Case report: Primary vulvar adenocarcinoma of mammary gland type-its genetic characteristics by focused next-generation sequencing.

Mammary-like vulvar adenocarcinoma (MLVA) is an exceedingly rare subtype of vulvar adenocarcinoma that shares features with mammary gland tissue. Due to its rarity and lack of consensus, MLVA presents diagnostic challenges to pathologists. We present the case of a 59-year-old female with an ulcerated mass on the right side of the external genitalia, diagnosed as MLVA. Comprehensive immunohistochemistry (IHC) and gene sequencing studies were performed to characterize the tumor. IHC analysis revealed triple expression of hormonal receptors (estrogen receptor, progesterone receptor, and HER2), supporting the mammary gland origin of the tumor. Gene sequencing identified unique genetic mutations associated with the expression of hormonal markers. One fusion gene (ERBB2-NAGLU) has not been reported in any tumors, and other mutations with unique mutation types have not been previously reported in MLVA. Our findings shed light on the molecular characteristics of MLV and may help improve the diagnosis and treatment of this rare type of vulvar adenocarcinoma.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Vulvar leiomyoma in a postmenopausal woman.

Leiomyomas of the uterus are the most common benign tumours of women in the reproductive age group, affecting up to 40%-50% of women older than 35. In postmenopausal women, the incidence is much lower with an estimated incidence of 1%-2% in women in the 60-80 years old age group. Vulvar leiomyomas are much rarer than their uterine counterparts, accounting for only 0.03% of all gynaecological neoplasms and 0.07% of all vulvar tumours. These tumours are well-circumscribed, painless, solitary growths that affect females of all ages. Given the presentation and rarity of vulvar leiomyomas, they are often misdiagnosed as a Bartholin gland cyst, abscess or even cancer preoperatively. We present a case of a woman in her 70s with a 1.5 cm firm mass that was palpated on the left lower vaginal side wall and was initially suspected to be a Bartholin gland cyst or abscess. Initial treatment included antibiotics and an incision and drainage. Two weeks later, the mass had grown to 3 cm in size. Wide excisional biopsy revealed the mass to be a vulvar leiomyoma.

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.

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

OBJECTIVES: Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. MATERIALS AND METHODS: Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. RESULTS: A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. CONCLUSIONS: The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Vulvar Carcinoma: Standard of Care and Perspectives.

PURPOSE: Treatment of vulvar carcinoma (VC) is challenging. The objectives of this review were to describe for clinicians the epidemiologic and clinical aspects of VC, the standard of care in terms of primary local treatment and systemic therapies, and the recent innovations and perspectives emerging from translational research in immuno-oncology. DESIGN: We conducted a comprehensive review outlying the clinical aspects and biologic background of vulvar cancer, highlighting modern treatment strategies on the basis of a personalized approach. RESULTS: Epidemiologic data showed a recent rise in incidence of VC, attributed to human papillomavirus. Surgery is the mainstay of primary treatment, but multimodal approaches are frequently required in the presence of adverse prognosis histopathologic factors. Chemoradiation is indicated when organ-sparing surgery is not feasible. However, inability to achieve high locoregional control rates in advanced cases and the morbidity associated with local treatments are still key issues. Recent clinical data showed the benefit of individualized strategies combining organ-sparing surgical strategies, less invasive lymph node staging procedures, and refinement in radiotherapy modalities. Among the most important research area, there is a sound rationale for testing modern systemic approaches such as immune checkpoint inhibitors in selected patients with recurrent and/or metastatic tumors. Although no specific data exist for VC, the role of supportive care and post-treatment rehabilitation strategies is also crucial. CONCLUSION: There are still insufficient studies dedicated to patients with VC. Public health programs for prevention, screening, and early diagnosis are required, and clinical research should be strengthened to provide high-quality clinical evidence and improve patients' oncologic and functional outcomes.

Recurrent ectopic primary breast adenocarcinoma of the vulva with a 19-year follow-up period.

We present a case of an ectopic breast adenocarcinoma of the vulva with metastatic local recurrence and a total follow-up period of 19 years, the longest documented in the literature to our knowledge. Following surgical excision, radiation therapy and hormonal treatment after the recurrence, the patient has remained disease free. This case demonstrates the potential for malignant transformation in accessory breast tissue and highlights the importance of close surveillance and regular physical examinations in patients with a history of ectopic breast malignancy.

Evaluation of the impact of a protocol for immediate vulvar reconstruction after vulvectomy.

Vulvar cancers are usually diagnosed at an advanced stage and require wide surgical resections in the form of vulvectomy. Immediate vulvar reconstruction can potentially reduce the reoperation rate and postoperative complications. With this objective, we introduced a protocol for immediate vulvar reconstruction. This study, five years after its introduction, assesses the impact of this intervention on the postoperative evolution of vulvectomy patients. In January 2017 we introduced a protocol for immediate vulvar reconstruction that considered four criteria of high risk for postoperative dehiscence. Patients who meet the criteria were reconstructed at the time of the vulvectomy. To assess the impact of the protocol, we prospectively registered all included patients over a 5 years period (2017-2022). As a control group, we reviewed the vulvectomised patients at our centre from January 2012 to January 2017 (5 years) who would have met the protocol. No statistically significant differences were found in the epidemiological data (age, diabetes mellitus diagnosis, and obesity diagnosis) or in the tumour characteristics (tumour size). We obtained a statistically significant difference in the incidence of complications and need for reintervention, in favour of the reconstruction group. Our study shows the medical and economic benefits for vulvar cancer patients of immediate vulvar reconstruction.

Immune Profiling of Vulvar Squamous Cell Cancer Discovers a Macrophage-rich Subtype Associated with Poor Prognosis.

The incidence rates of vulvar squamous cell cancer (VSCC) have increased over the past decades, requiring personalized oncologic approaches. Currently, lymph node involvement is a key factor in determining prognosis and treatment options. However, there is a need for additional immune-related biomarkers to provide more precise treatment and prognostic information. Here, we used IHC and expression data to characterize immune cells and their spatial distribution in VSCC. Hierarchical clustering analysis identified distinct immune subtypes, of which the macrophage-rich subtype was associated with adverse outcome. This is consistent with our findings of increased lymphogenesis, lymphatic invasion, and lymph node involvement associated with high macrophage infiltration. Further in vitro studies showed that VSCC-associated macrophages expressed VEGF-A and subsequently induced VEGF-A in the VSCC cell line A-431, providing experimental support for a pro-lymphangiogenic role of macrophages in VSCC. Taken together, immune profiling in VSCC revealed tumor processes, identified a subset of patients with adverse outcome, and provided a valuable biomarker for risk stratification and therapeutic decision making for anti-VEGF treatment, ultimately contributing to the advancement of precision medicine in VSCC. SIGNIFICANCE: Immunoprofiling in VSCC reveals subtypes with distinct clinical and biological behavior. Of these, the macrophage-rich VSCC subtype is characterized by poor clinical outcome and increased VEGF-A expression, providing a biomarker for risk stratification and therapeutic sensitivity.

Primary vulvar adenocarcinoma of intestinal type: Report of two cases showing molecular similarity with colorectal adenocarcinoma.

Primary vulvar adenocarcinoma is a particularly rare tumor with poorly understood histogenesis and unclear clinical characteristics and prognosis. Vulvar adenocarcinoma of intestinal type (VAIt) is a very uncommon subtype of primary vulvar adenocarcinoma and only 27 cases have been described in the literature in the past. Of these cases, two have been described as human papillomavirus (HPV)-associated VAIt. The current report presents two additional cases of primary VAIt showing variants in the KRAS, TP53, and DPYD genes and no evidence of HPV DNA by real-time polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) revealed TP53 pathogenic variants in both cases, but only one case had aberrant p53 protein immunohistochemical characteristics. KRAS and DPYD mutations were identified separately in the two cases. Due to their capacity to imitate the spread of more prevalent gastrointestinal carcinomas, these tumors may present diagnostic issues. Additional cases can contribute to a better understanding of the pathophysiology and prognosis of VAIt.

Large vulvar fibroepithelial polyp and review of differentials.

Vulval fibroepithelial polyps (FEPs) are a rare type of vulval fibroblastic tumour commonly found in premenopausal women. It is important to obtain an accurate pathological diagnosis because, despite being benign, the condition shares some characteristics with malignant vulva lesions in its differential diagnosis. We present a case of young woman in her 20s with a giant FEP. After surgical excision, the patient did not manifest any signs of recurrence after 1-year follow-up. Our review focuses on the distinguishing characteristics of these rare neoplasms as we explore their differential diagnosis.

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

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

A pilot study of p53 immunohistochemistry in atypical squamous lesions, using a vulvar scoring system.

BACKGROUND: Histopathologic overlap between cutaneous squamous cell carcinoma (cSCC) and its indolent mimics likely leads to the overdiagnosis of cSCC. OBJECTIVE: To perform a pilot study of the p53 immunohistochemical scoring system developed on vulvar squamous lesions in cSCC. METHODS: The consistency and reliability of p53 immunostaining using a scoring system developed on vulvar cases, as compared with TP53 genomic sequencing, was studied in an initial cohort of 28 cutaneous cases. p53 labeling was further assessed in an additional 63 cases of atypical squamous lesions, including 20 atypical squamous lesions classified by the authors as benign, 22 cases diagnosed as cSCC without high-risk features, and 21 cases of high-risk cSCC (cSCC-HR). RESULTS: The concordance of p53 labeling and TP53 sequencing was 82.1%. Four positive patterns of p53 mutation were identified: basal, parabasal/diffuse, null, and cytoplasmic. p53 positivity in atypical, benign squamous lesions (10%) was significantly lower than that of low-risk cSCC (63.6%, p = 0.0004) or cSCC-HR (90.5%, p < 0.0001). p53 positivity in low-risk cSCC versus cSCC-HR was not statistically significant (p = 0.07). CONCLUSION: p53 Labeling may be a helpful biomarker to support the diagnosis of cSCC and distinguish cSCC from atypical but benign mimics.

A Case Series on a Rare Gynecological Cancer and a Review of Recent Literature on Vulval Cancer.

Vulval cancer is a rare gynaecological malignancy. Though it has got excellent prognosis if diagnosed and treated early, but in most instances, women present late with advanced disease as they are too uncomfortable to discuss it with their doctors. Advanced vulval cancer is difficult to treat, has got poor prognosis and the treatment itself can cause morbidity and mortality. The authors describe three cases of isolated vulval cancer in a gynaecology centre in south Wales that had late presentation due to embarrassment despite noticing the lesion for long time and a brief review of the literature on its prevalence, clinical presentation, investigation and best management.

Single-cell analysis of the cellular landscape of vulvar melanoma provides new insight for immunotherapy administration.

BACKGROUND: Vulvar and vaginal melanoma (VuM & VaM) is a rare gynecologic malignancy with high mortality but low effectiveness to checkpoint immunotherapy compared to cutaneous melanoma. This article aims to elucidate the role of the disordered immune microenvironment in cancer progression in VuM. METHODS: At first, this article applied single-cell RNA sequencing (scRNA-seq) to the VuM obtained from a 68-year-old female patient, and constructed a single-cell atlas of VuM consist of 12,243 single cells. Then this article explores the genomic complexity and core signal channel in VuM microenvironment. RESULTS: This article provides new insights about the pathogenesis of VuM based on single-cell resolution data. It was found that the activation of CD8+ T cell contributed to induce tumor angiogenesis and immune escape, and the activation of the antigen-presenting molecular function participated in melanoma metastasis. CONCLUSION: This article provided new insights into underlining VuM molecular regulation and potential signaling involved in immunotherapy, which would benefit the clinical practice and administration.

Accuracy of ICG compared with technetium-99 m for sentinel lymph node biopsy in vulvar cancer.

PURPOSE: Sentinel lymph node biopsy with radioactive tracer is the standard-of-care in lymph node status assessment in vulvar cancer. Indocyanine green fluorescence-ICG is a promising detection method, due to its advantages over technetium-99 m. In vulvar cancer, the procedure is controversial due to study heterogeneity and the small sample size in previous studies. This study evaluates ICG sentinel lymph node detection compared with the criterion-standard with technetium (dual modality method). METHODS: Preoperative technetium and intraoperative ICG for sentinel lymph node have been prospectively evaluated in early-stage vulvar cancer. The primary endpoint was to determine accuracy in the detection rate for ICG compared with technetium. Secondary objectives included tracer modality relationship with obesity, tumor size and location. RESULTS: In total, 75 patients participated at 8 centers; 38 had lateral and 37 had midline vulvar tumors. The overall sentinel lymph node detection rate was 85.3 % for technetium and 82.7 % for ICG. For lateral tumors, the detection rate was 84.2 % vs. 89.5 %, while it was 86.5 % vs. 75.7 % for middle tumors, using technetium and ICG, respectively. The median sentinel node harvest was 1.7 (range 1-4), with 24 % metastatic involvement. The sensitivity and positive predictive value for ICG based on the standard technique with technetium was 91.08 % (95 % CI, 83.76-95.84) and 94.8 % (95 % CI, 84.84-96.48), respectively. No significant differences were found comparing the two tracers in patients with midline lesions, obesity (body mass index ≥ 30) and tumor size ≥ 2-4 cm. CONCLUSION(S): ICG shows comparable performance parameters to the gold-standard of radioisotope localization.

Surgery as primary treatment improved overall survival in vulvar squamous cancer: A single center study with 108 women.

OBJECTIVE: To describe a single-center experience managing women with vulvar squamous cancer and analyze factors influencing their survival. STUDY DESIGN: It is an observational longitudinal retrospective study that reviewed medical records of patients admitted for treatment at the University of Campinas between 2010 and 2019, followed up until June 2022. The final sample was 108 cases. The main outcomes were disease-free survival (DFS) and overall survival (OS). Other variables were age, stage, relapse, and race. Vital status was accessed by medical records, active search, or public online register. Survival analysis was performed by the Kaplan-Meier method and Log-rank Test, and Regression Cox-Model assessed risks. RESULTS: The mean age in stages IA and IB were 65.0 years, and in stages II + III + IVA 71.1 years. Women 70 years or older were more related to diagnosis in stages II + III + IVA (p = 0.019). Progression was observed in 7 (16.7 %) patients in stage IB and 30 (65.2 %) in stage II + III + IVA. Both five-year (5y) DFS and OS were significantly different in stage IB and II + III + IVA (5y-DFS 70.5 % and 39.3 %, p = 0.024; 65.1 % and 24.3 %, p < 0.001). In stages II + III + IVA, most deaths happened before 24 months of follow-up. The primary treatment was surgery in 81.0 % of stage IB and 47.8 % of stage II + III + IVA. A higher OS was observed in patients treated primarily by surgery compared to radiotherapy in stage IB (p = 0.008), and in stages II + III + IVA (p = 0.013). Surgery followed or not by adjuvant radiotherapy was independently associated with a 60 % adjusted death protection compared to radiotherapy alone as primary treatment (0.40, 0.23;0.70). CONCLUSIONS: Half of the patients have been diagnosed in stage I. The progression rate was high in the advanced stages of the disease. Overall survival by stage was improved when surgery was the primary treatment. Surgery was independently associated with death.

Sentinel Lymph Node Evaluation in Early-Stage Vulvar Cancer.

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