<?xml version="1.1" encoding="utf-8"?>
<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">JCNR</journal-id><journal-title-group><journal-title>Journal of Clinical and Nursing Research</journal-title></journal-title-group><issn>2208-3685</issn><eissn>2208-3693</eissn><publisher><publisher-name>Bio-Byword Scientific Publishing Pty. Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.26689/jcnr.v8i7.7891</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title>Evaluating the Association between Human Papillomavirus and Vulvar Cancer: A Comprehensive Analysis Using Bradford Hill Criteria</title><url>https://artdesignp.com/journal/JCNR/8/7/10.26689/jcnr.v8i7.7891</url><author>YazHamid</author><pub-date pub-type="publication-year"><year>2024</year></pub-date><volume>8</volume><issue>7</issue><history><date date-type="pub"><published-time>2024-08-09</published-time></date></history><abstract>Background: The role of human papillomavirus (HPV) in the development of vulvar cancer (VC) has been widely studied, but findings have been inconsistent. Despite numerous meta-analyses exploring the potential link between HPV and VC, the association remains controversial due to inherent limitations in meta-analytic methods. Objectives: To address this controversy, the study aims to investigate the potential link between HPV and VC using the Bradford Hill criteria, which offer a more comprehensive framework for establishing causation. Methodology: The study began by extracting all relevant studies on the association between HPV and VC from the PubMed database. The potential links were then assessed by examining the data using the major postulates of the Bradford Hill criteria. To ensure the reliability of the findings, the methodologies of the identified studies were critically evaluated to account for possible false-negative and false-positive results. Results: The assessment of previous studies against the Bradford Hill criteria revealed that the major postulates were not fulfilled. Conclusion: Based on the findings, it can concluded that there is no causal association between HPV and VC.</abstract><keywords/></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>Clancy A, Spaans J, Weberpals J, 2016, The Forgotten Woman’s Cancer: Vulvar Squamous Cell Carcinoma (VSCC) and a Targeted Approach to Therapy. Annals of Oncology, 27(9): 1696–1705.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B2" content-type="article"><label>2</label><element-citation publication-type="journal"><p>Bodelon C, Madeleine MM, Voigt LF, et al., 2009. Is the Incidence of Invasive Vulvar Cancer Increasing in the United States? Cancer Causes &amp; Control, 20(9): 1779–1782.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B3" content-type="article"><label>3</label><element-citation publication-type="journal"><p>Oonk MH, Planchamp F, Baldwin P, et al., 2017, European Society of Gynaecological Oncology Guidelines for the Management of Patients with Vulvar Cancer. International Journal of Gynecologic Cancer, 27(4).</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B4" content-type="article"><label>4</label><element-citation publication-type="journal"><p>Swarts DR, Voorham QJ, van Splunter AP, et al., 2018, Molecular Heterogeneity in Human Papillomavirus-Dependent and -Independent Vulvar Carcinogenesis. Cancer Med, 7(9): 4542–4553.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B5" content-type="article"><label>5</label><element-citation publication-type="journal"><p>Burger EA, Lee K, Saraiya M, et al., 2016, Racial and Ethnic Disparities in Human Papillomavirus-Associated Cancer Burden with First-Generation and Second-Generation Human Papillomavirus Vaccines. Cancer, 122(13): 2057–2066.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B6" content-type="article"><label>6</label><element-citation publication-type="journal"><p>Knopp S, Nesland JM, Trope C, et al., 2006, p14ARF, a Prognostic Predictor in HPV-Negative Vulvar Carcinoma. American Journal of Clinical Pathology, 126(2): 266–276.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B7" content-type="article"><label>7</label><element-citation publication-type="journal"><p>Alonso I, Fuste V, del Pino M, et al., 2011, Does Human Papillomavirus Infection Imply a Different Prognosis in Vulvar Squamous Cell Carcinoma? Gynecologic Oncology, 122(3): 509–514.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B8" content-type="article"><label>8</label><element-citation publication-type="journal"><p>Ansink AC, Krul MR, De Weger RA, et al., 1994, Human Papillomavirus, Lichen Sclerosus, and Squamous Cell Carcinoma of the Vulva: Detection and Prognostic Significance. Gynecologic Oncology, 52(2): 180–184.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B9" content-type="article"><label>9</label><element-citation publication-type="journal"><p>Antonets AV, Nerodo G, Dvadnenko KV, et al., 2013, Detection of Human Papillomavirus in Vulva Cancer Tissue. American Society of Clinical Oncology.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B10" content-type="article"><label>10</label><element-citation publication-type="journal"><p>Brandenberger A, Rudlinger R, Hanggi W, et al., 1992, Detection of Human Papillomavirus in Vulvar Carcinoma: A Study by In Situ Hybridisation. Archives of Gynecology and Obstetrics, 252(1): 31–35.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B11" content-type="article"><label>11</label><element-citation publication-type="journal"><p>Engelman DE, Andrade L, Vassallo J, 2003, Human Papillomavirus Infection and p53 Protein Expression in Vulvar Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma. Brazilian Journal of Medical and Biological Research, 36(9): 1159–1165.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B12" content-type="article"><label>12</label><element-citation publication-type="journal"><p>Felez-Sanchez M, Vergara M, de Sanjose S, et al., 2016, Searching Beyond the Usual Papillomavirus Suspects in Squamous Carcinomas of the Vulva, Penis and Head and Neck. Infection, Genetics and Evolution, 2016(45): 198–204.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B13" content-type="article"><label>13</label><element-citation publication-type="journal"><p>Fuste V, Alonso I, Castillo P, et al., 2010, Squamous Cell Carcinoma of the Vulva: Clinicopathological Correlations and Prognostic Significance of HPV Infection and FIGO Staging. Laboratory Investigation, 90(S1): 243A.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B14" content-type="article"><label>14</label><element-citation publication-type="journal"><p>Gargano JW, Wilkinson EJ, Unger ER, et al., 2012, Prevalence of Human Papillomavirus Types in Invasive Vulvar Cancers and Vulvar Intraepithelial Neoplasia 3 in the United States Before Vaccine Introduction. Journal of Lower Genital Tract Disease, 16(4): 471–479.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B15" content-type="article"><label>15</label><element-citation publication-type="journal"><p>Hampl M, Deckers-Figiel S, Hampl JA, et al., 2008, New Aspects of Vulvar Cancer: Changes in Localization and Age of Onset. Gynecologic Oncology, 109(3): 340–345.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B16" content-type="article"><label>16</label><element-citation publication-type="journal"><p>Hay CM, Lachance JA, Lucas F, et al., 2016, Biomarkers p16, Human Papillomavirus and p53 Predict Recurrence and Survival in Early-Stage Squamous Cell Carcinoma of the Vulva. Journal of Lower Genital Tract Disease, 20(3): 252–256.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B17" content-type="article"><label>17</label><element-citation publication-type="journal"><p>Huang FY, Kwok YK, Lau ET, et al., 2005, Genetic Abnormalities and HPV Status in Cervical and Vulvar Squamous Cell Carcinomas. Cancer Genetics and Cytogenetics, 157(1): 42–48.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B18" content-type="article"><label>18</label><element-citation publication-type="journal"><p>Kagie MJ, Kenter GG, Tollenaar RA, et al., 1997, p53 Protein Overexpression is Common and Independent of Human Papillomavirus Infection in Squamous Cell Carcinoma of the Vulva. Cancer, 80(7): 1228–1233.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B19" content-type="article"><label>19</label><element-citation publication-type="journal"><p>Karnezis A, Cheng A, McAlpine J, et al., 2015, Assessing the Accuracy of Histomorphology in Distinguishing Between HPV-Positive and HPV-Negative Vulvar Squamous Cell Carcinomas. Modern Pathology, 28(S2): 293A.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B20" content-type="article"><label>20</label><element-citation publication-type="journal"><p>Kim Y, Kim JY, Lee NK, et al., 2015, Treatment Outcomes of Curative Radiotherapy in Patients with Vulvar Cancer: Results of the Retrospective KROG 1203 Study. Radiation Oncology Journal, 33(3): 198–206.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B21" content-type="article"><label>21</label><element-citation publication-type="journal"><p>Kowalewska M, Szkoda MT, Radziszewski J, et al., 2010, The Frequency of Human Papillomavirus Infection in Polish Patients with Vulvar Squamous Cell Carcinoma. International Journal of Gynecologic Cancer, 20(3): 100–106.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B22" content-type="article"><label>22</label><element-citation publication-type="journal"><p>Koyamatsu Y, Yokoyama M, Nakao Y, et al., 2003, A Comparative Analysis of Human Papillomavirus Types 16 and 18 and Expression of p53 Gene and Ki-67 in Cervical, Vaginal, and Vulvar Carcinomas. Gynecologic Oncology, 90(3): 547–551.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B23" content-type="article"><label>23</label><element-citation publication-type="journal"><p>Larsson GL, Helenius G, Andersson S, et al., 2012, Human Papillomavirus (HPV) and HPV 16–Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden. International Journal of Gynecologic Cancer, 22(8): 1413–1419.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B24" content-type="article"><label>24</label><element-citation publication-type="journal"><p>Lavorato-Rocha AM, de Melo Maia B, Rodrigues IS, et al., 2013, Prognostication of Vulvar Cancer Based on p14 ARF Status: Molecular Assessment of Transcript and Protein. Annals of Surgical Oncology, 20(1): 31–39.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B25" content-type="article"><label>25</label><element-citation publication-type="journal"><p>Lee LJ, Howitt B, Catalano P, et al., 2016, Prognostic Importance of Human Papillomavirus (HPV) and p16 Positivity in Squamous Cell Carcinoma of the Vulva Treated with Radiotherapy. Gynecologic Oncology, 142(2): 293–298.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B26" content-type="article"><label>26</label><element-citation publication-type="journal"><p>Lindell G, Nasman A, Jonsson C, et al., 2010, Presence of Human Papillomavirus (HPV) in Vulvar Squamous Cell Carcinoma (VSCC) and Sentinel Node. Gynecologic Oncology, 117(2): 312–316.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B27" content-type="article"><label>27</label><element-citation publication-type="journal"><p>McAlpine J, Leung S, Cheng A, et al., 2017, HPV-Independent Vulvar Squamous Cell Carcinoma has a Worse Prognosis Than HPV-Associated Disease: A Retrospective Cohort Study. Histopathology, 2017(71): 238–246.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B28" content-type="article"><label>28</label><element-citation publication-type="journal"><p>Menczer J, Fintsi Y, Arbel-Alon S, et al., 2000, The Presence of HPV 16, 18 and p53 Immunohistochemical Staining in Tumor Tissue of Israeli Jewish Women with Cervical and Vulvar Neoplasia. European Journal of Gynaecological Oncology, 21(1): 30–34.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B29" content-type="article"><label>29</label><element-citation publication-type="journal"><p>Monk BJ, Burger RA, 1995, Prognostic Significance of Human Papillomavirus DNA in Vulvar Carcinoma. Obstetrics &amp; Gynecology, 85(5 Pt 1): 709–715.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B30" content-type="article"><label>30</label><element-citation publication-type="journal"><p>Ngamkham J, Boonmark K, Phansri T, 2016, Detection and Type-Distribution of Human Papillomavirus in Vulva and Vaginal Abnormal Cytology Lesions and Cancer Tissues from Thai Women. Asian Pacific Journal of Cancer Prevention, 17(3): 1129–1134.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B31" content-type="article"><label>31</label><element-citation publication-type="journal"><p>Pils S, Gensthaler L, Alemany L, et al., 2017, HPV Prevalence in Vulvar Cancer in Austria. Wiener Klinische Wochenschrift, 129(21): 805–809.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B32" content-type="article"><label>32</label><element-citation publication-type="journal"><p>Poblet E, Pascual-Martín A, Pariente-Martin M, et al., 2010, Prevalence and Genotype Identification of HPV Infection in Penile vs. Vulvar Carcinomas. Modern Pathology, 23: 120A–121A.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B33" content-type="article"><label>33</label><element-citation publication-type="journal"><p>Reuschenbach M, Roos J, Panayotopoulos D, et al., 2013, Characterization of Squamous Cell Cancers of the Vulvar Anterior Fourchette by Human Papillomavirus, p16INK4a, and p53. Journal of Lower Genital Tract Disease, 17(3): 289–297.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B34" content-type="article"><label>34</label><element-citation publication-type="journal"><p>Rumbold AR, Tan SE, Condon JR, et al., 2012, Investigating a Cluster of Vulvar Cancer in Young Women: A Cross-Sectional Study of Genital Human Papillomavirus Prevalence. BMC Infectious Diseases, 12(1): 1–8.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B35" content-type="article"><label>35</label><element-citation publication-type="journal"><p>Sagdeo A, Gormley RH, Abuabara K, et al., 2014, The Diagnostic Challenge of Vulvar Squamous Cell Carcinoma: Clinical Manifestations and Unusual Human Papillomavirus Types. Journal of the American Academy of Dermatology, 70(3): 586.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B36" content-type="article"><label>36</label><element-citation publication-type="journal"><p>Santos M, Landolfi S, Olivella A, et al., 2006, p16 Overexpression Identifies HPV-Positive Vulvar Squamous Cell Carcinomas. The American Journal of Surgical Pathology, 30(11): 1347–1356.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B37" content-type="article"><label>37</label><element-citation publication-type="journal"><p>Siriaunkgul S, Settakorn J, Sukpan K, et al., 2014, HPV Detection and Genotyping in Vulvar Squamous Cell Carcinoma in Northern Thailand. Asian Pacific Journal of Cancer Prevention, 15(8): 3773–3778.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B38" content-type="article"><label>38</label><element-citation publication-type="journal"><p>Sutton BC, Allen RA, Moore WE, et al., 2008, Distribution of Human Papillomavirus Genotypes in Invasive Squamous Carcinoma of the Vulva. Modern Pathology, 21(3): 345–354.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B39" content-type="article"><label>39</label><element-citation publication-type="journal"><p>Sznurkowski JJ, Zawrocki A, Biernat W, 2016, The Overexpression of p16 is Not a Surrogate Marker for High-Risk Human Papilloma Virus Genotypes and Predicts Clinical Outcomes for Vulvar Cancer. BMC Cancer, 16(1): 1–9.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B40" content-type="article"><label>40</label><element-citation publication-type="journal"><p>Tsimplaki E, Argyri E, Michala L, et al., 2012, Human Papillomavirus Genotyping and E6/E7 mRNA Expression in Greek Women with Intraepithelial Neoplasia and Squamous Cell Carcinoma of the Vagina and Vulva. Journal of Oncology, 2012(2012): 893275.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B41" content-type="article"><label>41</label><element-citation publication-type="journal"><p>van de Nieuwenhof HP, van Kempen LC, de Hullu JA, et al., 2009, The Etiologic Role of HPV in Vulvar Squamous Cell Carcinoma Fine Tuned. Cancer Epidemiology and Prevention Biomarkers, 18(7): 2061–2067.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B42" content-type="article"><label>42</label><element-citation publication-type="journal"><p>Wakeham K, Kavanagh K, Cuschieri K, et al., 2017, HPV Status and Favourable Outcome in Vulvar Squamous Cancer. International Journal of Cancer, 140(5): 1134–1146.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B43" content-type="article"><label>43</label><element-citation publication-type="journal"><p>Weberpals JI, Lo B, Duciaume MM, et al., 2017, Vulvar Squamous Cell Carcinoma (VSCC) as Two Diseases: HPV Status Identifies Distinct Mutational Profiles Including Oncogenic Fibroblast Growth Factor Receptor 3. Clinical Cancer Research, 23(15): 4501–4510.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B44" content-type="article"><label>44</label><element-citation publication-type="journal"><p>Narisawa-Saito M, Kiyono T, 2007, Basic Mechanisms of High-Risk Human Papillomavirus-Induced Carcinogenesis: Roles of E6 and E7 Proteins. Cancer Science, 98(10): 1505–1511.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B45" content-type="article"><label>45</label><element-citation publication-type="journal"><p>van der Avoort IA, Shirango H, Hoevenaars B, et al., 2006, Vulvar Squamous Cell Carcinoma is a Multifactorial Disease Following Two Separate and Independent Pathways. International Journal of Gynecological Pathology, 25(1): 22–29.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B46" content-type="article"><label>46</label><element-citation publication-type="journal"><p>Nerodo G, Ivanova V, Zykova T, et al., 2014, Human Papillomavirus Infection and Herpesvirus Infection in Vulvar Cancer Patients. Annals of Oncology, 2014(25): iv323.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B47" content-type="article"><label>47</label><element-citation publication-type="journal"><p>Al Dossary R, Alkharsah KR, Kussaibi H, 2018, Prevalence of Mouse Mammary Tumor Virus (MMTV)-Like Sequences in Human Breast Cancer Tissues and Adjacent Normal Breast Tissues in Saudi Arabia. BMC Cancer, 18(1): 1–10.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B48" content-type="article"><label>48</label><element-citation publication-type="journal"><p>Sasagawa T, Shimakage M, Nakamura M, et al., 2000, Epstein-Barr Virus (EBV) Genes Expression in Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer: A Comparative Study with Human Papillomavirus (HPV) Infection. Human Pathology, 31(3): 318–326.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B49" content-type="article"><label>49</label><element-citation publication-type="journal"><p>Alkatout I, Schubert M, Garbrecht N, et al., 2015, Vulvar Cancer: Epidemiology, Clinical Presentation, and Management Options. International Journal of Women’s Health, 2015(7): 305–313.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B50" content-type="article"><label>50</label><element-citation publication-type="journal"><p>Awadh A, Chughtai AA, Dyda A, et al., 2017, Does Zika Virus Cause Microcephaly-Applying the Bradford Hill Viewpoints. PLoS Currents, 2017: 9.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B51" content-type="article"><label>51</label><element-citation publication-type="journal"><p>Song D, Li H, Li H, et al., 2015, Effect of Human Papillomavirus Infection on the Immune System and its Role in the Course of Cervical Cancer. Oncology Letters, 10(2): 600–606.</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
