Will HPV Screening Replace the Pap Smear?

According to the American College of Obstetricians and Gynecologists (ACOG), the use of cytologic testing (ie, Pap smear) has reduced the incidence of cervical cancer by >50% in the past 30 years. Nevertheless, in its new practice guidelines (Obstet Gynecol. 2009;114:1409-1420) released on November 20, 2009, ACOG has made major changes to cervical cytology screening guidelines, representing a major shift from the current annual screening. The new guidelines include:

•  Raising first screening to age 21, avoiding screening earlier
• For patients aged 21 to 29 years, screening every 2 years only
• Optional screening every 3 years for patients aged 30 to 65 years
• Optional stopping screening between 65 and 70 years, in patients with 3 previous negative tests.

 Coming on the heels of these changes, a new debate has emerged on whether human papillomavirus (HPV) testing or the Pap smear should be used for primary screening. With HPV infection now established as the causative agent in most cases of cervical cancer, there is a move to replace the Pap smear with HPV DNA testing as the primary screening tool for cervical cancer. This debate was featured at the American Society of Clinical Pathology annual meeting in November 2009. Several studies have recently shown that HPV screening is more sensitive than cytologic screening, although less specific.

The following debate illustrates the pros and cons of each screening method for cervical cancer. Isam A. Eltoum, MD, Professor of Pathology and Director of Cytopathology at the University of Alabama, Birmingham, advocates HPV as the primary screening method. R. Marshall Austin, MD, PhD, of Magee-Women’s Hospital of University of Pittsburgh Medical Center, PA, opposes the change.

Rationale for HPV Screening
According to Dr Eltoum, in the proposed new paradigm, screening for cervical cancer will shift to screening for HPV infection, and targeted screening will replace mass screening. Using screening by HPV DNA test, women who test negative for HPV would be rescreened every 3 to 5 years. Those testing positive for HPV would have “reflex cytology” as a follow-up test. If the cytology test is negative, the woman would be tested by both methods 6 to 12 months later. If both tests are negative, she would be screened every 3 to 5 years. Women with positive results would be referred for treatment.

Dr Eltoum points out that only 15% of women are estimated to test positive for HPV, which would reduce the number of Pap smears from 68 million to 10 million a year. “Cytology has been very successful, but it has reached its limits,” he said, noting that cytology:

• Has a low sensitivity rate and a high false-negative rate
• Must be repeated often
• Has poor reproducibility
• Is labor-intensive, and therefore can be expensive.

HPV testing is more sensitive than cytology, especially in women aged ≥30 years, but it is slightly less specific. It is objective and reproducible, is automatable and therefore less labor-intensive, and is the best way to monitor the effects of HPV vaccination, he said.

The Cytopathology Education and Technology Consortium issued guidelines in 2009 for HPV testing (Am J Clin Pathol. 2009;131:768-769; discussion 770-773). Accordingly, routine HPV testing is considered inappropriate in women aged <30 years, or in conjunction with cervical cytology more often than every 3 years for older women whose tests were negative at last screening. It is also not recommended for women aged <20 years, or for the initial triage of women with abnormal Pap results.

It has been established that HPV testing is more sensitive than a Pap smear. “Common sense says to go with the most sensitive test first for screening, then add a more specific layer [ie, cytology] later,” Dr Eltoum noted. Cotesting with both methods as initial screening adds unnecessary procedures.

HPV testing detects more CIN2+ and CIN3+ lesions in the first round than cytology. Total abnormalities detected are the same; 5 years after HPV testing, the risk of developing lesions is reduced compared with cytology, and HPV testing lengthens the interval between screenings.

Many international trials are now comparing primary HPV screening with cytology in populations of between 7868 and 44,102 women. The evaluation of the co-testing concept in US studies should determine outcomes for the various scenarios. The focus will be on patients who are cytology-positive but HPV-negative. “If the lesions missed on HPV testing are insignificant, this will be convincing of the value of HPV first, and cytology second,” Dr Eltoum points out.

Pap Testing Should Remain Standard of Care
These arguments have not convinced Dr Austin, who argues that the Pap test should remain, at least for now, the centerpiece of cervical screening. “Medicine is a complex mix of science, business, and politics, and all 3 factors are at play here.” Dr Austin argues that the industry (ie, vaccine manufacturers) has been too involved in the push for HPV testing, that statements from supporting organizations are “closely associated with commercial messages,” and that cytopathologists and clinicians “in the trenches” have not been included in program development.

Under this new “manufacturerinspired prevention paradigm,” cervical cancer prevention will consist of primary prevention by HPV vaccination and secondary prevention by screening, according to Dr Austin. Funding to support vaccination would be gained by diverting funds from screening; increasing screening intervals, utilizing HPV testing, and decreasing the use of cytology.

HPV infection prevention with vaccines is key to this approach, but questions remain about its effectiveness, says Dr Austin. It is assumed that HPV vaccination will:  

• Prevent cervical cancer
• Be proved safe in large-scale, longterm use
• Have sufficient uptake in high-risk groups, despite cost, to decrease the rate of precancerous lesions.  

However, he noted, efficacy in clinical trials does not necessarily translate into reductions in high-grade dysplasia rates and cancer in the population.

Universal HPV vaccination of virginal girls would reduce CIN2/3 by 50% and cancer by 70%, but short of this, the population-wide impact would be much less, he notes. Just 18% of US teens have had all 3 shots, and coverage has been highest in low-risk states and lowest in highrisk states (MMWR. 2009;58:997-1001). “Vaccination is mainly for the next generation. Screening is the most effective prevention modality for the current generation of women,” Dr Austin said.

Dr Austin acknowledges that the importance of HPV and the availability of vaccines have triggered a paradigm shift. “But paradigm shifts tend to have messy transitional phases.”

When successfully implemented, the Pap test reduces cervical cancer rates by between 60% and 90% within 3 years of being introduced to populations not previously screened, Dr Austin says. Cytology sensitivity is 90% to 95% with newer methods, such as liquid-based cytology and computer-assisted screening. Furthermore, less-impressive studies for HPV screening have been disregarded. In a study of 61,000 Finnish women randomized to HPV testing or cytology, HPV testing was not superior in identifying CIN3 and cancer (Eur J Cancer. 2008;44:565-571). Primary HPV screening with reflex cytology finds more CIN lesions compared with conventional screening, but mild lesions are overrepresented, likely resulting in overdiagnosis, because most of the lesions will regress.

There is a proved relationship between the positive predictive value of cytology, the cost-effectiveness of diagnostic intervention, and the severity of the abnormality prompting diagnostic follow-up, Dr Austin says. “There are data indicating high sensitivity and safety with already widely used, FDA-approved cytology screening enhancements.”

A Change Raises New Issues
“The population has learned that Pap testing is effective. It’s an accepted practice. It has been part of women’s wellness visits for the last 50 years, and this is not a minor issue,” said Dr Austin. Women will view less frequent screenings as efforts to “economize, not deliver better care,” he predicts. “An HPV-negative test only represents the moment the test was done. We would never tell an active homosexual with a negative HIV test to check back in 5 years.”

Dr Austin is concerned that an HPV-positive test result would cause unnecessary concern among women, because most positive results represent transient infections that will regress. CIN2/3 that is likely to regress cannot now be reliably differentiated from CIN2/3 that is capable of progressing to cervical cancer, he emphasizes. “If you are trying to find who has disease, HPV testing has limited positive predictive value,” he notes. “You need additional testing to see who has disease and go after them.”

At the University of Pittsburgh, from 2005 to 2008, sensitivity rates for detecting CIN2/3, adenocarcinoma in situ, and cervical cancer were 96.06% for Pap testing, 95.41% for HPV DNA testing, and 99.91% for co-testing. “I argue that current methods have more power than is generally realized if done properly,” he said.

Furthermore, HPV vaccination does not lessen the need for vigilance. The current vaccines protect mostly against HPV 16 and 18, which cause 70% of cervical cancers but just 50% of CIN2/3 lesions. “Their type-restricted protection means that some serious HPV infections will still occur in vaccinated women,” Dr Austin points out.

Finally, the FDA has not approved stand-alone HPV testing for primary screening, and this could be a “daunting” challenge. “For the foreseeable future, cervical cancer screening will remain critical to cervical cancer prevention. The maximum reduction in HPV-associated cancer will require the development of second-generation vaccines, with activity against a broader range of HPV types,” suggests Dr Austin. “Such changes will come later, rather than sooner.”