Cervical cancer screening: new advances bring new controversies

In recent years, cervical cancer testing has seen many advances. Still, there is no silver bullet that further reduces cancer, decreases unnecessary invasive procedures, and is cost-effective. Earlier  this year, the Food and Drug Administration (FDA) approved the first frontline screen with a human papillomavirus (HPV) DNA test that could be used in place of the Pap test.¹ The agency’s move came despite objections from several parties, including a coalition of 17 patient and women’s health groups who expressed “grave concerns” that use of the HPV test as a primary screen lacked support from evidence-based guidelines and may result in more invasive procedures for clinically insignificant infections. To understand the controversy, a little background is necessary.

The success of the Pap test

The Papanicolaou (Pap) test is one of the great success stories in public health. The Pap test detects precancerous lesions and can identify cervical cancer before it becomes advanced. Since its introduction as a screening test six decades ago, cervical cancer incidence has declined; it has gone from being one of the most common cancers affecting women to 21st among all cancers. For 2014, National Cancer Institute researchers predict 12,360 new cases of cervical cancer and 4,020 deaths due to the disease.² 

Still, the Pap test has several limitations. It is subjective, has complex diagnostic categories and management algorithms, and cannot distinguish which abnormalities will resolve and which will progress to invasive cancer. Each year in the United States, three million or more women have unclear or abnormal Pap tests, and only about 12,000 actually will have cervical cancer.³ About 9 of 10 cases with abnormal Pap results revert to normal without treatment.⁴ 

Most cervical cancers are caused by persistent HPV infections, and initial use of the HPV DNA test as a co-test addresses some limitations of Pap testing. The HPV test is objective and can improve the sensitivity of the Pap test, and negative results can extend the period before re-testing. 

HPV infections are common. In the United States, approximately 79 million people are infected with HPV, and approximately 14 million become newly infected each year.⁵ In fact, most sexually active men and women will be infected at some point in their lives.⁶ Genital HPVs are a group of more than 40 related viruses of which 14 “high-risk” HPV types can cause cancer. The high-risk types HPV-16 and HPV-18 are responsible for approximately 70 percent of cervical cancers.¹ High-risk HPV infections usually self-resolve and do not cause any health problems. Half of new HPV infections are undetectable within six to 12 months, and more than 90% clear within two years.⁷ For the infections that persist, a subset will cause cervical precancer, and, if untreated, some will become invasive cancer. Typically, cervical cancer is the culmination of a decades-long process (10 to 20 years). At each step along the way, infections can resolve and abnormal cells may return to normal. 

Psychological effects of abnormal results

Although abnormal cervical cells and HPV infections usually self-resolve, to hear that “Your Pap test results are abnormal” or “You’re high-risk HPV-positive” can be disturbing for women. These test results often initiate a period of anxiety, typically with additional testing, possibly painful procedures, and potential complications.

Follow-up often includes a colposcopy/biopsy procedure where a tissue sample is removed from the cervix and examined under a microscope. Multiple tissue biopsies can weaken the cervix, leading to problems such as early labor or possible miscarriage in future pregnancies. Younger women, with their childbearing years ahead, are most impacted. 

After a woman receives abnormal Pap or positive HPV results, the following period of uncertainty can be stressful and filled with anxiety. A survey of women with findings of mildly abnormal cells found that 59% were worried or anxious about the results.⁸ Many women react with shock and say that it feels like a diagnosis of cancer. Their worries include “Will I have cancer soon? Can I have children? Am I really that sick? Am I going to die?” Even after the initial panic fades, many continue to fear for their fertility and worry about how much treatment they will undergo and for how long.⁹ The uncertainty and distress can impact sexuality, sexual health, and self-esteem. 

HPV vaccinations and cervical cancer screening

The HPV vaccine, introduced in the United States in 2006, is an important advance in the fight against cervical cancer, and fewer infections can mean fewer follow-up procedures. By 2013, about one-third (35%) of girls age 13 to 17 had received the full course of vaccine injections.¹⁰ Among girls age 14 to 19, infections with HPV-16 and HPV-18 have declined 50% (from 7.2% to 3.6%).¹¹ The vaccine targets high-risk HPV-16 and HPV-18, but does not protect against the other 12 high-risk HPV types. Because the vaccine does not protect against all high-risk HPV types, vaccinated women still must undergo routine cervical cancer screening.

HPV DNA test from co-test to primary screening

In 2003, the FDA approved the HPV DNA test as a co-test to the Pap for women age 30 and older. Eleven years later, in April 2014, the FDA approved an HPV test for use as a primary screening test without Pap in women 25 and older. 

The primary-screen HPV test detects 14 high-risk HPV types and provides specific genotyping information for HPV types 16 and 18. The FDA approval states that women who test positive for HPV-16 or HPV-18 should have a colposcopy, and women who test positive for one or more of the other 12 high-risk HPV types should have a Pap test to determine the need for a colposcopy. Women who test negative should be followed up in accordance with the physician’s assessment of screening and medical history, other risk factors, and professional guidelines.¹² 

A reflex test is one that is used after an inconclusive primary test. Some reports of the landmark ATHENA study compare the combination of the HPV test with reflex cytology (Pap) versus cytology with reflex HPV test. The HPV test with reflex cytology found 30% more CIN3 cases (severely abnormal cells and cancer cells) and reduced the number of colposcopies by 6%.^13,14 

Key concerns about the DNA screen

Objections to the use of the HPV DNA test as a primary screen include the following:

• There is no support from any evidence-based U.S. guidelines. 
• It is significantly more expensive than the Pap test. 
• The Pap test is a safe, effective, well-established primary screen that has prevented cervical cancer successfully. 
• A positive test for HPV-16 or -18 is directly referred for colposcopy/biopsy even though the HPV test identifies the presence of a virus and not abnormal cells.¹⁵ 

Further objections focus on the use in women in the 25-to-29-year-old age group. These young women were excluded from the HPV co-test indication. In this age group, more than 30% have high-risk HPV infections (10% have HPV-16 and -18 infections), but these infections generally clear on their own.¹¹ DNA testing skeptics fear that unnecessary colposcopy/biopsy procedures will become more frequent. 

Another concern centers on women who are HPV-negative but develop cervical cancer. The Quest Diagnostics Health Trends study (based on tests of 3.7 million women) found that nearly 5% of women with a CIN3+ Pap test had a negative HPV test. Within five years, nearly 25% of these women were found to have cervical cancer.¹⁶ 

The need for better specificity

Experts agree that while HPV testing increases the sensitivity of screening, it results in a lower specificity than cervical cytology (Pap test). When HPV is used as a screen, some form of triage is needed to reduce the number of HPV-positive women with clinically unimportant HPV infections from undergoing colposcopy/biopsy.¹⁷ To minimize unnecessary procedures, a simple, objective co-test or reflective test of high specificity is needed to complement the HPV DNA test. 

Such a test becomes even more imperative when we look beyond our borders to the developing world, where reliable colposcopy/biopsy procedures are largely unavailable. 

E6 and E7 oncoproteins may provide the solution. These functional proteins are integral to cellular transformations during cervical disease progression and could be the basis of a highly-specific co-test. In preliminary studies using residual cervical cells collected for Pap tests, E6 and E7 oncoproteins measured by ELISA and flow cytometry have been shown to have high specificity.^18,19 

As the U.S. healthcare system moves toward evidence-based medicine to reduce costs while maintaining quality care, the need to improve cervical cancer testing and treatment paradigms is paramount. Each year, billions of dollars are spent on millions of screening visits and follow-up procedures to address minor abnormalities that are exceedingly unlikely to become cancerous.^20,21  While the HPV test offers new strategies for primary screening, we still need major reductions in over-testing, unnecessary treatments, and related costs. We also must address the significant psychological burdens of stress and anxiety that impact the mental health of women who initially test positive.