Evidence supports cytology as primary screen for cervical cancer

More data needed before panel backs wide use of HPV-enhanced primary screening for women aged at least 30 years.

Issue: November 10, 2011

In an update to guidelines first issued in 2003, members of the US Preventive Services Task Force said liquid-based or conventional cytology appear to be equally effective as a screen for cervical cancer in women aged at least 30 years, but HPV screening was too likely to generate false-positive results to serve as a substitute for the other tests.

HPV screening, with or without cytology triage, appears to be more sensitive but less specific, and it is still unclear how much HPV screening improves early disease detection, according to a report published online.

“Although HPV-enhanced screening strategies offer a potential cancer prevention benefit compared with cytology alone, test performance studies alone are insufficient to justify substituting HPV testing for cytology,” Evelyn P. Whitlock, MD, MPH, of the Oregon Evidence-based Practice Center, and colleagues wrote. “Thus, experts agree that pragmatic, comparative randomized, controlled trials of repeated screening rounds are necessary, with increasing emphasis on the need to confirm the effect, not just on surrogates (such as cervical intraepithelial neoplasia) but also on cancer incidence and mortality.”

Whitlock and colleagues concluded that HPV screening is promising, but not yet ready for wide use. Ellen Blair Smith, MD, a gynecologic oncologist at Texas Oncology in Austin, took a similar position.

“It’s highly sensitive, but not highly specific. A woman can have HPV, but still have a completely normal Pap screen,” she told HemOnc Today. “The problem with the Pap smear is that it’s an 80% test at best — it only tests for cervical cancer. HPV screening added on to the Pap smear will eliminate that 20% false negative Pap smear result.

“But we also have an epidemic of HPV in this country and there are hundreds and thousands of women with low-level HPV changes that will never become cancer. Those women will never have normal Pap smear results. We spent $6 billion in 2000 to eradicate these low-level HPV changes that never kill anybody and only make patients worse.”

Whitlock and colleagues reviewed 4,262 abstracts and 641 full-text articles published from September 2010 to August 2011. They also added nine additional studies to the review. Researchers identified one fair-quality and one good-quality randomized controlled trial comprising 134,162 women aged 30 to 60 years. The review also included two fair-quality observational studies of 7,404 similarly aged women who reported absolute sensitivity and specificity of both tests in primary care applicable settings.

Based on these results, liquid-based cytology and conventional cytology were roughly equal for relative detection, absolute sensitivity and specificity for detection of cervical intraepithelial neoplasia (CIN) 2+/CIN3+ at any cytologic threshold.

Results from six diagnostic accuracy studies showed that one-time HPV testing was more sensitive but less specific than cytology. For CIN3+ outcomes, point estimates for sensitivity ranged from 86% to 97% for HPV testing compared with 46% to 50% for cytology. Sensitivity ranged from 63% to 98% for HPV testing vs. 38% to 65% for cytology of CIN2+ outcomes. However, the task force said specificity for CIN2+ and CIN3+ was consistently 3% to 5% lower for HPV testing. In one Italian study, more than twice as many women who underwent HPV screening were referred to colposcopy (5.8% vs. 2.5%).

Researchers conducting four large trials — ARTISTIC, NTCC phase 1, POBASCAM and Swedescreen — involving 82,390 participants compared cytology screening alone vs. cytology plus HPV screening. Cumulative CIN 3+ detection was the same between combination testing and cytology alone after two screening rounds in all four trials. Cumulative invasive cancer detection was similar or slightly higher for cytology alone than for the combination in all trials, except ARTISTIC.

NTCC phase 1 was the only trial to show a relative increase in any cumulative CIN measure after combination testing, but that trial used a lower threshold for immediate colposcopy than the other trials. In the other three trials, high-grade squamous intraepithelial lesion was the referral threshold for colposcopy, with colposcopy referral for HPV-positive results only after repeated testing revealed persistent HPV positivity or abnormal cytology, according to the report.

“Many doctors in the United States are doing cytology along with HPV. It’s not that expensive and if there’s an abnormal cytology but abnormal HPV, it’s considered a negative result,” Maurie Markman, MD, senior vice president of clinical affairs and national director of medical oncology for Cancer Treatment Centers of America and HemOnc Today gynecologic cancer section editor, said. “The problem with cytology is that it can be very nonspecific, and of course, the problem with HPV is that it can be nonspecific, as well. But the combination of an abnormal cytology and an abnormal potentially high-risk HPV is very powerful. One cannot make the argument today that it’s terribly cost-effective, but I think it’s a reasonable approach.”– by Jason Harris

For more information:

Whitlock EP. Ann Intern Med. 2011 [Published online ahead of print Oct. 17].

Disclosure: Drs. Markman and Smith report no relevant financial disclosures.