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.

Betapapillomaviruses in p16-Negative Vulvar Intraepithelial Lesions Associated with Squamous Cell Carcinoma.

Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (ß-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of ß-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. ß-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of ß-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva.

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.

Comparison of cisplatin and mitomycin C/5-FU as radiosensitisers in the treatment of locally advanced vulvar cancer: results of a retrospective, observational, single-institutional cohort study.

PURPOSE: We retrospectively investigated the widely used radiosensitisers cisplatin and mitomycin C/5-fluorouracil (5-FU) in patients with locally advanced vulvar cancer for outcome and toxicity. METHODS: We screened the archive for patients treated with chemoradiation for vulvar cancer diagnosed between 01/2010 and 08/2021 at our institution. The impact of both radiosensitisers on prognosis was compared using Kaplan-Meier method and Cox-regression analysis. RESULTS: One hundred and forty-three patients with vulvar cancer were screened. Twenty-nine patients received chemoradiation (mitomycin C/5-FU n = 14; cisplatin n = 12; others n = 3) as a primary, neoadjuvant or adjuvant treatment. Median follow-up was 15.5 months. Patients in the cisplatin group were older (mean age 54.4 vs. 70.7; p = 0.004). However, the mitomycin C/5-FU group had more advanced tumour stages. The 2-year recurrence-free survival (RFS) was comparable (44.5% vs. 33.3%; p = 0.932). The 2-year overall survival (OS) showed a numerical but not statistically significant difference in favour of the mitomycin C/5-FU group (59.7% vs. 31.7%; p = 0.37). 64.3% (9 out of 14) patients, who received mitomycin C/5-FU achieved clinical complete response (cCR) compared to 41.7% (5 out of 12) who received cisplatin (p = 0.505). Radiodermatitis was the most common adverse event in both groups (81%) and more severe in the mitomycin C/5-FU cohort. Myelotoxicity was frequently observed in both groups. Eighteen patients received an additional radiation boost with 10.0 (9-16) Gy and showed a significantly prolonged RFS (p = 0.027) and OS (p = 0.003). CONCLUSION: Mitomycin C/5-FU may be considered in the treatment of young and healthy patients with locally advanced vulvar cancer.

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.

Vulvar Intraepithelial Neoplasia: A Review of the Disease and Current Management.

IMPORTANCE: Vulvar intraepithelial neoplasia (VIN) represents an increasingly common, yet challenging diagnosis that shares many common risk factors with cervical intraepithelial neoplasia. However, unlike cervical intraepithelial neoplasia, effective screening and treatment strategies are much less defined for patients with VIN. OBJECTIVE: The objective of this article is to review the underlying risk factors leading to the development of VIN, identify special populations at risk for VIN, and outline acceptable treatment strategies. EVIDENCE ACQUISITION: This literature review was performed primarily using PubMed. RESULTS: Vulvar intraepithelial neoplasia can be separated into usual VIN (uVIN) and differentiated VIN (dVIN). The more common uVIN is related to underlying human papillomavirus infection, whereas dVIN occurs in the setting of other vulvar inflammatory conditions such as lichen sclerosis. Differentiated VIN carries a higher risk of progression to invasive malignancy. Extramammary Paget disease is a rare intraepithelial adenocarcinoma unrelated to uVIN and dVIN, although management is similar. CONCLUSIONS AND RELEVANCE: Vulvar intraepithelial neoplasia is a preinvasive neoplasia of the vulva with few robust strategies for surveillance or management. Careful examination with targeted biopsy is warranted for suspicious lesions, and a combination of surgical and medical management can be tailored for individual patient needs.

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.

Molecular pathways in vulvar squamous cell carcinoma: implications for target therapeutic strategies.

BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.

Human Papillomavirus-Independent Squamous Lesions of the Vulva.

The pathogenesis of vulvar squamous neoplasia has 2 pathways: human papillomavirus (HPV)-dependent and HPV-independent. The HPV-dependent pathway in the vulva follows the same progression as HPV-dependent lesions elsewhere in the gynecologic tract-HPV infection results in high-grade squamous intraepithelial lesion with subsequent progression to basaloid squamous cell carcinoma. The HPV-independent pathway is more complex, with a variety of precursor lesions and molecular alterations. Although the most recognized form of HPV-independent vulvar lesion is differentiated vulvar intraepithelial neoplasia, recent explorations have elucidated new precursors. This review provides an update on HPV-independent risk factors and precursor lesions for squamous cell carcinoma of the vulva.

Primary Clear Cell Adenocarcinoma of the Vulva: A Case Study With Mutation Analysis and Literature Review.

Primary vulvar clear cell carcinoma (CCC) is extremely rare. In this article, we report a primary vulvar CCC along with immunohistochemical and gene mutation analyses results and literature review to discuss the clinicopathological features and tumorigenesis of this rare tumor. A 70-year-old (gravida 2 para 2) Japanese woman complained of bleeding from a vulvar mass at a past episiotomy site. A 1.8 × 1.8 × 0.5 cm exophytic sessile mass was present on the vestibular area inside the left labium minora. Radical local excision of the tumor and resection of the inguinal lymph nodes on both sides were performed. Histopathology revealed a vulvar CCC with immunohistochemical positivity for PAX8, HNF-1ß, ER, and CA125, and negativity for p16, CD10, GATA3, PTEN, and PAX2, suggesting its Müllerian origin. No lymph node metastasis was observed. The tumor was a 5-mm exophytic growth without deep stromal invasion; thus, it was difficult to measure the invasion depth assuming a squamous cell carcinoma. To investigate pathogenic/oncogenic mutations in 50 cancer-related genes, we used the AmpliSeq Cancer Hotspot Panel. However, no pathogenic/oncogenic mutations were detected. Literature review revealed that most cases of vulvar CCC are associated with vulvar endometriosis. In particular, cases with clinically evident endometriosis at the episiotomy scar should be carefully observed. Evidence-based pathological stages of vulvar adenocarcinoma including CCC remain to be established owing to its rarity, with nationwide or global accumulation of cases required in future.

'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.

Estimates of the incidence of infection-related cancers in Italy and Italian regions in 2018.

INTRODUCTION: Chronic infections and infestations represent one of the leading causes of cancer. Eleven agents have been categorized by the International Agency for Research on Cancer (IARC) in Group 1, 3 in Group 2A and 4 in Group 2B. We previously estimated that the incidence of cancers associated with infectious agents accounted for the 8.5% of new cancer cases diagnosed in Italy in 2014. METHODS: In the present study we evaluated the incidence of cancer in Italy and in the 20 Italian regions in 2018, based on the data of Cancer Registries, and calculated the fraction attributable to infectious agents. RESULTS: Cancers of infectious origin contributed to the overall burden of cancer in Italy with more than 27,000 yearly cases, the 92% of which was attributable to Helicobacter pylori, human papillomaviruses, and hepatitis B and C viruses. With the exception of papillomavirus-related cancers, the incidence of cancers of infectious origin was higher in males (16,000 cases) than in females (11,000 cases). There were regional and geographical variations of cancers depending on the type of cancer and on the gender. Nevertheless, the overall figures were rather similar, the infection-related cancers accounting for the 7.2, 7.6, and 7.1% of all cancers in Northern, Central, and Southern Italy, respectively. CONCLUSIONS: The estimate of the incidence of cancers attributable to infectious agents in Italy in 2018 (7.3% of all cancer cases) is approximately half of the worldwide burden, which has been estimated by IARC to be the 15.4% of all cancer cases in 2012.

Vulvar Cancer as a Result of GATA2 Deficiency, a Rare Genetic Immunodeficiency Syndrome.

BACKGROUND: Vulvar cancer has become more prevalent, and its causes include chronic dermatoses and human papillomavirus (HPV)-mediated disease. Younger immunocompromised women can also be affected. We describe a case of vulvar carcinoma as a result of GATA2 deficiency. CASE: A 19-year-old woman presented to our gynecologic oncology clinic for management of a large vulvar mass. She was diagnosed with stage IB vulvar carcinoma after vulvectomy. GATA2 deficiency was the contributing factor causing vulvar carcinoma. CONCLUSION: GATA2 deficiency causes immunodeficiency in young women, and patients with early-onset HPV-related disease, a family or personal history of leukemia, recurrent infection, or immune irregularities should be screened. Health care providers for these women are often obstetrician-gynecologists, who can provide diagnosis, treatment, referral, and prevention of HPV-related diseases.

Cancer of the vulva.

Vulvar cancer is an uncommon gynecological malignancy primarily affecting postmenopausal women. There is no specific screening and the most effective strategy to reduce vulvar cancer incidence is the opportune treatment of predisposing and preneoplastic lesions associated with its development. While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer. Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion. Once established, the most common subtype is squamous cell carcinoma. Treatment of vulvar cancer depends primarily on histology and surgical staging. Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors. Management should be individualized, and carried out by a multidisciplinary team in a cancer center experienced in the treatment of these tumors.

Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis.

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC ) and women who did not develop VSCC during follow-up (VINnoVSCC ). HPV-testing resulted in 41 HPV-positive (16 VINVSCC , 14 VINnoVSCC , and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P = .009), but shared chromosome 8 alterations. HPV-positive VINnoVSCC had less CNA than VINVSCC (P = .022). Interestingly, 1pq gain was detected in 81% of HPV-positive VINVSCC and only in 21% of VINnoVSCC (P = .001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.