing of DNA and RNA, immunohistochemistry (IHC) antibodies of PD-L1 and P16, and in-situ hybridization (ISH) for high-risk HPV. ResultsAnalysis of DNA and RNA revealed six genes that were strongly differentially expressed between group A and B: TGM3, ACVR2A, ROS1, NFEL2, CCND1 and BCL6. Clinically relevant DNA mutations were significantly greater in group A versus B: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable and tumor mutational burden (TMB) was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. ConclusionsACVR2A and TGM3 are significantly under-expressed in tumors with poor outcome, suggesting they may play a role in tumor suppression. Clinical outcome of VSCC appears independent of MSI, TMB, or PD-L1 status.

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.

The development of in vitro organotypic 3D vulvar models to study tumor-stroma interaction and drug efficacy.

Vulvar squamous cell carcinoma (VSCC) is a rare disease with a poor prognosis. To date, there's no proper in vitro modeling system for VSCC to study its pathogenesis or for drug evaluation. We established healthy vulvar (HV)- and VSCC-like 3D full thickness models (FTMs) to observe the tumor-stroma interaction and their applicability for chemotherapeutic efficacy examination. VSCC-FTMs were developed by seeding VSCC tumor cell lines (A431 and HTB117) onto dermal matrices harboring two NF subtypes namely papillary fibroblasts (PFs) and reticular fibroblasts (RFs), or cancer-associated fibroblasts (CAFs) while HV-FTMs were constructed with primary keratinocytes and fibroblasts isolated from HV tissues. HV-FTMs highly resembled HV tissues in terms of epidermal morphogenesis, basement membrane formation and collagen deposition. When the dermal compartment shifted from PFs to RFs or CAFs in VSCC-FTMs, tumor cells demonstrated more proliferation, EMT induction and stemness. In contrast to PFs, RFs started to lose their phenotype and express robust CAF-markers α-SMA and COL11A1 under tumor cell signaling induction, indicating a favored 'RF-to-CAF' transition in VSCC tumor microenvironment (TME). Additionally, chemotherapeutic treatment with carboplatin and paclitaxel resulted in a significant reduction in tumor-load and invasion in VSCC-FTMs. We successfully developed in vitro 3D vulvar models mimicking both healthy and tumorous conditions which serve as a promising tool for vulvar drug screening programs. Moreover, healthy fibroblasts demonstrate heterogeneity in terms of CAF-activation in VSCC TME which brings insights in the future development of novel CAF-based therapeutic strategies in VSCC.

Immediate Lymphatic Reconstruction Using a Handheld Fluorescence Imaging Device.

Immediate lymphatic reconstruction (ILR) has traditionally required a fluorescent-capable microscope to identify lymphatic channels used to create a lymphaticovenous bypass (LVB). Herein, a new alternative method is described, identifying lymphatic channels using a commercially available handheld fluorescence imaging device. This was a single-center study of consecutive patients who underwent ILR over a 1-year period at a tertiary medical center. Intradermal injection of fluorescent indocyanine green dye was performed intraoperatively after axillary or inguinal lymphadenectomy. A handheld fluorescent imaging device (SPY-PHI, Stryker) rather than a fluorescent-capable microscope was used to identify transected lymphatic channels. Data regarding preoperative, intraoperative, and outcome variables were collected and analyzed. The handheld fluorescent imaging device was successfully able to identify transected lymphatic channels in all cases (n = 15). A nonfluorescent-capable microscope was used to construct the LVB in 14 cases. Loupes were used in one case. In 13 cases, ILR was unilateral. In two cases, bilateral ILR was performed in the lower extremities. All upper extremity cases were secondary to breast cancer (n = 7). Lower extremity cases (n = 8) included extramammary Paget disease of the penis, ovarian cancer, vulvar squamous cell carcinoma, squamous cell carcinoma of unknown origin, soft tissue sarcomas, cutaneous melanoma, and porocarcinoma. ILR, using indocyanine green injection with a handheld fluorescent imaging device, is both safe and effective. This method for intraoperative identification of lymphatic channels was successful, and LVB creation was completed in all cases. This approach makes ILR feasible when a fluorescent-capable microscope is unavailable, broadening access to more patients.

Vulvar squamous cell carcinoma in a captive female chimpanzee: A case report.

A necropsy was performed on a 43-year-old female zoo chimpanzee, with cancer in the vulvar and perivulvar region. She was diagnosed with squamous cell carcinoma, the presence of this tumor in domestic animals and non-human primates is very rare in the vulvar region and there were no previous reports found on it in chimpanzee, due to which this report contributes to the knowledge on chimpanzee pathologies.

Vulvar squamous cell carcinoma in women 80 years and older: Treatment, survival and impact of comorbidities

BackgroundDespite being a disease of mainly older women, little is known about the clinical management of older women with vulvar squamous cell carcinoma (VSCC). We evaluated their daily clinical management compared with younger women, and established the prevalence of comorbidities and its impact on overall survival (OS). MethodsAll Dutch women diagnosed with VSCC from 2015 to 2020 (n = 2249) were selected from the Netherlands Cancer Registry. Women aged ≥80 years (n = 632, 28%) were defined as “older” patients, women <80 years were considered as “younger”. Chi-square tests were performed to evaluate differences in treatment by age group and comorbidities. Differences in OS were evaluated using Kaplan-Meier Curves and log-rank test. ResultsThe vast majority of both older (91%) and younger (99%) patients with FIGO IA VSCC received surgical treatment of the vulva. Older FIGO IB-IV VSCC patients were less likely to undergo groin surgery than younger patients (50% vs. 84%, p < 0.01). Performance of surgical treatment of the vulva and groin(s) was not associated with the number of comorbidities in older patients (p = 0.67 and p = 0.69). Older patients with ≥2 comorbidities did have poorer OS compared to women with one or no comorbidities (p < 0.01). ConclusionThe vast majority of older patients underwent vulvar/local surgery. Older patients less often received groin surgery compared to younger patients. The majority of older patients had at least one comorbidity, but this did not impact treatment choice. The poorer survival in older VSCC patients may therefore be due to death of competing risks instead of VSCC itself.

Prognostic value of HPV-PCR, p16 and p53 immunohistochemical status on local recurrence rate and survival in patients with vulvar squamous cell carcinoma

AbstractThe primary aim of this study was to assess the association between human papilloma virus (HPV) and p53 expression and local recurrence (LR), disease specific survival (DSS), and overall survival (OS) in patients with vulvar squamous cell carcinoma (VSCC). Secondary, the accuracy of p16 immunohistochemistry for HPV status was assessed. The tumor tissue of 255 patients, surgically treated for primary unifocal VSCC between 2000 and 2010, was analyzed. HPV-PCR and P16 and p53 immunohistochemical stainings were performed. All histologic slides were independently reviewed by two expert gyneco-pathologists. Time to first LR, DSS, and OS for the variables p16, p53, and HPV-PCR were compared using univariable and multivariable Cox-regression analyses. In 211/255 (83.5%) patients, HPV-PCR was negative. The local recurrence rate was significantly lower in patients positive with HPV-PCR (10-year LR rate 24.6%) versus negative tumors (47.5%), p = 0.004. After multivariable analyses, this difference remained significant (HR 0.23 (95% CI 0.08–0.62) p = 0.004). There was no difference in LR rate correlated to the p53 expression. DSS and OS did not significantly differ after multivariable analyses for all different subgroups. Sensitivity and specificity of p16 staining for presence of HPV detected by HPV-PCR were 86.4% and 93.8%, respectively. In conclusion, patients with HPV-negative VSCCs have significantly more LR compared to patients with HPV-positive VSCCs, and p16 immunohistochemistry is a reliable surrogate marker for HPV status. No relevant subgroup for LR or survival based on HPV/p53 status could be identified. We advise to perform an HPV-PCR or p16 IHC staining in all patients with VSCC.

Time to extend the indication for sentinel node biopsy in vulvar cancer? Results from a prospective nationwide Swedish study

ObjectiveTo assess detection rates and negative predictive values of sentinel node biopsy in vulvar squamous cell carcinoma with tumors ≥4 cm, multifocal tumors, and in locally recurrent disease.MethodsBetween December 2019...