Materiały źródłowe

• #1 Vulvar Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567798/

  Vulvar SCC represents 90% of all vulvar cancers and typically develops by one of two pathways. Thirty to forty percent of vulvar cancer cases are associated with high-risk human papillomavirus (HR-HPV), resulting from the classic two-hit hypothesis for cancer development. HPV is known to have E6 and E7 oncoproteins, which inactivate the p53 and RB tumor suppressor proteins, respectively. The loss of these tumor suppressor genes leads to unregulated hyperproliferation. Another pathway involves inflammatory changes that result in cells with intact p53 status but the loss of cyclin-dependent kinase inhibitor 2A (p16), also resulting in unregulated cell cycle proliferation and eventually cancer. […] Pathophysiology of usual-type and differentiated VIN and its progression to SCC.

• #2 Vulvar Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/vulvar-cancer

  Most vulvar cancers are caused by persistent human papillomavirus (HPV) infection. The precursor to vulvar cancer is vulvar intraepithelial neoplasia (VIN). […] About 90% of vulvar cancers are squamous cell carcinomas; about 5% are melanomas. Others include adenocarcinomas and transitional cell, adenoid cystic, and adenosquamous carcinomas; all may originate in Bartholin glands. […] Risk factors for vulvar cancer include Human papillomavirus (HPV) infection, Vulvar intraepithelial neoplasia (VIN), Cigarette smoking, Lichen sclerosus, Immunodeficiency, Squamous hyperplasia, Squamous carcinoma or intraepithelial neoplasia of the vagina, cervix, or anus, Chronic granulomatous disease.

• #2 Molecular Events in the Pathogenesis of Vulvar Squamous Cell Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7749059/

  Vulvar squamous cell carcinomas (VSCC), which constitute over 90% of vulvar malignancies in adults, are classifiable into 2 subgroups that are mostly clinicopathologically distinct, a classification that is fundamentally based whether or not the tumors are HPV-mediated. […] In this review, we aim to summarize the recent advances in the understanding of molecular events in the pathogenesis of VSCC, including common and targetable mutations, copy number alterations, epigenetics, noncoding RNAs, and tumor immune microenvironment, which may provide insight into the future management of the disease. […] Recurrent, driver mutations appear to be substantially more prevalent in HPV() VSCC. […] TP53 mutations are the most common somatic mutations in VSCC overall, and are notably predominant in the HPV() VSCC, where 30-88% show a mutation.

• #3 Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment – UpToDate

  https://www.uptodate.com/contents/vulvar-cancer-epidemiology-diagnosis-histopathology-and-treatment

  Vulvar cancer is less common than other gynecologic malignancies, including uterine corpus, ovarian, and cervical cancer; in the United States, vulvar cancer is also less common than vaginal cancer. Squamous cell carcinoma is the most common histologic type of vulvar cancer, comprising at least 75 percent of cases. […] Human papillomavirus (HPV) infection is associated with the majority of vulvar squamous cell carcinomas. In addition, vulvar lichen sclerosus is associated with an increased risk of vulvar cancers.

• #3 Vulvar Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/vulvar-cancer

  Most vulvar cancers are caused by persistent human papillomavirus (HPV) infection. The precursor to vulvar cancer is vulvar intraepithelial neoplasia (VIN). […] About 90% of vulvar cancers are squamous cell carcinomas; about 5% are melanomas. Others include adenocarcinomas and transitional cell, adenoid cystic, and adenosquamous carcinomas; all may originate in Bartholin glands. […] Risk factors for vulvar cancer include Human papillomavirus (HPV) infection, Vulvar intraepithelial neoplasia (VIN), Cigarette smoking, Lichen sclerosus, Immunodeficiency, Squamous hyperplasia, Squamous carcinoma or intraepithelial neoplasia of the vagina, cervix, or anus, Chronic granulomatous disease.

• #4 Vulvar cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Vulvar_cancer_pathophysiology

  Development of vulvar cancer is the result of multiple genetic mutations. […] Human papillomaviruses subtypes 16 and 18 (High risk) play an essential role in the pathogenesis of vulvar cancer. Once HPV enters an epithelial cell, the virus begins to make the proteins it encodes. […] Two of the proteins made by high-risk HPVs (E6 and E7) interfere with cell functions that normally prevent excessive growth, helping the cell to grow in an uncontrolled manner and to avoid cell death. […] Many times these infected cells are recognized by the immune system and eliminated. Sometimes, however, these infected cells are not destroyed, and a persistent infection results. […] Persistently infected cells continue to grow, they may develop mutations in cellular genes that promote even more abnormal cell growth.

• #5 Biological relevance of human papillomaviruses in vulvar cancer | Modern Pathology

  https://www.nature.com/articles/modpathol2016197

  The carcinogenic role of high-risk human papillomavirus (HR-HPV) types in the increasing subset of vulvar intraepithelial neoplasia and vulvar cancer in young women has been established. […] Our data confirm the biological role of HR-/pHR-HPV types in the great majority of HPV DNA+ vulvar cancers, resulting in an HPV-attributable fraction of at least 21% worldwide. […] Most HPV DNA+ vulvar cancers were associated with HPV16 (85%), but a causative role for other, less frequently occurring mucosal HPV types (HPV26, 66, 67, 68, 70 and 73) was also confirmed at the mRNA level for the first time. […] The first pathway is activated by underlying autoimmune-related processes while the second pathway is triggered by mucosal human papillomavirus (HPV) infection. […] Usual-type vulvar intraepithelial neoplasia is HPV associated and appears in younger women.

• #6 Vulvar and vaginal cancer epidemiology and molecular pathogenesis | PPT

  https://www.slideshare.net/slideshow/vulvar-and-vaginal-cancer-epidemiology-and-molecular-pathogenesis/47789486

  1. Etiology – HPV Approximately, 40% vulvar cancers are HPV (Human Papilloma Virus) Positive. Of these HPV positive invasive vulvar cancers 85% are attributed to HPV 16. Prophylactic HPV vaccines have the potential to decrease the incidence of invasive vulvar cancer by about one-third overall, and to be even more effective in younger women. Smith JS et al. Human Papillomavirus Type-Distribution in Vulvar and Vaginal Cancers and Their Associated Precursors Obstet Gynecol. 2009; 113:917-24 […] 8. Etiology Vulval Intraepithelial Neoplasia (VIN) There has been a significant increase in the incidence of vulvar intraepithelial Neoplasia (VIN) in recent decades, and this has been attributed to changing sexual behavior, human papillomavirus (HPV) infection, and cigarette smoking. […] 11. Etiology The increased risk of a subsequent cancer to be 1.3-fold. Most of the second cancers were related to smoking (i.e., cancers of the lung, buccal cavity, pharynx, nasal cavity, or larynx) or human papillomavirus infections (e.g., cervix, vagina, or anus).

• #7 Vulvar Cancer | Concise Medical Knowledge

  https://www.lecturio.com/concepts/vulvar-cancer/

  Vulvar cancer develops when there is uncontrolled cellular proliferation in vulvar tissue. […] This cancer may progress from a premalignant lesion caused by an HPV infection, or it may develop from other mutations, unrelated to HPV. […] HPV-associated SCC vulvar cancer is most commonly due to HPV-16. […] HPV has the ability to affect host cell protein expression: […] HPV has 2 major oncoproteins: […] E6: inactivates p53 tumor suppressor protein […] E7: inactivates Rb tumor suppressor protein. […] After cells lose tumor suppressor proteins, unregulated proliferation occurs. […] Invasion through the basement membrane occurs in SCC. […] NonHPV-associated SCC vulvar cancer most commonly occurs in the setting of lichen sclerosus. […] Inflammation or autoimmunity leads to the loss of cyclin-dependent kinase 2A (p16) and unregulated proliferation. […] P53 remains intact in non-HPV associated SCC.

• #8 Vulvar Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/31276

  Vulvar SCC represents 90% of all vulvar cancers and typically develops by one of two pathways. […] Thirty to forty percent of vulvar cancer cases are associated with high-risk human papillomavirus (HR-HPV), resulting from the classic two-hit hypothesis for cancer development. […] HPV is known to have E6 and E7 oncoproteins, which inactivate the p53 and RB tumor suppressor proteins, respectively. The loss of these tumor suppressor genes leads to unregulated hyperproliferation. […] Another pathway involves inflammatory changes that result in cells with intact p53 status but the loss of cyclin-dependent kinase inhibitor 2A (p16), also resulting in unregulated cell cycle proliferation and eventually cancer.

• #9 Vulvar cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/vulvar-cancer/symptoms-causes/syc-20368051

  Vulvar cancer happens when cells in the vulva develop changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells. […] Exactly what causes the DNA changes that lead to vulvar cancer isn’t always known. Healthcare professionals believe some vulvar cancers are caused by human papillomavirus. Human papilloma virus, also called HPV, is a common virus passed through sexual contact. It’s associated with the most common type of vulvar cancer, which is vulvar squamous cell carcinoma.

• #10 Molecular Events in the Pathogenesis of Vulvar Squamous Cell Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7749059/

  TP53 mutations are associated with worse patient outcomes, and co-mutations between TP53 and either HRAS, PIK3CA or CDKN2A appear to define subsets with even worse outcomes. […] A wide variety of other somatic mutations have been identified, including a subset with different mutational frequencies between HPV(+) and HPV() VSCC. […] Hypermethylation of CDKN2A is the most frequently reported epigenetic alteration in VSCC and the expression of some microRNAs may be associated with patient outcomes. […] The PTEN/PI3K/AKT/mTOR pathway is commonly altered in HPV(+) VSCC, and is accordingly potentially targetable. […] HPV-positivity/p16 block expression by immunohistochemistry has been found to be an independent prognostic marker for improved survival in VSCC, and may have some predictive value in VSCC patients treated with definitive radiotherapy.

• #11 Pathological variants in HPV-independent vulvar tumours | Scientific Reports

  https://www.nature.com/articles/s41598-024-84688-3

  The mutational profile of HPV-associated tumors in the current study was considerably different from HPV-independent cases. […] The HPV-independent group harboured more SNVs in comparison to HPV-associated tumors that more frequently presented with gene amplifications. […] The PI3K/AKT/mTOR1 pathway was affected in both the groups either by the presence of SNVs or gene fusions. […] The cell cycle regulation pathway genes TP53 och CDKN2A were mutated only in the HPV-negative group while the MYC, CDK2 and CDK4 were mutated in both groups. […] The present study added further knowledge in the characterization of the genomic changes in vulvar carcinoma that is a very rare form of cancer, and identified various pathological mutations in HPV-independent cancers. Our study together with others, suggests that HPV-independent tumours are molecularly very heterogeneous.

• #11 Pathological variants in HPV-independent vulvar tumours | Scientific Reports

  https://www.nature.com/articles/s41598-024-84688-3

  Vulvar cancer is a rare gynaecological disease that can be caused by infection with human papillomavirus (HPV). The mutational frequencies and landscape for HPV-associated and HPV-independent vulvar tumor development are supposedly two distinctly different pathways and more detailed knowledge on target biological mechanisms for individualized future treatments is needed. […] The main outcome of this study show that vulvar cancer harbour genetic variations of different types and specifically, HPV-independent tumours are molecularly very heterogeneous and harboured more SNVs while HPV-associated tumors more frequently presented with gene amplifications. […] The mutational frequencies and landscape for HPV-associated and HPV-independent tumour development are supposedly two distinctly different pathways and early studies have revealed p53 alterations as drivers for HPV-independent tumors.

• #12 Vulvar cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Vulvar_cancer_pathophysiology

  HPV- related vulvar carcinoma is most commonly seen in younger women. Vulvar intraepithelial neoplasia (VIN), related to HPV infection, subsequently leads to invasive vulvar cancer. […] The development of both vulvar low-grade squamous intraepithelial lesions (LSIL) and vulvar high-grade squamous intraepithelial lesions (HSIL; formerly VIN usual type) is associated with human papillomavirus (HPV) infection, as is the corresponding vulvar cancer of the warty and basaloid subtypes. […] Multifocal vulvar HSIL and multicentric vulvar HSIL are most often associated with high-oncogenic-risk HPV subtypes 16, 18, and 31 and should be considered premalignant lesions. […] The pathogenesis of differentiated VIN is less well understood than vulvar LSIL or HSIL. […] It is typically associated with lichen sclerosus. The risk of vulvar squamous cell carcinoma in women with lichen sclerosus is approximately 5 percent.

• #13 Vulval Cancer: Symptoms, Staging, and Outcomes — DermNet

  https://dermnetnz.org/topics/vulval-cancer

  Over 80% of vulval cancers are squamous cell carcinomas (SCC) including both precursor lesions and invasive disease. […] The pathogenesis, epidemiology, clinical features, and specific treatment options for each of these are covered in more detail below. […] The precursor lesion for vulval SCC is vulval intraepithelial neoplasia (VIN) which can be classified as: Vulval high-grade squamous intraepithelial lesion (HSIL, formerly called usual type VIN) associated with HPV 16, 18, and 33 in women aged 2040 years. […] HPV vaccination introduced as a primary prevention strategy for cervical cancer is showing a promising reduction in HPV-related VIN and vulval SCC. […] Pathogenesis may include immunosuppression, chronic irritation, pelvic radiation, trauma.

• #14 Management of Vulvar Intraepithelial Neoplasia | ACOG

  https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2016/10/management-of-vulvar-intraepithelial-neoplasia

  The risk of progression to cancer has been documented in treated and untreated patients, and prognostic factors are not sufficiently reliable to select women for treatment. […] Occult invasive cancer has been reported in 3% of women undergoing surgery for VIN. […] The focus of this Committee Opinion is the management of usual type VIN, which was renamed in 2015 by the International Society for the Study of Vulvovaginal Disease (ISSVD) as high-grade squamous intraepithelial lesions of the vulva (vulvar HSIL). […] Usual type VIN commonly is associated with carcinogenic genotypes of HPV and other HPV persistence risk factors, such as cigarette smoking and immunocompromised status. […] Differentiated VIN associated with lichen sclerosus is more likely to be associated with a squamous cell carcinoma of the vulva than usual type VIN.

• #14 Management of Vulvar Intraepithelial Neoplasia | ACOG

  https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2016/10/management-of-vulvar-intraepithelial-neoplasia

  Vulvar intraepithelial neoplasia (VIN) is an increasingly common problem, particularly among women in their 40s. […] VIN should be considered a premalignant condition. […] Women with vulvar HSIL (VIN usual type) are at risk of recurrent disease and vulvar cancer throughout their lifetimes. […] There are no screening strategies for the prevention of vulvar cancer through early detection of vulvar HSIL (VIN usual type). […] Detection is limited to visual assessment with confirmation by histopathology when needed. […] Treatment is recommended for all women with vulvar HSIL (VIN usual type). […] Because of the potential for occult invasion, wide local excision should be performed if cancer is suspected, even if biopsies show vulvar HSIL. […] When occult invasion is not a concern, vulvar HSIL (VIN usual type) can be treated with excision, laser ablation, or topical imiquimod (off-label use).

• #15 Vulvar Cancer | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/1001/p1269.html

  Vulvar cancer was reported in 3,200 women in 1998, resulting in 800 deaths. Recent evidence suggests that vulvar cancer comprises two separate diseases. The first type may develop from vulvar intraepithelial neoplasia caused by human papillomavirus infection and is increasing in prevalence among young women. The second type, which more often afflicts older women, may develop from vulvar non-neoplastic epithelial disorders as a result of chronic inflammation (the itch-scratchlichen sclerosus hypothesis). […] It has been suggested that vulvar cancer exists as two separate diseases. The first type involves human papillomavirus (HPV) infection, which leads to VIN and predisposes the patient to vulvar cancer. The second type involves vulvar non-neoplastic epithelial disorders (VNED) and advanced age, leading to cellular atypia and cancer.

• #16 Vulvar cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Vulvar_cancer_pathophysiology

  Differentiated VIN is found adjacent to 80 percent of vulvar squamous cell carcinomas. The diagnosis of solitary differentiated VIN is very challenging and appears to be associated with rapid progression to squamous cell carcinoma. […] Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia, and/or basal cellular atypia tend to have the highest risk of progression to squamous cell carcinoma. There are no known biomarkers to reliably identify the patients at highest risk.

• #17 Vulvar cancer: epidemiology, clinical presentation, and management opt | IJWH

  https://www.dovepress.com/vulvar-cancer-epidemiology-clinical-presentation-and-management-option-peer-reviewed-fulltext-article-IJWH

  Vulvar cancer can be classified into two groups according to predisposing factors: the first type correlates with a HPV infection and occurs mostly in younger patients. The second group is not HPV associated and occurs often in elderly women without neoplastic epithelial disorders. […] The second type of vulvar cancer includes vulvar nonneoplastic epithelial disorders (VNED) and advanced age that lead to cellular atypia and eventually to cancer. Elderly patients (55-85 years), in particular, show a low rate of HPV infections and consequently seldom any association with cervical neoplasia. […] Lichen sclerosus, a subgroup of VNED, is mooted as a predisposing risk factor in the development of HPV-negative vulvar cancer. Because of a severe pruritus caused by the lichen, the itch-scratch cycle leads to a squamous cell hyperplasia and over time a progression to atypia, followed by VIN and eventual invasive cancer.

• #18 Molecular Landscape of Vulvar Squamous Cell Carcinoma

  https://www.mdpi.com/1422-0067/22/13/7069

  Mutations in TP53 have been identified in a significant proportion of these tumors. […] The mutational landscape of VSCC has been poorly investigated over the past three decades. […] Knowledge on recurrent mutations in VSCC will certainly open doors to better prognostic stratification and the identification of new targets for therapy. […] The largest targeted NGS study showed that HPV-associated VSCC harbor alterations in the PI3K/mTOR pathway (PIK3CA, PTEN, STK11, FBXW7, and SOX2), whereas HPV-independent VSCC showed more frequent mutations in TP53, TERT, CDKN2A, and CCND1, as well as amplifications in EGFR and PD-L1. […] The evidence of EGFR amplifications in 11% of HPV-independent VSCC, as shown by Williams et al., might open doors to prognostic stratification or treatment with Cetuximab. […] Despite it being known that a number of mutations are druggable, the clinical utility of them is still unknown in patients with VSCC.

• #19 Vulvar Cancer | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/1001/p1269.html

  Over the past decade, the prevalence of VIN in young women has increased significantly. VIN is clearly a premalignant finding and is associated with HPV infection, particularly subtypes 16 and 18. […] Lichen sclerosus, a type of VNED, is thought to be a predisposing factor in the development of HPV-negative vulvar cancer. According to the itch-scratchlichen sclerosus hypothesis, lichen sclerosus, by causing a severe pruritus, sets up an itch-scratch cycle that over time causes the development of squamous cell hyperplasia. Further progression results in atypia formation, followed by VIN and eventual invasive squamous cell cancer. This hypothesis suggests that treatment of lichen sclerosus with topical steroids would prevent vulvar cancer in these patients, and some early research supports this suggestion. Aggressive evaluation and treatment of VNEDs could have a dramatic impact on the incidence of vulvar cancer in this subgroup of patients.

• #20 Pathological variants in HPV-independent vulvar tumours | Scientific Reports

  https://www.nature.com/articles/s41598-024-84688-3

  The mutational profile of HPV-associated tumors in the current study was considerably different from HPV-independent cases. […] The HPV-independent group harboured more SNVs in comparison to HPV-associated tumors that more frequently presented with gene amplifications. […] The PI3K/AKT/mTOR1 pathway was affected in both the groups either by the presence of SNVs or gene fusions. […] The cell cycle regulation pathway genes TP53 och CDKN2A were mutated only in the HPV-negative group while the MYC, CDK2 and CDK4 were mutated in both groups. […] The present study added further knowledge in the characterization of the genomic changes in vulvar carcinoma that is a very rare form of cancer, and identified various pathological mutations in HPV-independent cancers. Our study together with others, suggests that HPV-independent tumours are molecularly very heterogeneous.

• #21 Vaginal and Vulvar Cancer – Gynecologic Cancer Initiative

  https://gynecancerinitiative.ca/vaginal-and-vulvar-cancer/

  Vulvar cancer forms on the outer lips of the external genitalia (or vulva). […] At both these sites, changes to cells of the vulva or vagina can lead to precancerous conditions. […] New research, done in BC, definitively shows that HPV and non-HPV diseases are distinct conditions as they behave differently and have different treatment needs. […] Non-HPV lesions are associated with more frequent recurrence and a higher risk of death. […] The data in BC suggests that aggressive surgery may be more important in HPV-independent lesions; the higher recurrence rate seen in recent years may be secondary to a change in surgical practice where less morbid surgical interventions had been favoured. […] In addition, this team has demonstrated that HPV-independent lesions are less sensitive to radiation therapy.

• #22 Vaginal and Vulvar Cancer – Gynecologic Cancer Initiative

  https://gynecancerinitiative.ca/vaginal-and-vulvar-cancer/

  This research provides one step in improving outcomes for women faced with a diagnosis of vulvar cancer. […] Based on our previous work on the molecular stratification of ovarian and endometrial cancer, we propose to use a similar approach to better understand the etiology and pathogenesis of vulvar cancer with the goal of developing management strategies that are biologically-informed. […] While the diagnosis of HPV-related tumours has been perfected over the years and there is little difficulty distinguishing between benign and cancerous forms of the disease, this is unfortunately not the case for HPV-independent cancers which are much more difficult to diagnose. […] Also non-HPV related vulvar cancers tend to be more resistant to radiation therapy in comparison to its HPV-related counterparts.

• #23

  http://waocp.com/journal/index.php/apjcc/article/view/1300

  Vulvar cancer remains a significant health concern for women worldwide. This comprehensive review provided an overview of biomarkers in vulvar cancer, focusing on the significance of EGFR, GLUT1, MUC1, MRP1, P16, PD-L1, and P53. It explores their prognostic value and pathophysiology, delving into the intricate landscape of these biomarkers. It was aimed to elucidate the roles of these biomarkers in predicting outcomes, offering insights into their potential as prognostic indicators for vulvar cancer. This analysis can contribute to the evolving understanding of molecular markers in the context of vulvar cancer prognosis and informs future research directions in the field. […] Dysregulation of cell signaling pathways can result from mutations in the EGFR gene or overexpression of the receptor, which can accelerate the development of cancer.

• #24

  http://waocp.com/journal/index.php/apjcc/article/view/1300

  Higher than normal amounts of EGFR on the cell surface can lead to enhanced signaling, which in turn encourages angiogenesis and cell division, ultimately aiding in the formation of tumors. […] EGFR triggers the activation of intracellular signaling pathways that control cell survival, proliferation, and differentiation, including the PI3K/AKT and Ras/MAPK pathways. Tumor development may be aided by these pathways dysregulation. […] When vulvar cancer cells overexpress GLUT1, this leads to an increase in the uptake of glucose, which supplies the energy required for the tumors to develop and proliferate quickly. […] Elevated GLUT1 expression may serve as a prognostic factor in vulvar cancer, providing insights into the potential aggressiveness of the tumor and aiding in predicting patient outcomes.

• #25

  http://waocp.com/journal/index.php/apjcc/article/view/1300

  Overexpression can encourage tumor cell motility and invasion and disrupt healthy cell adhesion processes. […] MUC1 has the ability to activate the angiogenesis process, which results in the development of new blood vessels that carry oxygen and nutrients to the expanding tumor. […] The pathogenesis entails MRP1 actively releasing a wide range of medications from cancer cells, including chemotherapy medicines. The lethal action of these medications is diminished as a result of this efflux, which lowers their concentration inside cancer cells. […] Elevated P16 expression is often seen in precancerous lesions (such as vulvar intraepithelial neoplasia or VIN) and vulvar cancer. The persistent overexpression of P16 indicates dysregulation of the cell cycle due to HPV infection, contributing to the development and progression of vulvar cancer. […] The P53 biomarker in vulvar cancer is often associated with mutations in the TP53 gene, which encodes the P53 protein. Normally, P53 functions as a tumor suppressor by regulating the cell cycle, promoting DNA repair, and inducing apoptosis (Programmed cell death) in cells with irreparable damage.

• #26 Biological relevance of human papillomaviruses in vulvar cancer | Modern Pathology

  https://www.nature.com/articles/modpathol2016197

  In the vulva, up to 20% of cancers carry CDKN2A mutations but these are usually silencing mutations primarily identified in HPV DNA cancers and resulting in a loss of p16INK4a expression. […] Our findings demonstrate p16INK4a upregulation in all HPV DNA+/HPV mRNA+ vulvar cancers harboring single pHR-HPV types 26, 66, 67, 70 or 73 (1 case each) and HPV DNA+ (no RNA assay available) pHR-HPV types 30 (1 case) or 69 (2 cases). […] A clear definition of HPV-driven vulvar cancer is important for assessing potential clinical differences in HPV-associated vulvar cancers compared with those vulvar cancers that develop through autoimmune processes.

• #27 Molecular Events in the Pathogenesis of Vulvar Squamous Cell Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7749059/

  Recurrent chromosomal gains in VSCCs have been found at 1q, 2q, 3q, 4p, 5p, 7p, 8p, 8q, and 12q, and there may be differential patterns of alterations depending on HPV-status. […] At least one-third of VSCC patients may potentially benefit from immune checkpoint inhibition therapy, based on a high frequency of PD-L1 expression or amplification, or a high tumor mutational burden. […] Additional studies are ultimately required to better understand the global landscape of genetic and epigenetic alterations in VSCC, and to identify and test potential targets for clinical application.

• #28 Vulvar Cancer: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/6220-vulvar-cancer

  Vulvar cancer usually develops slowly over several years. Precancerous areas of tissue (lesions) typically develop first. Healthcare providers usually discover the abnormal growth in the outermost layer of your skin. These precancerous lesions are called vulvar intraepithelial neoplasia (VIN). […] The most common type of vulvar cancer, vulvar squamous cell carcinoma, arises in association with one of two conditions: Human papillomavirus (HPV) infection: A common sexually transmitted infection (STI) that spreads through skin-to-skin contact. Some types of HPV increase your risk of certain cancers, including cervical cancer, anal cancer, rectal cancer and vulvar cancer. […] Risk factors for vulvar cancer include: Age: Your likelihood of developing vulvar cancer increases with age. Exposure to HPV: Not all strains of HPV cause cancer, but some can lead to cell changes that eventually become vulvar cancer. Skin conditions involving your vulva: Growths associated with lichen sclerosus may progress to vulvar cancer. […] With vulvar cancer, cells begin multiplying out of control. Without treatment, these cancer cells can spread to other parts of your body.

• #29 Vulvar Cancer | HPV | Dysplasia | MedlinePlus

  https://medlineplus.gov/vulvarcancer.html

  Vulvar cancer is a rare type of cancer. It forms in a woman’s external genitals, called the vulva. The cancer usually grows slowly over several years. First, precancerous cells grow on vulvar skin. This is called vulvar intraepithelial neoplasia (VIN), or dysplasia. Not all VIN cases turn into cancer, but it is best to treat it early. […] Your health care provider diagnoses vulvar cancer with a physical exam and a biopsy. Treatment varies, depending on your overall health and how advanced the cancer is. It might include surgery, radiation therapy, chemotherapy, or biologic therapy. Biologic therapy boosts your body’s own ability to fight cancer.

• #30 Precancerous conditions of the vulva | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/vulvar/what-is-vulvar-cancer/precancerous-conditions

  Precancerous conditions of the vulva are changes to vulvar cells that make them more likely to develop into cancer. These conditions are not yet cancer. But if they arent treated, there is a chance that these abnormal changes may become vulvar cancer. […] Usual-type VIN is the most common type of VIN. It is more common in younger women aged 35 to 55 and is linked to the human papillomavirus (HPV) infection. […] Differentiated-type VIN is less common. It usually occurs in older women aged 55 to 85. It is not linked to HPV infection but can occur along with skin conditions of the vulva such as lichen sclerosis. […] One of the most common risk factors of VIN is HPV infection. Other risk factors include smoking, immunosuppression, and lichen sclerosis. […] VIN 2 and VIN 3 are often grouped together as high-grade VIN and usually require treatment.

• #31 Biological relevance of human papillomaviruses in vulvar cancer | Modern Pathology

  https://www.nature.com/articles/modpathol2016197

  True estimation of the HPV-attributable fraction in vulvar cancer is still imprecise. […] In the continuous effort to better define HPV-driven vulvar cancer, we focused on collecting biological evidence of HPV-transformed phenotype in the vulva by investigating the expression and concordance of HPV mRNA and p16INK4a in 447 HPV DNA+ cases of vulvar cancer. […] The etiological role of HPV in the development of vulvar cancer has been well recognized. […] It has become increasingly evident that a functional evidence of HPV activity or HPV transformation is necessary in addition to the HPV DNA presence, in order to define true HPV-driven tumors outside of the cervix uteri. […] Our study also demonstrates that HR-HPV types other than HPV16 and 18, as well as a subset of pHR-HPV types, have an etiological role in the development of vulvar cancer.

• #32 Vulvar Cancer | Foundation For Women’s Cancer

  https://foundationforwomenscancer.org/gynecologic-cancers/gynecologic-cancer-types/vulvar-cancer/

  Vulvar cancer begins in the vulva, which is the external genitalia that comprises of the inner and outer labia (lips), clitoris, urethra where urine exits, opening of the vagina and its glands, as well as the area of skin between the vagina and anus. It is a rare cancer that can be associated with smoking, human papillomavirus (HPV) infections, as well as conditions of the vulva associated with chronic irritation and inflammation. […] Protection from infection with the Human Papillomavirus (HPV), including HPV vaccination, reduces the risk of vulvar cancer. Examination of the vulva for changes by a person at home or by their gynecologist during their annual pelvic examination can lead to the detection of preinvasive disease or early vulvar cancer. […] For vulvar cancer, the final stage depends on the pathologic review of the surgical specimens from the vulva and regional lymph nodes. Assignment of a stage helps guide therapy or surveillance.

• #33 Identification of molecular targets in vulvar cancers | Caris Life Sciences

  https://www.carislifesciences.com/research/publications/identification-molecular-targets-vulvar-cancers/

  To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment. […] Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.

• #34

  https://link.springer.com/article/10.1007/s11912-019-0833-z

  The aim of this article is to provide clinicians and pathologists with an understanding of the aetiopathology, pathogenesis and classification of vulval neoplasia and their molecular correlates. […] There is an increased understanding of subcellular changes in vulvar malignancies. These provide the direction for further research and aid personalised treatment for patients. […] The article explores concepts of the aetiology of vulvar cancer and updates the reader with the equivalence of terminology of preneoplastic vulval disease. The differential diagnosis of squamous neoplasia and their clinicopathological correlation is detailed. The salient findings from recent literature into the understanding of the disease of squamous cell neoplasia and rare vulvar malignancies are summarised.

• #35 Vaginal and Vulvar Cancer – Gynecologic Cancer Initiative

  https://gynecancerinitiative.ca/vaginal-and-vulvar-cancer/

  All these factors combined, there is a clear need to develop better ancillary tests for early detection and diagnosis and more personalized treatment approaches for specific vulvar cancer types based on their unique molecular alterations. […] Our research is charting a course for improved diagnostics and treatments.

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