Background:

Evidence of HPV infection linked to pathogenesis of CIN 2& 3

l  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

l  Non-infected cervical keratinocytes are immortalized by oncogenic HPV infection.

l  Histologic features of CIN 2 & 3 can be reproduced in vitro and iv vivo by oncogenic HPV infection of previously normal human keratinocytes.

l  Progressive potential of minor cervical atypia is influenced by HPV type HPV Infection linked to progressin from CIN 2 to 3 to invasive cancer

l  Cross sectional data show strong, consistent relationship between specific

l  HPV types and both precursor and invasive disease.

l  The HPV-immortalized human cells can eventually develop tumorigenic

(invasive) properties with long term culture.

l  HPV Viral genome (especially E6 & E7) is continuously transcribed within cancer cells andcervix cancer derived cell lines.

l  The E6 & E7 viral proteins bind tow cellular anti-oncogenes (p53 and pRb) that control cell growth rated.

l  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

THEORY

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.

APPLICATION

HPV high risk positivity in older women is indicative of long term persistent infection, and higher risk for developing dysplasia.

BENEFIT

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

THEORY

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.

APPLICATION

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.

BENEETTS

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

THEORY

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.

APPLICATION

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.

BENEFIT

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.

APPLICATION

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.

BENEFIT

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

THEORY

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.

APPLICATION

If subsequent to treatment Pap smears are negative, & HPV high risk negative, the women can return to normal screening.

BENEFIT

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.