Introduction and commentary, strategic science symposium: Human papillomavirus testing-are you ready for a new era in cervical cancer screening?

Archives of Pathology & Laboratory Medicine,  Aug 2003  by Davey, Diane D,  Zarbo, Richard J

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Cervical cytology screening represents the prototype of a successful cancer screening test. Mortality has decreased by more than 70% in the 5 decades since cytology screening became widely available in the United States. Cervical cancer, once the leading cause of cancer deaths in women in the United States, now ranks 13th,1 although it is still extremely common worldwide.

Despite these successes, a single cervical cytology test is associated with a significant false-negative rate. The Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy Research) estimated the sensitivity of a single conventional Papanicolaou test to be 51%.2 More recent well-controlled clinical trials with verification of positive and some negative results have found sensitivities of 70% to 80% for conventional Papanicolaou tests and 85% to 95% for liquid-based cytology tests.3,4 Such calculations are based on detection of biopsy-proven, high-grade lesions and cancers when a cytology result of at least atypical squamous cells is considered positive.

Another significant issue is the large number of women with borderline atypical cytology findings who require additional management to determine the presence of a significant lesion. The only way to maintain sufficient sensitivity with cytology screening is to set a low threshold for abnormal results. In the past, women with atypical squamous cells of undetermined significance (ASC-US) on cytology were generally managed by either several repeat cytology examinations or by colposcopic examination. The former represented both an inconvenience and a risk to both patients and clinicians; women had to return 2 or 3 times for cytology to achieve sufficient sensitivity, and some women would inevitably be lost to follow-up. Colposcopy was seen as a safer, more immediate management approach, yet very expensive and inconvenient, causing anxiety to many women.

Human papillomavirus (HPV) DNA testing has emerged as another testing modality for cervical cancer and precursor lesions. Human papillomavirus testing can be used as an adjunct for atypical cytology results, as a primary screening test, as a follow-up test after colposcopy or treatment, and as a quality assurance measure. The College of American Pathologists was aware of the tremendous impact HPV testing will have on future laboratory testing and cervical cancer screening. For this reason, a Strategic Science seminar, entitled "HPV Testing: Are You Ready for a New Era in Cervical Cancer Screening?," convened September 21-22, 2002, in Rosemont, Ill.

Strategic Science is a new multimodal continuing medical education series integrating science with numerous aspects of laboratory management. This new education model, in which expert speakers address a new or evolving scientific issue from both the clinicians' and pathologists' perspectives, is offered in 3 continuing medical education-generating formats. These include an online preconference, a day-and-a-half live symposium, and peerreviewed publications. Strategic Science is designed for the practicing pathologist and comprehensively addresses pertinent aspects of new technology assessment, practice guidelines, quality assurance, regulatory compliance, risk and liability, billing and coding, cost analysis, consultation, utilization and information management, and results reporting. This issue of Archives of Pathology & Laboratory Medicine contains 12 additional papers from this Strategic Science seminar on HPV testing. Our summary conclusion is that this conference demonstrated that HPV testing has the potential to lead to a major paradigm shift in cervical cancer testing methods.

In these proceedings, the role of HPV in the epidemiology and pathogenesis of cervical cancer is addressed by Mark Schiffman, MD, and Philip E. Castle, PhD,5 and by Mark Stoler, MD.6 It is now recognized that HPV infection always precedes cervical cancer and is a necessary but insufficient agent for the development of cervical cancer. Many women become infected with HPV, but only a fraction of them develop high-grade squamous intraepithelial lesions, and even fewer progress to cancer. Other cofactors include smoking, oral contraceptive use, multiparity, and possibly inflammation. The current impact of insufficient screening worldwide translates into a major risk factor, as the majority of cancers occur in women with no screening in the previous 5 years. Those experiencing persistent infection with oncogenic or high-risk types of HPV are highly likely to progress to a significant high-grade lesion or cancer. Proteins encoded by HPV genes E6 and E7 are known to interact with the tumor suppressor genes p53 and pRb, causing cell transformation. Trials for HPV vaccines based on viruslike particles are underway, but it will likely be years until these vaccines influence cancer mortality.

The basis of HPV testing methods are discussed by Dr Stoler6 and Roger Hubbard, PhD,7 and David Bolick, MD,8 discusses business aspects of the most commonly used methods. Important considerations in any laboratory test include biologic correlation, clinical validity, and utility; analytic sensitivity, specificity, accuracy, and precision; and technical feasibility, costs, validation, and quality control/quality assurance mechanisms. Early testing methods included nonamplified techniques, such as Southern blot and dot-blot. In situ hybridization is an example of a non-amplified method that is currently applicable for both tissue and cytology specimens, and that can be useful for cytologic/histologic correlation. Hybrid capture and polymerase chain reaction (PCR) methods represent sensitive amplified methods currently in use. Surrogate methods, such as immunohistochemical assessment of p16 are also being investigated.