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MILFORD, Conn.

Sin Hang Lee, M.D., a Milford (Conn.) Hospital pathologist and lead author of “From Human Papillomavirus (HPV) Detection to Cervical Cancer Prevention in Clinical Practice,” a medical-scientific paper published last week in Cancers, a quarterly oncology journal http://www.mdpi.com/2072-6694/6/4/2072, said that to properly validate HPV test results and to ensure optimum patient care every HPV-positive report should also include a DNA sequence.

“To avoid false negatives, common in standard HPV testing, and unnecessary, harmful cervical biopsies, only analytically sensitive and specific HPV DNA tests should be used for patient management to reliably distinguish between persistent and transient HPV infections. The results, as physicians know, dictate different courses of appropriate treatment,” said Lee.

Using an extremely sensitive heminested PCR and a highly reliable DNA sequencing-based HPV genotyping for routine assays, the authors reported in the paper, “a true negative HPV PCR invariably indicates the absence of precancerous cells in the cytology samples. However, 80.5% of single positive HPV-16 tests and 97.3% of single positive HPV-18 tests were associated with a negative or a largely self-reversible Pap cytology.”

The research was based on retrospective reviews of 8,461 women’s Pap cytology samples referred to Milford Hospital’s Department of Pathology for testing as part of regular women’s health care services from 2007 to 2010. The Milford Hospital team analyzed these samples of patients from a population consisting of 93.6% non-Hispanic white Americans who were under the care of board-certified gynecologists in private solo practice.

“It is common knowledge among practicing gynecologists and pathologists that most of the 4-quadrant cervical biopsies on the women referred to colposcopy because of HPV-16 and HPV-18 positives show a normal histology or reactive changes to inflammation only. The practice guidelines written by the American Society for Colposcopy and Cervical Pathology (ASCCP) whose members perform colposcopies promote invasive procedures, and we must develop a paradigm to distinguish persistent HPV infections from transient HPV infections to reduce the number of these unnecessary and harmful procedures. It is widely known that cervical cancer risk is only associated with persistent unresolved HPV infection, not sequential transient HPV infections,” said Lee.

The Milford Hospital pathology team developed an “extremely sensitive PCR-based method as the first step in a cervical cancer screening program for community hospitals,” according to the authors, a step recommended by Mark Stoler, M.D., a recognized leader in the HPV testing industry.

Regarding false-negative results found in standard HPV testing, “Everybody’s afraid to talk about these cases at their institutions,” according to Marshall Austin, M.D., director of cytopathology at Pittsburgh’s Magee-Women’s Hospital in a 2013 story reported in USA Today, http://www.usatoday.com/story/news/nation/2013/01/13/hpv-testing-false-negatives/1830897/.

Most commercial HPV assay kits were developed with a clinical sensitivity goal of 92% ± 3% in detecting severe precancerous CIN3 lesions. This means about 10% of the CIN3 lesions would remain undetected, said Dr. Lee.

Of the 37 HPV-18 isolates from this group of patients, 30 belonged to the HPV-18 European/Asian American subtypes and 7 to the HPV-18 African subtype, the authors reported. Certain HPV kits may not be able to detect the HPV-18 African subtype which is more prevalent among African American women than in the non-Hispanic white women and certain HPV-18 subtypes are known to be more carcinogenic than HPV-16 in certain specific populations, reported the authors.

Dr. Lee’s team reported previously that there are several novel Milford HPV variants in this population which have not been entered in the GenBank database and cannot be detected by any of the commercial test kits except by DNA sequencing. The cancer-causing ability of these Milford HPV variants is unknown, and warrants further follow-up, Dr. Lee said.

The authors concluded, “Pap smear cytology is widely used and based on evaluation of cell morphology by pathologists, i.e., highly trained medical doctors. It cannot be replaced by a virology test in spite of the ASCCP guidelines which recommended referral to colposcopy of HPV-16/HPV-18+ women withnegative cytology. To avoid excessive and unnecessary harmful cervical biopsies, highly sensitive, type-specific or perhaps even variant-specific methods must be used in routine HPV testing for patient management to reliably distinguish persistent HPV infections from transient HPV infections if a viral DNA test is to be implemented as a primary cervical screen tool in conjunction with the traditional Pap smear cytology.”