HPV Screening Alone May Miss Cervical Cancer

Roxanne Nelson, RN

April 22, 2015

Human papillomavirus (HPV) screening used on its own can miss cervical cancer, according to a study that found that more cases were detected when it was used in combination with cytology.

The study was published online April 10 in Cancer Cytopathology.

In a "real-world" population of more than 250,000 women, 526 cases of confirmed cervical cancer were detected. HPV results were negative in 18.6% of these women, Pap test results were negative in 12.2%, and both test results were negative in 5.5%.

This translates into an almost three-fold improvement in the rate of cancer detection with cotesting, compared with HPV testing alone, the researchers report. So women who actually have cervical cancer are more likely to have a negative result with HPV testing alone than with cotesting.

In addition, for the detection of grade 3 cervical intraepithelial neoplasia (CIN), a positive Pap test is better than either a positive HPV test alone or positive cotests (26.3% vs 25.6% vs 10.9%; P < .0001).

These data are "a reminder that the limitations of HPV testing are greater than have been advertised, especially in the most important group — the women who are developing cervical cancer," said study author R. Marshall Austin, MD, PhD, medical director of cytopathology and staff pathologist in gynecologic and breast surgical pathology at Magee–Womens Hospital in Pittsburgh.

It well established that persistent carcinogenic HPV infections underlie virtually all cases of cervical cancer, and testing for HPV is an attractive proposition for detecting this cancer.

"But what isn't acknowledged or taken into account in studies is that by the time patients are diagnosed with cancer, they may be HPV-negative because of a low viral load," Dr Austin told Medscape Medical News. In addition, "there are some cancers without underlying HPV, and not all types of HPV are included in the standard test."

What has been misleading in the development of an HPV standalone test is that the clinical trials did not use cancer as an end point. "Instead, they looked at precancerous lesions, most of which will never progress to cancer," Dr Austin pointed out. "This is almost never discussed, but our paper adds evidence as to why it is important to look at women with invasive cancer."

"The recommended strategy is cotesting," he said. "That is the most effective method and gives patients the most protection."

In 2011, the US Food and Drug Administration (FDA) approved the use of HPV testing in conjunction with or as a follow-up to cell cytology for women 30 years and older. It was also approved for use in women 21 years and older as a follow-up if cytology results were abnormal.

In April 2014, the cobas HPV test was approved as a standalone screening test for cervical cancer. The test can recognize DNA from 14 high-risk types of HPV, including types 16 and 18, which are responsible for 70% of cervical cancers. Data from the prospective ATHENA study, which involved 47,208 women 25 years and older who underwent routine cervical exams, supported its approval as a primary screening tool for cervical cancer.

Recent studies have argued that HPV-only screening might be more effective than Pap-only screening for both CIN and cancer, Dr Austin and his colleagues note. However, those prospective trials were conducted in well-defined, controlled circumstances in select populations, and they usually compared HPV-only testing with Pap-only testing, rather than the guideline-recommended cotesting.

In their study, Dr Austin's team reviewed data from 256,648 women who were 30 to 65 years at the time of cotesting and who had a cervical biopsy specimen obtained within 1 year of screening.

In this cohort, 74.7% of the samples were positive for HPV, 73.8% had an abnormal Pap test (atypical squamous cells of undetermined significance or worse), 89.2% had a positive cotest, and 1.6% exhibited CIN of at least grade 3.

Sensitivity was higher for CIN of at least grade 3 in women who had positive cotest results, and specificity was higher in women who had only a positive Pap test.

Table. Accuracy of Testing

Measure Cotesting Pap Only HPV Only
Sensitivity, % 98.80 91.30 94.00
Specificity, % 10.90 26.30 25.60
Positive predictive value, % 1.76 1.97 2.00
Negative predictive value, % 99.83 99.50 99.62


This study was conducted by Quest Diagnostics Health Trends. Dr Austin has disclosed no relevant financial relationships. Some of his coauthors are employees of Quest Diagnostics.

Cancer Cytopathol. Published online April 10, 2015. Abstract


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