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.

Differential etiopathogenic features of vulvar squamous cell carcinomas in sub-Saharan Africa and Europe.

Two pathways have been described for vulvar squamous cell carcinomas (VSCC), one associated with human papillomavirus (HPV), and the other HPV-independent. We compared the etiopathogenic features of a series of VSCC from Mozambique, a sub-Saharan country with high prevalence of HPV and HIV, with those of Spain, a European country with low prevalence of HPV and HIV. All VSCC diagnosed at the two institutions from January 2018 to December 2020 were included (n = 35 and n = 41, respectively). HPV DNA detection and genotyping, and immunohistochemistry for p16 and p53 were performed. Tumors showing p16 positive staining and/or HPV DNA positivity were considered HPV-associated. 34/35 tumors (97%) from Mozambique and 8/41 (19%) from Spain were HPV-associated (P < .001). Mean age of the patients from Mozambique and Spain was 45 ± 12 and 72 ± 14, respectively (P < .001). No differences were found in terms of HPV genotypes or multiple HPV infection rates. 1/35 tumors (3%) from Mozambique and 29/41 (70%) from Spain showed abnormal p53 immunostaining (P < .001). In contrast with the predominance of HPV-independent VSCC affecting old women in Europe, most VSCC in sub-Saharan Africa are HPV-associated and arise in young women. This data may have important consequences for primary prevention of VSCC worldwide.

Assessment and Reporting of Perioperative Adverse Events and Complications in Patients Undergoing Inguinal Lymphadenectomy for Melanoma, Vulvar Cancer, and Penile Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Inguinal lymph node dissection (ILND) plays a crucial role in the oncological management of patients with melanoma, penile, and vulvar cancer. This study aims to systematically evaluate perioperative adverse events (AEs) in patients undergoing ILND and its reporting. METHODS: A systematic review was conducted according to PRISMA. PubMed, MEDLINE, Scopus, and Embase were queried to identify studies discussing perioperative AEs in patients with melanoma, penile, and vulvar cancer following ILND. RESULTS: Our search generated 3.469 publications, with 296 studies meeting the inclusion criteria. Details of 14.421 patients were analyzed. Of these studies, 58 (19.5%) described intraoperative AEs (iAEs) as an outcome of interest. Overall, 68 (2.9%) patients reported at least one iAE. Postoperative AEs were reported in 278 studies, combining data on 10.898 patients. Overall, 5.748 (52.7%) patients documented ≥1 postoperative AEs. The most reported ILND-related AEs were lymphatic AEs, with a total of 4.055 (38.8%) events. The pooled meta-analysis confirmed that high BMI (RR 1.09; p = 0.006), ≥1 comorbidities (RR 1.79; p = 0.01), and diabetes (RR 1.81; p = < 0.00001) are independent predictors for any AEs after ILND. When assessing the quality of the AEs reporting, we found 25% of studies reported at least 50% of the required criteria. CONCLUSION: ILND performed in melanoma, penile, and vulvar cancer patients is a morbid procedure. The quality of the AEs reporting is suboptimal. A more standardized AEs reporting system is needed to produce comparable data across studies for furthering the development of strategies to decrease AEs.

LDOC1 as Negative Prognostic Marker for Vulvar Cancer Patients.

So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas as a tumor-relevant protein influencing patients' survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-κB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-κB inhibitor C-DIM 12 (3,3'-[(4-chlorophenyl)methylene]bis[1 H-indole]) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough.

'Primary gingival and later primary vulval carcinomas arising in lichen planus: report of a case and clinical suggestions for diagnosis of a neglected disease'.

Lichen planus (LP) is a chronic immune-mediated dermatosis mainly affecting skin, oral, and genital mucosa. The heterogeneous clinical presentation, spectrum of symptoms depending on subtype and overlap with other vulval and cutaneous disorders can lead to challenging in diagnosis. We report an unusual case of vulval SCC arising within a patient with initial oral mucosal lichen planus who later developed lichen planus of the vulva. Discussion of this case is important as it typifies the difficulties in diagnosis of vulvo-vaginal disorders and potential complications. Evidence is available that lichen planus may be potentially precancerous condition and is associated with SCC development. This case may confirm an inherent oncologic potential of the disease. All efforts must be made by specialists involved in the management of this disease to obtain an early diagnosis, ensure proper treatment and adequate follow up. This highlights the need to perform vulval examination in patients with symptoms or with a history muco-cutaneous LP and if necessary consider referral to specialist center for biopsy and management.

Lichen sclerosus in women: a review.

Female lichen sclerosus is a chronic inflammatory dermatitis, with a predilection for the anogenital area, which in some cases can become seriously distorted (atrophy of the labia minora, phimosis, introital stenosis, etc.). Most cases are diagnosed in postmenopausal women, but it can affect women of any age. Lichen sclerosus is usually a pruriginous condition, although it can also be asymptomatic. It is associated with an increased risk of vulvar cancer, even though it is not a premalignant condition itself. The true precursor of cancer associated with lichen sclerosus is vulvar intraepithelial neoplasia, differentiated type. The diagnosis is usually clinical, but in some cases a biopsy can be performed, especially to exclude vulvar intraepithelial neoplasia or cancer. The treatment of lichen sclerosus aims at controlling the symptoms, stopping further scarring and distortion and reducing the risk of cancer. The gold standard in treatment is ultra-potent topical steroids (clobetasol propionate). Second-line treatments include calcineurin inhibitors, retinoids, and immunosuppressors. Surgery is used only for the treatment of complications associated with lichen sclerosus. Follow-up must be kept indefinitely.

Vulvar, Perianal and Perineal Cancer After Hidradenitis Suppurativa: A Systematic Review and Pooled Analysis.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that frequently involves the perineal and perianal regions. The association between HS and malignant transformation is a rare but under recognized phenomenon. OBJECTIVE: This systematic review aims to summarize all available cases of vulvar and perianal/perineal cancer emerging in patients with HS, describing clinical and therapeutic particularities of these coexisting conditions in female patients. MATERIALS AND METHODS: This systematic review and pooled analysis was performed in accordance with the PRISMA guidelines; end-of-search date was June 15, 2015. RESULTS: A total of 13 eligible articles were identified; 7 cases of vulvar cancer and 6 cases of perineal/perianal carcinomas in patients with HS were noted. A majority of published cases pertained to rather advanced carcinomas; only occasionally early stage carcinomas were identified. The optimal modifications in the treatment scheme of vulvar, perianal, and perineal cancer in patients with HS have not been established; detailed reporting of recurrence- and survival-related aspects is advised. CONCLUSION: Vulvar, perianal, and perineal cancer represent a rare but serious complication of HS.

Recurrent Vulvar Carcinoma in a Skin Graft: A Case Reiort and Review of the Literature.

In recentyears, theincidence ofvul- var carcinoma has increased over 400%, specifically in the population of young women. We present a patient with an extensive history of recurrent vulvar carcinoma in situ who underwent multiple surgi- cal procedures and subsequent reconstruction with a skin graft, who then returned with a rare recur- rence in the graft. Multiple hypotheses have been proposedto explain the recurrence ofthis type ofcar- cinoma; however, none provides a solid explanation. It has been noted that the increase in the incidence of vulvar cancer correlates with the increased incidence of HPV infection; the relationship between the two has been well-established. In conclusion, we recommend close and long-term follow-up for high-risk patients with this type of neoplasm.

The role of RhoA in vulvar squamous cell carcinoma: a carcinogenesis, progression, and target therapy marker.

Ras homologue gene family member A (RhoA) is involved in tumor mobility, invasion, and metastasis. We detected RhoA expression in vulvar squamous cell carcinoma (VSCC) tissue, measured RhoA expression in the VSCC cell phenotype, and measured the expression of the relevant molecules after RhoA small interfering RNA (siRNA) transfection in SW962 cells. RhoA has a higher expression level in VSCC than normal vulva skin tissue and was positively associated with the International Federation of Gynecology and Obstetrics (FIGO) stage and differentiation; besides, VSCC patients with lymph node metastasis had higher positive RhoA expression. RhoA messenger RNA and protein expression was significantly reduced in the RhoA siRNA transfectants as compared with the negative control (NC) and mock-transfected cells (p < 0.05). The RhoA siRNA transfectants lead to low growth, G1 arrest, high apoptosis, low migration and invasion (p < 0.05), and suppressed lamellipodia formation as compared to NC and mock-transfected cells. Besides, matrix metalloproteinase-2 (MMP2), MMP9, and cyclinA1 protein expression was downregulated, while that of Bax was upregulated in the RhoA siRNA transfectants (p < 0.05). SW962 cell proliferation rates were significantly lovastatin dose-dependent. Lovastatin caused G1 arrest, high apoptosis, low migration and invasion (p < 0.05), and suppression of lamellipodia formation. Similar to the RhoA siRNA transfectants, lovastatin treatment downregulated RhoA, MMP2, MMP9, and cyclinA1 protein expression, while upregulating that of Bax as compared to that of the NC (p < 0.05). Abnormal RhoA expression in vulvar carcinoma is involved in tumor proliferation and invasion and may be a treatment target. The RhoA inhibitor lovastatin alters VSCC cell migration and proliferation and may be effective for treating VSCC.

Over-expression of DNMT3A predicts the risk of recurrent vulvar squamous cell carcinomas.

OBJECTIVE: Cancer initiation and progression has been linked to aberrant expression of the DNA methyltransferases (DNMT), the enzymes which establish and maintain DNA methylation patterns throughout the genome. In this study, we investigated if DNMT expression in vulvar squamous cell carcinomas (VSCC) was related to clinical outcome. METHODS: DNMT1, DNMT3A and DNMT3B expression was measured in a subset of cases drawn from a cohort of consecutive women treated for primary VSCC at the Pan Birmingham Gynaecological Cancer Centre between 2001 and 2008. Univariable and multivariable competing risk modelling was performed to identify whether DNMT expression was associated with local disease recurrence or disease morbidity. RESULTS: Over-expression of DNMT3A in the invasive component of the tumour was seen in 44% of tumours and was associated with an increased risk of local vulvar recurrence (LVR) (HR=4.51, p=0.012). This risk was found to increase further after adjustment for disease stage (HR=6.00, p=0.003) and groin node metastasis (HR=4.81, p=0.008). Over-expression of DNMT3B was associated with an increased risk of LVR (HR=5.69 p=0.03), however this ceased to be significant after adjustment for groin node metastasis. In a subset analysis, over-expression of DNMT3A was found to be significantly more common in VSCCs that stained negative for CDKN2A. CONCLUSIONS: These observations are consistent with the possibility that epigenetic changes contribute to vulvar neoplasia and DNMT3A over-expression may be useful in predicting local disease recurrence.

Clinical outcomes of primary surgical treatment for acquired vulvar lymphangioma circumscriptum.

OBJECTIVE: To assess the clinical outcomes of surgical treatment for acquired vulvar lymphangioma circumscriptum in patients who received radical surgery and/or adjuvant radiation therapy for cervical cancer. METHODS: A retrospective chart review of eight patients was performed to assess the demographic information, chief complaints, treatment modality for cervical cancer, location, and primary treatment modality for vulvar LC, postoperative changes in symptoms, and/or signs, the development of local recurrence and the outcome of patients. RESULTS: All eight patients were previously diagnosed with cervical cancer FIGO clinical stage IA to IIA and received surgery, radiation therapy, or concurrent chemoradiation therapy. Microscopic examination revealed multiple, dilated, D2-40-positive dermal vascular channels containing eosinophilic proteinaceous material, consistent with LC. Most chief complaints showed considerable improvements on assessment at the outpatient clinic after the primary surgery. No patient showed aggravation of symptoms. Two patients developed local recurrences. One patient developed recurrence on the opposite side 13 months after local excision. We performed a second wide local excision. Another patient developed recurrence 47 months after the primary surgery. Since the lesion was very small and localized, we decided to manage it conservatively, but monitor it very closely. The remaining six patients remained free of recurrence. CONCLUSION: It is not easy for gynecologists to have an initial clinical diagnosis of LC, because there are a number of diseases that exhibit similar clinical manifestation to that of vulvar LC. Even if it is diagnosed correctly, local recurrence often occurs. Relevant symptoms associated with LC are not only distressing, but also affect patients' quality of life. Based on our data, we propose that surgical treatment could provide a more long-lasting answer compared to other treatment modalities, since it is beneficial in terms of clinical outcomes. In the future, a long-term follow-up investigation is required to assess the prognosis and to compare the efficacy and side effects of each modality.

Vulvar Lichen Sclerosus and Neoplastic Transformation: A Retrospective Study of 976 Cases.

OBJECTIVE: The aim of the study was to estimate the neoplastic potential of vulvar lichen sclerosus (VLS). MATERIALS AND METHODS: This was a retrospective study of 976 women with VLS. We recorded age at diagnosis of VLS, length of follow-up, and type of neoplasia, categorized as the following: (1) vulvar intraepithelial neoplasia (VIN), further subdivided in differentiated VIN (dVIN) and high-grade squamous intraepithelial lesion; (2) superficially invasive squamous cell carcinoma; and (3) frankly invasive squamous cell carcinoma. Neoplasia incidence risk, neoplasia incidence rate, and cumulative probability of progression to neoplasia according to the Kaplan-Meier method were estimated. Log-rank test was used to compare the progression-free survival curves by age at diagnosis of VLS. RESULTS: The mean age at diagnosis of VLS was 60 (median = 60; range = 8-91) years. The mean length of follow-up was 52 (median = 21; range = 1-331) months. The following 34 patients developed a neoplasia: 8 VIN (4 dVIN, 4 high-grade squamous intraepithelial lesions), 6 keratinizing superficially invasive squamous cell carcinoma (5 with adjacent dVIN), and 20 keratinizing invasive squamous cell carcinoma (1 with adjacent dVIN). The neoplasia incidence risk was 3.5%. The neoplasia incidence rate was 8.1 per 1,000 person-years. The cumulative probability of progression to neoplasia increased from 1.2% at 24 months to 36.8% at 300 months. The median progression-free survival was significantly shorter in older women (≥70 years) when compared with that in younger women (p = .003). CONCLUSIONS: Vulvar lichen sclerosus has a nonnegligible risk of neoplastic transformation and requires a careful and lifelong follow-up in all patients, particularly in elderly women. Early clinical and histological detection of preinvasive lesions is essential to reduce the risk of vulvar cancer.

Reduction in ERRα is associated with lichen sclerosus and vulvar squamous cell carcinoma.

OBJECTIVE: ERRs (estrogen-related receptors) regulate energy metabolism, the cell cycle and inflammatory processes in both normal and cancer cells. Chronic inflammation induced by lichen sclerosus (LS) or human papilloma virus (HPV) precedes vulvar squamous cell carcinoma (vulvar SCC). We investigated the expression of ERRα, ERRß and ERRγ in normal vulvar skin, LS as well as LS-dependent and LS-independent/HPV-related vulvar SCC. METHODS: A total of 203 samples were analyzed for ERRα, ERRß and ERRγ by using immunohistochemistry. These included 37 normal vulvar skin samples, 110 LS samples, 6 vulvar intraepithelial neoplasia (VIN) samples and 50 vulvar SCC samples. RESULTS: A substantial reduction in or disappearance of ERRα was detected in all vulvar SCC samples. A total of 79% of childhood-onset LS and 51% of adulthood-onset LS lesions showed decreases in ERRα staining. A gradual reduction in ERRα cytoplasmic staining was observed from healthy vulvar skin to precursor lesions and further to SCC. Nuclear ERRα staining was observed in 8/33 (24%) LS-dependent and 10/17 (59%) LS-independent SCC samples. CONCLUSIONS: ERRα, a key regulator of cell energy metabolism, may play a role in the pathogenesis of both LS and vulvar SCC.

[AN HPV-ASSOCIATED DISEASES AND CERVICAL CANCER AND PROPHYLACTIC HUMAN PAPILLOMAVIRUS (HPV) VACCINES].

Human papillomavirus (HPV) infection is the central cause of invasive cervical cancer (ICC) and its precursor lesions. Both vaccines can prevent most cases of cervical cancer. In addition, both can prevent vaginal and vulvar cancer in women, and HPV-related cancers. HPV4 can prevent genital warts in women and men. Routine vaccination of 12-year-old girls with HPV4 vaccine appears to be cost-effective in addition to providing both short-term and long-term health gains.

Morbus Bourneville: a case report and review of the literature.

Tuberous sclerosis (TS) or tuberous sclerosis complex (TSC), also known as Bourneville disease or Bourneville-Pringle disease, is an autosomal dominant disorder classically characterized by the presence of hamartomatous growths in multiple organs. A combination of symptoms may include seizures, developmental delay, behavioral problems, skin abnormalities, and lung and kidney diseases. The authors present a case of a 18 year-old female patient with a history of TS, epileptic episodes, mental retardation, and papillary formations in multiple organs located at the abdominal, axillary, cervical, facial, and genital region.

Vulvar squamous cell carcinoma developing in a young black African HIV woman.

Vulvar cancers are uncommon, represented in 90% of cases by squamous cell carcinoma (SCC). The reduction of the frequency and the severity proceed by recognition of precancerous or beginning lesions. They occur most often in the third age in postmenopausal women. The diagnosis is almost difficult and often late and therefore prognosis is severe. Conditions for diagnosis and treatment are difficult in underdeveloped countries due to the inaccessibility of proper equipment in the healthcare system. The authors report a case of SCC diagnosed late in a young human immunodeficiency virus (HIV) women who have been treated with neoadjuvant chemotherapy and radical surgery of the vulva.

Vulvar melanoma and endometrial polyp following breast carcinoma: a case report.

The authors describe the occurrence of a 55-year-old female patient presenting with a vulvar melanoma, endometrial polyp, and a prior history of breast carcinoma excised from the left chest wall, radiotherapy, chemotherapy, and tamoxifen maintenance for two years. This case exemplified second primary vulvar melanoma following breast cancer and supported that radiotherapy might play a role in the onset of secondary cancer. This case report also emphasizes the onset of endometrial polyp induced by tamoxifen.