HPV (Human Papilloma Virüs) Aşısı ve Rahim Ağzı Kanseri

Dr. Burak Hacıhanefioğlu

polycysticovary.net internet sitesinde yer alan tıp içerikli yazı ve videoların tümü Kadın Hastalıkları ve Doğum Uzmanı Dr. Burak Hacıhanefioğlu tarafından hazırlanmış olup, telif hakları yasal koruma altına alınmıştır. İzinsiz kaynak gösterilerek dahi başka bir yerde yayınlanamaz.

Human Papilloma Virüsü (HPV) rahim ağzı kanserine (cervical cancer) neden olmaktadır(97,129). Son yıllarda HPV’ ye karşı korunmak amacıyla bazı aşılar üretilmiştir(92,95,124). HPV aşıları bazı ülkelerde yaygın olarak önerilmekte olmasına rağmen rahim ağzı kanserinin önlenmesi amacıyla kullanılabilecek tek yöntem aşı değildir(45,104). HPV aşısı yapılan bir kadının rahim ağzı kanseri olma ihtimali, belirli aralıklarla rahim ağzından akıntı örneği alınarak yapılan HPV DNA testi ve pap smear testi ile takip edilen bir kadından daha az değildir(21,31,32,45,83,92,93,95,100,101,104,108,115,121). Kongo gibi afrika ülkelerinde (Sub-Saharan Africa) ve Fuji gibi pasifik okyanusundaki adalarda rahim ağzı kanseri dünya ortalamasından çok daha fazla görülmektedir(28,29,109,129). Bu ülkelerde yaşayan kadınlara doktora ulaşma, HPV DNA testi ve pap smear testi yaptırma şansları oldukça düşük olduğu için toplu olarak (mass vaccination) HPV aşısı yapılması doğru olabilir(108,109,129). Fakat, kadınların doktora ulaşma, HPV DNA testi ve pap smear testi yaptırma şanslarının yüksek olduğu ülkelerde HPV aşısının kişinin tercihine ve isteğine bağlı olarak (voluntary vaccination) yapılması daha doğru bir yöntemdir(104,109). Rahim ağzı kanserini engellediği kesinleşmemiş olmasına rağmen, aşı olmayan kişinin rahim ağzı kanseri olacağı ve de aşı olmak istemeyen bir kişinin aşıdan başka çaresi yokmuş gibi gösterilmesi doğru değildir. HPV aşısı üreten ilaç firmalarının maddi desteğiyle yapılan bazı çalışmalarda HPV DNA testi ve pap smear testinin başarısı düşük bulunmakta ve hatta bu testlerin yapılmasına gerek olmadığı bile söylenmektedir(101,110). Halbuki, aşı olmayan bir kişinin, aşının tahmin edilen koruyuculuğundan daha fazla etkili olduğu yıllar önce gösterilmiş yöntemlerle (HPV DNA testi ve pap smear testi) korunması mümkündür.(21,31,32,55,77,80,81,83,85,87,88,90,93,94,95,97,100,101,104,110,115,120,121).

HPV’ nin 200′ den fazla çeşidi (genotypes) vardır(105). HPV nin genetik yapısında oluşan değişiklikler (mutasyonlar) her geçen gün yeni çeşitlerin ortaya çıkmasına neden olmaktadır(105,123,125). Bunlardan şimdilik yaklaşık 20 tanesinin rahim ağzı kanserine neden olduğu bilinmektedir(97,105). HPV aşısı ise rahim ağzı kanserine neden olan bu 20 HPV çeşidinden sadece bir kısmına etki etmektedir(11,15,97). HPV’ ye bağlı rahim ağzı kanserinin ortaya çıkması 25 ile 40 yıl kadar uzun bir süreyi bulabilmektedir(131). HPV aşısı kullanılmaya başlandığından beri yaklaşık 10-12 yıl bu kadar bir süre geçmiştir. Bu nedenle aşının rahim ağzı kanserine karşı koruyuculuğu da henüz bilinmemektedir.

HPV aşısı rahim ağzı kanseri yapan HPV çeşitlerinin sadece bir kısmına karşı etkilidir(97). HPV aşısı HPV’ nin rahim ağzı hücrelerine yapışma (capsid) yerinde bulunan protein (L1) için antikor oluşturmaktadır(122). Rahim ağzı kanseri yapan HPV çeşitlerinde (genotypes)  oluşan genetik mutasyonlar (L1 protein variants) aşının etkinliğini azaltmaktadır(123,125,126,127). HPV aşısı yapıldıktan sonra aşının koruyuculuğu (seropositivity) takip eden yıllarda giderek azalmaktadır(111,113,117,118,119). HPV enfeksiyonu (positive) olan bir kişiye HPV aşısı yapıldığı zaman aşının rahim ağzı kanserini önleyici bir etkisi yoktur(106,107). Bu nedenlerle HPV aşısı yaptıran kişinin de yaptırmayanlar gibi aşı yapıldıktan sonra HPV DNA testi ve pap smear testi ile aynı şekilde takip edilmesi gerekmektedir(100,112,114,116,118). Rahim ağzı kanseri olan kadınların büyük çoğunluğunda HPV çeşitlerinden biri veya bir kaçı saptanmasına rağmen, bir kısmında ise HPV tespit edilememektedir(128,129,130). Demek ki aşının tahmin edilen koruyuculuğunun kapsamadığı rahim ağzı kanserleri de görülmektedir(128,129,130). Bu nedenle HPV aşısı yaptırdıktan sonra aşının koruyuculuğuna güvenerek takibi bırakıp, pap smear testi ve HPV testi yaptırmayı ihmal eden kişilerde tam tersine rahim ağzı kanseri riski artabilir. Pap smear testi ve HPV DNA testi için muayene sırasında rahim ağzından, rahim ağzı kanserinin en çok görüldüğü bölgeden (transformation zone) çubuk şeklinde, ince bir fırça yardımıyla akıntı örneği alınır(65,70,71). Bu akıntı örneğinde görülen hücrelerde HPV DNA’ sının varlığını tespit etmek için HPV DNA PCR testi yapılır, pap smear testinde de akıntı örneğindeki rahim ağzı hücreleri mikroskop ile incelenerek HPV enfeksiynunun neden olduğu değişiklikler görülür(41,51,54,57,58,59,65,70,71,75,77,86,91).

HPV aşısının kalıcı hasar bırakan ve ölümle sonuçlanan yan etkileri vardır(7,73,78,89). HPV aşısında bulunan bazı maddeler (antijen) beyinde bulunan sinir hücrelerini taklit etmektedir (crosreactivity)(4,8,89). HPV aşısının bağışıklık (immün) sistemini uyarması sonucunda HPV aşısına karşı oluşan antikorlar görme sinirine (neuromyelitis optica) ve beyin hücrelerine (acute disseminated encephalomyelitis) zarar verebilmektedir(3,4,5,6,7,8,9,10,62,73,89). HPV aşısı ailesel (genetik) eğilimi olan kadınlarda multiple sclerosis (MS) gibi bağışıklık sistemi (otoimmün) hastalıklarının ortaya çıkmasına neden olmaktadır(96). Japonya ve bazı Avrupa ülkelerinde yan etkileri nedeniyle HPV aşısı yasaklanmıştır(1,2,44,46,48,66,74).

HPV enfeksiyonu genellikle akıntı, kanama ve ağrı gibi şikayetler yapmamaktadır. Gözle görülemeyen, ancak mikroskop ile görülebilen hücre içinde bazı değişikliklere (Squamous Intraepithelial Lesion) (SIL) neden olmaktadır(35,36,41,43,49,51,54). Bu hücresel değişiklikler ancak pap smear testi ile görülebilmektedir. HPV DNA testinde HPV enfeksiyonu tespit edilenlerin (pozitif) bir kısmında ise erken teşhis nedeniyle pap smear testinde henüz hücreye zarar verecek kadar süre geçmediği için hücresel değişiklik (SIL) görülmemektedir(12,13,14,15,16,17,18,19,20,22,24,34,40,82,102,132). HPV DNA testi ve Pap smear testi birlikte yapıldığında bir kişide HPV enfeksiyonu olduğu halde bu testlerin yanlışlıkla yok deme ihtimali de, bir kişide HPV enfeksiyonu olmadığı halde yanlışlıkla var deme ihtimali de oldukça düşüktür(53,55,57,59,63,80,81,86,90,93,99,101,103,104).

Rahim ağzında görülen HPV enfeksiyonlarının büyük çoğunluğu (%90) normal bağışıklığa sahip olan kişilerde yaklaşık 1 yıl içinde, daha küçük bir kısmında da 2 yıl içinde kendiliğinden vücuttan temizlenmektedir (clearance)(23,24,25,26,27,30,33,37,39,42,43,47,56,60,64,69,76,79,84,98). Rahim ağzında yaptıkları hücresel değişikliklerin (SIL) büyük bir kısmı da (%90) 2 yıla kadar iyileşmektedir(23,24,25,26,27,30,36,38,50,52,56,60,61,67,68,69). Vücuttan temizlenmeyenlerin (persistence) büyük çoğunluğunu rahim ağzı kanserine neden olan HPV çeşitleri oluşturmaktadır(25,27,37,38,84). Rahim ağzında ortaya çıkan ileri derecede hücresel değişikliklere (Cervical Intraepithelial Neoplasia) (CIN+2) genellikle 3 yıl içinde vücuttan temizlenmeyen HPV çeşitleri neden olmaktadir(36,37,38,39,50,52,69,72,75,76,79,98). Rahim ağzı kanserlerinin büyük bir kısmına 2 yıl içinde vücuttan temizlenmeyen HPV-16 ve HPV-18 çeşitleri neden olmaktadır(27,30,60,98). Demek ki burada doğru olan 100 kişiden 90’ına kendiliğinden iyileşeceğini bile bile gereksiz yere ciddi yan etkileri olabilen bir aşının yapılması değil, rahim ağzı kanseri riski taşıyan kişinin tespit edilerek onun HPV DNA testi ve pap smear testi ile takibinin ve tedavisinin yapılmasıdır(75,80,81,83,93,97,99). Rahim ağzı kanseri ve ona bağlı gelişen ölümler çoğunlukla Pap smear testi ve HPV DNA testi yaptırmayanlarda görülmektedir(77,83,87,94,121).

∗Cinsel olarak aktif hayata başladıktan sonra belirli aralıklarla yaptırılan HPV DNA testi ve Pap smear testi ile HPV’nin neden olduğu ileride rahim ağzı kanserine dönüşebilecek hücresel değişiklikler erken dönemde kişi rahim ağzı kanseri olmadan teşhiş ve tedavi edilebilmektedir.

∗Belirli aralıklarla HPV DNA testi ve Pap smear testi yaptıran bir kişinin rahim ağzı kanseri olma ihtimali, rahim ağzı kanseri aşısı yaptıran bir kişiden daha düşüktür.

∗Herhangi bir yan etkisi olmayan HPV DNA testi ve Pap smear testi ile takibi yapılan bir kişinin kalıcı hasar ve ölüme neden olabilen yan etkilere sahip hpv aşısını yaptırmasına gerek yoktur.

Kaynaklar

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84-Type-specific persistence of high-risk human papillomavirus infections in the New Independent States of the former Soviet Union Cohort Study. Kulmala SM, Shabalova IP, Petrovitchev N, Syrjänen KJ, Gyllensten UB, Johansson BC, Syrjänen SM; New Independent States of the former Soviet Union Cohort Study Group. Cancer Epidemiol Biomarkers Prev. 2007 Jan;16(1):17-22.

85-Distribution of 37 mucosotropic HPV types in women with cytologically normal cervical smears: the age-related patterns for high-risk and low-risk types. Jacobs MV, Walboomers JM, Snijders PJ, Voorhorst FJ, Verheijen RH, Fransen-Daalmeijer N, Meijer CJ. Int J Cancer. 2000 Jul 15;87(2):221-7.

86-HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer. Ogilvie GS, Krajden M, van Niekerk D, Smith LW, Cook D, Ceballos K, Lee M, Gentile L, Gondara L, Elwood-Martin R, Peacock S, Stuart G, Franco EL, Coldman AJ. Int J Cancer. 2017 Jan 15;140(2):440-448.

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90-Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up. Castle PE, Glass AG, Rush BB, Scott DR, Wentzensen N, Gage JC, Buckland J, Rydzak G, Lorincz AT, Wacholder S. J Clin Oncol. 2012 Sep 1;30(25):3044-50.

91-Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population. Cuschieri KS, Cubie HA, Whitley MW, Seagar AL, Arends MJ, Moore C, Gilkisson G, McGoogan E. J Clin Pathol. 2004 Jan;57(1):68-72. 

92-Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, Unger ER. J Infect Dis. 2013 Aug 1;208(3):385-93.

93-Five-year risks of CIN 3+ and cervical cancer among women with HPV-positive and HPV-negative high-grade Pap results. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK. J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S50-5.

94-Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. Andrae B, Kemetli L, Sparén P, Silfverdal L, Strander B, Ryd W, Dillner J, Törnberg S. J Natl Cancer Inst. 2008 May 7;100(9):622-9. 

95-US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, Steinau M, Watson M, Wilkinson EJ, Hopenhayn C, Copeland G, Cozen W, Peters ES, Huang Y, Saber MS, Altekruse S, Goodman MT; HPV Typing of Cancers Workgroup. J Natl Cancer Inst. 2015 Apr 29;107(6):djv086.

96-Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. Langer-Gould A, Qian L, Tartof SY, Brara SM, Jacobsen SJ, Beaber BE, Sy LS, Chao C, Hechter R, Tseng HF. JAMA Neurol. 2014 Dec;71(12):1506-13. 

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98-Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, Rozendaal L, Remmink AJ, Risse EK, van der Linden HC, Voorhorst FJ, Kenemans P, Meijer CJ. Lancet. 1999 Jul 3;354(9172):20-5.

99-Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, Yates M, Rollason TP, Young LS. Lancet. 2001 Jun 9;357(9271):1831-6.

100-Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, Kitchener H, Castellsague X, Teixeira JC, Skinner SR, Hedrick J, Jaisamrarn U, Limson G, Garland S, Szarewski A, Romanowski B, Aoki FY, Schwarz TF, Poppe WA, Bosch FX, Jenkins D, Hardt K, Zahaf T, Descamps D, Struyf F, Lehtinen M, Dubin G; HPV PATRICIA Study Group. Lancet. 2009 Jul 25;374(9686):301-14. 

101-Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; International HPV screening working group. Lancet. 2014 Feb 8;383(9916):524-32.

102-Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. de Sanjosé S, Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, Bosch FX. Lancet Infect Dis. 2007 Jul;7(7):453-9. 

103-Discrepant HPV/cytology cotesting results: Are there differences between cytology-negative versus HPV-negative cervical intraepithelial neoplasia? Tracht JM, Davis AD, Fasciano DN, Eltoum IA. Cancer Cytopathol. 2017 Oct;125(10):795-805. 

104-Cervical cancer risk for women undergoing concurrenttesting for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, Demuth F, Schiffman M, Wacholder S, Castle PE. Lancet Oncol. 2011 Jul;12(7):663-72.

105-International standardization and classification of human papillomavirus types. Bzhalava D, Eklund C, Dillner J. Virology. 2015 Feb;476:341-344.

106-Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR; Costa Rican HPV Vaccine Trial Group. JAMA. 2007 Aug 15;298(7):743-53.

107-Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection. Haupt RM, Wheeler CM, Brown DR, Garland SM, Ferris DG, Paavonen JA, Lehtinen MO, Steben M, Joura EA, Giacoletti KE, Radley DR, James MK, Saah AJ, Sings HL; FUTURE I and II Investigators. Int J Cancer. 2011 Dec 1;129(11):2632-42. 

108-HPV Screening and Vaccination Strategies in an Unscreened Population: A Mathematical Modeling Study. Milwid RM, Frascoli F, Steben M, Heffernan JM. Bull Math Biol. 2019 Nov;81(11):4313-4342.

109-Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Bray F, et al. CA Cancer J Clin. 2018.

110-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. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, Garcia FA, Moriarty AT, Waxman AG, Wilbur DC, Wentzensen N, Downs LS Jr, Spitzer M, Moscicki AB, Franco EL, Stoler MH, Schiffman M, Castle PE, Myers ER; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.

111-Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15-55 years of age. Schwarz TF, Galaj A, Spaczynski M, Wysocki J, Kaufmann AM, Poncelet S, Suryakiran PV, Folschweiller N, Thomas F, Lin L, Struyf F. Cancer Med. 2017 Nov;6(11):2723-2731. 

112-Adapting cervical cancer screening for women vaccinated against human papillomavirus infections: The value of stratifying guidelines. Pedersen K, Burger EA, Nygård M, Kristiansen IS, Kim JJ.Eur J Cancer. 2018 Mar;91:68-75.

113-A ten-year study of immunogenicity and safety of the AS04-HPV-16/18 vaccine in adolescent girls aged 10-14 years. Schwarz TF, Huang LM, Valencia A, Panzer F, Chiu CH, Decreux A, Poncelet S, Karkada N, Folschweiller N, Lin L, Dubin G, Struyf F. Hum Vaccin Immunother. 2019;15(7-8):1970-1979.

114-Optimal Cervical Cancer Screening in Women Vaccinated Against Human Papillomavirus. Kim JJ, Burger EA, Sy S, Campos NG. J Natl Cancer Inst. 2016 Oct 18;109(2):djw216.

115-Effectiveness of cervical cancer screening over cervical cancer mortality among Japanese women. Aklimunnessa K, Mori M, Khan MM, Sakauchi F, Kubo T, Fujino Y, Suzuki S, Tokudome S, Tamakoshi A; JACC Study Group, Motohashi Y, Tsuji I, Nakamura Y, Iso H, Mikami H, Inaba Y, Hoshiyama Y, Suzuki H, Shimizu H, Toyoshima H, Wakai K, Ito Y, Hashimoto S, Kikuchi S, Koizumi A, Kawamura T, Watanabe Y, Miki T, Date C, Sakata K, Nose T, Hayakawa N, Yoshimura T, Shibata A, Okamoto N, Shino H, Ohno Y, Kitagawa T, Kuroki T, Tajima K. Jpn J Clin Oncol. 2006 Aug;36(8):511-8.

116-Cervical Cancer Screening Programs in Europe: The Transition Towards HPV Vaccination and Population-Based HPV Testing. Chrysostomou AC, Stylianou DC, Constantinidou A, Kostrikis LG. Viruses. 2018 Dec 19;10(12):729.

117-Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5 years of follow-up. Huang T, Liu Y, Li Y, Liao Y, Shou Q, Zheng M, Liao X, Li R. Vaccine. 2018 Mar 7;36(11):1368-1374. 

118-Detection of High-Risk Human Papillomavirus in Cervix Sample in an 11.3-year Follow-Up after Vaccination against HPV 16/18. Teixeira CSC, Teixeira JC, Oliveira ERZM, Machado HC, Zeferino LC. Rev Bras Ginecol Obstet. 2017 Aug;39(8):408-414. 

119-Long-term immunogenicity, effectiveness, and safety of nine-valent human papillomavirus vaccine in girls and boys 9 to 15 years of age: Interim analysis after 8 years of follow-up. Olsson SE, Restrepo JA, Reina JC, Pitisuttithum P, Ulied A, Varman M, Van Damme P, Moreira ED Jr, Ferris D, Block S, Bautista O, Gallagher N, McCauley J, Luxembourg A. Papillomavirus Res. 2020 Jul 11;10:100203.

120-Impact of scaled up human papillomavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, 2020-99: a modelling study. Simms KT, Steinberg J, Caruana M, Smith MA, Lew JB, Soerjomataram I, Castle PE, Bray F, Canfell K. Lancet Oncol. 2019 Mar;20(3):394-407.

121-Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, Bray F. Lancet Glob Health. 2020 Feb;8(2):e191-e203.

122-Crystal structures of four types of human papillomavirus L1 capsid proteins: understanding the specificity of neutralizing monoclonal antibodies. Bishop B, Dasgupta J, Klein M, Garcea RL, Christensen ND, Zhao R, Chen XS. J Biol Chem. 2007 Oct 26;282(43):31803-11. 

123-Naturally occurring capsid protein variants L1 of human papillomavirus genotype 16 in Morocco. El-Aliani A, Alaoui MAE, Chaoui I, Ennaji MM, Attaleb M, Mzibri ME. Bioinformation. 2017 Aug 31;13(8):241-248.

124-Currently approved prophylactic HPV vaccines. Harper DM. Expert Rev Vaccines. 2009 Dec;8(12):1663-79. 

125-Abundance of HPV L1 Intra-Genotype Variants With Capsid Epitopic Modifications Found Within Low- and High-Grade Pap Smears With Potential Implications for Vaccinology. Shen-Gunther J, Cai H, Zhang H, Wang Y. Front Genet. 2019 May 24;10:489. 

126-Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections. van der Weele P, Meijer CJLM, King AJ. J Virol. 2017 Sep 12;91(19):e00844-17.

127-Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome. Hirose Y, Onuki M, Tenjimbayashi Y, Mori S, Ishii Y, Takeuchi T, Tasaka N, Satoh T, Morisada T, Iwata T, Miyamoto S, Matsumoto K, Sekizawa A, Kukimoto I. J Virol. 2018 May 29;92(12):e00017-18. 

128-Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. Bosch FX, Manos MM, Muñoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV. J Natl Cancer Inst. 1995 Jun 7;87(11):796-802.

129-Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz N. J Pathol. 1999 Sep;189(1):12-9. 

130-HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis. Rodríguez-Carunchio L, Soveral I, Steenbergen RD, Torné A, Martinez S, Fusté P, Pahisa J, Marimon L, Ordi J, del Pino M.BJOG. 2015 Jan;122(1):119-27.

131-Reframing cervical cancer prevention. Expanding the field towards prevention of human papillomavirus infections and related diseases. Bosch FX, Tsu V, Vorsters A, Van Damme P, Kane MA. Vaccine. 2012 Nov 20;30 Suppl 5:F1-11. 

132-Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce E, Matos E, Molano M, Qiao YL, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Meijer CJ, Muñoz N. Int J Cancer. 2006 Dec 1;119(11):2677-84.

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