{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:54:13Z","timestamp":1785153253740,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T00:00:00Z","timestamp":1640822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Vulvar cancer is a rare gynaecological malignancy, accounting for 2\u20135% of cancers of the female genital tract. Squamous cell carcinoma is the most frequently occurring subtype and, historically, has been a disease of older post-menopausal women, occurring with a background of lichen sclerosus and other epithelial conditions of the vulvar skin that may be associated with well-differentiated vulvar intra-epithelial neoplasia (dVIN). An increase in human papillomavirus (HPV) infections worldwide has led to an increase in vulvar squamous carcinomas in younger women, resulting from HPV-associated high-grade vulvar squamous intra-epithelial lesions (vHSIL). Surgical resection is the gold standard for the treatment of vulvar cancer. However, as approximately 30% of patients present with locally advanced disease, which is either irresectable or will require radical surgical resection, possibly with a stoma, there has been a need to investigate alternative forms of treatment such as chemoradiation and targeted therapies, which may minimise the psychosexual morbidity of radical surgery. This review aims to provide an update on management strategies for women with advanced vulvar cancer. It is hoped that investigation of the molecular biologies of the two different pathways to vulvar squamous cell carcinoma (HPV-associated and non-HPV-associated) will lead to the development of targeted therapeutic agents.<\/jats:p>","DOI":"10.3390\/cancers14010167","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T21:41:21Z","timestamp":1640900481000},"page":"167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Management of Advanced Squamous Cell Carcinoma of the Vulva"],"prefix":"10.3390","volume":"14","author":[{"given":"Linda J.","family":"Rogers","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Groote Schuur Hospital, The University of Cape Town, Cape Town 7505, South Africa"},{"name":"SAMRC\/UCT Gynaecological Cancer Research Centre, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,30]]},"reference":[{"key":"ref_1","unstructured":"(2021, December 10). Cancer Research UK Vulval Cancer\u2014UK Incidence Statistics. Available online: http:\/\/info.cancerresearchuk.org\/cancerstats\/types\/vulva\/incidence\/#Worldwide."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.7196\/SAMJ.2017.v107i11.12497","article-title":"Vulvar cancer is not a disease of the elderly: Treatment and outcome at a tertiary referral centre in South Africa","volume":"107","author":"Butt","year":"2017","journal-title":"SAMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"F12","DOI":"10.1016\/j.vaccine.2012.07.055","article-title":"Global burden of human papillomavirus and related diseases","volume":"30","author":"Forman","year":"2012","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ijgo.13880","article-title":"FIGO staging for carcinoma of the vulva: 2021 revision","volume":"155","author":"Olawaiye","year":"2021","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_5","unstructured":"Howlander, N., Noone, A.M., Krapcho, M., Neyman, N., Aminou, R., Waldron, W., Altekruse, S.F., Kosary, C.L., Ruhl, J., and Tatalovich, Z. (2012). SEER Cancer Statistics Review, 1975\u20132008, National Cancer Institute."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.ygyno.2016.12.007","article-title":"Locally advanced vulva cancer: A single centre review of anovulvectomy and a systematic review of surgical, chemotherapy and radiotherapy alternatives. Is an international collaborative RCT destined for the \u201ctoo difficult to do\u201d box?","volume":"144","author":"Verleye","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"272","DOI":"10.3802\/jgo.2014.25.4.272","article-title":"Defining the concept of locally advanced squamus cell carcinoma of the vulva: A new perspective based on standardization of criteria and current evidence","volume":"25","author":"Aragona","year":"2014","journal-title":"J. Gynecol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejogrb.2020.05.054","article-title":"British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: Recommendations for practice","volume":"252","author":"Morrison","year":"2020","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1097\/IGC.0000000000000975","article-title":"European society of gynaecological oncology guidelines for the management of patients with vulvar cancer","volume":"27","author":"Oonk","year":"2017","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_10","first-page":"7","article-title":"Cancer of the Vulva. FIGO Cancer Report 2021","volume":"155","author":"Olawaiye","year":"2021","journal-title":"IJOG"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/cncr.10969","article-title":"Vulvar carcinoma. The price of less radical surgery","volume":"95","author":"Hollema","year":"2002","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1111\/1471-0528.14560","article-title":"Current Insights into the aetiology, pathobiology and management of local disease recurrence in squamous cell carcinoma of the vulva: A review paper","volume":"124","author":"Yap","year":"2017","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.ygyno.2017.11.006","article-title":"Prognostic factors for local recurrence of squamous cell carcinoma of the vulva: A systematic review","volume":"148","author":"Pouwer","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/j.1525-1438.2006.00769.x","article-title":"Squamous cell carcinoma of the vulva with bulky positive groin nodes\u2014Nodal debulking versus full groin dissection prior to radiation therapy","volume":"17","author":"Hyde","year":"2007","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.ygyno.2015.09.081","article-title":"Groin surgery and risk of recurrence in lymph node positive patients with vulvar squamous cell carcinoma","volume":"139","author":"Nooij","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1200\/JCO.2007.14.0566","article-title":"Sentinel node dissection is safe in the treatment of early-stage vulvar cancer","volume":"26","author":"Oonk","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.ygyno.2017.06.004","article-title":"Lymphedema following gynecological cancer: Results from a prospective, longitudinal cohort study on prevalence, incidence and risk factors","volume":"146","author":"Hayes","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1002\/1097-0142(20001001)89:7<1520::AID-CNCR15>3.0.CO;2-N","article-title":"Preservation of the saphenous vein during inguinal lymphadenectomy decreases morbidity in patients with carcinoma of the vulva","volume":"89","author":"Zhang","year":"2000","journal-title":"Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/IGC.0000000000001146","article-title":"Do groin drains reduce postoperative morbidity in women undergoing inguinofemoral lymphadenectomy for vulvar cancer?","volume":"28","author":"Pontre","year":"2018","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/IGC.0000000000000311","article-title":"The effect of groin treatment modality and sequence on clinically significant chronic lymphedema in patients with vulvar carcinoma","volume":"25","author":"Berger","year":"2015","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.ygyno.2015.03.056","article-title":"Impact of adjuvant chemotherapy with radiation for node-positive vulvar cancer: A National Cancer Data Base (NCDB) analysis","volume":"137","author":"Gill","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1097\/00000421-198704000-00055","article-title":"Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer","volume":"10","author":"Boronow","year":"1987","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1002\/1097-0142(19841115)54:10<2056::AID-CNCR2820541003>3.0.CO;2-L","article-title":"Preoperative radiation therapy for locally advanced vulvar cancer","volume":"54","author":"Hacker","year":"1984","journal-title":"Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0090-8258(89)90157-1","article-title":"Concurrent radiation and chemotherapy in vulvar carcinoma","volume":"34","author":"Thomas","year":"1989","journal-title":"Gynecol. Oncol."},{"key":"ref_25","first-page":"CD003752","article-title":"Neoadjuvant chemoradiation for advanced primary vulvar cancer","volume":"3","author":"Ansink","year":"2006","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_26","first-page":"CD003752","article-title":"Chemoradiation for advanced primary vulvar cancer","volume":"4","author":"Shylasree","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1006\/gyno.1995.1267","article-title":"Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva","volume":"59","author":"Eifel","year":"1995","journal-title":"Gynecol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1006\/gyno.1996.0150","article-title":"Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin-C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma","volume":"61","author":"Landoni","year":"1996","journal-title":"Gynecol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/S0360-3016(00)00762-8","article-title":"Preoperative chemo-radiation for carcinoma of the vulva with N2\/N3 nodes: A gynecologic oncology group study","volume":"48","author":"Montana","year":"2000","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0360-3016(98)00193-X","article-title":"Preoperative chemoradiation for advanced vulvar cancer: A phase II study of the Gynecologic Oncology Group","volume":"42","author":"Moore","year":"1998","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3109\/02841869309092448","article-title":"Combined bleomycin and irradiation in preoperative treatment of advanced squamous cell carcinoma of the vulva","volume":"32","author":"Scheistron","year":"1993","journal-title":"Acta Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ygyno.2011.11.003","article-title":"A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva:a gynecologic oncology group study","volume":"124","author":"Moore","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ygyno.2005.06.068","article-title":"Neoadjuvant chemotherapy in vulvar cancer: Avoiding primary exenteration","volume":"100","author":"Geisler","year":"2006","journal-title":"Gynecol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/IGC.0b013e3181c93adc","article-title":"Neoadjuvant chemotherapy in advanced vulvar cancer","volume":"20","author":"Domingues","year":"2010","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1159\/000487435","article-title":"Brief report on 3-Weekly paclitaxel carboplatin efficacy in locally advanced or metastatic squamous vulvar cancer","volume":"83","author":"Amant","year":"2018","journal-title":"Gynecol. Oncol. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejogrb.2017.03.030","article-title":"Neoadjuvant and definitive chemotherapy or chemoradiation for stage III and IV vulvar cancer: A pooled Reanalysis","volume":"212","author":"Forner","year":"2017","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1093\/annonc\/mdw242","article-title":"The forgotten woman\u2019s cancer: Vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy","volume":"27","author":"Clancy","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrc3430","article-title":"MDM2, MDMx and p53 in oncogenesis and cancer therapy","volume":"13","author":"Wade","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.ygyno.2007.05.006","article-title":"Treatment of squamous cell vulvar cancer with the anti-|EGFR tyrosine kinase inhibitor Tarceva","volume":"106","author":"Olawaiye","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ygyno.2012.06.028","article-title":"Phase II trial of erlotinib in women with squamous cell carcinoma of he vulva","volume":"127","author":"Horowitz","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_41","first-page":"100631","article-title":"Neoadjuvant chemotherapy with paclitaxel\/carboplatin\/bevacizumab in advanced vulvar cancer: Time to rethink standard of care?","volume":"34","author":"Klavans","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.arcmed.2009.06.001","article-title":"HPV-related carcinogenesis: Basic concepts, viral types and variants","volume":"40","author":"Lizano","year":"2009","journal-title":"Arch. Med. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/his.12034","article-title":"Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma","volume":"62","author":"Ordi","year":"2013","journal-title":"Histopathology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ygyno.2020.09.024","article-title":"Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes","volume":"159","author":"Kortekaas","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1136\/ijgc-2019-000793","article-title":"Association of human papilloma virus status and response to radiotherapy in vulvar squamous cell carcinoma","volume":"30","author":"Proctor","year":"2020","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/ijc.25400","article-title":"Association between toll-like receptor expression and human papillomavirus type 16 persistence","volume":"128","author":"Daud","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1440-1711.2004.01291.x","article-title":"Activation of dendritic cells by human papillomavirus-like particles through TLR4 can NF-kappa B-mediated signalling, moderated by TGF-beta","volume":"83","author":"Yan","year":"2005","journal-title":"Immunol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/ijc.28364","article-title":"Genetic variation in the TLR and NF-kB pathways and cervical and vulvar cancer risk: A population-based case control study","volume":"134","author":"Bodelon","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1158\/1078-0432.CCR-05-1178","article-title":"Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine","volume":"12","author":"Haas","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_50","first-page":"701","article-title":"Imiquimod in the treatment of multifocal vulvar intraepithelial neoplasia 2\/3. Results of a pilot study","volume":"47","author":"Fons","year":"2002","journal-title":"J. Reprod. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ygyno.2007.06.003","article-title":"Topical imiquimod can reverse vulvar intraepithelial neoplasia: A randomised double-blinded study","volume":"107","author":"Mathieson","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Borella, F., Preti, M., Bertero, L., Collemi, G., Castellano, I., Cassoni, P., Cosma, S., Carosso, A.R., Bevilacqua, F., and Gallio, N. (2021). Is there a Place for Immune Checkpoint Inhibitors in vulvar neoplasma? A State of the Art Review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010190"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1200\/JCO.2017.74.5471","article-title":"Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results from the Phase Ib KEYNOTE-028 Trial","volume":"35","author":"Frenel","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1200\/JCO.19.00739","article-title":"Safety and Efficacy of Nivolumab Monotherapy Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I\/II CheckMate 358 Trial","volume":"37","author":"Naumann","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.pathol.2016.02.015","article-title":"Squamous precursor lesions of the vulva: Current classification and diagnostic challenges","volume":"48","author":"Hoang","year":"2016","journal-title":"Pathology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1158\/1538-7445.AM2015-2662","article-title":"A dual P13K\/mTOR inhibitor as a potential therapeutic option in vulvar cancer","volume":"75","author":"Rodrigues","year":"2015","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ygyno.2014.11.002","article-title":"Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: A review of the current literature","volume":"136","author":"Trietsch","year":"2015","journal-title":"Gynecol. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/167\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:48Z","timestamp":1760169348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,30]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cancers14010167"],"URL":"https:\/\/doi.org\/10.3390\/cancers14010167","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,30]]}}}