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18 e 23 de julho de 2011, no Instituto do Cncer do Estado de So Paulo (ICESP)

HPV E CNCER

Adhemar Longatto Filho, PhD, PMIAC LIM14 FMUSP

Human immunodeficiency virus (HIV) Human papillomavirus (HPV) Herpes viruses

Hepatitis B and C viruses

Epstein-Barr viruses (EBV) Retroviruses

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General Information: Ether-resistant, acid & heat stable Circular dsDNA ~8kb, non-enveloped Icosahedral,72 capsomeres, 55nm diameter Surface Antigen Over 100 genotypes*, High & Low Risk strains Causes warts; transforms cells Polycistronic (mRNA carrying information for the synthesis of more than one protein) , 8 ORF Genome: 3 Regions Replicates in Nucleus Plasmid-like state

PAPILLOMAVIRUSES Non-enveloped dsDNA viruses Circular genome ~8kb 55-nm spherical capsid coat Widely distributed in higher vertebrates Tigh species specificity Tropism for squamous epithelium Associated with verrugas & cancer

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O GENOMA DO HPV

O GENOMA DO HPV

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Human Papillomavirus Cell Cycle

Classification of Papillomaviruses

de Villiers EM et al. Classification of Papillomaviruses. Virology 2004;324:17-27

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Family: Papillomaviridae

Genus: Polyomavirus
Mice Monkey SV40 Vacuolating Agent Man BK Virus, GU Tract, Renal Transplant Patients, JC Virus, Leucoencephalopathy

Genus: Papillomavirus

Human, Bovine, Rabbit, Deer, Horse, Dog, Monkey

Zonotic PV
Animal Tumor Rabbit (Shope) Papilloma Bovine Papilloma Deer Sarcoma Human (Wart) Papilloma Associated Tumor Type Squamous Cell Carcinoma Squamous Cell Carcinoma Fibrosarcoma Squamous Cell Carcinoma

Exemplos de papillomavirus em outras espcies

Equine warts: papilloma virus

Pescoo de boi

Focinho de cavalo

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Exemplos de papillomavirus em outras espcies

TIPOS DE PAPILLOMAVIRUS HUMANO

The most common genital and non-genital HPV types in benign and malignant disease.
Manifestation Common Skin warts
Plantar warts Common warts Flat warts 1 2,27 3,10 2,4,63 1,4,7,26,28,29,57,60,65 2,26,27,28,29,41,49

HPV Types Less Common

Anogenital lesions
Condyloma accuminata CIN, VIN, VAIN, PIN, PAIN

6,11 16,18,31

2,16,30,40,41,42,44,45,54,55,61 6,11,30,34,35,39,40,42-45,51,52, 56-59,61,62,64,66,67,69

Malignancies
Cervical cancer Other anogenital cancers Laryngeal cancer Oral cancer

16,18,31,45 6,16,18 6,11 16,18 3,6,57 16

6,10,11,26,33,35,39,51,52,55,56, 58,59,66,68 11,31,33 16,18,35

http://www.ashastd.org/hpvccrc/overview.html

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Common warts

Common warts

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HPV Oropharyngeal Warts

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Epidermodysplasia verruciformis

Rare inherited disease characterized by chronic infection with human papillomavirus (HPV). Widespread skin eruptions of flat-to-papillomatous, wart-like lesions and reddish-brown pigmented plaques on the trunk, the hands, the upper and lower extremities, and the face are typical.

32-year-old: "Tree Man of Java" for massive bark-like warts growing

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Classification of Papillomaviruses

de Villiers EM et al. Classification of Papillomaviruses. Virology 2004;324:17-27

Genital Warts Male

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Penile squamous cell carcinoma

Partial penectomy shows polypoid lesion: squamous cell carcinoma

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Genital Warts Female

In situ carcinoma

Benign lesion

Squamous Carcinoma of the Vulva. (arrows).

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Anal Warts

SCC

Bowenoid papulosis

Anal Giant Condiloma

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HPV & cervical cancer

HISTRIA DA RELAO DO HPV E AS VERRUGAS VAGINAIS

Data
Sculo 1 1842 1890 1907 1930 1949 1954 1956 1960 1976 1986 1999

Evento
Celsius (Roma) descreve as verrugas genitais Rigoni-Stern (Verona) associa o cancro genital a actividade sexual Verrugas disseminam-se por contacto Extractos infecciosos obtidos em clulas Progresso para malignidade requer co-factor (estudo em coelhos) Ayre descreve o Coilcito, chamando-o de Complexo pr cancro A natureza infecciosa das verrugas demonstrada epidemiologicamente Koss & Durfee introduzem o termo Koilocytosis (coilocitose) Sugere-se etiologia viral para o cancro de colo uterino: HSV Meisels & Fortin associam coilocitose e disqueratose como aco do HPV HPV demonstrado nas leses precursoras Infeco persistente pelo HPV precursora necessria para o cancro cervical. HPV causa 99.7% dos carcinomas cervicais.

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HISTRIA DA RELAO DO HPV E AS VERRUGAS VAGINAIS

1842 Rigoni-Stern (Verona) associa o cancro genital a atividade sexual

HPV Gene Products and Their Function

Gene E1 E2 E3 E4 E5 E6 E7 E8 L1 L2 Function Initiation of DNA replication Transcriptional regulation/DNA replication ? Disrupts cytoskeleton? Transforming protein, interacts with growth factor receptors Transforming protein, binds to p53, leading to degradation Transforming protein, binds to pRB ? Major capsid protein Minor capsid protein

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Cases of cervical cancer worldwide

< 91.5
Source GLOBOCAN 2000; IARC

< 33.2 <9.7

< 25.3 per 100,000 women

< 15.4

Trottier H, Franco EL. Vaccine. 2005. The epidemiology of genital human papillomavirus infection.

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0 5.8 12.2 21.0 34.7 57 Age-standardised incidence rates per 100,000

GLOBOCAN 2008, International Agency for Research on Cancer

0 1.9 4.9 9.7 17.3 42 rates per 100,000 0Age-standardised 1.9 4.9 9.7 mortality 17.3 42
GLOBOCAN 2008, International Agency for Research on Cancer

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Incidncia de HPV e Cncer por Idade

25

20 18

HPV Prevalncia (%)

20

16

Casos por 100,000

Cncer
15

14 12 10

HPV

10

8 6

4 2

0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 > 75

Idade (anos)
NCI SEER Data, 1990-94; Melkert et al., 1993. Int J Canc 53:919

Schiffman & Castle (2005) New Eng J Med 353:2101

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HPV & Cncer Cervical TIPO CARGA VIRAL INTERAO COM CLULA EPITELIAL RESPOSTA IMUNOLGICA

INTERAO COM ONCOPROTENAS

Schneider & Koutsly - IARC, 119, 1992 (mod)

FACTORES DE RISCO
Comportamento sexual: mltiplos aumentam o risco de infeco por HPV. parceiros

Mulheres em clnicas de DST tem aumento de 4 a 13 vezes infeco por HPV. Indivduos com comprometimento do sistema imune tm chance 17 vzes maior de ter doenas associadas ao HPV. Estudo com 207 mulheres expostas ao HIV mostrou prevalncia de 23% em HIV- e 46% nas HIV + (Ho et al, 1994). Idade um factor de risco: mulheres de 15 a 25 anos tem o dobro de chance de infeco por HPV do que as mulheres acima dos 35. Outros factores (no concludentes): contraceptivo oral (reduo?), gravidez, cigarro, HSV, Chlamydia. Variveis scio-econmicas: pobreza, violncia domstica, abuso sexual, cuidados de sade inadequados.

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ROUTES OF HPV TRANSMISSION

HPV and CERVICAL CANCER

High risk HPV (oncogenic) types HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82

Possible high risk HPV (oncogenic) types

HPV 26, 53, 66 Low risk HPV (non-oncogenic) types HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108

Munoz N. et al. N Engl J Med 2003;348:518-527

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Representao esquemtica do trajeto da infeco pelo HPV.

Nature Reviews Cancer 2; 342-350 (2002); doi:10.1038/nrc798 PAPILLOMAVIRUSES AND CANCER: FROM BASIC STUDIES TO CLINICAL APPLICATION

The biology of HPV infection

a. HPV virions infect basal cells of stratified mucosal epithelium at the junction between the vagina and ectocervix. b. When the break occurs in the E2 region, the lifting of E2-mediated transcriptional repression of E6 and E7 oncogenes predisposes infected cells to cellular transformation (dysplasia). c. Invasive tumour ruptures the basement membrane and invades the sub-epidermal tissue. Inset shows the HPV genome.

Nature Reviews Cancer 2; 59-64 (2002)

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HPV and CERVICAL CANCER

(-) (+)
HPV CARGA VIRAL RESPOSTA IMUNOLGICA

(+) (-)

ASCUS

NORMAL

HGSIL

CANCER

LGSIL

INTEGRAO ANEUPLOIDIA

ONCOGNESE CERVICAL
Clula Epitelial Madura

Padro Abortivo
Queratincito Imaturo

Queratincito HPV infectado

HPV

Padro Produtivo
HPV 6 ou 16 HPV 16

Coilcito

Cancro Padro Carcinognico Via HSIL

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Vias de sinalizao da imortalizao das clulas pelo HPV

Nature Reviews Cancer 2; 342-350 (2002); doi:10.1038/nrc798 PAPILLOMAVIRUSES AND CANCER: FROM BASIC STUDIES TO CLINICAL APPLICATION

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Human Papillomavirus Infection

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Progresso das leses induzidas pelo HPV

Histria natural da neoplasia intraepitelial induzida pelo HPV. Adaptada de Syrjnen baseada em estudos com 18 anos de seguimento Regresso (%) Progresso (%)

HPV- CIN1 HPV- CIN2 HPV- CIN3

56.7 50.4 12.2

Tempo de progresso do HPV Tipo de HPV

14.2 22.4 64

Latncia (em anos) 20-50 3-12

Zur Hausen Hmatol Bluttransf 31, 2004

HPV HPV

16, 18, 31, 33, 35 5, 8, 14, 17

Precursor Lesions of Cervical Carcinoma

LSIL CIN 1 Mild Dysplasia HSIL

Normal

CIN 2 Moderate Dysplasia

CIN 3
Severe Dysplasia Carcinoma in situ

From Figure 6.13, DeMay RM. The Art and Science of Cytopathology. CD-ROM. ASCP. 1999. Wright TC, Kurman RJ, Ferenczy A: Precancerous Lesions of the Cervix. In Kurman RJ, ed: Blaustein's Pathology of the Female Genital Tract. 4th ed. New York: Springer-Verlag NY Inc, 1994.

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Progression scheme depicting the stages leading to the development cervical cancer from HPV infection to invasive disease.A. Functional progression model. B. Morphology based description of progression; arrows, HPV oncogene expression. C. Representative p16 staining patterns associated with morphologic and functional disease stages. Cancer Epidemiol Biomarkers Prev 2008;17(10):253645)

Pap test

IARC confirms efficacy of cervix cancer screening for women 25-65 in reducing mortality

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HPV e Cncer por Regio Cervical

15 tipos esto associados com cncer cervical
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
frica Amrica do Sul sia Europa Amrica do Norte

68 59 58 56 52 51 45 39 35 33 31 18 16

Risco com tipos especficos

Tipo
HPV 16 HPV 18 HPV 45 HPV 31 HPV 52 HPV 33

Cncer
53% 11% 4% 3% 2% 2%

Controle
3.0% 1.0% 0.5% 0.6% 0.2% 0.2%

OR
434 248 197 123 200 373

Munoz et al. (2003) NEJM

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HPV e Cncer Cervical

Contextualizando o risco:
A chance de uma mulher com cancro cervical ter infeco persistente por HPV 16 434 maior que uma mulher sem cancro Nos E.U.A., homens fumadores tm somente 8 vezes mais chance de desenvolver cancro de pulmo que fumadores Mulheres com TRH tm 1,3 vezes mais chance de desenvolver cancro de mama

Different options for cervical cancer screening

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Pap cytology and HPV DNA testing in cervical cancer screening.

n engl j med 357;16 www.nejm.org october 18, 2007

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CERVICAL CANCER PREVENTION Issues that remain

Because PAP test are relatively insensitive a program of regular Paps is required for maximum protection.

Ian Hector Frazer Australian Immunologist

Harald zur Hausen The Nobel Prize in Medicine 2008

Detection of HPV Types in Cervix Cancers from Different Regions of the World
from Clifford Br J Cancer 2003;88:63

11.4 0.4 0.6 3.20.2 3.9 3.3 54.9 22.1

16 18 45 31 33 58 52 35 Others

Europe
0.5 0.5 13.5

Europe
Asia

0.5

HPV Types

2.9

4.4 0.5 2.2 4.2 0.8 4.4 4.2 2.9

0.8 56 17.2

20.8 1 4.2 5.4

17.2
1.4

Africa

3.4 2

Latin America
2 3.3 2.9 4 7 5.5 10.6 51.7 13

1.6 1.6 3.1 2.6

17.5

16 18 45
14.1 33

50.2

7.9 31

16 4.5 56 18 45 31 33 58 52 35 Others

16 18 45 31 33 58 52 35 15.3 Others

16 18
43.4

45 31 33 58 52 35

16 18 45 31 33 58 52 35 Others

Others

58 52 35 Others

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AIS: adenocarcinoma in situ; ATP: according to protocol; CIN: cervical intraepithelial neoplasia; CIN1+: CIN grade 1 or worse; CIN2+: CIN grade 2 or worse; FUTURE: Females united to unilaterally reduce endo/ectocervical disease; GSK: GlaxoSmithKline Biologicals, Rixensart, Belgium; ITT: intention to treat; Merck: Merck & Co., Inc., Whitehouse Station, NJ USA; MITT: modified intention to treat; NR: not reported; PATRICIA: Papilloma trial against cancer in young adults, CI: confidence interval. a 95% confidence intervals, except 97.9% confidence intervals used in PATRICIA. b A post-hoc analyses of PATRICIA including HPV -specific causal attribution in 3 CIN 2/3 cases with multiple HPV types generated efficacy estimates of 100%.

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Summary of Cervical Cancer Prevention Options

Current options
Abstinence Lifelong mutual monogamy Screening (followed by diagnosis and treatment)
HPV DNA or Pap testing Both HPV DNA and Pap testing

Future options
Screening or triage by more accurate and less costly biomarkers (e.g., p16INK4a protein, DNA methylation markers) Prophylactic and therapeutic vaccine

Laura Koutsky, PhD Professor of Epidemiology University of Washington Seattle, WA, USA

Impact of condom use

Anal HPV, LSIL and HSIL
Unadjusted incidence densities
Incidence per 100 person-years

70 60 50 40 30 20 10 0 1.0 0.7-1.0 Proportion condom use

P=0.54 P=0.035 P<0.001

HPV LSIL HSIL

<0.7

HPV: human papillomavirus; LSIL: low-grade squamous intraepithelial lesions; HSIL: high-grade squamous intraepithelial lesions.

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Total Body Condom ??

How effective the condom is?

Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection
Winer RL, et al N Engl J Med. 2006;354:2645-54..

We did not observe a significant association with condom use

Cancer Epidemiol Biomarkers Prev. 2006;15:326-33. Vaccarella S, and IARC HPV Prevalence Surveys Study Group.

Epstein RJ Eur J Cancer. 2005 Nov;41(17):2595-600. Primary prevention of human papillomavirus-dependent neoplasia: no condom, no sex.

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If all else fails

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