2. Biología, Patobiología, Bioclínica y
escenciales en
Infección por HPV e Histopatología
del Cérvix Uterino
GRÉGORY ALFONSO GARCÍA MORÁN, MD
MIEMBRO CUERPO CIENTIFICO Y ACADÉMICO-ORGANIZACIÓN SÁNITAS
INTERNACIONAL-OSI-
CORREO DE CONTACTO:
GAGM GREGALFGM D.R.A.
3. • ACLARACIÓN DERECHOS DE AUTOR(D.R.A.):
– LA PRESENTACIÓN INTITULADA «ESCENCIALES Y
ACTUALIZACIÓN EN AVANCES Y PROGRESOS EN BIOLOGÍA,
PATOBIOLOGÍA, BIOCLÍNICA Y MEDICINA
HEMATOINMUNE: 1ra PARTE», TIENE D.R.A EN CUANTO A
LA METODOLOGÍA DE DESARROLLO PERSONAL POR PARTE
DEL AUTOR, RESPETANDO AL MÁXIMO LAS FUENTES DE
INFORMACIÓN QUE LA SUSTENTAN.
– LAS IMÁGENES HAN SIDO EN LO POSIBLE CONSIGNADAS
MENCIONANDO Y RESPETANDO SU ORIGEN, SIEMPRE CON
LA FINALIDAD DE SER Y ESTAR BAJO UN ESTRICTO USO
ACADÉMICO, AUNQUE SE ADVIERTE QUE HAY IMÁGENES
DE AMPLIA UTILIDAD DIDÁCTICA EN LAS CUALES NO SE
LOGRA RASTREAR EL AUTOR O LA PÁGINA WEB ORIGINAL.
7. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
10. 1ra. PREMISA
• El uso de la citología cérvico-vaginal
convencional ha logrado reducir la mortalidad
por cáncer de cuello uterino en países
desarrollados
• “There were about 500 000 incident cases of
and 275 000 deaths due to cervical cancer
worldwide in 2002” Parkin DM, Bray F, Ferlay J, Pisani P. Global
cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108.
11. 2da. PREMISA
• Estudios recientes han demostrado que aún
con adecuado control de calidad, la citología
convencional tiene en promedio una
sensibilidad de 53% (95%IC: 48.6–57.4%) en
Europa y Estados Unidos.Cuzick J, Clavel C, Petry KU,
Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North
American studies on HPV testing in primary cervical cancer screening. Int
J Cancer 2006;119(5):1095-1101.
12. Bulletin of the World Health Organization | September 2007, 85 (9)
13. 3ra.PREMISA
• El éxito de algunos de estos programas no
reside en la sensibilidad de la prueba, sino en
la repetición constante de la misma y en el
seguimiento sistematizado de mujeres con
anormalidades citológicas que aseguran el
diagnóstico y el tratamiento definitivo de
lesiones detectadas, modelo que no se ha
logrado replicar en regiones con escasos
recursos.
14. 4ta.PREMISA
• El cáncer de cuello uterino es el segundo
cáncer más frecuente en mujeres en el mundo
con 86% de los casos y 88% de las muertes en
países en vías de desarrollo
15. 5ta.PREMISA
• HPV es la ETS más común en el mundo.
Aral S, Holmes K. Social and behavioral determinants of
epidemiology of STDs: industrialized and developing countries.
In: Holmes KK, Mardh PA, Sparling PF, Wiesner PJ, eds. Sexually
Transmitted Diseases. 3rd ed. New York, NY: McGraw-Hill;
1999:39-76.
19. • Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: cancer
incidence, mortality and prevalence worldwide. Lyon: IARC
Press; 2004 [IARC CancerBase No.5. version 2.0].
20. Murillo R, Pineros M, Hernández G. Atlas de mortalidad por cáncer en
Colombia. Bogotá: Instituto Nacional de Cancerología. Instituto Geográfico
Agustín Codazzi; 2004.
21.
22. • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.
GLOBOCAN 2008 v1.2, Cancer incidence and mortality Worldwide:
International Association Cancer Registries (IARC) CancerBase No.
10 [Internet]. Lyon, France: International Agency for Research on
Cancer; Available from: http://globocan.iarc.fr
“Cervical cancer is responsible for approximately 1% of all causes of female mortality
worldwide, killing more than 273,000 women per year”
23.
24.
25. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et
al. Cancer incidence in five continents, vol. IX. Lyon: IARC Press;
2007 [IARC scientific publications no. 160].
26.
27. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
36. • Human papillomavirus
particles consist are
icosaedric, of 8000 base-
pair (bp) long circular DNA
molecules
• Both sets of genes are
separated by an upstream
regulatory region (URR) of
about 1000 bp that does
not code for proteins but
contains cis-elements
required for regulation of
gene expression,
replication of the genome,
and its packaging into virus
particles
37.
38. The EVER proteins as
a natural barrier against
papillomaviruses: a new insight
into the pathogenesis of human
papillomavirus infections.
Lazarczyk M, Cassonnet P, Pons
C, Jacob Y, Favre M.
Microbiol Mol Biol Rev. 2009
Jun;73(2):348-70.
54. HPV5 Y HPV8: EPIDERMODISPLASIA
VERRUCIFORME
• Certain HPV types,
referred to as ‘‘EV-
HPVs,’’ are
specifically linked
to the
development of
EV, including HPV
types 3, 5, 8, 9, 10,
12, 14, 15, 17, 19
to 25, 28, 29, 36,
46, 47, 49, and 50
55.
56. The biology and life-
cycle of human papillomaviruses.
Doorbar J, Quint W, Banks L, Bravo IG,
Stoler M, Broker TR, Stanley MA.
Vaccine. 2012 Nov 20;30 Suppl 5:F55-
70.
57.
58.
59.
60.
61.
62. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
63. • HPV is transmitted through contact with infected genital skin or
mucosa.
• Virus is transmitted by skin to skin contact via intimate contacts of
the genitalia or other mucosal surfaces .
• Genital warts are highly infectious because of their high viral load:
up to 65 percent of sexual contacts develop an infection.
• The usual incubation period for clinical warts is three weeks to eight
months, with an average of 2.9 months.
• Oral infection with genital HPV types may occur, but the risk of
transmission is less.
• Perinatal transmission also can occur, but this is rare.
• Receptive anal intercourse has been associated with intra- and
perianal warts, but these warts are not always associated with anal
intercourse.
• Cervical and anal infections often coexist in persons without a
history of anal intercourse.
65. • HPV infection may be latent, subclinical, or clinical.
• It may take the pathway of low viral-load infection without clinical
disease, or high viral-load infection with clinical disease.
• Such disease may manifest as genital warts or as low- or high-
grade intraepithelial lesions.
• Up to 90 percent of persons infected with high- or low-risk HPV
clear the infection within about two years.
• The median time to clearance of genital warts after treatment is
about six months.
• In women, up to 30 percent of cases of genital warts
spontaneously regress within four months.
66. Y MÁS DATOS
• The small minority who fail to clear the
infection are at risk of progression to
malignancy.
• Precancers are usually detected around age
25–30 years (about 10 years after sexual
debut) in regions with cytological screening.
Schiff man M, Castle PE. The promise of global cervical-cancer prevention.
N Engl J Med 2005; 353: 2101–04.
67. • The peak prevalence of HPV infection in women occurs in
their early 20s.
• A smaller second peak occurs in postmenopausal women in
some geographic areas. This may be attributed to viral
persistence or perhaps new acquisition.
FIGURE 22-15 Age-dependent prevalence of HPVs
in cervical smears in women with normal Pap test
results in the US
population. (Adapted from Dunne EF et al.:
Prevalence of HPV infection among females in the
United States. JAMA
297:813, 2007.)
68. • The interval between infection and diagnosis
of cancer is 10 to 20 years.
• Because the peak incidence of cervical cancer
does not occur until 40 years of age, testing
for persistent HPV infection is most useful
between 30 and 40 years of age.(Naucler P, Ryd W,
Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical
cancer [published correction appears in N Engl J Med. 2008;359(15):1637]. N Engl J
Med. 2007;357(16):1589-1597. )
69. • PERO HAY RAZONES ESTRUCTURALES PARA
ESTE PROBLEMA?
72. UNA METAPLASIA FISIOLÓGICA!
• En el cuello uterino, el cambio metaplásico
implica la transformación del epitelio
endocervical en un epitelio escamoso.
• Tres etapas histológicas han sido
identificadas:
73. Etapa 1 : Hiperplasia de células de
reserva - las células de reserva en el
epitelio endocervical empiezan a
dividirse.
74. Etapa 2: Metaplasia plana inmadura - las células de reserva
proliferan para formar múltiples capas de células
indiferenciadas. Una capa superficial de células cilíndricas
mucinosas se puede ver frecuentemente en la superficie.
75. Etapa 3: Metaplasia plana madura - las células indiferenciadas se
diferencian en epitelio plano maduro que es casi indistingible del
epitelio plano original.
76.
77.
78. PERO POR QUÉ?
• Durante la pubertad y el primer embarazo el
cuello uterino aumenta de volumen en
respuesta a cambios hormonales.
• El epitelio endocervical se evierte al ectocérvix
(portio vaginalis) exponiéndose al pH ácido de
la vagina.
• Esto proporciona un estímulo para el cambio
metaplásico del epitelio cilíndrico.
79. • CÉLULAS QUE SUFREN ESTE PROCESO: MUY
SENSIBLES A CARCINÓGENOS(EJM.: HPV)
85. Alta paridad????
• “The mechanisms through which high parity is
thought to increase the risk of cervical
carcinoma is through the maintenance of the
transformation zone on the exocérvix for
many years in which may facilitate exposure to
HPV, although hormonal factors may also be
involved”.
86.
87. HPV Y EPITELIO CERVICAL
The biology and life-
cycle of human papillomaviruses.
Doorbar J, Quint W, Banks L, Bravo IG,
Stoler M, Broker TR, Stanley MA.
Vaccine. 2012 Nov 20;30 Suppl 5:F55-
70.
88.
89. The evolving field
of human papillomavirus receptor research:
a review of binding and entry.
Raff AB, Woodham AW, Raff LM, Skeate JG, Yan L,
Da Silva DM, Schelhaas M, Kast WM.
J Virol. 2013 Jun;87(11):6062-72.
90.
91.
92.
93.
94.
95.
96. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
106. HISTOPATOLOGÍA
-Pierde los bordes angulados
usuales de la célula escamosa
superficial y su forma tiende a
ser redondeada y ovoide.
-El citoplasma muestra una
condensación periférica que le
da un aspecto en “asa de
alambre”.
-Se observa una gran cavidad o
halo halo perinuclear más
atipia nuclear (las células se
ven hipercromaticas, de mayor
tamaño y cambian de forma).
-El núcleo de la célula se localiza
de manera excéntrica.
107.
108. ARGOT TÉCNICO
• LSIL: LESIÓN INTRAEPITELIAL DE BAJO GRADO
• HSIL: LESIÓN INTRAEPITELIAL DE ALTO GRADO
• NIC: NEOPLASIA INTRAEPITELIAL CERVICAL
111. Spectrum of cervical intraepithelial neoplasia: normal squamous epithelium
for comparison;
-LSIL (CIN I) with koilocytic atypia;
-HSIL (CIN II) with progressive atypia and expansion of the immature basal -
cells above the lower third of the epithelial thickness;
-HSIL (CIN III) with diffuse atypia, loss of maturation, and expansion of the
immature basal cells to the epithelial surface.
121. PERO AÚN NO
ENTENDEMOS QUÉ PASA…
The biology and life-cycle of human
papillomaviruses.
Doorbar J, Quint W, Banks L, Bravo IG, Stoler M,
Broker TR, Stanley MA.
Vaccine. 2012 Nov 20;30 Suppl 5:F55-70.
122. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
124. • Effective immunity consists of a cell mediated
response to the early proteins, principally E2
and E6, necessary for lesion regression
accompanied or followed by sero-conversion
and antibody to the major capsid protein L1.
133. PLAN DE TRABAJO
• 1.CONTEXTO MUNDIAL Y PREMISAS DE TRABAJO
• 2.QUIÉNES SON LOS PAPILOMAVIRUS Y EL
TROFISMO POR LOS EPITELIOS
• 3.HISTORIA NATURAL, Y BIOLOGÍA-PATOBIOLOGÍA
DEL EPITELIO CERVICAL
• 4.FUNDAMENTOS DE PATOLOGÍA
• 5.RESPUESTA INMUNOLÓGICA FRENTE A
PAPILLOMAVIRUS
• 6.EL TAMIZAJE, LA PREVENCIÓN Y LAS VACUNAS
Figure 1: The cervical transformation zone
The cervical transformation zone is a ring of active squamous metaplasia where the stratifi ed squamous epithelium
of the ectocervix progressively undermines and replaces the glandular epithelium of the endocervix. For unclear
reasons, metaplastic tissue is especially susceptible to the carcinogenic potential of persistent HPV infections.
Figure 3: Major steps in the development of cervical cancer
Top row shows cytology, bottom row colposcopy. The major steps in cervical cancer development can be
understood best in relation to age at fi rst sexual intercourse as a proxy for age at fi rst infection. The typical age of
cervical HPV infection is similar to other sexually transmitted infections, with a large peak rapidly following average
age of sexual initiation. This average age of HPV infection varies by culture, aff ecting average ages of subsequent
stages. Incident HPV infection is best measured by molecular tests. Cross-sectionally, most HPV infections show no
concurrent cytological abnormality. About 30% of infections produce concurrent cytopathology, usually
non-classical (equivocal) changes. Most HPV infections clear within 2 years; the 10% that persist for 2 years are
highly linked to precancer. Detection of precancers is delayed by their initially small size and the typically low
sensitivity of screening methods. Precancers are usually detected around age 25–30 years (about 10 years after
sexual debut) in regions with cytological screening. Adapted from Schiff man and Castle.24
Figure 2: The HPV genome and its expression within the epithelium
The HPV genome consists of about 8000 bp of single-stranded, circular DNA. There are eight open reading frames and an upstream regulatory region. HPV genes are
designated as E or L according to their expression in early or late diff erentiation stage of the epithelium: E1, E2, E5, E6, and E7 are expressed early in the
diff erentiation, E4 is expressed throughout, and L1 and L2 are expressed during the fi nal stages of diff erentiation. The viral genome is maintained at the basal layer of
the epithelium, where HPV infection is established. Early proteins are expressed at low levels for genome maintenance (raising the possibility of a latent state) and
cell proliferation. As the basal epithelial cells diff erentiate, the viral life cycle goes through success stages of genome amplifi cation, virus assembly, and virus release,
with a concomitant shift in expression patterns from early genes to late genes, including L1 and L2, which assemble into viral capsid. L1 is the major capsid protein
while L2 serves as the link to the plasmid DNA. Adapted from Doorbar.21
FIGURE 22-18 A, LSIL—routine H&E staining. B, In situ hybridization test for HPV DNA. The dark granular staining
denotes HPV DNA, which is typically most abundant in the koilocytes. C, Diffuse immunostaining for the proliferation
marker Ki-67, illustrating abnormal expansion of the proliferating cells from the normal basal location to the superficial
layers of the epithelium. D, Up-regulation of p16INK4 (seen as intense brown immunostaining) characterizes high
oncogenic risk HPV infections.
Papillomavirus virus-like particle (VLP) vaccine production. Genetic material from HPV isolated from a clinical lesion was subjected to
PCR using primers specific for the L1 gene. The amplified L1 segment, which for HPV16 excluded the first translation initiation site
in the L1 open reading frame (41), was inserted into an appropriate intermediate expression vector and used to produce recombinant
L1 vaccinia (41), yeast (153), or baculovirus (42). These were used to express L1 in eukaryotic cells, which self-assembled to form VLPs
immunologically similar to the native virion. VLPs produced in insect cells or yeast, disassembled and reassembled in vitro to ensure
relative freedom from nonpapillomavirus proteins and DNA, and combined with alum-based adjuvants are the basis of the currently
available prophylactic vaccines.
