Abstract
Cervical cancer ranks as the fourth most common cancer in women globally with an estimated 604,000 new cases and 342,000 deaths in 2020. Most cases (75–85%) are squamous cell carcinomas (SCC), with a smaller proportion (15–25%) being adenocarcinomas. Persistent infection by high-risk human papillomavirus (HPV) accounts for nearly 95% of cervical cancer cases. Specifically, HPV16 and 18 collectively contribute to about 70% of cases. A multistep carcinogenesis model outlines the progression from HPV infection to precancerous stages and eventual invasion leading to cancer. A minority of cases, primarily adenocarcinomas, develop through HPV-independent mechanisms, carrying significant implications. Preventive measures such as HPV vaccination, coupled with screening and treatment of precancerous lesions, offer effective strategies in preventing cervical cancer. This chapter aims to provide an overview of our current understanding of HPV-associated and HPV-independent cervical carcinogenesis and briefly discuss the strategies related to cervical cancer screening and prevention.
References
Adcock R, Cuzick J, Hunt WC et al (2019) Role of HPV genotype, multiple infections, and viral load on the risk of high-grade cervical neoplasia. Cancer Epidemiol Biomarkers Prev 28(11):1816–1824
Adegoke O, Kulasingam S, Virnig B (2012) Cervical cancer trends in the United States: a 35-year population-based analysis. J Womens Health (Larchmt) 21:1031–1037
Arbyn M, Sasieni P, Meijer CJ et al (2006) Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 24(Suppl 3):78–89
Arbyn M, Bergeron C, Klinkhamer P et al (2008) Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol 111:167–177
Beglin M, Melar-New M, Laimins L (2009) Human papillomaviruses and the interferon response. J Interf Cytokine Res 29:629–635
Belleudi F, Leone L, Purpura V et al (2011) HPV16 E5 affects the KGFR/FGFR2b-mediated epithelial growth through alteration of the receptor expression, signaling and endocytic traffic. Oncogene 30:4963–4976
Berggrund M, Gustavsson I, Aarnio R et al (2019) HPV viral load in self-collected vaginal fluid samples as predictor for presence of cervical intraepithelial neoplasia. Virol J 16(1):146
Bosch FX, Lorincz A, Munoz N et al (2002) The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55:244–265
Caberg JH, Hubert P, Herman L et al (2009) Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20. Cancer Immunol Immunother 58:39–47
Casey S, Harley I, Jamison J et al (2015) A rare case of HPV-negative cervical squamous cell carcinoma. Int J Gynecol Pathol 34:208–212
Centers for Disease Control and Prevention NCI. U.S. Cancer Statistics Working Group. United States cancer statistics: 1999–2014 incidence and mortality web-based report. http://www.cdc.gov/uscs. Accessed 11 Oct 2017
Chen Z, Schiffman M, Herrero R et al (2011) Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. PLoS One 6:e20183
Cuschieri K, Fellner MD, Arroyo Mühr LS et al (2023) Quality assurance in human papillomavirus testing for primary cervical screening. Int J Gynecol Cancer 33(5):802–811
Cuzick J, Clavel C, Petry KU et al (2006) Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119:1095–1101
Day PM, Schelhaas M (2014) Concepts of papillomavirus entry into host cells. Curr Opin Virol 4:24–31
de Martel C, Plummer M, Vignat J et al (2017) Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 141:664–670
Doorbar J, Quint W, Banks L et al (2012) The biology and life-cycle of human papillomaviruses. Vaccine 30(Suppl 5):F55–F70
Duan L, Du H, Wang C et al (2020) The application of BMRT-HPV viral load to secondary screening strategies for cervical cancer. PLoS One 15(5):e0232117
Egawa N, Egawa K, Griffin H et al (2015) Human papillomaviruses; epithelial tropisms, and the development of neoplasia. Viruses 7:3863–3890
Filippova M, Parkhurst L, Duerksen-Hughes PJ (2004) The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J Biol Chem 279:25729–25744
Filippova M, Johnson MM, Bautista M et al (2007) The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity. J Virol 81:4116–4129
Fonseca-Moutinho JA (2011) Smoking and cervical cancer. ISRN Obstet Gynecol 2011:847684
Groves IJ, Coleman N (2015) Pathogenesis of human papillomavirus-associated mucosal disease. J Pathol 235:527–538
Gustafsson L, Ponten J, Zack M et al (1997) International incidence rates of invasive cervical cancer after introduction of cytological screening. Cancer Causes Control 8:755–763
Hasan UA, Zannetti C, Parroche P et al (2013) The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the toll-like receptor 9 promoter. J Exp Med 210:1369–1387
Herfs M, Yamamoto Y, Laury A et al (2012) A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci USA 109:10516–10521
Herfs M, Vargas SO, Yamamoto Y et al (2013) A novel blueprint for ‘top down’ differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia. J Pathol 229:460–468
Herfs M, Soong TR, Delvenne P et al (2017) Deciphering the multifactorial susceptibility of mucosal junction cells to HPV infection and related carcinogenesis. Viruses 9:E85
Holowaty P, Miller AB, Rohan T et al (1999) Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 91:252–258
Hoover RN, Hyer M, Pfeiffer RM et al (2011) Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365:1304–1314
Horvath CA, Boulet GA, Renoux VM et al (2010) Mechanisms of cell entry by human papillomaviruses: an overview. Virol J 7:11
Hosono S, Kawase T, Matsuo K et al (2010) HLA-A alleles and the risk of cervical squamous cell carcinoma in Japanese women. J Epidemiol 20:295–301
Hubert P, Herman L, Roncarati P et al (2014) Altered alpha-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment. J Pathol 234:464–477
Huh WK, Ault KA, Chelmow D et al (2015) Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol 136:178–182
Jiang A, Bloom O, Ono S et al (2007) Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27:610–624
Johansson C, Schwartz S (2013) Regulation of human papillomavirus gene expression by splicing and polyadenylation. Nat Rev Microbiol 11:239–251
Kulasingam SL, Hughes JP, Kiviat NB et al (2002) Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 288:1749–1757
Kulasingam SL, Havrilesky L, Ghebre R et al (2011) Screening for cervical cancer: a decision analysis for the US preventive services task force. Agency for Healthcare Research and Quality (US), Rockville
Laara E, Day NE, Hakama M (1987) Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. Lancet 1:1247–1249
Laurson J, Khan S, Chung R et al (2010) Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. Carcinogenesis 31:918–926
Lee KR, Flynn CE (2000) Early invasive adenocarcinoma of the cervix. Cancer 89:1048–1055
Levine PH, Elgert PA, Mittal K (2003) False-positive squamous cell carcinoma in cervical smears: cytologic-histologic correlation in 19 cases. Diagn Cytopathol 28:23–27
Luo H, Du H (2019) Belinson JL, et al evaluation of alternately combining HPV viral load and 16/18 genoty** in secondary screening algorithms. PLoS One 14(7):e0220200
Martinelli M, Giubbi C, Saderi L et al (2023) Evaluation of human papilloma virus (HPV) genoty** and viral load determination as diagnostic biomarkers of cervical cancer risk. Int J Mol Sci 24(2):1320
Martinez-Zapien D, Ruiz FX, Poirson J et al (2016) Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529:541–545
Mayrand MH, Duarte-Franco E, Rodrigues I et al (2007) Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 357:1579–1588
McGowan L, Young RH, Scully RE (1980) Peutz-Jeghers syndrome with “adenoma malignum” of the cervix. A report of two cases. Gynecol Oncol 10:125–133
Mills AM, Paquette C, Terzic T et al (2017) CK7 immunohistochemistry as a predictor of CIN1 progression: a retrospective study of patients from the quadrivalent HPV vaccine trials. Am J Surg Pathol 41:143–152
Mirabello L, Yeager M, Cullen M et al (2016) HPV16 sublineage associations with histology-specific cancer risk using HPV whole-genome sequences in 3200 women. J Natl Cancer Inst 108:djw100
Moody CA, Laimins LA (2010) Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10:550–560
Mount S, Harmon M, Eltabbakh G et al (2004) False positive diagnosis in conventional and liquid-based cervical specimens. Acta Cytol 48:363–371
Moyer VA, Force USPST (2012) Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 156(880–91):W312
Munger K, Werness BA, Dyson N et al (1989) Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 8:4099–4105
Munoz N, Bosch FX, de Sanjose S et al (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348:518–527
National Cancer Institute (1969–2014) Surveillance, epidemiology, and end results (SEER) program stat database: mortality – all COD, aggregated with state, total U.S. http://www.seer.cancer.gov
National Cancer Institute (2017) Surveillance, epidemiology, and end results (SEER) program SEER*Stat database: incidence – SEER 9 Regs research data. http://www.seer.cancer.gov. Accessed 11 Oct 2017
Nguyen CL, Munger K (2009) Human papillomavirus E7 protein deregulates mitosis via an association with nuclear mitotic apparatus protein 1. J Virol 83:1700–1707
Paquette C, Mills AM, Stoler MH (2016) Predictive value of cytokeratin 7 immunohistochemistry in cervical low-grade squamous intraepithelial lesion as a marker for risk of progression to a high-grade lesion. Am J Surg Pathol 40:236–243
Park KJ, Kiyokawa T, Soslow RA et al (2011) Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus. Am J Surg Pathol 35:633–646
Peto J, Gilham C, Fletcher O et al (2004) The cervical cancer epidemic that screening has prevented in the UK. Lancet 364:249–256
Pett M, Coleman N (2007) Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 212:356–367
Ramachandran B (2017) Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis. Endocr Relat Cancer 24:R99–R108
Rao A, Sandri MT, Sideri M et al (2013) Comparison of hybrid capture 2 high-risk HPV results in the low positive range with cobas(R) HPV test results from the ATHENA study. J Clin Virol 58:161–167
Sano T, Oyama T, Kashiwabara K et al (1998) Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 153:1741–1748
Saslow D, Solomon D, Lawson HW et al (2012) American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol 137:516–542
Schapiro F, Sparkowski J, Adduci A et al (2000) Golgi alkalinization by the papillomavirus E5 oncoprotein. J Cell Biol 148:305–315
Schiffman M, Rodriguez AC, Chen Z et al (2010) A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia. Cancer Res 70:3159–3169
Senkomago V, Duran D, Loharikar A et al (2017) CDC activities for improving implementation of human papillomavirus vaccination, cervical cancer screening, and surveillance worldwide. Emerg Infect Dis 23:S101–S107
Sherman ME, Lorincz AT, Scott DR et al (2003) Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst 95:46–52
Sherman ME, Dasgupta A, Schiffman M et al (2007) The Bethesda Interobserver Reproducibility Study (BIRST): a web-based assessment of the Bethesda 2001 system for classifying cervical cytology. Cancer 111:15–25
Siebers AG, Klinkhamer PJ, Grefte JM et al (2009) Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA 302:1757–1764
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30
Snijders PJ, Steenbergen RD, Heideman DA et al (2006) HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol 208:152–164
Spence AR, Goggin P, Franco EL (2007) Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med 45:93–106
Stoler MH, Schiffman M (2001) Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study G. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL triage study. JAMA 285:1500–1505
Stoler MH, Wright TC Jr, Sharma A et al (2011) High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol 135:468–475
Stolnicu S, Allison D, Praiss AM et al (2023) Incidence and clinic opathologic characteristics of human papillomavirus-independent invasive squamous cell carcinomas of the cervix: a morphologic, immunohistochemical, and human papilloma-virologic study of 670 cases. Am J Surg Pathol 47(12):1376–1389
Swid MA, Monaco SE (2022) Should screening for cervical cancer go to primary human papillomavirus testing and eliminate cytology? Mod Pathol 35(7):858–864
Thomas M, Banks L (1999) Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 80(Pt 6):1513–1517
Tomaic V, Pim D, Thomas M et al (2011) Regulation of the human papillomavirus type 18 E6/E6AP ubiquitin ligase complex by the HECT domain-containing protein EDD. J Virol 85:3120–3127
Tomaic V, Ganti K, Pim D et al (2013) Interaction of HPV E6 oncoproteins with specific proteasomal subunits. Virology 446:389–396
Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108
Troisi R, Hatch EE, Titus-Ernstoff L et al (2007) Cancer risk in women prenatally exposed to diethylstilbestrol. Int J Cancer 121:356–360
Vandermark ER, Deluca KA, Gardner CR et al (2012) Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization. Virology 425:53–60
Walboomers JM, Jacobs MV, Manos MM et al (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19
Wheeler CM, Hunt WC, Schiffman M et al (2006) Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer. J Infect Dis 194:1291–1299
Woodman CB, Collins SI, Young LS (2007) The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 7:11–22
Wright TC Jr, Massad LS, Dunton CJ et al (2007) 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis 11:223–239
Wright TC, Stoler MH, Behrens CM et al (2015) Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 136:189–197
** LF, Koutsky LA, Hildesheim A et al (2007) Risk for high-grade cervical intraepithelial neoplasia associated with variants of human papillomavirus types 16 and 18. Cancer Epidemiol Biomarkers Prev 16:4–10
Zielinski GD, Snijders PJ, Rozendaal L et al (2003) The presence of high-risk HPV combined with specific p53 and p16INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix. J Pathol 201:535–543
Zoodsma M, Sijmons RH, de Vries EG et al (2004) Familial cervical cancer: case reports, review and clinical implications. Hered Cancer Clin Pract 2:99–105
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Liu, Y., Zheng, W. (2024). Cervical Cancer Development, Screening, and Prevention. In: Zheng, W., Fadare, O., Quick, C.M. (eds) Gynecologic and Obstetric Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-19-7696-4_52-1
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