College of American Pathologists
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In search of better methods

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October 2000
William Check, PhD

Even as physicians seek the place of HPV testing in the detection of cervical neoplasia, newer potential adjuncts to Pap cytology are emerging.

"I think there is going to be a better answer than HPV testing along the lines of a novel cellular marker," predicts Dr. Elizabeth Unger, acting chief of the Human Papillomavirus Section, Centers for Disease Control and Prevention. Only a small fraction of HPV infections transform into oncogenic processes. A downstream cellular marker might specifically identify infections that are most likely to proceed to neoplasia. Using gene expression arrays, Dr. Unger is searching for cellular changes in a population with well-characterized HPV types and variants.

A group in Germany, she says, has found that a tumor suppressor gene, p16INK4a, is upregulated in some cervical lesions. The German group further discovered that p16INK4a disinhibition is actually a surrogate for activity of E7, an HPV protein known to be crucial to transformation. "The advantage of measuring a cellular gene such as p16INK4a," Dr. Unger says, "is that the same effect will be seen for all HPV types." Protein E7 differs among HPV types. There is evidence that immunostaining for p16INK4a helps identify CIN3 lesions on Pap cytology slides.

Another innovation is HPV testing by polymerase chain reaction. Roger A. Hubbard, PhD, director of molecular pathology and president and CEO of Molecular Pathology Laboratory, Maryville, Tenn., notes that HPV testing was started more than 10 years ago, but early kits were incomplete. "HPV testing only came back into widespread use with the advent of Digene’s Hybrid Capture II kit," Dr. Hubbard says.

"Now we are trying to be more specific in phenotyping HPV," he adds. Hybrid Capture II segregates HPV types into high-risk and low-risk groups. "The cocktail approach is better than nothing, but I don’t think it’s going to be adequate in the long run," Dr. Hubbard says. "Different HPV types vary dramatically in their oncogenic potential. Using PCR, we are categorizing which HPV types are present in cells obtained during cervical sampling."

HPV viral load, measured by PCR, may also be an independent predictor of progress to cervical lesions and cervical cancer. "What I foresee," Dr. Hubbard says, "is a risk matrix in which HPV type and viral load are considered along with cervical cytology."

Viral load and viral type probably will not be clinically useful in the short term. "But viral load and HPV type will eventually be important in terms of individual frequency of followup and therapy," Dr. Hubbard predicts. Only a small proportion of women who have persistent infections with oncogenic HPV types develop cervical cancer. Determining the HPV type may help identify which patients will progress.

William Check, PhD