HPV Testing May Detect More Precancerous Cells Than Conventional Cytology

From MedscapeCME Clinical Briefs
HPV Testing May Detect More Precancerous Cells Than Conventional Cytology
News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD
May 4, 2010 — As part of a well-established organized screening program, primary human papillomavirus (HPV) screening with cytology triage is more sensitive than conventional cytology in the detection of cervical intraepithelial neoplasia (CIN) grade III, according to the results of a randomized trial reported online April 28 in the BMJ.

"The incidence of invasive cancer is the most informative standard in the evaluation of cervical cancer screening programmes and screening methods," write Ahti Anttila, PhD, research director, Mass Screening Registry of the Finnish Cancer Registry in Helsinki, Finland, and colleagues. "We evaluated the impact of primary HPV DNA screening with cytology triage on cervical cancer, severe …CIN, or adenocarcinoma in situ (as a composite outcome referred to as CIN III+)."
In southern Finland from 2003 to 2005, a total of 58,076 women (aged 30 – 60 years) were invited to take part in the routine population-based screening program for cervical cancer. Participants were randomly selected to undergo a primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive, or to conventional cytologic screening. The primary study endpoint was CIN III+ occurring from 2003 to 2007, as determined from record linkage between files from the screening registry and the national cancer registry.
Total follow-up was 95,600 woman-years in the HPV group and 95,700 woman-years of follow-up in the conventional group. During follow-up, there were 76 and 53 cases of CIN III+, respectively, including 6 and 8 cervical cancers, respectively. For the HPV group vs the conventional group, the relative rate (RR) of CIN III+ was 1.44 (95% confidence interval [CI], 1.01 – 2.05) for all women invited for screening and 1.77 (95% CI, 1.16 – 2.74) for women who participated in the screening.
The RR of subsequent CIN III+ was 0.28 (95% CI, 0.04 – 1.17) among women with a normal or negative test result, and the rate of cervical cancer between groups was 0.75 (95% CI, 0.25 – 2.16) among women invited for screening and 1.98 (95% CI, 0.52 – 9.38) among those who took part in the screening.
"When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions," the study authors write. "The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention."
Limitations of this study include relatively low screening attendance rate, potential fluctuations in diagnostic criteria during the study period, and limited statistical power to analyze any impact on invasive cervical cancer.
"Primary HPV screening should be piloted in an organised programme, and extension towards a national implementation should be considered if the outcome is favourable," the study authors conclude. "As characteristics and organisational details between cervical cancer screening programmes are highly variable in different countries, each programme needs to evaluate the new methods in their own context…. We think that gradual implementation of HPV screening in regions other than those in this trial is justified."
The European Commission, Europe Against Cancer action programme through European Cervical Cancer Screening Network; the Academy of Finland; and the Cancer Organisation of Finland supported this study. The study authors have disclosed no relevant financial relationships.
BMJ. Published online April 28, 2010.
Additional Resource
More information on cervical cancer screening guidelines is available on the Center for Disease Control and Prevention's Web site.
Clinical Context
Screening methods to improve the prevention of cervical cancer have been proposed. In the April 2, 2009, issue of the New England Journal of Medicine, Sankaranarayanan and colleagues reported that HPV testing reduced cervical cancer mortality rates and cases of advanced cervical cancer.
This population-based randomized trial assesses the use of HPV DNA screening with cytology triage vs the reference of conventional cytology testing to detect cervical cancer and severe precancerous lesions.
Study Highlights
• 58,282 women aged 30 to 60 years were invited to a routine screening program for cervical cancer in Finland from 2003 to 2005.
• 29,144 (50%) were randomly assigned to a primary HPV DNA test with cytology triage if the result was positive.
• 29,138 women were randomly assigned to conventional cytology screening as the reference group.
• 107 from the HPV group and 99 from the reference group were excluded for emigration, earlier cervical cancer, or death.
• Conventional practice included colposcopy and biopsy referral if cytology result was equal to Papanicolaou class III to V, intensified screening (repeated screening after 12 – 24 months) if Papanicolaou class II result or negative colposcopy and histology results, colposcopy if borderline cytology results 2 or 3 times during intensified screening, and treatment of CIN I lesion in women 30 years or older.
• HPV screening protocol was an HPV test of an endocervical sample, immediate referral for a clearly positive cytology result, intensified screening for borderline cytology or negative cytology plus positive HPV result, and colposcopy for repeated borderline cytology findings or 3 consecutive positive HPV tests with negative cytology results.
• 58,076 women had data for analysis.
• Cytologic sampling included vaginal, cervical, and endocervical samples with a cytobrush from the junction and endocervix and with 2 spatulas from the ectocervix and vaginal fornices.
• Follow-up started from first invitation and ended at whichever occurred first of emigration, death, diagnosis of CIN III, adenocarcinoma in situ, or cervical cancer, or the end of 2007.
• Mean follow-up was 3.3 years, with a maximum of 5 years.
• Screening registry records were linked to the national cancer registry.
• The primary outcome measures were rate of cervical cancer, CIN III, and adenocarcinoma in situ (combined as CIN III+).
• Negative results were defined as the ratio of relative light units less than 1.00 on an HPV test or Papanicolaou class I on a cervical smear test.
• Positive results were defined as the ratio of relative light units of at least 1.00 (equivalent to HPV DNA concentration of 1 pg/mL) or abnormal result on cervical smear.
• More positive screening episodes occurred in the HPV group vs the reference group (110 vs 72).
• More recommendations for intensified screening occurred in the HPV group vs the reference group (1244 vs 1053).
• CIN III+ occurred in 76 women in the HPV group vs 53 women in the reference group.
• Among all invited women, the RR of CIN III+ in the HPV group vs the reference group was 1.44 (95% CI, 1.01 – 2.05).
• Among women who attended screening, CIN III+ was detected in more women in the HPV group vs those in the reference group (59 vs 33; RR, 1.77; 95% CI, 1.16 – 2.74).
• Among invited women, cervical cancer occurred in 6 in the HPV group vs 8 in the reference group (RR, 0.75).
• Among women who attended screening, cervical cancer occurred in 6 in the HPV group vs 3 in the reference group (RR, 1.98).
• Among women with a normal or negative test result, CIN III+ occurrence was less common in the HPV group vs the reference group but this was not significant (RR, 0.28).
• The rate of cervical cancer between groups was 0.75 for invited women and 1.98 for women who attended.
• Analysis by age groups showed no difference vs overall results.
• Study limitations included relatively low screening attendance rate, possible effect of screening method on subsequent healthcare services, potential variations in diagnostic criteria, and limited power to analyze the impact on invasive cervical cancer and those with negative test results.
Clinical Implications
• HPV screening with cytology triage vs conventional cytology testing is more sensitive in detecting severe precancerous lesions of the cervix.
• In women with negative screening test results, the rate of severe precancerous lesions of the cervix appeared lower for HPV screening than conventional cytology testing but was not significant.
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