Background:
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Cancer
associated HPV’s
are found in 95% of CIN 2 & 3 vs. 10% of normal women, yielding a relative
risk estimate of 80:1
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Non-infected
cervical keratinocytes are immortalized by oncogenic HPV infection.
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Histologic
features of CIN 2 & 3 can be reproduced in vitro and iv vivo by oncogenic
HPV infection of previously normal human keratinocytes.
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Progressive
potential of minor cervical atypia is influenced by HPV type HPV Infection
linked to progressin from CIN 2 to 3 to invasive cancer
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Cross
sectional data show strong, consistent relationship between specific
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HPV
types and both precursor and invasive disease.
l
The
HPV-immortalized human cells can eventually develop tumorigenic
(invasive)
properties with long term culture.
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HPV
Viral genome (especially E6 & E7) is continuously transcribed within
cancer cells andcervix cancer derived cell lines.
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The
E6 & E7 viral proteins bind tow cellular anti-oncogenes (p53 and pRb) that
control cell growth rated.
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The
HPV DNA is episomal in benign lesions but is integrated into cellular genome
of most cancer cells.
Application
for High Risk Human Papillomavirus Test
1.
HPV is a Diagnostic Test supplementing a screening program
“Screening
tests are relative simple procedures, designed to separate healthy persons
from those who may have disease. They are not intended to be diagnostic but to
identify patients who require a formal evaluation…….the
use of HPV testing conforms to the basic philosophy of clarifying the nature
and prognosis of any underlying disease”
R. Reid, A. Lorincz New Generation of HPV Tests 1996.
2.
Management
of Equivocal Cytology results
THEORY
HPV
is found un at least 95% of all HSIL
APPLICATION
AS
a supplement or Triage for Atypical / ASCUS / AGUS Smears, either in
conjunction with second smear or on its own (this way a test can be performed
earlier than the 3-5 month delay necessary before a second smear can be taken,
and referral based on the HPV shows better sensitivity than second Pap smear.
BENEFIT
Patient
is able to get information earlier than waiting for second Pap smear, which
can relieve some anxiety and validate an earlier referral to colposcopy.Women
could avoid a colposcopy and less colposcopies would be performed.(Pathology
services are retained and increases market value before being referred to
gynecological services)
Subsequent
screening cycles and management could be improved.
3.
Screening
Applications, Older women
Cytology
in peri-and post mennopausal women is problematic; relative proportion of
positive smears representing invasive cancer increases 17 times in 40 year
olds vs 20 year olds; cytologic false negative ratea rise with age due to
transformation zone recession into the cervical canal; falis positives rise in
this age group becaouse of the confounding effects of estrogen deficiency.
HPV
high risk positivity in older women is indicative of long term persistent
infection, and higher risk for developing dysplasia.
Ease
the concern of some clinics about the biannual not being sufficient as a
screening cycle. They continue to recommend annual. HPV testing would identify
those that would benefit from annual screens, as well as alternate
technologies.
Risk Assessment
THEORY
HPV
High Risk Detection in Pap Smear negative women is predictive
of an increased risk of subsequent detection of CIN, Cox Obstet & Gyn
Clinics of Nth America 1996; Vol 23:811-851
APPLICATION
Women
over 30 could be assessed for theur HPV status as a means of determining
risk for developing cervical disease.Test for the cause rather than wait for
the effect.
BENEFIT
Suggestive
of closer scrutiny and more reqular Pap smears.
Validate
the ejpense
of additional Pap smears technology, Papnet/thinPrep/AutoCyte
Detect
Lesions before more extensive treatment would be needed.(No referral would
be based on HPV positivity/ normal Cytology results.)
4.
Management
of Low-Grade Cervical Disease; Predicting Regression, a Persistence, or
Progression of Untreated CIN1
Most
LSIL will regress (median value from # studies is 48% regress,and 12%
progress),and trestment (intervenyion) should be based on presence of high
risk HPV.Research has demonstrated that greater than 95% of HSIL and cancers
contain oncogenic HPV, whereas very few non specific inflammatory/reparative
changes will be colonized by such viruses. Alternative screening technologies
are increasing the number of LSIL smears, if all were referred the additional
vvisits will overwelm the colposcopic services and result in unnecessary
intervention.
Treatment
of CIN 1 or LSIL would be specifically indicated if patient was HPV high risk
postive. A more conservative or “wait
and see”
approach could be adopted on the HPV negative patients.
Patients
would have a treatment option. Gynaecologists would prioritize referrals based
on HPV result, and could immediately treat evev where there was minimal aceto
white presence. It situations where the colposcope was normal, the HPV result
would support regular cytologic follow up.
5.
Management
of Equivocal histology
Postive
HPV test would identify a subset of women who have either occult SIL missed at
initial colposcopy or an emerging lesion that will manifest in the near
future.
A
negative or equivocal result is reported in approx 30% of patients who have
directed biopsy for LSIL (Montz 1992). The decision to continue to triage or
treat versus suspending work-up or returning patient to cytological follow up
is difficult.
A
normal Coposcope and negative HPV result confer a negative predictive valug
greater than 98%.Virus testing obviates any clinical concern over sighificant
cyto-histologic discrepancy.
HPV
could be used to manage biopsy equivocal patients, to determine follow
up and cytology and/or colposcopic cycles. Reduce anxiety in proportion of
patients.
6.
Viral Load significant marker to managem and follow-up of LSIL Post
Treatment
THEORY
Measuring
quantitative levels of HPV DNA may increase the predictive vaiue of HPV
testing as a detection tool for HSIL.
Additional
consideration when considering management options in HPV positive women.
Assists in determining a conservative treatment approach or a more aggressive
approach in CIN 1 and equivocals.
Assist
in women determining what management option they should consider.
7.
Detect
the Presence of HPV as a follow up for Treatment; Predicting Recurrence of
Disease Post Treatment
The
recurrence rate of CIN post treatment is usually around 10-15%.After treatment
for HSIL, presence of HPV determines the screening and management options for
the patient.
If
subsequent to treatment Pap smears are negative, & HPV high risk negative,
the women can return to normal screening.
Ability
to give some long term prognosis to the patient, and a way of indicating
whether there is further risk, or chances of re-occurrence of disease.
In
young women where repeated cervical ablation or may have severe consequences
on fertility, HPV may be an objective method of determining patients at
greatest risk.