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Review ISSN 1975-7425(Print) / ISSN: 2288-016X(Online) http://dx.doi.org/10.14777/kjutii.2014.9.2.79 Korean J Urogenit Tract Infect Inflamm 2014;9(2):79-85 남성인유두종바이러스감염의치료 한준현 한림대학교동탄성심병원비뇨기과 Recommended Managements for the Male Human Papillomavirus Infection Jun Hyun Han Department of Urology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea Genital human papillomavirus (HPV) is a common, usually transient, dermatologic infection transmitted by genital contact which can cause a variety of anogenital diseases, including warts (condyloma), dysplasia (cervical, vaginal, vulvar, anal), and squamous cell carcinoma. A number of treatment modalities are available for treatment of anogenital warts, both patient- and provider-applied. Genital warts are benign and resolve spontaneously in some patients, and removal of lesions does not guarantee elimination of all organisms or confer protection from recurrence. Treatment consists of diverse drug application locally and surgical therapy. Urethral warts are an uncommon presentation of HPV and could be treated by endoscopic surgery accompanied by intraurethral instillation of medications. Bivalent and quadrivalent vaccines are approved for prevention of HPV infection. Both are indicated for prevention of cervical cancer, while the quadrivalent vaccine is also approved for prevention of vaginal/vulvar cancers as well as genital warts in males and females. Keywords: Condyloma acuminate; Uterine cervical neoplasms; Papillomavirus infections Copyright 2014, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 28 February, 2014 Revised: 19 March, 2014 Accepted: 21 March, 2014 Correspondence to: Jun Hyun Han Department of Urology, Hallym University Dongtan Sacred Heart Hospital, 7, Keunjaebong-gil, Hwaseong 445-907, Korea Tel: +82-31-8086-2730, Fax: +82-31-8086-2728 E-mail: junuro@naver.com 서론 생식기인유두종바이러스 (human papilloma virus, HPV) 는 DNA 바이러스로, 주로인간을포함한동물의피부와점막에감염을유발하는바이러스로현재약 130여형 (type) 의 HPV가알려져있다. 1 이중약 40여개는성적접촉을통하여항문과생식기부위에감염을유발하는데, 일부는생식기사마귀등의양성종양을일으키고, 15-20 종류의고위험 HPV에감염된경우, 일부에서는지속적인감염 (persistent infection) 을유발하여자궁경부암을비롯한일부암의발생원인이되는것으로알려졌다. 2 세계보건기구 (World Health Organization) 에따르면생식기 HPV의전세계유병율은 9-13% 로추정되고있다. 3 생식기 HPV는주로성적접촉을통해서전파되며, 가장흔한성전파성감염 (sexually transmitted infection, STI) 이다. 일생동안 HPV 를접촉할확률은최소한 50% 이상이며, 첫성적접촉이후 2-10년안에감염될가능성이많다. 4 HPV 감염은미혼인경우, 성적으로활발한경우, 성교파트너수가많은경우, 79

80 Jun Hyun Han. Managements for the Male HPV Infection 교육수준이낮거나, 사회경제적수준낮은경우에감염률이높은것으로알려져있다. 5 자궁경부암과그전암병변인자궁경부상피내이형성증은 HPV 감염이주요원인이다. 주로성적접촉에의해전파되며 14세에서 60세여성의 HPV 유병률은약 25-30% 에이른다. 5 HPV 유병률은지역마다차이가있고같은국가내에서도농촌과도시간에도차이가있다. 6,7 성적으로활발한여성의일생동안 HPV의누적감염빈도는 80-90% 에이르지만, 대부분의 HPV 감염은무증상으로 80% 의경우는약 2년이내에자연소멸된다. 8 그러나면역기능이저하된여성이나나이든여성에서는상대적으로지속감염으로존재하기쉽다. 현재 100 종류이상의 HPV 아형이발견되었고, 암을유발하는능력의차이에따라서고위험군과저위험군으로분류한다. 9 생식기감염을일으키는약 40여종의 HPV 아형중저위험군인 HPV 6, HPV 11은생식기사마귀 (condyloma) 를일으키며, 유병률은낮지만, 분만중바이러스의수직전파로발생한다고알려진재발성호흡기유두종 (recurrent respiratory papillomatosis) 의원인으로알려져있다. 10 고위험군아형인 HPV 16, HPV 18 및이들과유사한 HPV 31, 33, 35, 52, 58, 39, 45, 59, 56, 66, 51 등은자궁경부암과밀접한관계가있다. 9,11 특히, HPV 16, 18형은지역에따라약간씩다르지만, 전세계적으로자궁경부암의원인중 70% 를차지한다. 11 HPV 감염이자궁경부암을유발시키는기전은 HPV의 E6 단백과 E7 단백의역할에관하여많은기전들이연구되고있다. 대표적인기전으로는 E6 단백은 p53 기능을억제하여세포분열주기조정기능을교란시킴으로써종양이유발하는것이알려져있으며 E7 단백의경우는 prb 의기능을억제하여세포의 DNA 생성을촉진하고세포분열주기조절기능을교란시키는것으로알려져있다. 12,13 HPV 감염은흔한감염으로서성활동을시작한이후 3-4 년이내그누적감염률이약 50% 에달하는것으로보고하고있다. 14 HPV가자궁경부를감염시키는경우그감염의자연경과는 HPV형에따라차이가있으나 2-3 년이내에약 90% 에서감염이소실 (clear) 되며저위험 HPV 는고위험 HPV에비해빨리소실되는양상을보여주고있다. 15,16 HPV 감염의소실에는세포면역기전이중요한역할을하는것으로알려졌다. HPV 감염의일부에서감염이소실되지못하고지속되면자궁경부의세포변화를동반하게된다. 자궁경부상피내종양 (cervical intraepithelial neoplasia, CIN) 은 CIN1 의저등급병변및 CIN2, CIN3 의고등급병변으로구분된다. CIN1의경우약 57% 에서소실되며, 32% 지속, 11% 에서진행되나침윤성자궁경부암으로진행되는확률은 1% 정도로보고하고있다. 반면에 CIN2의경우약 43% 에서소실되며, 35% 지속 22% 에서 CIN3 로진행되고, 약 5% 에서침윤성자궁경부암으로진행되며, CIN3의경우약 32% 에서소실되며 56% 지속 12% 에서침윤성자궁경부암으로진행되고있어 CIN2 이상의병변이전암병변으로판단된다. 17-21 HPV 감염이자궁경부암으로발전되는과정에관여하는요인들은연령, 흡연, 배우자수, HPV형, 복합 HPV 감염, human leukocyte antigen, 영양, 클라미디어감염등의위험요인들에관한보고들이있으나이와같은위험요인들에역할에관해서아직일치되는연구결과들을보여주지못하고있다. 18 자궁경부암이외에도 HPV 감염으로유발되는암의종류를보면항문암, 남성성기암, 질암, 외음부암, 인두암, 구강암등이알려져있으며, 자궁경부암의경우그귀속위험도가 100% 로, 전부가 HPV에의해서유발되는암으로판단되며, 항문암의경우그귀속위험도가 90%, 남성성기암, 여성의질및외음부암의경우 40%, 인두암 12%, 구강암 3% 의귀속위험도를보고하고있다. 22 본 론 1. 역학 HPV는가장흔한성매개감염중의하나로, 성인인구의 70% 는일생동안적어도한번의생식기 HPV 감염을경험한다고한다. 23 HPV 에의한첨규콘딜롬의잠복기는 1-8 개월정도이고, HPV 감염은 10대후반의어린연령층에서도일어나는데, 24 HPV 감염의 80% 이상은 18개월이내에자연치유되는것으로알려져있다. 25 국내성인여성에서 HPV 감염률은약 12-17% 이며, 다른연령층에비해 30대미만의젊은여성층에서가장감염률이높은것으로보고되었다. 26,27 가장최근보고에의하면국내여성의 HPV 감염률은 34.2% 이고, 감염자중 87.7% 는한종류에, 12.3% 는여러종류의 HPV 에감염된것으로나타났다. 28 부산의대학생들을대상으로한 2007년의보고에서대상남녀학생의각각 44% 와 74% 에서성경험이없다고응답하였는데, 성경험이있는여학생의 25% 와성경험이없는 13% 의여학생에서 HPV 양성반응이나와성경험이있는여학생의 HPV 감염률이더높음을보여주었지만, 남학생에서는성경험이있는경우와없는경우각각 13% 와 11% 로차이가없었다. 29 국내성매매여성을대상으로조사한결과, 전체적인감염률이 47% 로나타났고, 이들중고위험군 HPV는 87% 에서나타났다. 30 2. 진단전형적인외부생식기사마귀인첨규콘딜롬 (condylomata acuminate) 은항문생식기의피부혹은점액질막에서구진성으로성장하며, 주로꽃양배추 (cauliflower) 모양으로나타난다. 하지만편평한모양이거나, 돔형태 (dome-shape) 를보이기도한다. 색깔은비각질화콘딜롬인경우핑크혹은붉은색을과각질화콘딜롬의경우는회백색에서흑갈색등으로착색이되는경향이있다. 콘딜롬은비착색성경향을가지나대음

Jun Hyun Han. Managements for the Male HPV Infection 81 순이나음경몸통, 치골부위, 사타구니, 회음부및항문등착색피부에서는짙은색을띠는경우가흔하다. 포경수술을하지않은남성에서는음경포피의안쪽면에서흔하고, 포경한남성에서는음경몸통에흔하다. 31 또한음낭, 사타구니, 회음부와항문주위에서도발생할수있다. 여성에서첨규콘딜롬의가장흔한위치는자궁경부, 질, 외음부혹은항문이다. 단독으로나타날수도있으나대개는다발성으로나타나며면역억제환자나당뇨환자에서는큰판상으로합쳐지기도한다. 첨규콘딜롬의요도구발생률은남성 20-25%, 여성 4-8% 이고, 항문에발생하는첨규콘딜롬의경우, 치상선 (dentate line) 근위부에서는거의발견되지않으며, 항문성교시에흔하게발생하지만, 항문성교가없더라도발생할수있다. 32 전형적인양상을보이는성기사마귀에대하여조직검사를시행할필요는없지만, 표준치료에반응하지않거나오히려악화되는경우, 환자가면역저하되어있는경우, 병변에색소침착이있거나주변조직에유착되어단단히고정된경우, 출혈, 경결, 궤양성변화를보일때에는조직검사를필요로한다. 33,34 첨규콘딜롬은양성질환이지만장기간방치될경우공격적으로성장하여거대한크기로자랄수있으며이를 giant condyloma (Buschke-Lowenstein tumor) 라고부른다. 이경우심한위생문제뿐아니라양성콘딜롬이비정형상피세포혹은편평세포암병소와섞여서나타날수도있는등악성병변의혼재를염두에두어야한다. 따라서광범위한외과적절제술을시행하게되는데술후피부이식이필요한경우가많다. 35,36 첨규콘딜롬과감별해야할다른질환으로는매독병변인 condyloma latum, 흔한국소색소침착피부병변인지루성각화증 (seborrheic keratosis), 전염성연속종 (molluscum contagiosum), 진피내모반 (intradermal nevus), 남성성기의 corona에정상적으로나타나며치료가필요없는 angiofibroma 인 pearly penile papule 이있다. Bowen 씨병은표피에국한된편평세포암으로첨규콘딜롬과감별해야하며, HPV 와도연관성이있는것으로알려져있다. 37-39 Bowenoid papulosis 또한종종성기사마귀양상으로나타나기도하나조직검사에서국한된편평세포암으로확인되며여성에서는외음부상피내암 (vulvar intraepithelial neoplasia) 으로나타나기도한다. 40-44 Bowenoid papulosis 에서도저위험및고위험아형의 HPV가검출되었다. 43 외음부상피내암환자의삼분의일정도는자궁상피내암 (CIN), 혹은질상피내암 (vaginal intra-epithelial neoplasia) 과연관이있다. 45 따라서항문생식기사마귀를가진모든여성들에대해서는질경검사로질혹은자궁사마귀가같이있는지확인하여야한다. 3. 치료성기사마귀치료의일차목표는육안으로확인된사마귀의완전한제거이다. 치료되지않은사마귀는이후에자연치유되거나, 크기의변화없이유지되거나, 수및크기가증가될수있다. 현재까지성기사마귀의치료로 HPV의전염력을감소시키기는하나완전히소멸시키지는못한다. 성기사마귀의치료에는불확실한부분이많은데, 주로바이러스를완전히제거할수없다는것과설령완전히제거할수있다하더라도바이러스제거가재발방지를보장할수없다는것이다. 46 어찌되었던간에성기사마귀치료의현실적, 구체적인목표는가시적인모든병변을제거하는데있다. 현재사용되는구체적인치료법을살펴보면환자가직접몸에바르게되는자가치료법으로는 imiquimod 5% 크림이나 podophyllotoxin 0.5% 용액또는겔이있다. 치료접근성은좋지만치료의순응도와환자가신체적조건상시술가능한지가선행조건이다. 치료자에의해행해지는외래치료법에는 bi- 혹은 tri-chloroacetic acid (BCA or TCA) 80-90%, podophyllin 10-25% 등의약물요법이있다. 수술적요법으로는액화질소등의매질을이용한냉동프로브를사용하여병변을냉동시키는냉동치료법과그외전기소작술, 레이저를사용한절제술, 외과적절제술등을사용할수있다. 47-49 1) 환자자가치료법 (1) Imiquimod/imidazoquinolinamine (Aldara cream; inova Pharmaceuticals, Thornleigh, NSW, Australia) Imiquimod는면역조정제로직접적인항바이러스작용은없으나, 대식세포에서의 cytokine (interferon-alpha, tumor necrosis factor, interleukin-2) 분비를유도한다. 50 Imiquimod 는 5% cream 형태가가장효과적으로알려져있으며치료율은 30-84% 로알려져있고남자보다여자에서더좋은반응을나타낸다. 51,52 재발률은 15% 정도로보고된다. 53 Imiquimod는외부에보이는성기사마귀에만적용하여야하며질점막이나자궁경부에직접적으로사용해서는안된다. 또한라텍스재질의콘돔을약화시킬수있으며, 성기피부에바른후직접적인성교는피해야한다. 투여방법은주 3회취침시자가도포하고아침에비누와물로씻어내며 16주까지반복한다. 임신시안전성은확립되지않았으므로치료중피임이권유된다. (2) Podophyllotoxin/podofilox (Condylox Gel; CDPT Lab, San Antonio, TX, USA) Podofilox는세포분열을차단하여세포괴사를유도하는분열저지성 (antimitotic) 약제이다. 1주일에 3일은 12시간마다사마귀에도포하고이어진 4일은휴식한다. 하루총량이 0.5 ml를넘지않도록하여 4-6주동안반복한다. 치료율은 45-80% 이며재발률은 5-30% 이다. 52 자궁경부, 요도구, 질점막, 항문부위의치료에사용하면안되며, 임산부에도사용금

82 Jun Hyun Han. Managements for the Male HPV Infection 기이다. (3) Sinecatechins (Polyphenon E Veregen 15% ointment) 녹차추출물로세포성장을억제하고염증관련효소를억제한다. 하루 3회도포하여 16주혹은사마귀가없어질때까지사용한다. 남자보다여자에서더효과적인것으로알려져있으며치료율은약 50% 정도이다. 52 2) 시술자치료법 (1) BCA/TCA TCA는피부와점막을부식시켜서성기사마귀를치료하는약제이다. 피부를통해흡수되지않는장점이있으며 80-90% 농도를사용한다. 치료율은 50-80%, 재발률은 35% 로보고된다. 1-3 주마다 frosting 현상이나타날때까지국소도포를해주며과량도포시에는물이나비누로씻어주면된다. 질점막, 자궁경부, 요도점막에는사용해서는안되며, 빠르게중화시킬수있고, 전신독성이없어임산부에도안전하게사용할수있다. 52 (2) Podophyllin Podophyllin은 podofilox와같이국소조직괴사를유도하여성기사마귀를치료하는분열저지성약제로서가장오래된성기사마귀치료제중하나이다. 다양한부작용때문에 podophyllin은치료제로선택되지않는추세이다. 치료율은 30-80% 재발률은 20-65% 정도이며치료중피임이필수적이다. 3) 수술적치료 (1) 외과적절제 (surgical excision), 전기소작 (electrosurgery) 치료율은 35-70%, 재발률은 20% 정도이다. 시술자나시술보조자가첨규콘딜롬의소작시발생하는연기를흡입하는것은호흡기유두종증을유발할수있으므로특별히주의하여야한다. 전기소작술이나 CO 2 레이저소작술을시행할때는필터를갖춘연기흡입장치를갖추어야하며, 시술시최대한공기중에입자가날리지않도록흡입기를시술부위에가깝게하여야한다. 또한시술공간에대한적절한환기를유지하며, 흡입감염의위험을최소화할수있도록시술자는특수마스크를착용하여야한다. (2) 냉동치료 (cryotherapy) 액화질소를사용하여병변부위를동결-해동을반복시키는냉동치료는치료후병변부위가탈락하고이후염증반응후재생되는과정을거친다. 60-90% 의치료율을보이며재발률은 20-40% 로다양하게보고된다. (3) 레이저치료 (laser therapy) CO 2 레이저가가장흔하게사용되며, 치료율은 20-50%, 재발율은 5-50% 정도이다. 연기를흡입하는것은호흡기유두종증을유발할수있어주의를요한다. (4) 요도내성기사마귀 (urethral warts) 요도내성기사마귀의경우대개외요도구나요도주상와 (fossa navicularis) 에호발하나근위부의요도나방광에서도동반되어나타날수있다. 54 요도내성기사마귀의증상은혈뇨, 요도출혈, 빈뇨, 절박뇨및요도분비물등이있으며특별한자각증상없이외요도구의종물이발견되거나외성기의성기사마귀에대한진단과정에서요도내시경에의해확인되는경우도있다. 피부에나타나는병변과마찬가지로대개조직검사없이진단이가능하며치료에반응이없거나요도암의감별진단이필요한경우에한해병리조직검사를시행한다. 요도내성기사마귀의치료는아직확립된것은없는상태이며과거에는외과적절제, 전기소작또는냉동치료등이많이시행되어왔으나재발률이높고요도점막의손상으로인해추적관찰시요도협착이문제가되었다. 5% 5-FU 연고를요도내주입하여치료에성공하였다고보고가있다. 55,56 하지만이러한약물의요도내주입과더불어외과적절제나전기소작등의처치가추가로필요한경우가있었고피부나요도자극으로인한부작용또한있었다. 최근요도내성기사마귀를치료하는데 CO 2, argon, pulsed dye, holmium, neodymium-doped yttrium aluminum garnet (Nd:YAG), thulium의다양한 laser 의사용이보고되고있다. 57 최근요도내성기사마귀의수술적치료법으로레이저의활용은고무적이며요도내약물주입등의부가적치료는재발성경향을보이는환자에서선별적으로행하는것이효과적인치료전략이라할수있을것이다. 58 4. 예방평생동안의성배우자의수가많을수록성기사마귀의이환율이높다고확인된바있으며 5년이상의장기간의경구피임제복용, 다빈도임신, 다른 STI의존재, 불충분한상태나면역억제상태등도성기사마귀의높은이환율과연관된위험인자로알려져있다. 이외에도어린나이의성관계경험과유전적감수성도위험인자로알려져있으며이러한위험인자를조절하는것이예방의한방법이될수있다. 58 콘돔의사용에관하여는콘돔이 HPV의전염을막는다고명확히말할수는없으나다른공동위험인자들을막는효과도부가되므로 HPV 예방에일정부분도움이된다고할수있다. 특히, 새로운성파트너와의관계가있을경우콘돔이추천된다. 59 임산부가성기사마귀를가지고있을경우아이에게 HPV가수직감염되는것을막기위해제왕절개술을하는것은추천되지않는다. 제왕절개술이 HPV의수직감염을막는데효과적이라고입증된바없으며산도를병변이막는상황이아니라면제왕절개술이시행될필요는없다. 예방백신은감염성질환에대한가장효과적인치료법이라할수있는데, HPV 백신은유전자재조합 (recombinant

Jun Hyun Han. Managements for the Male HPV Infection 83 technology) 을이용하여 HPV의 capsid protein인 L1 단백질로이루어진 virus like particle (VLP) 을항원으로한다. 60 HPV 백신은 HPV virion 과형태적으로유사한 VLPs 를통해인체에서 HPV에대한중화항체 (neutralizing anti-body) 생성을유발하지만 HPV DNA 를포함하고있지않기때문에감염의위험은없다. HPV 백신의방어기전은백신으로인해유도된항HPV 항체가혈청에서자궁경부점막으로전달되어 HPV의지속적감염을예방하는것으로생각되고있다. 현재허가되어시판중인 HPV 백신은두종류가있으며 4가백신인 Gardasil (Merck & Co., Inc.) 은 HPV 6, 11, 16, 18의 L1 단백질을항원으로하고있으며 2가백신인 Cervarix (GlaxoSmithKlein) 는 HPV 16, 18의 L1 단백질을항원으로하고있다. 두백신모두 1회투여량인 0.5 ml를근육주사로접종하며총 3회를 6개월에걸쳐투여한다. 3회접종후항체는 100% 의여성에서형성되며, 자연감염시형성되는항체가 (antibody level) 보다 10배에서많게는 104 배까지높은항체가를나타낸다. 61 우리나라에서도두가지백신모두시판허가가되었으며 Gardasil 은 2007 년 6월, Cervarix 는 2008 년 7월에각각허가되어임상에도입되었다. 결론 생식기 HPV는주로성적접촉을통해서전파되며, 가장흔한성전파성감염으로일생동안 HPV를접촉할확률은최소한 50% 이상이다. HPV에의하여발생하는성기사마귀치료의일차목표는관찰되는모든사마귀를깨끗하게제거하는것이다. 성기사마귀를치료하지않고그냥두어도자연치유되기도하지만, 수및크기가일정하게유지되거나, 증가가나타나며성파트너에게바이러스를전파시킨다. HPV에의한성기사마귀의치료에불확실한부분이많은데, 바이러스를완전히제거할수있는방법이현재까지는없어서, 육안으로보이는성기사마귀를완전히제거하여도재발방지를보장할수없다. 하지만 HPV에의한치료효과를높이고전염력을감소시키기위하여재발여부를지속적으로추적관찰하고, 재발시신속하게병변을제거하는것은무엇보다도중요하다. 치료법은약물의병변내국소도포와수술적요법등다양하나타치료에비해뚜렷하게우수한단일치료법은없다. 성기사마귀가양성질환으로자연소실을보이기도하지만, 재발방지를보장할수있는완벽한치료가없기때문에 HPV에대한지속적인연구와고찰이필요하다. 치료에대한불확실성때문에예방백신에거는기대가클수밖에없는데, 예방접종의효과와안전성에대한지속적인감시뿐아니라방어기간, HPV 관련질환이나바이러스형의감시, 동시접종, 남성에서효능, 백신보급과수행을위한적절한전략등에대해지속적인연구가필요하다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27. 2. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer 2007;111: 145-53. 3. World Health Organization. Vaccines against human papillomavirus [Internet]. World Health Organization; 2010 [cited 2010 Jan 19]. Available from: http://www.who.int/vaccines/ en/hpvrd.shtml/shtml/shtml. 4. Centers for Disease Control and Prevention. Genital HPV infection STD fact sheet [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2010 [cited 2010 Sep 2]. Available from: http://www.cdc.gov/std/hpv/stdfact-hpv. htm. 5. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA 2007;297:813-9. 6. Pham TH, Nguyen TH, Herrero R, Vaccarella S, Smith JS, Nguyen Thuy TT, et al. Human papillomavirus infection among women in South and North Vietnam. Int J Cancer 2003;104: 213-20. 7. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796-802. 8. Stanley M. Immune responses to human papillomavirus. Vaccine 2006;24(Suppl 1):S16-22. 9. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004;324: 17-27. 10. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope 2008;118:1236-47. 11. Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL. Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 2006;24(Suppl 3):S3/26-34. 12. Mantovani F, Banks L. The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 2001;20:7874-87. 13. Münger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M, et al. Biological activities and molecular targets of the

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