HPV & Pap Smears
HPV TESTING IMPROVES ACCURACY OF PAP
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HPV Testing a Promising New Option in Cervical Cancer Screening CME
News Author: Allison Gandey
CME Author: Charles Vega, MD
Release Date: October 22, 2007; Valid for credit through October 22, 2008
October 22, 2007 — A new study suggests that testing for human papillomaviruses (HPV) may surpass the Papanicolaou (Pap) test as clinicians shift from cellular to viral testing. Reporting in the October 18 issue of the New England Journal of Medicine, researchers show that HPV testing has greater sensitivity in detecting cervical cancer.
The results are from the first screening round of the Canadian Cervical Cancer Screening Trial, a randomized controlled study that so far has confirmed the findings of previous studies. The collaborators are led by Marie-Hélène Mayrand, MD, from McGill University in Montreal, Quebec.
“HPV testing for primary screening for cervical cancer would be far superior to Pap testing,” senior author Eduardo Franco, DrPH, also from McGill, told Medscape Oncology. “This is mostly due to the exquisite sensitivity of HPV testing,” he said. “You would think you would pay a price in terms of specificity, but we found it was not very much lower than the Pap test.”
Dr. Franco says the sensitivity of the Pap test was almost the equivalent of tossing a coin to predict disease — just 55% — compared with the HPV test, which had a specificity of 95%.
But, he added, the Pap test is not on its way out yet. “It would still be desirable to look at the Pap test to sort out any molecular abnormalities identified in the HPV test.”
Pap Test Still a Valuable Screening Method
In an accompanying editorial, Carolyn Runowicz, MD, from the University of Connecticut Health Center in Farmington, calls the Canadian trial “well designed,” but she agrees with Dr. Franco that the Pap test is not on its way out. “We are not there yet,” she writes.
“The ultimate goal is to reduce the incidence of and mortality from invasive cervical cancer worldwide with a cost-effective and readily available test. The optimal approach will depend on the prevalence of disease, access to screening, and available resources,” she adds.
The investigators compared HPV testing with conventional cervical cytologic testing as stand-alone screening tests for identifying cervical cancers and their high-grade precursors in more than 10,000 women aged 30 to 69 years.
The researchers used an HPV DNA assay approved by the US Food and Drug Administration and conventional cervical cytologic testing in a North American population of women at average risk for cervical cancer who had access to quality care.
Patients were referred for colposcopy if they had a positive Pap test or HPV screening test result or if they were randomly selected from among women with a normal result on the index test.
In the same issue of the New England Journal of Medicine, Swedish researchers report the results of a population-based, randomized controlled trial comparing conventional cytologic testing with this method plus HPV testing.
Led by Pontus Naucler, MD, PhD, from Malmö University Hospital at Lund University in Sweden, the research team studied more than 12,500 women aged 32 to 38 years participating in a cervical cancer screening program.
Adding the HPV Test to Conventional Screening Bolstered Detection
The researchers reported that women with grade 2 or 3 cervical intraepithelial neoplasia or cancer at enrollment who received HPV testing in addition to conventional cytologic testing were 51% more likely to have lesions detected than women receiving cytologic testing alone.
Dr. Naucler and colleagues report that at subsequent screening, there was a 42% reduction in the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer in the intervention group compared with the control group. These results are consistent with other trials of both cervical cytologic testing and HPV testing.
In her editorial, Dr. Runowicz points out that the Swedish authors used a very sensitive method of HPV DNA detection, which is not widely available. And she notes that while the authors suggest that HPV testing protects against grade 2 or 3 cervical intraepithelial neoplasia or cancer, they acknowledge that the increased sensitivity of HPV testing results in the diagnosis of lesions that could have regressed spontaneously or might never have been detected.
“Their data support the idea that grade 2 cervical intraepithelial neoplasia lesions regress spontaneously,” she notes, but this may not be true for grade 3 lesions. “The extent of over diagnosis and the long-term protection against grade 3 cervical intraepithelial neoplasia and invasive cancer after a negative test for HPV will need additional study.”
Dr. Naucler and colleagues also point out that they followed up the women for an average of only 4.1 years. “This period covers the next screening round (scheduled to take place 3 years later) in terms of Pap smears and immediate referrals,” they write. “It does not cover the associated follow-up of low-grade lesions, which may take several years. To evaluate fully the effect of over diagnosis in the subsequent screening round, a longer follow-up that extends the next screening round for several years will be needed.”
Speaking to Medscape Oncology, Dr. Franco suggested that if study results continue in the current direction, it may be possible to prolong the time between screenings. However, since this was the first screening round for the Canadian trial, the authors could not address the length of protection afforded by a negative HPV test.
“It can be argued that if HPV DNA testing becomes a standard primary screening tool for cervical cancer, more women will be referred for colposcopy, thereby considerably increasing the use of health care resources,” Dr. Runowicz writes in her editorial. “The Canadian authors caution that triage algorithms that identify HPV DNA positive women at high risk for cervical intraepithelial neoplasia, such as HPV DNA testing followed by Pap testing, are essential and need to be assessed in controlled trials.”
Dr. Franco suggests that shifting from cellular or cytologic to viral or molecular testing coupled with education and vaccination will contribute to more efficient control of cervical cancer. And he says he is eagerly awaiting future guidelines — especially with respect to new cervical cancer vaccines.
“In a way, we are victims of our own success,” Dr. Franco said. “Our research has reaped good dividends and now it will be a matter of sorting everything out in future guidelines and recommendations.”
The Canadian Cervical Cancer Screening Trial was supported by a grant from the Canadian Institutes of Health Research and by an unrestricted grant from Merck Frosst Canada. Dr. Mayrand has disclosed receiving consulting and lecture fees from Merck Frosst, Pfizer, Roche, and GlaxoSmithKline. Drs. Ferenczy, Ratnam, Coutlée, and Franco also have disclosed various financial relationships. The researchers of the Swedish study and editorialist Dr. Carolyn Runowicz have disclosed no relevant financial relationships.
N Engl J Med. 2007;357:1579-1588, 1589-1597, 1650.
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Clinical Context
As researchers understand more regarding HPV as a causative agent in cervical cancer, there has been an effort to determine whether HPV testing has a role in clinical practice. An editorial by Runowicz, which accompanies the current studies, reviews the role of HPV in cervical cancer. The prevalence of HPV in cervical cancer exceeds 99%, although most infections resolve spontaneously without causing cervical dysplasia. Available HPV testing has proven to be more sensitive than cytologic testing for cervical dysplasia, albeit at the cost of a worse specificity.
Two studies in the current issue of the New England Journal of Medicine compare HPV screening vs Pap testing for cervical cancer screening.
Study Highlights
- Mayrand and colleagues
- Women eligible for study participation were between the ages of 30 and 69 years old and lived in 1 of 2 cities in Canada.
- Participants underwent conventional Pap tests along with HPV screening. A positive Pap or HPV test result prompted referral for colposcopy, and a number of women with normal test results were also referred for colposcopy.
- The main study outcomes were the sensitivity and specificity of HPV testing vs Pap testing for the detection of cervical intraepithelial neoplasia 2 or worse lesions.
- 10,154 women underwent testing. 7.1% of women with normal results underwent colposcopy, as did more than 90% of subjects with a positive screening examination.
- The sensitivity of the Pap test was lower vs HPV testing (55.4% and 94.6%, respectively), but the specificity of Pap testing was slightly better (96.8% and 94.1%, respectively).
- Negative predictive values for high-grade cervical dysplasia exceeded 99% for both HPV and Pap testing.
- Naucler and colleagues
- 12,527 women presenting for cervical cancer screening in Sweden were randomized to have a Pap test plus HPV testing (intervention group) or a Pap test alone (control group). Eligible patients were between the ages of 32 and 38 years old.
- Women with a positive HPV test result but a negative Pap test result were offered repeat HPV testing 1 year later. If the HPV test yielded persistently positive results, women were offered colposcopy. Researchers performed repeat Pap tests and colposcopies on a random number of women in the control group to avoid ascertainment bias.
- The main study outcome was the incidence of grade 2 or 3 cervical intraepithelial neoplasia. These data were obtained from a central registry, and the average length of follow-up was 4.1 years.
- During the entire study, 139 women in the intervention group were found to have cervical intraepithelial neoplasia 2 or 3, which was similar to the number of 119 in the control group.
- 51% more cases of cervical intraepithelial neoplasia 2 or 3 were diagnosed during the first screening round in the intervention vs control groups, a significant difference. However, at subsequent screening examinations, the diagnosis of cervical intraepithelial neoplasia 2 or 3 was 42% less frequent in comparing the intervention and control groups.
- The diagnosis of cervical intraepithelial neoplasia 3 or cancer was 47% less frequent during subsequent screening rounds in the intervention vs control groups.
- Of 72 women with an initial negative colposcopy finding in spite of the presence of high-risk HPV types, 24% eventually developed cervical intraepithelial neoplasia 2 or 3 or cancer.
Pearls for Practice
- HPV is present in nearly all cases of cervical cancer, although most cases of HPV infection resolve spontaneously. HPV testing has previously been demonstrated to be more sensitive but less specific than cervical cytology in detecting cervical dysplasia.
- Two new studies confirm that HPV testing is more sensitive than Pap testing in diagnosing cervical intraepithelial neoplasia, and adding HPV testing to Pap testing increases the detection of high-grade cervical dysplasia at the first examination and reduces this rate in subsequent examinations