VIRUS DE PAPILOMA HUMANO INFECCIN y CNCER GINECOLGICO

Dr. PEDRO HERNNDEZ MORN GINECLOGO ONCLGO Jefe del Servicio de Ginecologa Oncolgica INSTITUTO REGIONAL DE ENFERMEDADES NEOPLSICAS IREN NORTE -2011

VPH y CNCER

PEDRO HERNNDEZ MORN

PVH y CNCER

Dr. PEDRO HERNNDEZ MORN

Grupo de riesgo

Imagen adulta y joven

Dr. PEDRO HERNNDEZ MORN

Virus papiloma humano

VPH , es virus que contiene cadena doble circular dentro de un cascarn esfrico(Cpside)

VPH infectan los tejido epitelial de la piel y mucosa genital

PAHO

PEDRO HERNNDEZ MORN

Crvix normal
UEC original

Orificios glandulares

Epitelio escamoso original Epitelio escamoso metaplsico

UEC nueva

Identify (1) the stratified squamous epithelium, (2) the columnar epithelium, and (3) the SCJ.
Dr. PEDRO HERNNDEZ MORN

Incidencia Mundial y Distribucin de Cnceres Atribubles a Tipos Oncognicos de VPH, 20021

500,000
100% Total Cancer Cases HPV-related Cases

400,000

Total Cancers

300,000

3%

200,000

100,000
40% 90% 12% 40%

0 Cervix Vulva, Vagina Anus Oral Cavity Oropharynx Penis

PEDRO HERNNDEZ MORN 1. Parkin DM. Int J Cancer. 2006;118:3030 3044.

OMS
Hait 99 Bolivia 59 Ecuador 44 Per 40 Brasil 31 Amrica

Incidencia 40.0 Per Mortalidad 15.8

Latina y el Caribe
Zimbabwe 53

Finlandia 5

Premalignas Invasor Incidencia Mortalidad

INEN 22% 78% 26.1 9.3

LIMA MP 65-70% 25-30% 23.5 10.9

1 causa muerte en mujeres Per Mayor incidencia: Trujillo 43.2 x 100,000 Arequipa con 35.2.

PEDRO HERNNDEZ MORN

Virus del papiloma humano

Existen ms de 200 VP (~100 VP afectan humanos) Es un virus de 8 kb de doble cadena de ADN, dentro de una cpside esfrica de 72 capsmeros

VPH cpside, ~55 nm en dimetro

Imagen: Stannard L, UCT/Science Photo Library

VIRUS DEL PAPILOMA - VPH

>100 VPH

Como se inicia el Cncer cervical?

Representan 70%

VIRUS PAPILOMA HUMANO

AR:16,18,45,31,33, 52,58,35
Dr. PEDRO HERNNDEZ MORN

INFECCIN TRANSMISIN SEXUAL

Como se inicia NIC BG y Condilomas

Representan 90%

VIRUS PAPILOMA HUMANO

Bajo Riesgo: 6,11,26,42
INFECCIN TRANSMISIN SEXUAL
Dr. PEDRO HERNNDEZ MORN

TIPOS DE VPH Oncognicos y de BR

15-20 tipos de VPH son clasificados con oncgenicos(AR: Alto riesgo)

Tipos VPH 16 53% VPH 18 17% OtrosTipos (20%): 45,31, 33, 52, 58 and 35, etc. Los 8 tipos ms frecuentes: 90%
30 Tipos de VPH afectan la mucosa genital (BR)
Muoz N et, N Engl J Medi 2003 PEDRO HERNNDEZ MORN 13

VPH No oncognicos
Los tipos de BR ( No oncognicos) producen lesiones y verrugas genitales

90% de verrugas genitales son producidas VPH 6 10% por el VPH 11

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Human Papillomavirus (HPV)

Non-enveloped double-stranded DNA virus >100 types identified ~30-40 types sexually transmitted Antigens against vacines:
HPV 6 and 11
Account for 90% of anogenital warts Primary cause of recurrent respiratory papillomatosis

HPV 16 and 18
Account for 60%-95% of HPV-related anogenital and oropharyngeal cancers in men

Tipos de VPH en Cncer cervical

16 18 45
53.5

17.2
6.7

31
33 52 Genotipo VPH 58 35

2.9
2.6 2.3 2.2

1.4
1.3

53.5% 70.7% 77.4% 80.3% 82.9% 85.2% 87.4% 88.8%

70%

90%

59
56 51 39 68 73 82 Otros X 0 10 20 30 40 50 60 70 80

1.2 1.0
0.7 0.6 0.5 0.3 1.2 4.4

90

100

Casos de cncer cervical atribuidos a genotipos VPH ms frecuentes (%)

Munoz N y col. Int J cancer 2004; 111: 27885.

Factores de Riesgo Infeccin por Papiloma Virus Humano.

Inicio de relaciones coitales antes de los 18 aos. Mltiples compaeros sexuales. Madre o hermana Ca Crvix. Cervicitis crnica. Otras ITS: VHS, Tricomonas, etc. Tabaquismo. Anticonceptivos Inmunodepresin: VIH, SIDA, Corticoides Dieta deficiente en vitaminas Bajo nivel socio econmico: Pobreza y extrema pobreza que condiciona no tengan acceso a los servicios de Salud.

Gynecology Oncology, OBG, PATH, IARC;2005.

Dr. PEDRO HERNNDEZ MORN

 Contacto Sexual

Mecanismos de Transmisin del VPH y adquisicin

Relaciones sexuales Genitalgenital, manualgenital, oralgenital24 Infeccin por PVH en virgenes es raro, pero puede resultar de contacto sexual no penetrante.2 El uso apropiado del condon no protege completamente pero puede reducir el riesgo de la infeccin5

Rutas No sexuales
Madre recien nacido (transmisin vertical)6

La mayora de los individuos infectados ignoran que estan infectados y diseminan el virus.9
1. Kjaer SK, Chackerian B, van den Brule AJ, et al. Cancer Epidemiol Biomarkers Prev. 2001;10:101106. 2. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218226. 3. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Epidemiol Infect. 1995;115:169 176. 4. Herrero R, Castellsagu X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:17721783. 5. Manhart LE, Koutsky LA. Sex Transm Dis. 2002;29:725735. 6. Smith EM, Ritchie JM, Yankowitz J, et al. Sex Transm Dis. 2004;31:5762. 7. Ferenczy A, Bergeron C, Richart RM. Obstet Gynecol. 1989;74:950954. 8. Roden RBS, Lowy DR, Schiller JT. J Infect Dis. 1997;176:10761079. 9. Anhang R, Goodman A, Goldie SJ. CA Cancer J Clin. 2004;54:248259.

Riesgo Infeccin: Pareja sexual

Dr. PEDRO HERNNDEZ MORN

HPV virion

HPV Infection and Productive Life Cycle

Release of virions within desquamati ng cells

Expression of viral proteins and chang of cell growth

Differentiation of infected cells

Infection of basal cells of epithelium

HPV Infeccin viral

Clearance
1 Ao 70% 2 Ao 90 %

10 %

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CNCER INVASOR
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HISTORIA NATURAL DEL CNCER CERVICAL

Meses
Inicio actividad sexual

1-15 Aos

Dcadas

Epitelio Normal

Infeccin VPH LSIL

CIN1
80%

CIN2 HSIL

CIN3/CIS Carcinoma invasor

20%

Prevencin primaria

Tamizaje-Cribado

Tratamiento

INFECCIN PERSISTENTE
CIN = Cervical Intraepithelial Neoplasia SIL= Squamous Intraepithelial Lesion

Continuum of Care for Cervical Cancer Control

PERSISTENCIA

Virus Papiloma Humano

15 years

30 years

45 years

Vaccination

Screening and treatment

Dr. PEDRO HERNNDEZ MORN

Cancer treatment
Source: WHO 2006

Progresin Clnica

Schiffman et al Lancet 70,p890,2007

BN2010 BN 2009

Prevalencia Global de Infeccion por VPH: IARC* Basado en estudios poblacionales

Morelos State, Mexico1

14.5%

Barcelona, Spain5

3.0%

PER 17.7 %

Bogot, Colombia2

14.8%

Ho Chi Minh City Tamil Nadu, India7 6 and Hanoi, Vietnam10 Ibadan, Nigeria Songkla and Lampang, Thailand8

28.3%

16.9% 10.9%; 2.0%

3.9%; 9.1%

Busan, South Korea9

10.4%

Concordia, Argentina3
Santiago, Chile4
*IARC = International Agency for Research on Cancer 1. Lazcano-Ponce E, Herrero R, Muoz N, et al. Int J Cancer. 2001;91:412420. 2. Molano M, Posso H, Weiderpass E, et al. Br J Cancer. 2002;87:324333. 3. Matos E, Loria D, Amestoy GM, et al. Sex Transm Dis. 2003;30:593599. 4. Ferreccio C, Prado RB, Luzoro AV, et al. Cancer Epidemiol Biomarkers Prev. 2004;13:22712276. 5. de Sanjos S, Almirall R, Lloveras B, et al. Sex Transm Dis. 2003;30:788 793. 6. Thomas JO, Herrero R, Omigbodun AA, et al. Br J Cancer. 2004;90:638645. 7. 8. Informe verbal Dr. Herrero y Dra. Nubia Munoz. PER: Santos et al (2001)

16.6%

14.0%

Prevalencia de Tipos VPH en Cncer de Crvix*,1

14.6

Tipo VPH 16 18

69.7 25.7

45
Norte America/ Europa

31
33

17 52.5 67.6

52
Sud Asia
12.6

58 Otros

Norte Africa
57

Central/Sud America
*A pooled analysis and multicenter case control study (N = 3607) 1. Muoz N, Bosch FX, Castellsagu X, et al. Int J Cancer. 2004;111:278285.

Prevalencia

IARC-Globocan 2002 PEDRO HERNNDEZ MORN 27

PVH y Cncer Cervical, Lima-Per

TIPOS DE PVH 16 = 59.1%
18 = 13.4%

TOTAL 72.5%
Santos y col, Per

Santos et al. Br J Ca, 2001

PREVALENCIA MUNDIAL ESPECFICA POR EDAD DE ADN DE VPH EN MUJERES DE LA POBLACIN GENERAL PREVALENCIA DE VPH
30 25
20
24-9

Enero 1995 Enero 2005

108 estudios
139,777 mujeres con citologa normal
17-7 16-3 13-2

15 10
5

11-7

10-2

8-9

8-8

8-8

10-2 7-5

0
<20 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65+

EDAD
DE SANJOS ET AL.

PREVALENCIA VPH EN MUJERES SANAS

n 347

Positivo 70

% 20.17

Santos et al. INEN-Maes Heller, Lima, 1992.

Prevalencia con citologa normal

DR. PEDRO HERNNDEZ MORON

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VPH y Cncer de Crvix, Lima

Prevalencia VPH en controles
20

Age standardized prevalence (%)

17,7

15

10 6,9 5 4,0 6,8

0 Todos VPH VPH 16 Otros VPH Alto Riesgo VPH Bajo Riesgo

Santos y col. Br J Ca, 85 (7), 966 2001

Risiko for progression til cervical cancer: Global

Healthy, uninfected individuals
Progressio n
Subclinical HPV infection
(214,275,360 cases)

27% cases HPV 16/18+ 27% cases HPV 16/18+

Low-grade dysplasia (CIN1)

High-grade dysplasia (CIN2/3) Cancer
(500,000 cases)

Usually several years (up to > 20 years)

Regression *

52% cases HPV 16/18+ 70% cases HPV 16/18+

* Most cases of CIN spontaneously regress; less likely with higher grade lesions (cervical cancer does not regress). Estimated from total number of global females aged > 15 years. Data available at: http://www.who.int/hpvcentre/en (accessed Sept 2008); BN2010 Castellsagu X, et al. Vaccine 2007; 25S:C1C26; Clifford GM, et al. Lancet 2005; 366:991998.

Ten most frequent HPV types among women with and without cervical lesions in Peru compared to South America and the World

Data sources: a Data have been compiled by the IARC Infection and Cancer Epidemiology Group and have been published as a systematic review and meta-analysis in: Clifford G, Br J Cancer 2003;88:63 | Clifford G, Int J Cancer 2008; 122: 1684 Specific for Peru: Santos C, Br J Cancer 2001; 85: 966 b Data have been compiled by the IARC Infection and Cancer Epidemiology Group and have been published as a systematic review and meta-analysis in: Clifford G, Br J Cancer 2003;89:101 | Smith JS Int J Cancer 2007;121:622 c Data have been compiled by the IARC Infection and Cancer Epidemiology Group and have been published as a systematic review and meta-analysis in: Clifford GM, Cancer Epidemiol Biomarkers Prev 2005; 14: 1157 d Data have been compiled by the HPV Information Centre in the Unit of Infections and Cancer at the Institut Catala dOncolog ia and have been published as meta-analysis in: De Sanjos S, Lancet Infect Dis 2007; 7: 453 and Bruni L, 25th IPV Society Meeting, Malmo, Sweden, 8-14 May 2009 (Manuscript in preparation). Specific for Peru: Garcia PJ, Bull World Health Organ 2004; 82: 483 | Santos C, Br J Cancer 2001; 85: 966

DR. HERNNDEZ

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Citologa y HPV ADN Testing

Especificidad ADN HPV 96%

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VPH Y CNCER DE CRVIX

EVIDENCIA

Clnica/ molecular
Experimental Epidemiolgica

VPH Genoma

Late Proteins Early Proteins

Long control region (LCD)

VPH Funcin

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Sequence of cervical cancer screening and prevention

The classical steps of cancer screening and prevention are screening, diagnosis and treatment, in bold capitals. Triage and Diagnosis and Risk Clarification are steps to clarify the risk of respective subpopulations (adapted from Solomon, 2003).

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Genoma viral

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Infeccin: Mecanismo

VPH - VACUNAS

Profilcticas
Teraputicas

L1 L2
E7

Quimricas

L1, E7

Sistema de Expresin de VLP-L1

Gene L1 cpside viral genticamente diseado en vector Baculovirus

Virus P apiloma Humano

expresadas clulas Hi-5 .

Capsomeros se ensamblan en partculas semejante a virus

( VLP)

Protena L1 extrada en forma de pentmero subunidad de la cpside i.e.capsmeros.

partculas semejantes a VPH no infecciosas

Cmo trabaja la vacuna PPV?

Virus Infeccioso

PPVs

Y
3 inyecciones El cuerpo fabrica anticuerpos contra PPVs

Unin de anticuerpos

Virus no infeccioso

HPV gene expression y persistenciaprogression

HPV
E4 Viral DNA E4 Viral DNA E7 L1

CIN1

E7

E4

L1

E7

CIN2

Viral DNA

CIN3
BN2010

CaCx
Doorbar J. Clin Sci (Lond) 2006; 110:525541.

E7

Lesiones: Historia natural cncer

INFECCIN PERSISTENTE

Servicio Ginecologa Oncolgica IREN NORTE

Dr. PEDRO HERNNDEZ MORN

NIA

VIRUS PAPILOMA HUMANO

ALTO RIESGO

NIC AG

VAIN

VIN
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VPH BR: Infeccin genital

Servicio Gineologa Oncolgica, IREN NORTE 2009.

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VPH BR: Infeccin genital

VIRUS DE PAPILOMA HUMANO Serotipos: 6, 11.

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VPH AR: Precncer AG

Cambios colposcpicos

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VPH AR:Ca Invasor

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VPH AR: Precncer genital

NIC Asocia con VIN, NIVA, NIPA, NIA, NIP

VIN
NIPA, NIA

40%
90%

NIVA 20%
NIP 40%
56

PEDRO HERNNDEZ MORN

VPH Y CA CRVIX

MS DEL 90% DE CANCERES INVASORES DE CRVIX CONTIENEN ADN-PVH ( 8 Virus AR )

Precncer: > 90%

Control Cncer Cuello Uterino Prevencin

Prevencin primaria: Prevencin secundaria:

Factor epidemiolgico Y Vacunas

Deteccin Diagnstico Tratamiento

Prevenci n terciaria: Manejo multidisciplinario

Gynecologic Oncology, Bereck 2005: 180-182.

Rehabilitacin
Seguimiento

Dr. PEDRO HERNNDEZ MORN

Infeccin Viral, NIC y Cncer Sntomas

Pre cncer
Asintomtica
Condilomas Flujo vaginal Sangrado post-coital Dolor plvico o sacro

Cncer Inicial

Cncer Avanzado
Dr. PEDRO HERNNDEZ MORN

Sangrado - Anemia Hematuria-Rectorraga

Insuficiencia renal

Dr. PEDRO HERNNDEZ MORN

Cmo prevenir y detectar Cncer de Crvix?

Prevencin

Primaria:

EDUCACIN-I-C. VACUNAS

Prevencin

Secundaria:

DETECCIN:

PAP, IVVA, COLPOSCOPIA, BIOPSIA

Dr. PEDRO HERNNDEZ MORN

Current Indication
GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

Cervical, vulvar, and vaginal cancer

caused by HPV types 16 and 18

Genital warts (condyloma acuminata) caused by HPV types 6 and 11

Current Indication
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:
Cervical

Intraepithelial Neoplasia (CIN) grade

2/3 and Cervical Adenocarcinoma in situ (AIS)

Cervical Intraepithelial Neoplasia (CIN) grade 1

Vulvar Intraepithelial Neoplasia (VIN) grade 2

and grade 3.

Vaginal Intraepithelial Neoplasia (VaIN) grade 2 and grade 3

PEDRO HERNNDEZ MORN 63

PREVENCIN PRIMARIA VACUNAS

Vacuna lquida recombinante de virus inactivados (VLP L1) proteccin contra las cepas VPH. Administracin:antes de los 15 aos. Nias de 10 aos de edad hasta 11 m y 29 das Dosis : 03; 0, 2 y 6 meses

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Quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine*
L1 VLP Constituent HPV 6 HPV 11 HPV 16 HPV 18 Mercks AAHS Adjuvant

Dose (g)

20

40

40

20

225

VLPs manufactured in Saccharomyces cerevisiae (yeast) The VLPs are not viruses, so cannot cause infection or disease

*GARDASIL

Amorphous aluminum hydroxyphosphate sulfate.

Adolescent Boys and Men

Adolescent and young adult men acquire HPV at a high rate Genital warts due to HPV types 6 and 11 are one of the most common STD.
Warts commonly recur despite different therapies

HPV types 16 and 18 cause precancers, as well as penile and anal cancer in men
There is no standardized screening to detect precancerous lesions in men

VPH Men

HPV types 6,11,16, and 18 cause persistent infection in men Men play an important role in transmitting HPV to women
PEDRO HERNNDEZ MORN 67

HPV Causes Penile Cancer

HPV detected in 42% to 80%1 HPV types 16 and 18 - most frequently identified types in tumors2,3 High-grade penile/perianal/perineal intraepithelial neoplasia (PIN 2/3) considered precancerous4 No standardized screening in men for early detection of precancerous lesions and prevention of progression to cancer

1 2 3 4

Partridge JM, Koutsky LA. Lancet Infect Dis. 2006;6:21-31. Cupp MR, et al. J Urol. 1995;154:1024-9. Pascual A, et al. Histol Histopathol. 2007;22:177183. Cubilla, et al. Int J Surg Pathol. 2004;12:351-64.

Penile Cancer Screening

Citologa Androscopia

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Vacunas

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Vacunas, respuesta y Efectividad

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Efectividad

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Vacunas

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Precncer en otras localizaciones

NIC Asocia con VIN, NIVA, NIPA, NIA, NIP

VIN
NIPA, NIA

40%
90%

NIVA 20%
NIP 40%
74

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Evolucin final: CNCER

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INEN

Finish

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IREN NORTE

Dr. PEDRO HERNNDEZ MORN Dr. PEDRO HERNNDEZ MORN

GRACIAS