small molecules

2026-09-06 | Molecular subtypes of stage III vulvar squamous cell carcinoma predict recurrence and survival outcomes.

Although molecular classification has been associated with outcomes in vulvar squamous cell carcinoma (vSCC), its relevance in patients with stage III disease is less well characterized. We evaluated the association between molecular subtype and oncologic outcomes among patients with 2021 FIGO stage III vSCC. We conducted a retrospective study of patients with primary stage III vSCC treated at a single institution from 2000 to 2021. Tumors were classified as HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 mutant (HPV-/p53mut) using HPV RNA in situ hybridization and p16 immunohistochemistry (IHC) for HPV status and p53 IHC as a surrogate for TP53 mutation status. Primary outcomes were recurrence and disease-specific mortality within five years from primary treatment evaluated using Cox proportional hazards and Kaplan-Meier survival analysis. Fifty-two patients had complete molecular data: 32.7% HPV+, 21.2% HPV-/p53wt, and 46.2% HPV-/p53mut. Smoking was associated with HPV+ tumors (p < 0.001). Within five years, 46.2% experienced recurrence (median 11 months, IQR 7.3-29.2). The highest proportion of recurrences occurred in the HPV-/p53mut group, and most groin recurrences occurred in HPV-independent tumors; however, HPV/p53 status was not significantly associated with five-year recurrence (p = 0.22). For disease-specific survival, HPV-/p53mut tumors were associated with a 5.7-fold increased risk of disease-specific death compared with HPV+ tumors (HR 5.70, 95% CI 1.66-19.62). Molecular classification distinguishes clinically meaningful subgroups in stage III vSCC. HPV-independent tumors, particularly those with TP53 mutation, are associated with worse disease-specific survival and supports further evaluation of molecularly informed risk stratification and treatment approaches.

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2026-07-01 | Inhibition of Plasminogen Activator Inhibitor-1 (PAI-1) by Tiplaxtinin Attenuates the Aggressive Phenotype of Vulvar Squamous Cell Carcinoma Cells In Vitro.

Vulvar squamous cell carcinoma (VSCC), while relatively rare, is associated with significant morbidity. Activation of G-protein coupled estrogen receptor 1 (GPER1), which has a tumor-suppressing effect in VSCC, leads to reduced expression of plasminogen activator inhibitor-1 (PAI-1). PAI-1, a key regulator of the plasminogen activation system, is overexpressed in various cancers and is linked to poor prognosis. Its role and potential as a therapeutic target in VSCC remain poorly explored. This study investigated the effects of the specific PAI-1 inhibitor tiplaxtinin (PAI-039, TPX) on the aggressive behavior of VSCC cells in vitro. Expression of PAI-1 was verified by western blot. The effects of TPX treatment on viability, proliferation, migration, and invasion of A431 and Cal-39 VSCC cells were assessed using AlamarBlue, crystal violet, gap closure, and Boyden chamber assays, respectively. Apoptosis was examined using the Annexin V/propidium iodide (PI) assay. Both VSCC cell lines showed PAI-1 expression. With increasing TPX concentrations, viability and proliferation of the VSCC cells decreased significantly. Cell migration and invasion were both significantly reduced under treatment with the PAI-1 inhibitor. Apoptosis was not significantly induced by TPX. PAI-1 inhibitor TPX showed a strong inhibitory effect on VSCC cells, significantly reducing their viability, proliferation, migration and invasive capacity. This compound showed a strong ability to suppress important cell functions associated with cancer progression, making it a promising candidate for VSCC therapy to specifically inhibit growth and spread of VSCC.

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2026-06-19 | Use of the dual tyrosine kinase inhibitor lapatinib for the treatment of vulvovaginal squamous cell carcinoma in a dog.

Vulvovaginal squamous cell carcinoma (SCC) is an uncommon neoplasm in dogs. An 11-year-old female spayed German Shepherd dog presented with a history of excessive peri-vulvar grooming and a 3 cm × 3 cm irregular mass involving the vagina and vulva. Incisional biopsy confirmed a diagnosis of primary vulvovaginal SCC. Abdominal ultrasonography and thoracic radiographs indicated no evidence of systemic or regional metastasis. Surgical excision and adjuvant radiation therapy were declined, and the patient was treated with lapatinib, an orally administered dual tyrosine kinase inhibitor. Treatment resulted in a partial response within 1 month and complete resolution of the primary lesion within 3 months. No recurrence of the initial lesion was observed after 1 year of treatment despite development of perivulvar cutaneous lesions that were not associated with clinical signs. Lapatinib was well tolerated but did result in acute hepatic injury that was resolved using hepatoprotective antioxidant medication and intermittent treatment cessation.

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2026-06-18 | Advanced Squamous Cell Carcinoma of the Vulva (FIGO IIIb): Clinical Presentation, Imaging and Multidisciplinary Management

Background: Squamous cell carcinoma of the vulva is a rare malignancy accounting for less than 5% of gynecological cancers. In locally advanced stages (FIGO III–IVA), the prognosis remains poor, particularly when surgical resection is not feasible. Case Presentation: We report the case of a 69-year-old woman presenting with a moderately differentiated, keratinizing and infiltrating squamous cell carcinoma of the vulva, classified as FIGO IIIb, with large bilateral necrotic inguinal lymphadenopathy. Pelvic MRI revealed a tissue process measuring 62 × 39 × 20 mm and inguino-perineal lymph nodes reaching 47 × 60 mm. The multidisciplinary team decided on neoadjuvant concurrent chemoradiotherapy (CCRT) with curative intent. The course was unfavorable, with the patient dying during a hospitalization for metabolic complications and tumor-related infection. Conclusion: This case illustrates the diagnostic and therapeutic challenges of locally advanced vulvar cancer and underlines the importance of early detection and prompt multidisciplinary management.

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2026-06-17 | A clinically concordant vulvar cancer patient-derived xenograft model retaining primary molecular signature for preclinical drug sensitivity assessment.

Establish and validate a patient-derived xenograft (PDX) model for vulvar cancer (VC). Evaluate the efficacy of commonly used clinical drugs both in vitro and in vivo using this model. Fresh primary vulvar cancer tumor tissues were then subcutaneously implanted into the scapular regions of immunodeficient mice, with tumor formation monitored and recorded in these mice. Hematoxylin and eosin (H&E) staining was performed to observe and compare the histopathological features of the primary and xenograft tumors, while immunohistochemical (IHC) staining was used to assess the consistency of protein expression profiles between the primary and xenograft tumors. Polymerase chain reaction (PCR) methods were employed to confirm the human origin of the xenograft tumors. Finally, the sensitivity of guideline-recommended chemotherapy drugs was evaluated using both HDST and in vivo efficacy studies, aiming to validate the drug responses observed in vitro with those seen in vivo. Tumor tissue from a primary vulvar squamous cell carcinoma patient was successfully transplanted into the subcutaneous region of mice and stably passed to the fourth generation. H&E staining results showed that the PDX model retained the atypia and original histological features of the primary tumor cells. IHC staining further confirmed that the protein expression profile of the xenograft tumors in the PDX model was consistent with that of the primary tumor. PCR humanization identification confirmed that the tumor tissues were of human origin. HDST drug screening results, combined with in vivo efficacy experiments, validated the sensitivity of the PDX model to guideline-recommended chemotherapy drugs, demonstrating clinical consistency. We have successfully established a vulvar cancer PDX model. This model retains the fundamental molecular characteristics of the primary human vulvar cancer tumor, thus offering an advantageous approach for preclinical assessment of novel therapies and investigation into the disease's pathogenesis.

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antibodies

2026-06-17 | Field Cancerization of the Cervix and Vulva in a Young HIV-Positive Woman: Diagnostic Challenges in Multifocal HPV Disease - A Case Report and Literature Review.

Human Papillomavirus (HPV) is a well-established cause of cancers of the cervix, vulva, and vagina, particularly high-risk types such as HPV-16 and 18. In women living with HIV, impaired immune function reduces viral clearance, leading to persistent infection, faster progression of precancerous lesions, and involvement of multiple sites within the lower genital tract. This phenomenon is often explained by the concept of "field cancerization", where widespread HPV exposure results in synchronous neoplastic changes in adjacent mucosal tissues. A 36-year-old HIV-positive woman presented with abnormal vaginal bleeding and post-coital bleeding. Testing revealed infection with multiple high-risk HPV genotypes, including HPV-16, and cervical cytology showed High-grade Squamous Intraepithelial Lesion (HSIL). Histopathological evaluation confirmed two concurrent HPV-related lesions: invasive squamous cell carcinoma of the cervix (FIGO stage IB1) and vulvar HSIL (VIN 3). She underwent a radical hysterectomy with pelvic lymph-node dissection along with wide local excision of the vulvar lesion, followed by adjuvant pelvic radiotherapy. This case illustrates the uncommon coexistence of cervical squamous cell carcinoma and vulvar HSIL in an HIV-positive woman, emphasizing the role of immunosuppression in persistent HPV infection and multifocal disease. Thorough evaluation of the entire lower genital tract, along with vigilant follow-up, is crucial for early detection and improved outcomes in this high-risk population.

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2026-06-09 | PRAME Expression in HPV-associated and Differentiated Vulvar Intraepithelial Neoplasia-associated Vulvar Squamous Neoplasia.

Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry was initially used diagnostically in melanoma but is increasingly evaluated across malignancies for diagnostic, prognostic, and therapeutic purposes. PRAME protein acts as a dominant repressor of retinoic acid signaling and may help stratify patients for retinoic acid-based therapy. Multiple PRAME-targeted immunotherapy trials are ongoing, supported by its selective tumor expression. Vulvar intraepithelial neoplasia (VIN) is an appealing setting for PRAME assessment because lesions are often multifocal or extensive, and treatment by excision can be disfiguring. Immunotherapy is also of rising interest in advanced vulvar squamous cell carcinoma (VSCC). We aimed to evaluate PRAME expression in HPV-associated and differentiated vulvar intraepithelial neoplasia (dVIN)-associated squamous lesions of the vulva. Full tissue sections from 106 vulvar squamous neoplasms (31 HSIL, 29 VSCC arising in HSIL, 20 dVIN, 26 VSCC arising in dVIN) were stained with PRAME antibody. Expression was recorded as the percentage of positive tumor cells, with intensity (0-3+) and staining localization documented, and an H-score was subsequently calculated. Groups were compared using the Wilcoxon rank-sum or Kruskal-Wallis tests. Most VSCCs (78%) expressed PRAME, with significantly higher expression in dVIN-associated lesions (P=0.006). Subgroup analysis showed the highest PRAME expression in dVIN-associated VSCC and the lowest in HSIL (P<0.00001). These findings suggest that distinct biological drivers of HPV-associated and dVIN-associated vulvar neoplasia contribute to differential PRAME expression. The strongest expression in dVIN-associated VSCC highlights a possible link between aggressive tumor behavior and PRAME. dVIN-associated lesions may therefore represent promising candidates for PRAME-targeted therapy.

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2026-06-01 | Hypertrophic Lichen Sclerosus: A Form of "Atypical" Lichen Sclerosus in the Pathway to HPV-Independent Squamous Cell Carcinoma of the Vulva.

Hypertrophic lichen sclerosus (HLS) is poorly characterized. A recent study described an atypical form of LS (p53 wild type) with a CK17/D2-40 immunohistochemical profile intermediate between classic LS and differentiated vulvar intraepithelial neoplasia (dVIN). Our study aims to characterize HLS through IHC and molecular profiling to determine if it is a classic or atypical LS lesion. We reviewed HLS diagnosed in 12 biopsies (2014 to 2025) and 5 resections for vulvar squamous cell carcinoma (vSCC) (1998 to 2015) from our institution (mean patient age 59; range: 37 to 97). We defined HLS by nonexophytic acanthosis, hyperkeratosis +/- parakeratosis, granular layer retention, irregular dermal-epidermal junction, lack of severe basal layer atypia, homogenization of the superficial dermis, and +/- lichenoid inflammatory infiltrate. In the 5 resections, CK17 expression was suprabasal in 4 (80%) and superficial in 1 (20%) of HLS adjacent to vSCC. D2-40 intensity was moderate in all 5 (100%). All 5 vSCC were p16-/p53 aberrant with intense D2-40 expression and showed diffuse CK17 in 4 (80%) and suprabasal staining in 1 (20%). All 12 HLS biopsies were p16-; 7 (58%) were p53 wild type and 5 (42%) were aberrant. Seven (58%) showed CK17 suprabasal staining; 5 (42%) were diffuse. D2-40 intensity ranged from absent (1/12; 8%) to faint (3/12; 25%) to moderate (3/12; 25%) to intense (5/12; 42%). Frequently altered genes were SDHA (3/6; 50%) and TP53 (2/6; 33%). HLS shows neither the classic morphology of LS nor dVIN but can be p53 aberrant/mutant. Because of its CK17/D2-40 immunophenotype, it should be considered as atypical LS.

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2026-06-01 | Nectin-4 expression in vulvar squamous cell carcinoma (VSCC) – a possible target for the treatment approach with the antibody drug conjugate enfortumab vedodin (EV)?

Background The development of antibody-drug conjugates (ADC) for cancer treatment has achieved promising results in different solid tumors and targets. Enfortumab-Vedotin (EV), a humanised anti-Nectin4-IgG1 monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE), is an FDA-approved Nectin4-directed ADC for the treatment of locally advanced or metastatic pre-treated urothelial cancer. Targeted therapy with EV requires the expression of Nectin4 within the tumor cells. The present study evaluates Nectin4 expression in vulvar squamous cell carcinomas (VSCC) and its correlation to different VSCC molecular subtypes. Methods Immunohistochemical Nectin4-expression was evaluated semiquantitatively on diagnostic biopsies of VSCC using an immunoreactive score (IRS). There was a correlation between IRS and different molecular subtypes of VSCC. Results All 55 cases showed at least weak Nectin4 expression within the tumor cells with a median IRS of 6.0 (range 2 – 6) indicating high expression levels in most tumors. Moderate/high expression (IRS>4) was more frequent in HPV-associated tumors (p16+ve/p53wt molecular subtype: 12/14 (85.7%) when compared to HPV-independent VSCC (22/35 (62.9%) in p16-ve/p53abn and 0% in four p16-ve/p53wt) VSCC, a difference that is not statistically significant. Conclusion Most VSCC show high expression of Nectin4, including the HPV-independent VSCC containing a TP53-mutation (p16-ve/p53abn molecular subtype), that are associated with the worst prognosis. Therefore, Nectin4-directed ADC such as Enfortumab-Vedotin (EV) may present a potential treatment option in VSCC. Nectin4-expression can easily be assessed by immunohistochemistry on diagnostic biopsies. Clinical trials exploring Nectin4-directed ADCs such as EV are necessary. Publication History Article published online: 10 June 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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2026-06-01 | TROP-2 expression in vulvar squamous cell carcinoma (VSCC) – correlation to molecular subtype

Background The Trophoblast Cell Surface Antigen 2 (TROP-2) is associated with invasiveness and tumor progression in several malignancies. Strong TROP-2-expression is associated with poor prognosis in cervical carcinoma. Recently, TROP-2 was identified as a target protein for treatment of solid tumors using antibody-drug conjugates (ADC). There are no details about the expression profiles of TROP-2 in vulval cancer (VCX). Methods 55 cases of squamous cell carcinomas oft he vulva were immunohistochemically analysed for TROP-2 expressio using a H-score. The staining intensity (SI) was score das negative (0), weak (1), moderate (2) and strong (3). The percentage of positive stained tumor cells was calculated as 0 (complete negative staining of tumor cells), 1 (1-10% positive stained tumor cells), 2 (11-50%) and 3 (51-100%). Overall staining results were calculated by SI x percentage staining score as follows: negative (core 0),+(scores 1;2;3),++(scores 4-6) and+++(score 7-9) as previously described. Overall staining scores were compared to the molecular subtypes of vulval carcinoma, defining p16+ve/p53wt, p16-ve/p53mut and p16-ve/p53wt VCX. Staining evaluation of TROP-2 was blinded to the molecular subtype. Results All cases were positive for TROP-2 (7 cases+, 31 cases++and 17 cases+++) p16+ve/p53wt 16 cases mean value h-score 7,25 p16-ve/p53mut 31 cases mean value h-score 6,44 p16-ve/p53wt 2 cases mean value h-score 4 Conclusion It has been shown that the antibody drug conjugate (ADC) topoisomerase-1-inhibitor irinotecan, coupled via a linker to a humanised IgG-1ntibody hRS7 binding to TROP-2 (i.e. sacitumzumab) represents an effective treatment approach to several carcinoma types. Virtually all examined VCX showed at least weak staining for TROP-2 within the tumor cells. So, TROP-2 may represent a potential target for ADC in vulval cancer. There are no differences of TROP-2 expression within the different molecular subtypes of VCX. Publication History Article published online: 10 June 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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vaccines

2025-07-29 | The future of research on vulvar intraepithelial neoplasia: towards precision diagnostics and risk stratification.

Vulvar intraepithelial neoplasia (VIN) represents a heterogeneous group of premalignant lesions arising through distinct human papillomavirus (HPV)-associated and HPV-independent pathways. Despite well-characterized differences in etiology, prognosis, and progression risk, current management remains largely uniform and predominantly surgical. This one-size-fits-all approach neglects opportunities for individualized care and exposes patients, particularly younger women and those with multifocal disease, to potentially avoidable psychosexual morbidity. Recent advances in molecular pathology, including immunohistochemistry, genomic profiling, DNA methylation analysis, and copy number alteration detection, offer promising avenues for refining diagnostic precision and enabling risk stratification. Integration of markers such as p16INK4a, p53, and emerging methylation panels into diagnostic workflows may improve differentiation between lesion subtypes, guide surveillance, and identify candidates for conservative therapy. Moreover, the unique pathogenesis of vulvar high-grade squamous intraepithelial neoplasia, which diverges from squamocolumnar junction (SCJ)-driven models seen in other HPV-associated cancers, highlights the need for focused research on host-virus interactions and early oncogenic events in non-SCJ epithelium. Future directions include non-invasive sampling methods, molecularly-guided surveillance protocols, therapeutic HPV vaccines, and combined immunomodulatory treatments to reduce the burden of excisional therapy. Establishing precision-based approaches for VIN could not only preserve vulvar integrity and function but also improve oncological outcomes through targeted prevention and early intervention strategies.

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2025-06-05 | High Prevalence of Human Papillomavirus in Vulvar Cancer Among Vietnamese Women: Implications for Vaccination Strategies.

Vulvar cancer (VC) is rare; however, its incidence has steadily increased, likely due to increased human papillomavirus (HPV) infections. HPV infection rates vary significantly with age and ethnicity. Data on the VC incidence in Vietnam are limited. This study aimed to determine HPV infection rates and high-risk HPV types (HR-HPVs) and to model HPV causality in co-infections using a Proportional Attribution (PropAttr) model in Vietnamese VC patients. We investigated primary VC cases (invasive carcinoma) diagnosed at our hospital during 2020-2021. Tumor samples were tested for HPV using quantitative polymerase chain reaction. Recurrent cases and poor-quality preserved tumor samples were excluded. HPV infection status, HR-HPV status, and relevant clinicopathological features were analyzed. To estimate the most likely causative HPV genotype in co-infected lesions, the PropAttr model was applied, attributing genotypes based on their prevalence in mono-infections. Model reliability was validated using Spearman's correlation analysis. Of the 95 cases, 95% were squamous cell carcinoma, and 40% were clinical stage I. The HPV infection rate was approximately 77% (68.4-85.2), and HPV-16 was the most common subtype. Patients infected with HPV (mean age: 62.8) were younger than those who were not infected (mean age: 71.4) in univariate (p = 0.004) and multivariate (p < 0.001) analyses. While the vulvar pathohistological type was significantly associated with HPV infection in multivariate analysis (p < 0.001), no significant relationship was observed with other factors in univariate and multivariate analyses. The PropAttr model showed significant correlations between attribution estimates and mono-infection prevalence (HPV-16: ρ = 0.806, p < 0.001; HPV-18: ρ = 0.992, p < 0.001; 12 other HR-HPVs: ρ = 0.880, p < 0.001). A strong negative correlation between HPV-16 and 12 other HR-HPVs (ρ = -0.751, p < 0.001) suggested competitive interactions in genotype assignment. The HPV infection rate in Vietnamese VC cases was substantially higher than in other Asian populations, indicating a significant public health burden. Our findings reinforce the importance of expanding national HPV vaccination programs and incorporating advanced attribution models to improve HPV-related cancer risk assessment.

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2022-07-28 | New Perspectives in Therapeutic Vaccines for HPV: A Critical Review.

Human Papillomavirus is the main cause of cervical cancer, including squamous cell carcinoma of the oropharynx, anus, rectum, penis, vagina, and vulva. In recent years, considerable effort has been made to control HPV-induced diseases using either prophylactic or therapeutic approaches. A critical review of the literature about the therapeutic Human Papillomavirus vaccine was performed to analyze its efficacy in the treatment of female lower genital tract lesions and its possible perspective application in clinical practice. The most important medical databases were consulted, and all papers published from 2000 until 2021 were considered. We retrieved a group of seven papers, reporting the role of anti HPV therapeutic vaccines against the L2 protein in the order of their efficacy and safety in female lower genital tract disease. In addition, the immune response due to vaccine administration was evaluated. The development of therapeutic vaccines represents an interesting challenge for the treatment of HPV infection of the lower genital tract. Literature data underline that the L2 protein may be an interesting and promising target in the development of therapeutic HPV vaccines, but the possible strengths and the unclear longevity of L2 immune responses are factors to be considered before clinical use.

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2021-09-30 | What to do when nothing else is left to be done - metastatic non-HPV vulvar squamous cell carcinoma with multiple lines of chemotherapy

Recurrent vulvar squamous cell carcinoma with multiple site metastases is a rare entity – (up to 14.2% of the total number of recurrences), with a poor prognosis (only 15% of the patients alive at 5 years). Due to its “hard to find” character, there are no standardized guidelines available and the treatment is extrapolated from advanced cervical carcinoma, anal carcinoma and other squamous cell carcinomas. Immunotherapy has shown some positive results in vulvar carcinoma with PD-L1 positive, high TMB, high MSI or with MMR deficiency. An alternative for selected cases without therapeutic resources could be the HPV vaccine. We present the case of a 64-year-old woman diagnosed in 2014 with vulvar squamous cell carcinoma stage II for which she underwent radical vulvectomy with bilateral inguinal lymphadenectomy followed by external radiotherapy. In 2019 she developed local recurrence associated with lung, pleural, lymph nodes and subcutaneous metastasis, treated with three lines of chemotherapy: paclitaxel/carboplatin followed by cisplatin/5-fluorouracil and carboplatin/gemcitabine. The patient’s general health status altered progressively, and she died after the 4th cycle of carboplatin/gemcitabine. This case’s management could be a starting point for the vulvar carcinoma cases where the standard therapeutical options do not represent a choice anymore, providing the necessary example on how to approach it.

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2020-06-29 | The human papillomavirus vaccine as a treatment for human papillomavirus-related dysplastic and neoplastic conditions: A literature review.

Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.

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oligonucleotides

2023-12-12 | 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.

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2023-11-03 | Association of LncRNA PCBP1-AS1 with cancer occurrence and development: A review.

Long-stranded noncoding RNAs (LncRNAs) are noncoding RNAs >200 nucleotides in length. Polycytidine binding protein 1 antisense LncRNA is abbreviated as LncRNA polycytosine binding protein 1 antisense1 (PCBP1-AS1). Since studies in recent years have revealed the importance of PCBP1-AS1 in human genetic analysis, it is an important member of the LncRNA family. Genetically engineered group analysis of PCBP1-AS1 regulates the progression of cancer in biology. Therefore, it may be an important RNA in the regulation of human cancer. This article summarizes the molecular mechanism and clinical role of PCBP1-AS1 in various tumor types. Taking "PCBP1-AS1" and "cancer" as keywords, this paper analyzed the relationship between PCBP1-AS1 and various tumors by searching PubMed and Geen Medical, and summarized the related regulatory mechanism of PCBP1-AS1. PCBP1-AS1 is a valuable tumor-associated LncRNA that plays different biological roles in different cancers. Overall, it can both promote and inhibit the development of cancer. For example, abnormally high expression in castration-resitant prostate cancer, hepatocellular carcinoma, cervical cancer, glioma, and colorectal cancer promotes the proliferation and progression of these cancers; in contrast, PCBP1-AS1 inhibits cancer proliferation, metastasis, invasion, and recurrence when highly expressed in vulvar squamous cell carcinoma, Hodgkin lymphoma, and lung adenocarcinoma. PCBP1-AS1 regulates the development of multiple tumors, and the specific mechanism needs to be further investigated, which may become a new tumor marker and potential therapeutic target.

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2022-10-01 | 2022-RA-1543-ESGO Human papillomavirus-associated and -independent vulvar squamous cell carcinomas: clinical, pathological and prognostic distinct entities

Introduction/Background

The 2020 WHO classification of gynaecological tumors has introduced as the main criteria for classification of vulvar squamous cell carcinomas (VSCC) their etiological relationship with human papillomavirus(HPV) infection, dividing VSCC into two categories: HPV-associated and HPV-independent VSCC. Additionally, recent evidence suggests that HPV-independent tumors should be further divided according to p53 mutational status. We aimed to evaluate the clinical and prognostic implications of these new criteria.

Methodology

We retrospectively identified patients treated for VSCC in our hospital from 1985 to 2022 (n=196). Tumors were reviewed and classified in compliance with 2020 WHO criteria, according to p16 immunohistochemistry and HPV testing. HPV-independent tumors were subclassified as p53 wild-type and mutant. The clinical and pathological features of tumors were compared and disease free-survival (DFS) and disease-specific survival (DSS) were evaluated using univariate and multivariate analysis.

Results

Thirty-six (18%) patients had HPV-associated and 160(82%) HPV-independent tumors, 88% of whom showed mutant p53. Patients with HPV-independent tumors were significantly older (76 vs 62 years,p<0.05) and had bigger tumors (29 vs 20 mm,p<0.05). HPV-independent tumors with mutant p53 were more deeply invasive than those with wild-type p53 (8 vs 5 mm,p<0.05). Mean follow-up was 53 months. HPV-independent tumors were associated with shorter DFS (recurrence rate 48% vs 17%, p<0.05), both in the univariate and multivariate analysis (Figure 1). A tendency to worse DSS was identified in patients with HPV-independent tumors, particularly in patients with p53 mutant tumors (mortality rate 15% for p53 mutant, 10% for p53 wild-type, and 5% for HPV-associated VSCC, p=0.2; Figure 1), despite the differences did not reach statistical significance.

Conclusion

The 2020 WHO classification of VSCC has clinical and prognostic implications. Among patients with HPV-independent VSCC, patients with mutant p53 show specific clinical features. Different treatment of VSCC patients, according to HPV-association or not, should be considered in the future.

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2021-05-09 | Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

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2019-09-17 | MicroRNA‑4712‑5p promotes proliferation of the vulvar squamous cell carcinoma cell line A431 by targeting PTEN through the AKT/cyclin D1 signaling pathways

The aim of the present study was to screen differentially expressed miRNAs in vulvar squamous cell carcinoma (VSCC), observe the role of microRNA‑4712‑5p in VSCC and investigate its targets and regulatory mechanism. Differentially expressed miRNAs in human VSCC tissues were screened. microRNA‑4712‑5p was selected and its expression level was verified in clinical tissue samples and the VSCC cell line A431 by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. The overexpression vector of microRNA‑4712‑5p was prepared and transfected into A431 cells; subsequently, cell invasion and metastasis were examined by Cell Counting Kit‑8 and Transwell migration assays. Furthermore, the target gene of miRNA‑4712‑5p was predicted by bioinformatics and verified by The Dual‑Luciferase® Reporter (DLR™) Assay System. The expression of phosphatase and tensin homologue (PTEN) and its downstream proteins, such as protein kinase B (PKB; AKT), glycogen synthase kinase (GSK)3β and cyclin D1, were detected by western blot assays. The expression level of microRNA‑4712‑5p in VSCC tissues and the A431 cell line was found to be significantly increased, promoting proliferation and invasion of VSCC. The DLR™ assay indicated that PTEN was a target of miR‑4712‑5p. RT‑qPCR revealed that PTEN expression was markedly lower in VSCC tissues compared with that in adjacent tissues. After A431 cells were transfected with the miRNA‑4712‑5p overexpression vector, phospho‑AKT (p‑AKT) and cyclin D1 expression were notably increased, but miRNA‑4712‑5p‑targeted PTEN and phospho‑GSK3β (p‑GSK3β) protein markedly decreased. Therefore, microRNA‑4712‑5p can reduce the expression of PTEN, further affecting its downstream p‑AKT, p‑GSK3β and cyclin D1 signaling pathways, promoting the proliferation and invasion of VSCC.

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2026-06-01 | Molecular classification of squamous cell carcinoma of the vulva (VSCC) on diagnostic biopsy is highly concordant with final resection specimen: Earlier prognostic information to guide personalized medicine

Einleitung Die molekulare Subtypisierung des Vulvakarzinoms (VC) ist prognostisch bedeutsam. HPV-assoziierte VC (immunhistochemisch p16-positiv, p53-Wildtyp) weisen eine günstigere Prognose auf als HPV-unabhängige Tumoren, die meist mit Lichen sclerosus assoziiert sind und durch p53-Überexpression (Surrogatmarker für eine TP53-Mutation) sowie fehlender p16-Blockfärbung gekennzeichnet sind. Ein dritter, seltener Subtyp zeigt sich negativ für p16 und mit nicht aberranter p53-Expression. Es gibt Hinweise, daß p53-alterierte Tumoren häufiger von radikaler Chirurgie profitieren und HPV-assoziierte Tumoren besser auf eine Radiochemotherapie ansprechen. Fragestellung Ziel dieser Studie war es, die Übereinstimmung der molekularen Subtypisierung zwischen diagnostischer Biopsie und dem Vulvektomiepräparat (VFR-Technik) zu untersuchen. Methodik Es wurden 56 gepaarte Proben aus diagnostischer Biopsie und operativem Resektionspräparat (radikale Vulvektomie; VFR) immunhistochemisch hinsichtlich der Expression von p16 und p53 untersucht. Die Bewertung erfolgte gemäß den Empfehlungen der International Society of Gynecological Pathologists (ISGyP), der British Association of Gynecological Pathologists (BAGP) sowie des LAST-Projekts. Bei uneindeutiger Immunhistochemie erfolgte eine zusätzliche molekulare Analyse auf HPV-DNA bzw. TP53-Mutationen. Die Befunde des Resektionspräparats dienten als Referenz. Die Beurteilung der Biopsien erfolgte verblindet. Ergebnisse Die paarweise Analyse zeigte eine hohe Übereinstimmung der molekularen Subtypisierung zwischen Biopsien und Resektionspräparaten: 93,7 % (16 von 17 Fällen) bei p16-positiven/p53-Wildtyp-Tumoren 94,4 % (34 von 36 Fällen) bei p16-negativen/p53-mutierten Tumoren 50 % (2 von 4 Fällen) bei p16-negativen/p53-Wildtyp-Tumoren Schlussfolgerung Die hohe Übereinstimmung (gesamt 94 %) bezüglich der molekularen Subtypisierung beim VC im paarweisen Vergleich zwischen prä-operativ-diagnostischer Biopsie und VFR-Präparat bestätigt die diagnostische Aussagekraft der präoperativen Biopsie. Die immunhistochemische Untersuchung von p16 und p53 als von der WHO und internationalen Organosatiponen (ISGyP, BAGP) empfohlenen Surrogatmarker für HPV-assoziierte bzw. HPV-unabhängige Karzinome ermöglicht eine frühzeitige, prognostisch relevante Einordnung. Das eröffnet möglicherweise mittelfristig einen individualisierten Therapieansatz (Therapiemodalität, operative Radikalität) basierend auf dem an der Biopsie ermittelten molekularen Subtyp des VC. Damit würde die molekulare Subtypisierung auf Biopsiebasis ein robustes Tool zur Therapiestratifizierung beim VC darsstellen. Publication History Article published online: 10 June 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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2025-12-29 | VULVAR CANCER: CLINICAL AND ONCOLOGICAL MANAGEMENT STRATEGIES

Vulvar cancer is a gynecological neoplasm with low incidence, yet with significant clinical impact due to its frequently late diagnosis and the morbidity associated with treatment. In recent decades, a shift in its epidemiological profile has been observed, with an increase in cases among younger women, especially related to persistent infection with human papillomavirus (HPV) (OLAWAIYE; CUELLO; ROGERS, 2021; NOGUEIRA-RODRIGUES et al., 2025). Squamous cell carcinoma is the predominant histological subtype and develops through two etiopathogenic pathways: an HPV-dependent pathway, associated with high-grade vulvar intraepithelial neoplasia and a better prognosis, and an HPV-independent pathway, related to lichen sclerosus and differentiated vulvar intraepithelial neoplasia, which is more aggressive (SANCHEZ; RAFFI; KRAUS, 2022). Staging and inguinofemoral lymph node status are key prognostic determinants, reinforcing the importance of early diagnosis (PLANCHAMP et al., 2023). Treatment has evolved toward more conservative and individualized approaches, aiming to reduce morbidity without compromising oncological control (OLAWAIYE; CUELLO; ROGERS, 2021; JHINGRAN, 2022).

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2024-01-31 | Characteristics of vaginal and vulvar microbiota in patients with vulvar precancerous lesions and vulvar squamous cell carcinoma

The aim of the study was to analyze the composition of the microbiota of the vagina and vulva in patients with precancerous lesions of the vulva in comparison with healthy controls and in women with vulvar cancer. Materials and methods. 286 women with vulvar lesions aged from 25 to 70 years and 60 gynecologically healthy women (30 under 50 years and 30 after 50 years) were included in the study. Patients with vulvar lesions were divided into 5 groups: 87 women with high-grade intraepithelial neoplasia of the vulva (VHSIL) dependent on the human papilloma virus (HPV) (Group 1 - G1), 154 women with differentiated vulvar intraepithelial neoplasia (dVIN) independent of HPV (Group 2 – G2), 9 patients with Paget's disease (Group 3 – G3),, 8 women with melanoma in situ of the vulvar skin (Group 4 – G4), and 28 patients with vulvar squamous cell carcinoma (VSCC) (Group 5 – G5). The results of the study showed that among patients with precancerous lesions of the vulva, the vaginal microbiota of persons with VHSIL is characterized by an increase in facultative and obligate anaerobes, fungi of the genus Candida spp., as well as Ureaplasma spp., Mycoplasma hominis, compared to patients with dVIN. A characteristic feature of the vaginal microbiota of dVIN patients was a high concentration of Prevotella spp.Healthy vulvar skin of patients with precancerous lesions resembled the vaginal and skin microbiome composition of control groups, including genera of Prevotella, Lactobacillus, Gardnerella, Staphylococcus and Corynebacterium. The affected vulvar skin of patients with VHSIL showed an increase in taxa from the genus Prevotella spp., Fusobacteria spp. and Peptostreptococcus spp. Affected vulvar skin of patients with dVIN was characterized by enrichment of taxa from the genus Prevotella sgp., Fusobacteria spp., Atopobium vaginae and depletion of Corynebacterium spp., Lactobacillus spp., Staphylococcus spp., Peptostreptococcus spp. compared to unaffected skin. Conclusions. The study showed a change in the composition of the vaginal microbiota in precancerous diseases and cancer of the vulva. A deeper understanding of the complex interaction between the host and microorganisms in the vaginal area is promising for identifying new strategies in the field of cancer prevention and treatment.

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2024-01-10 | Intratumoural microbiota: a new frontier in cancer development and therapy

Abstract Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.

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2023-06-01 | Current Methods and Advances in the Immunotherapy Treatment of Non-Ovarian Gynaecological Cancers

Endometrial cancer (EC) and cervical cancer (CC) are common malignancies in women in clinical practice. More uncommon non-ovarian malignancies, such as vulval cancer (VC), are also becoming more prevalent in women of all ages. Currently, there are few comprehensive reviews on the management of these conditions, despite the recent advances in the use of immunotherapy in the management of other forms of cancer. The treatment modalities for EC, CC and VC vary; however, platinum-based chemotherapy, surgical resection and radiotherapy are the main forms of treatment. In more advanced or recurrent disease, there is a limited number of efficacious treatments, with many clinicians relying on adjuvant chemotherapy despite the increased rationale for the use of immunotherapy. With the development of the novel adoptive T-cell therapy, intra-tumoural oncolytic viral therapy and cancer vaccines, the landscape of gynaecological cancer management is changing, and it is likely that treatment efficacy and outcomes will improve dramatically. This review aims to summarise the current management of endometrial, cervical and vulval cancer and to evaluate the novel therapies under development, as well as the future of the management of non-ovarian gynaecological malignancies.

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