Natural history and pathogenesis of hpv

1. NATURAL
HISTORY
AND
PATHOGENESIS
OF
HPV.
HASSAN
M
LATIFAH
MD
FRCSC
GYNECOLOGIC
ONCOLOGY
KFSH&RC
-­‐
JEDDAH

2. § Incidence
and
worldwide
burden
of
cervical
cancer.
§ Phylogenetic
tree
of
HPV.
§ Pathogenesis
and
natural
history.
§ Genomic
background.
§ HPV
infection
at
cellular
level.
§ Conditions
required
for
transition
into
cervical
cancer
.
§ Cofactor
interaction
with
HPV.
§ Summary.

3. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004.
The most frequent cancers in women: incidence and
mortality
Global data
Incidence Mortality
Age-standardized rate per 100,000
Breast
Cervix
Colon/
Rectum
Lung
Stomach
Ovary
Corpus
0 5 10 15 20 25 30 35 40
37.4
16.2
14.6
12.1
10.3
6.6
6.5
Breast
Lung
Cervix
Stomach
Colon/
Rectum
Liver
Ovary
0 2 4 6 8 10 12 14
13.2
10.3
9.0
7.9
7.6
5.7
4.0
Age-standardized rate per 100,000

4. Worldwide Cancer Burden*
471
379
154
193
142
101
75
132
117
55
65
39
0 100 200 300 400 500 600
579
91
292
125
175
91
114
34
16
66
47
61
100200300400500600
Breast
Cervix uteri
Colon/Rectum
Stomach
Lung
Ovary
Corpus uteri
Liver
Oesophagus
Non-Hodgkin lymphoma
Leukaemia
Pancreas
More developed Less developed
2,176,000 2,562,000
Thousands
Total
Women

5. PAPILLOMAVIRUS
INFECTIONS
OF
THE
HUMAN
GENITAL
TRACT
§ Over
100
HPV
types
have
been
identified
to
date,
of
which
over
40
infect
the
genital
tract.
§ HPVs
primarily
target
infections
of
the
basal
cells
in
the
stratified
squamous
epithelium
and
metaplastic
cells
within
squamocolumnar
junctions.

6. Muňoz N, et al. Int J Cancer 2004; 111:278–285.
HPV
types
in
cervical
cancer
worldwide
HPVgenotype
35
58
52
33
31
45
18
16 53.5
70.7
77.4
80.3
82.9
85.2
87.4
88.8
0 10 20 30 40 50 60 70 80 90 100
Cervical cancer cases attributed to
the most frequent HPV genotypes, %
53.5
17.2
6.7
2.9
2.6
2.3
2.2
1.4
Cumulative
percentage

7. Papillomavirus
phylogenetics
important
to
understand
cross
protection
HPV18-­‐
Related
45,
39,
59,
51,
56
HPV16-­‐
Related
31,
33,
35,
52,
58

8. Normal
epithelium
Basement
membrane
Basal
(stem)
cells
Parabasal
cells
Squamous
layer
Mature
squamous
layer
Infected
epithelium
Cervical
canal
HPV
Lifecycle
in
the
Cervix
Frazer
IH.
Nat
Rev
Immunol
2004;4:46–54
Infection
of
basal
cells
Viral
assembly
Shedding
of
virus-­‐
laden
epithelial
cells
Episomal
viral
DNA
in
cell
nucleus
Viral
DNA
replication
Uptake
&
internalisation
of
HPV
occurs
within
2
hours

11. Co-factors: OC use,
parity, other STDs
Co-factors: smoking, host
(HLA, p53 polymorphism)
Persistent HPV
infection with
oncogenic types
Transient
HPV
infection
Sexual activity:
woman and her
male partners
Invasive
cervical
cancer
Low grade
lesions
High grade
lesions
Normal
cervical
epithelium
Viral
factors:
variants
and viral
load
Co-factors: nutrition
A Multifactorial Model of Cervical Cancer Etiology
Spence, et al. AJC 2005.

12. Natural
Course
of
Genital
HPV
Infection
First
Lesion
Immune
Response
Incubation
Active Growth
Sustained
clinical
remission
Persistent or
recurrent
disease
Infection
Seroconversion
Average time
9mo
Low risk HPVs clear more rapidly than high risk HPVs
HPV 16 infection lasts on average 12-18 months

13. Genomic
background
§ All
PV(s)
share
a
similar
genomic
organization
consisting
of
an
early
(E)
gene
region
,
a
late(L)
gene
region
and
a
regulatory
region.
§ The
5
early
proteins
(E1,E2,E5,E6and
E7)
are
required
for
viral
replication
and
/or
cellular
transformation.

14. Role
of
E6
and
E7.
§ Expression
of
the
E6
oncoprotein
allows
the
infected
cell
to
be
insensitive
to
antigrowth
signals
and
to
evade
apoptosis.
§ Expression
of
the
E7
oncoprotein
leads
to
insensitivity
to
antigrowth
signals
and
the
immortalization
of
keratinocytes.

15. § HPV
mediated
oncogenesis
requires
accumulation
of
additional
genetic
mutations
over
time
.
§ This
suggests
a
long
precancerous
state
in
most
cases
of
invasive
cancer
that
allows
the
accumulation
of
secondary
genetic
mutations
along
with
other
cofactors
such
as
smoking
,
carcinogens
and
hormonal.

16. Human
PV(s)
and
cervical
neoplasia.
§ 4
steps
in
the
development
of
cervical
cancer
:
1-­‐Infection
of
the
metaplastic
epithelium
of
the
TZ
with
one
or
more
carcinogenic
HPV.
2-­‐Viral
persistence
.
3-­‐Progression
to
CIN3.
4-­‐Invasion.

17. Anatomy
of
the
TZ
§ The
TZ
is
defined
as
that
area
lying
between
the
original
SCJ
and
the
colposcopic
new
SCJ
§ Cervical
Cancer
originates
within
the
TZ.

18. Squamous
metaplasia
:
a
pivotal
process
in
cervical
carcinogenesis
§ The
increase
in
E2
level
during
puberty
leads
to
eversion
of
the
endovervical
columnar
epithelium.
§ The
process
of
repair
results
in
replacement
with
squamous
metaplastic
epithelium.

19. § Potential
carcinogens
at
times
of
active
metaplasia
can
deviate
it
to
a
neoplastic
pathway.
§ The
lifetime
risk
for
development
of
cervical
cancer
is
increased
26
folds
if
age
at
first
intercourse
is
within
1
yr
of
menarche
.

21. Steps
in
the
development
of
cervical
cancer.

22. HPV
Immunology
§ Unlike
Hepatitis,
HPV
is
stealthy
&
evades
the
immune
system
§ Natural
infection
with
HPV
does
not
reliably
protect
against
future
infection
or
reactivation
§ Antibodies
are
considered
an
important
mediator
of
vaccine-­‐induced
protection
by
preventing
entry
of
the
virus
into
the
basal
cell

23. Turn off the alarm systems
Keep a low profile
Don’t cause trouble – no violence
HPV – a Lesson in How to Evade
the Forces of Law and Order

24. § Most
HPV
infections
are
transient
and
usually
cleared
within
several
months
to
2
yrs.
§ 90%
of
women
clear
a
specific
HPV
type
after
2
yrs
of
observation.
§ Only
persistent
high
risk
infection
of
the
cervical
epithelium
appears
to
trigger
neoplastic
progression.
§ HPV
type
is
the
strongest
factor
affecting
the
risk
of
viral
persistence
.

25. § Only
1
in
10
to
1
in
30
HPV
infections
are
associated
with
abnormal
cervical
cytology.
§ HPV
16
is
highly
carcinogenic
with
an
absolute
risk
of
CIN
3
approaching
40%
at
3-­‐5
yrs.
§ Up
to
1/3
of
women
have
more
than
1
HPV
type
.
§ The
average
time
from
HPV
infection
to
CIN
3
is
7-­‐15
yrs
,
peaking
at
25-­‐30
yrs.

26. Transition
into
invasive
cancer
§ The
seed
:
High
risk
HPV.
§ The
soil
:
Immature
metaplastic
epithelium
of
the
TZ.
§ The
median
age
of
women
with
cervical
cancer
is
2-­‐3
decades
later
than
for
CIN
3.
§ This
suggests
generally
a
long
average
transit
time
for
CIN
3
to
invasive
cancer.

27. Time to acquisition of HPV
infection among women free of
HPV infection at enrollment
630 college-age women
followed from 1996-01
Richardson, et al. CEBP 2003; 42:485-490.
McGill-Concordia
University
Student
Cohort:
0 10 20 30 40
Time since enrollment (months)
0
0.1
0.3
0.2
0.5
0.4
0.6
0.7
Probabilityof
incidentHPVinfection
0 10 20 30 40
Time since enrollment (months)
0
0.1
0.3
0.2
0.4
0.5
Probabilityoflow-riskHPV
0 10 20 30 40
Time since enrollment (months)
0
0.1
0.3
0.2
0.4
0.5
Probabilityof
incidenthigh-riskHPV Any types
Non-oncogenic
types
Oncogenic
types

28. Clearance of a New HPV Infection:
Ludwig-McGill and McGill-Concordia Cohorts
1.00
0.75
0.50
0.25
0.00
0 4 12 16 20 24 28 32 368
1.0
0.8
0.6
0.4
0.2
0.0
Time Since Diagnosis of Infection
ProportionRemainingPositive
ForAnyHPVType
0 12 24 36
40
Franco, et al. JID 1999; 180:1415-1423.
Richardson, et al. CEBP 2003; 42:485-490.

29. Cofactor
Interaction
with
HPV.
§ Cigarette
smoking
has
been
demonstrated
to
be
a
risk
factor
for
cervical
and
vulvar
carcinoma.
§ Nicotine,
cotinine,
hydrocarbons,
and
tars
are
found
in
cervical
secretions
of
smokers.
§ The
mutagenic
activity
of
these
products
in
cervical
cells,
similar
to
that
observed
in
lung
cells,
point
to
an
important
role
for
these
compounds
in
cervical
carcinogenesis.
International
Collaboration
of
Epidemiological
Studies
of
Cervical
Cancer.
Carcinoma
of
the
cervix
and
tobacco
smoking
:collaborative
reanalysis
of
individual
data
on
13
541
women
with
carcinoma
of
the
cervix
and
23
017
women
without
carcinoma
of
the
cervix
from
23
epidemiological
studies.
Int
J
Cancer
2006

30. Infection
by
Other
Microbial
Agents.
§ Disruption
of
epithelial
integrity
and
reparative
metaplasia
associated
with
acute
cervicitis
caused
by
Chlamydia
trachomatis,
NG,
HSV,
or
Trichomonas
vaginalis
may
increase
susceptibility
to
genital
HPV
infection.
§
Chlamydial
infection
in
HPV-­‐positive
women
is
also
associated
with
development
of
high-­‐grade
CIN
and
invasive
cancer
suggesting
a
possible
cofactor
role
.
Samoff
E,
et
al.
Association
of
Chlamydia
trachomatis
with
persistence
of
high-­‐risk
human
papillomavirus
in
a
cohort
of
femal
eadolescents.
Am
J
Epidemiol2005:668–675

31. Sex
hormonal
influences
§ Condylomata
acuminata
increase
rapidly
in
size
and
number
in
pregnancy.
§ Epidemiologic
studies
have
shown
an
increased
risk
of
CIN
in
long-­‐term
oral
contraceptive
pill
(OCP)
users.
§ Prospective
follow-­‐up
of
high-­‐risk
HPV-­‐positive
women
does
not
demonstrate
an
increased
risk
of
CIN
3
among
OCP
users
.
§ There
has
been
no
demonstrable
clinical
value
to
ceasing
oral
contraceptives
in
the
management
of
HPV-­‐associated
disease.
Castle
PE
et
al
Hormonal
contraceptive
use,
pregnancy
and
parity,
and
the
risk
of
cervical
intraepithelial
neoplasia
3
among
oncogenic
HPVDNA-­‐positive
women
with
equivocal
or
mildly
abnormal
cytology.
Int
J
of
Cancer
2005;117:1007–1012.

32. Exogenous
and
endogenous
immunosuppression.
§ Renal
transplant
patients
have
16
times
higher
chance
of
developing
CIN
compared
to
general
population.
§ The
risk
of
CIN
and
Cx
Cancer
is
increased
in
HIV
positive
women
.
§ Hodgkin s
disease
,
leukemia
and
collagen
vascular
diseases
are
associated
with
an
increased
incidence
and
recalcitrancy
of
HPV
associated
disease.

33. Dietary
factors
§ Deficiencies
of
vitamin
A
or
beta
carotene
may
increase
the
risk
of
CIN
and
cervical
cancer
.
§ >
50
%
reduction
in
persistence
of
high
risk
HPV
DNA
has
been
shown
in
patients
with
higher
levels
of
Vit
A
byproducts
within
their
system
.

34. Summary
§ There
are
over
40
common
genital
HPV
types
that
are
primarily
sexually
transmitted.
§ The
vast
number
of
women
will
be
infected
with
one
or
more
HPV
types
in
their
sexual
lifetime.
§ Persistent
infection
with
HPV
types
can
cause
abnormal
cytology
(Pap
tests)
including
diagnoses
of
ASC,
AGC,
LSIL,
and
HSIL,
as
well
as
abnormal
histology
identified
following
biopsy
diagnosis
as
CIN
1
to
3,
AIS,
and
cancer.

35. § Only
a
small
subset
of
women
infected
with
high-­‐risk
carcinogenic
HPV
will
develop
invasive
cervical
cancer.
§ Although
carcinogenic
HPV
is
a
necessary
cause
of
invasive
cervical
cancer,
a
number
of
cofactors
have
been
associated
with
HPV
persistence
and
HPV-­‐related
disease
progression
including:
(1)
viral
factors
such
as
genotype
(eg,
HPV
16)
(2)
tobacco
and
long-­‐term
oral
contraceptive
use
(3)
genetic
and
immunologic
host
factors
including
innate
immunity.

36. Thank
you