Vulvar Lesions Research Articles

The Role of Predictive and Prognostic Biomarkers in Lower Female Genital Tract Pathology: PD-L1, MMR, HER2, p16, p53, and Beyond.

Biomarkers play a crucial role in the diagnosis, treatment planning, and prognosis of premalignant and malignant lesions and are increasingly used in neoplasia of the lower female genital tract (LFGT) including the cervix, vagina, and vulva. This review will discuss key biomarkers routinely used in LFGT pathology, including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR), and tumor mutational burden (TMB) testing, which are FDA-approved companion diagnostics for anti-PD-1 checkpoint inhibitors. Recent developments in HER2 testing as a marker for anti-HER2 therapies, and prognostic biomarkers such as p53 in HPV-independent vulvar intraepithelial lesions and carcinomas, are also reviewed.

Bowen's Disease of Vulva: A Case Report

Bowen's disease is an intraepidermal carcinoma that can progress to invasive carcinoma and can affect several organs, including the vulva. This clinical case presents a 45-year-old patient with vulvar BOWEN'S disease, with hyperpigmented, dyschromic vulvar and anal exophytic lesions on the clinical examination. The Skin and vulvar biopsy showed a squamous cell carcinoma in situ with no invasive sites. Cytological sampling of ASC-H cervix, showed at colposcopy: endocervical TAG2A, ZT3. The nail biopsy showed a squamous cell carcinoma in situ (Bowen's disease) with no signs of invasion. The patient was operated for a conization, and the histological examination revealed a squamous cell carcinoma in situ with microinvasive focus 3mm wide and 2mm deep with upper tumour border. Therefore, a total vulvectomy with hysterectomy without adnexal preservation was performed. The aim of the current treatment is to have a conservative approach, and to preserve the anatomical and functional integrity of the vulva as far as possible.

Vulvar Lactating Adenoma: A Rare Representation of Mammary-Like Anogenital Glands.

Mammary-like anogenital glands are considered a normal constituent of the anogenital area. These glands can have epithelial components with eccrine or apocrine features. They often undergo transformation into mammary-like lesions, including lactational changes that occur during pregnancy and the breastfeeding period. When they form mass lesions they are referred to as lactating adenomas. Their appearance can clinically be mistaken for other more common benign and malignant entities in the vulva. We describe a vulvar lesion in a 26-year-old woman. The lesion was excised and determined by histologic examination to be a benign lactating adenoma. Subsequent immunohistochemistry was performed. The epithelial cells were positive for GATA3 and estrogen receptor while negative for PAX8, supporting mammary-like differentiation. The myoepithelial markers p63 and calponin were positive at the periphery of the ducts, supporting the benign nature of this lesion.

High Risk of HPV Related Preneoplastic and Neoplastic Vulvar Lesions in Women Living With HIV.

We aimed to investigate the epidemiology of human papilloma virus (HPV)-related preneoplastic and neoplastic vulvar lesions in a large cohort of women living with HIV (WLWH). We retrospectively selected 1,796 WLWH who had a gynecological examination, cervical cytology, high-risk (HR-) HPV test, vulvoscopy, and colposcopy with targeted biopsies when necessary between 1987 and 2020 at 2 Italian institutions. Univariable and multivariable regression analyses were carried out to test the association of the anamnestic and clinical data with the development of precancerous and cancerous lesions. At baseline, 348 (19.4%) of 1,796 WLWH had genital warts, 30 (1.7%) had vulvar high-grade intraepithelial neoplasia (VHSIL), and 2 (0.1%) had squamous cell carcinoma of the vulva. Among 895 WLWH who had more than 1 year of follow-up, we found 40 (4.5%) new cases of VHSIL and 7 (0.8%) cases of vulvar cancer. The cumulative incidence of VHSIL and vulvar cancer was respectively 0.56 and 0.10 per 100 person-years. Risk factors independently associated with the development of vulvar HSIL and cancer included history of injection drug use (p < .01), genital warts at baseline (p < .001), HR-HPV test positivity at diagnosis (p < .001), and severe immunodepression (CD4 cell count <200 cells/mL) at diagnosis (p < .01). WLWH are at high risk of vulvar high-grade intraepithelial neoplasia and cancer, especially those with severe immunodepression. A careful inspection of vulva, perineum and anus, possibly with the aid of colposcopy, should become part of the surveillance protocol of HIV-infected women.

Expression of CK17 and SOX2 in Vulvar Intraepithelial Neoplasia: A Comprehensive Analysis of 150 Vulvar Lesions.

Recently, the immunohistochemical markers cytokeratin 17 (CK17) and SRY-box2 (SOX2) have been evaluated as adjuncts for the diagnosis of high-grade vulvar intraepithelial neoplasia (VIN). In the present study, the aim was to assess CK17 and SOX2 expression in VIN by studying 150 vulvar lesions, originally reported as high-grade VIN and to assess the diagnostic accuracy. All slides (H&E, p16INK4a, p53, Ki-67, CK17, and SOX2 stains) were independently assessed by six pathologists and the final diagnosis was reached in consensus meetings, as follows: 46 human papillomavirus (HPV)-independent VIN (including 30 p53 mutant and 16 p53 wild-type lesions), 58 high-grade squamous intraepithelial lesions (HSILs), 4 low-grade SILs (LSILs), 37 non-dysplastic lesions, and 5 lesions where the histology was inconclusive. CK17 positivity was observed in 100% p53 wild-type HPV-independent VIN, compared to 73% p53 mutant HPV-independent VIN, 14% HSILs, 0% LSILs, and 24% non-dysplastic lesions. SOX2 positivity was observed in 13% p53 wild-type HPV-independent VIN, 43% p53 mutant HPV-independent VIN, 2% HSILs, 0% LSILs, and 3% non-dysplastic lesions. The highest diagnostic accuracy (89%) for HPV-independent VIN was obtained when combining p53 and CK17 immunohistochemistry. The addition of SOX2 did not further increase diagnostic accuracy. To conclude, aside from p53, both CK17 and SOX2 can be of value for reaching an accurate diagnosis of HPV-independent VIN.

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.

Squamoid eccrine ductal carcinoma of the vulva: A case report

Abstract Introduction/Objective A 53-year-old female sought medical attention for left vulvar pain and a vulvar lesion. Methods/Case Report Physical examination revealed a 1.0 x 1.0 cm lesion within a background of lichen sclerosus. Biopsy demonstrated a carcinoma with tubular and glandular architecture, areas of squamoid differentiation and widespread perineural invasion. Ancillary immunohistochemistry testing with keratin 7 highlighted foci of ductal differentiation. Tumor cells were also positive for p53, p63, pankeratin, and keratin 5/6. The Ki-67 proliferation index was approximately 15%. Tumor cells were negative for Keratin 20, PAX 8, p16, and CD 34. We diagnosed the lesion as a vulvar sweat gland adenocarcinoma of the squamoid eccrine ductal subtype. Results (if a Case Study enter NA) N/A Conclusion Carcinomas of vulvar sweat gland origin are extremely rare, comprising less than 1% of all vulvar cancers. To the best of our knowledge, this is the first case report of squamoid eccrine ductal carcinoma afflicting the vulva.

Paget Disease of the Vulva: One Case Report

Extramammary Paget's disease is a rare neoplasm that usually develops in apocrine gland-bearing areas. Paget's disease of the vulva is a rare form of extramammary Paget's disease affecting postmenopausal women. We report the case of a 39-year-old woman who presented with a vulvar lesion suggestive of Paget's disease involving only the labia majora and minora. Biopsy confirmed the diagnosis of non-invasive Paget's disease. Extension examination was negative. The patient underwent a superficial vulvectomy with healthy margins on histopathology. Postoperative management was uncomplicated.

Vaginal Natural Oxygenation Device (VNOD) and Lichen: A Pilot Study on the Assessment of Effectiveness of the Simultaneous and Local Administration of High Concentration Oxygen and Hyaluronic Acid to treat Vulvar Lichen Scleroatrophicus

Background This is a pilot study to assess the effectiveness of simultaneous and local administration of high concentration oxygen and hyaluronic acid by a specific medical device (VNOD) to improve vulvar lichen symptoms healing vulvar lesions. Methods 17 women with histological diagnosis of vulvar lichen were included. Five weekly administrations of concomitant oxygen-hyaluronic acid therapy with VNOD were performed. The severity of the pathology was evaluated using the Vaginal Health Index (VHI). Patients’ symptoms were evaluated with two questionnaires: VAS and FSFI. VAS, FSFI and VHI were evaluated at the start and at the end of the therapy. The statistical analysis was performed according to the Kruskal-Wallis method and using the t-test calculator. Results The study has showed that each subsequent treatment determined a significant increase in all parameters, especially for VHI hydration index, VAS fluidity index and FSFI lubrication index, however all the patients reported a recovery of their sexuality at the end of the five treatment sessions. All the parameters maintain their value at six weeks of follow-up. No adverse effects were observed. Conclusions Combined topical oxygen therapy with hyaluronic acid by VNOD seems to be a valid and totally painless treatment for vulvar lichen scleroatrophicus, improving symptomatology, and sexual wellbeing.

Carbon Dioxide Laser as Adjuvant Therapy for Human Papillomavirus-Related Squamous Intraepithelial Vulvar Lesions in Chronically Immunosuppressed Women: A Long-Term Real-Life Study

Carbon Dioxide Laser as Adjuvant Therapy for Human Papillomavirus-Related Squamous Intraepithelial Vulvar Lesions in Chronically Immunosuppressed Women: A Long-Term Real-Life Study

Vulvar Paget’s Disease with Inguinal Lymph Node Metastasis: A Case Report

Vulvar Paget's disease is a clinical condition with an invariable course affecting women of advanced age, and is associated with a significant rate of recurrence and dissemination, especially in its invasive form, which has a high metastatic potential. Here we present details of a unique case involving a 77-year-old woman with a history of disease progression over more than a decade. She initially presented with an erythematous lesion in the vulvar region, which was later diagnosed as adenocarcinoma in situ. During follow-up, the affected area extended to the perineal and gluteal regions, indicating an invasive aspect of the tumor. Due to surgical oncology recommendations, tissue resection was not feasible. The pacient experienced a significant worsening of symptoms, including local peeling of the affected region, and a biopsy confirmed Paget's disease in the vulvar region. Subsequently, imaging tests indicated changes in the volume of the inguinal lymph nodes. The patient underwent lymphadenectomy for histological analysis and to prevent systemic dissemination. Indicators of lymph node metastasis, suggestive of a gynecological primary site, were observed. Our case provides valuable insights for pathologists to consider the differential diagnosis of vulvar lesions.

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.

Therapeutic effects of focused ultrasound on vulvar squamous intraepithelial lesions in rat

Objective In this study, we established a Sprague-Dawley rat model of vulvar squamous intraepithelial lesions and investigated the impact of focused ultrasound on the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and mutant type p53 (mtp53) in the vulvar skin of rats with low-grade squamous intraepithelial lesions (LSIL). Materials and methods The vulvar skin of 60 rats was treated with dimethylbenzanthracene (DMBA) and mechanical irritation three times a week for 14 weeks. Rats with LSIL were randomly allocated into the experimental group or the control group. The experimental group was treated with focused ultrasound, while the control group received sham treatment. Results After 14 weeks treatment of DMBA combined with mechanical irritation, LSIL were observed in 44 (73.33%) rats, and high-grade squamous intraepithelial lesions (HSIL) were observed in 14 (23.33%) rats. 90.91% (20/22) of rats showed normal pathology and 9.09% (2/22) of rats exhibited LSIL in the experimental group at four weeks after focused ultrasound treatment. 22.73% (5/22) of rats exhibited LSIL, 77.27% (17/22) of rats progressed to HSIL in the control group. Compared with the control-group rats, the levels of HIF-1α, VEGF and mtp53 were significantly decreased in experimental-group rats (p < 0.05). Conclusions These results indicate that DMBA combined with mechanical irritation can induce vulvar squamous intraepithelial lesion in SD rats. Focused ultrasound can treat LSIL safely and effectively, prevent the progression of vulvar lesions, and improve the microenvironment of vulvar tissues by decreasing the localized expression of HIF-1α, VEGF, and mtp53 in rats.

5-Aminolevulinic acid photodynamic therapy is a safe and effective treatment for female patients with intractable vulvar lichen sclerosus

BackgroundFemale vulvar lichen sclerosus (VLS) is a chronic inflammatory skin disease of the vulva and its etiology is unknown. The main clinical symptoms are itching, burning and dyspareunia, and there is a lack of effective treatment. MethodsClinical and follow-up data of women with VLS who underwent 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) from January 2023 to December 2023 in the department of obstetrics and gynecology, Qilu Hospital of Shandong University, were retrospectively analyzed. According to the inclusion and exclusion criteria, 36 patients with VLS who received ineffective conventional treatment (intractable VLS) were enrolled. Objective signs and subjective symptoms of vulvar lesions were recorded before treatment and 6 months after the end of treatment according to corresponding scoring criteria. Quality of life was evaluated using the Dermatology Life Quality Index (DLQI). ResultsAll patients received six sessions of ALA-PDT treatment and follow-up visits. After ALA-PDT treatment, 24 of 36 (66.67 %) patients' itching symptoms completely disappeared, 10 of 36 (27.78 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients' symptoms were not significantly relieved. 16 of 36 (44.4 %) patients' itching symptoms completely disappeared, 9 of 36 (25 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients still had severe pain. Compared to 22 patients with dyspareunia before treatment, only 9 patients still had dyspareunia with varying degrees of dyspareunia relief after treatment. Clinical signs improved significantly in the patients after ALA-PDT treatment. The total scores of clinical signs were (5.31 ± 1.67 vs 3.67 ± 1.71) before and after treatment. All patients showed improvement in DLQI after treatment. The main side effects of ALA-PDT were pain, erythema and swelling which were transient and tolerable. All patients were “satisfied” or “very satisfied” with the results of the treatment. ConclusionsALA-PDT is a safe and effective treatment for women with intractable vulva lichen sclerosus.

MR imaging of benign vulvar lesions: a pictorial essay.

Benign vulvar lesions can be difficult to differentiate with few publications on their imaging appearances. While many vulvar lesions may be clinically diagnosed and treated, more are being detected incidentally with the increasing prevalence of magnetic resonance imaging (MRI) of the pelvis. In addition, clinicians may find imaging of benign vulvar lesions helpful for greater anatomical correlation. After reviewing the important MRI sequences for vulvar imaging and the anatomy of the vulva on MRI, this pictorial essay illustrates variety of cystic and solid benign vulvar lesions to familiarize radiologists with their common MRI appearances. Other miscellaneous pelvic lesions that can affect the vulva are also described.

Acantholytic Dyskeratoses of the Vulva: Clinicopathologic Characterization of 16 Cases and Review of the Literature.

The vulva and perineum are rarely involved by acantholytic dyskeratoses, including Hailey-Hailey disease, Darier disease, papular acantholytic dyskeratosis of the genitocrural area, acantholytic dyskeratotic acanthoma, and warty dyskeratoma. These entities show broad histomorphologic overlap, generally requiring clinical correlation for definitive classification. This institutional series aims to better characterize vulvar acantholytic dyskeratoses and provide a practical literature review and diagnostic aid for gynecologic pathologists. Our institutional archives contained 16 vulvar acantholytic dyskeratoses diagnosed between 1990 and 2023. Affected patients were 36 to 79 (mean, 58) years old and presented with one or more asymptomatic (n = 9) or pruritic (n = 6) lesions involving the vulva (predominantly the labia majora), with additional perineal involvement in 2. Four patients have known Hailey-Hailey disease. Eleven cases comprised singular, raised, erythematous, or skin-colored papules, measuring 0.2 to 0.6 (mean, 0.3) cm. Two patients had oligofocal (both with known Hailey-Hailey disease) vulvar lesions, and 2 had multifocal vulvar lesions (one with known Hailey-Hailey disease). Histologically, all showed acantholysis and dyskeratoses (abundant in 8, focal in 8, with corps ronds generally more conspicuous than corps grains). Additional features included suprabasal clefting (n = 14), dermal papillomatosis (n = 12), and acanthosis (n = 8). Adnexal involvement was rare (n = 1). No histologic features reliably distinguished sporadic versus syndromic acantholytic dyskeratoses. Sporadic lesions were cured by local excision. Patients with Hailey-Hailey disease were variably responsive to corticosteroids. Neither our series nor the literature indicate a significant correlation between sporadic or syndromic acantholytic dyskeratosis and squamous cell carcinoma. Important differential diagnoses include pemphigus vulgaris and pemphigus vegetans, for which direct immunofluorescence may be performed, when indicated.

Prophylactic antibiotics for excision of premalignant vulvar lesions: A pilot randomized controlled trial

No prospective data have been described to inform guidelines on antibiotic prophylaxis for partial vulvectomies. Thus, we conducted a single-center, pilot, double-blind randomized controlled trial to assess the effectiveness of prophylactic antibiotics to prevent wound complications after partial vulvectomies. Patients were randomly assigned 1:1 to preoperative antibiotics or no preoperative antibiotics. The primary outcome of 30-day postoperative wound complications occurred in 31 (62 %) of all patients, with no differences between groups. The most common wound complications were superficial separation (54.2 % antibiotic prophylaxis vs. 65.3 % no prophylaxis, p = 0.37) and surgical site infection (0 % antibiotic prophylaxis vs 7.7 % no prophylaxis, p = 0.49). However, this study was limited by differences in patient characteristics between the groups. This study provides data to perform power calculations for a trial examining the effect of preoperative antibiotics on surgical site infection.

Large Vulval Lesion During Pregnancy: A Diagnostic Challenge

Large Vulval Lesion During Pregnancy: A Diagnostic Challenge

Penile intraepithelial neoplasia incidence, clinical classification, microenvironment and implications for imiquimod treatment.

To provide an outline of the existing data on penile intraepithelial neoplasia (PeIN), as well as a narrative review on imiquimod (IQ; a toll-like receptor 7 agonist) treatment and immune microenvironment markers that may predict response to treatment. A narrative review of the literature from 2000 to the present was conducted on PubMed, and we describe the most relevant data and cross references. The incidence of PeIN is increasing. Local therapy with IQ may offer an easy applicable treatment with complete response rates of up to 63% but can be associated with considerable side-effects. There is no conclusive data on the optimal treatment schedule for PeIN, but evaluation of treatment results for other human papillomavirus-related pre-malignancies suggest three times a week for a duration up to 16 weeks. There are no published studies concerning the PeIN immune microenvironment. However, findings from the few studies on penile cancer and pre-cancerous vulvar and cervical lesions imply that specific immune cell subpopulations can serve as future predictors for successful immunomodulation treatments such as IQ. Overall, limited data are available on IQ treatment for PeIN and no published data exists on the PeIN immune microenvironment. Further translational studies are warranted to gain more understanding on the pathophysiology of PeIN and potential predictors of progression and of response to topical treatments.

Tirbanibulin decreases cell proliferation and downregulates protein expression of oncogenic pathways in human papillomavirus containing HeLa cells.

Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 ( +) squamous cell carcinoma (SCC), HPV-16 ( +) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against theSrc canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half-maximal inhibitory concentration (IC50) of HeLa cells to be 31.49nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src(p < 0.001), phospho-Src(p < 0.001), Ras(p < 0.01), c-Raf(p < 0.001), ERK1(p < 0.001), phospho-ERK1(p < 0.001), phospho-ERK2(p < 0.01), phospho-Mnk1(p < 0.001), eIF4E(p < 0.01), phospho-eIF4E(p < 0.001), E6(p < 0.01), E7(p < 0.01), Rb(p < 0.01), phospho-Rb(p < 0.001), MDM2(p < 0.01), E2F1(p < 0.001), phospho-FAK(p < 0.001), phospho-p130 Cas(p < 0.001), Mcl-1(p < 0.01), and Bcl-2(p < 0.001), but upregulates cPARP(p < 0.001), and cPARP/fPARP(p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.