Hpv Cervical Dysplasia - Research

Nayar R, Tabbara SO. Department of Pathology, Northwestern University, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, USA.

Besides all the confusion and associated problems that the use of ASC has created, it has initiated substantial investigational interest that has resulted in a better understanding of squamous intraepithelial lesions and the biology of cervical neoplasia. Although the category of ASC has created, and will continue to create, controversy in the diagnostic and management fields, it allows the pathologist to convey uncertainty that may be the result of poor sampling or difficulty in interpretation of a case. It is a valuable tool that the cytopathologist can use to make it known that the Papanicolaou test has its limitations and may need and benefit, in some instances, from support from ancillary studies. Similar limitations are recognized in other areas of pathology and the use of immunohistochemistry or molecular studies is widely accepted as an aid to a more specific and definitive interpretation. The time for the Papanicolaou test to be considered similarly has arrived. HPV DNA testing may not be the perfect test for cervical cancer screening because of high prevalence of HPV infection in the general population; however, it is currently the best-studied ancillary test and has been proven to be cost-effective for the triage of Papanicolaou tests with equivocal squamous cells. It is important for the cytopathologist to have well-developed diagnostic skills in interpreting gynecologic preparations, and to classify cases as ASC only when deemed appropriate. Downgrading cytologic findings that are diagnostic of a squamous intraepithelial lesion to ASC with the hope of supporting it by an HPV test will only result in a devaluation of the Papanicolaou test. Such recourse may, however, be acceptable in specific situations, such as in patients who have complex histories, atypical clinical presentations, or during pregnancy. Quality assurance measures to closely monitor the ASC:SIL ratio and the rate of HPV positivity in ASC cases will be essential to ensure the appropriate use of this interpretive category. The coordination of the 2001 Bethesda and ASCCP consensus meetings resulted in the new subcategories of ASC-US and ASC-H, along with well-defined management strategies for these interpretations. This new and clinically relevant terminology should lead to a reduction in difficulties at the clinical level and a more uniform management of patients, unlike the situation following Bethesda 1991 where the gynecologist was faced with a new "diagnosis" without specific management recommendations. The standardization of reporting and clinical management will also allow more reliable evaluation of patient outcomes and cost analysis. The 2002 American Cancer Society guidelines did not make specific recommendations regarding HPV DNA testing for the triage of patients who have a cytology result of ASC-US [64]. The FDA approved the expanded use of HPV testing in conjunction with the Papanicolaou test for cervical cancer screening in March of 2003. The future is likely to bring additional testing modalities that may be more specific for detecting squamous lesions that are more likely to persist or progress to carcinoma, than the currently available HPV tests. In addition, looking to the more distant future, recently published data from HPV vaccine trials suggests that immunizing women who are negative for HPV-16 may eventually reduce the incidence of cervical cancer [65]. At the present, however, the most effective method to decrease the mortality of this disease process is to make sure that all women have access to, and receive, effective cervical cytologic screening.

Publication Types:
• Review

Clin Lab Med. 2003 Sep;23(3):755-74.

Cervical cytology automation: an update for 2003. The end of the quest nears?

Wilbur DC. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The field of cytology automation, through long investigation, trial and error, and finally, commercial success and failure, has arrived at the first levels of the "grail" of improvements in accuracy and productivity in cervical cytology screening. It remains to be seen how much further the road will lead toward so-called "diagnostic" instrumentation that would actually provide us with a fully automated system of "specimen in-diagnosis out" with little, or no, human input. Will commercial ventures or academic institutions continue to support investigations to further the applications that have been developed to date? This remains to be seen and is directly dependent on parallel processes that are detailed elsewhere in this issue. Will HPV vaccines eliminate the need for screening? Possibly, but probably not for many years [70]. Will more sensitive and specific genetic or protein markers (or combinations thereof) be found to be more accurate and cost-effective? Certainly the possibility of mass screening by high-risk HPV DNA testing, as a viable alternative, is being discussed at present. Despite all of these uncertainties, the present (or nearly available) technology has the potential to improve the practice of cervical cytology. Improvements in accuracy that are necessary to provide the highest possible level of patient care and to protect practitioners from unreasonable levels of medico-legal risk are a reality. Improvements in productivity that are necessary to help in the impending labor shortage in the field of cytotechnology are also a reality. Automation is clearly the short-term solution to the most difficult of the challenges that we face.

Publication Types:
• Review

Arch Pathol Lab Med. 2003 Aug;127(8):946-9.

Findings to date from the ASCUS-LSIL Triage Study (ALTS).

Schiffman M, Solomon D. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Md 20852, USA.

Controversy exists in the United States regarding the proper evaluation and management of low-grade squamous intraepithelial lesion (LSIL) and equivocal (atypical squamous cells of undetermined significance [ASCUS, now ASC-US]) cervical cytologic interpretations. To address this issue, the National Cancer Institute initiated the ASCUS-LSIL Triage Study (ALTS). ALTS is a multicenter, randomized clinical trial designed to evaluate 3 alternative methods of management, namely, immediate colposcopy, cytologic follow-up, and triage by human papillomavirus (HPV) DNA testing. This article summarizes the major findings of ALTS that have been published to date. Patients with ASCUS (n = 3488) or LSIL (n = 1572) were randomly assigned to research arms between November 1996 and December 1998, and were monitored for 2 years. The disease outcome was histologic cervical intraepithelial neoplasia (CIN) 3/cancer. The prevalence of oncogenic HPV was too high to permit effective triage of LSIL using HPV DNA testing by Hybrid Capture 2. However, for the women referred with a cytologic interpretation of ASCUS, HPV triage proved useful, with sensitivity equivalent to immediate colposcopy and a halving of colposcopic referrals. Among older women with ASCUS, HPV testing remained sensitive for detecting CIN 3 and cancer, but the referral percentage was dramatically lower compared to younger women. ALTS yielded insight into the performance of cytology and histopathology; experienced pathologists differed significantly in their interpretations of cervical abnormalities, especially histologic CIN 1 and cytologic ASCUS. Nonetheless, it was possible to distinguish a relatively uncommon type of ASCUS, equivocal for high-grade squamous intraepithelial lesion, that has a high positive predictive value for identifying women with underlying high-grade CIN. Many additional analyses are underway.

Publication Types:
• Review
• Review, Tutorial

J Natl Cancer Inst. 2005 Apr 20;97(8):577-86.

Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women.

Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Schlecht NF, Melnick S, Palefsky JM. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., Belfer #1308, Bronx, NY 10461, USA.

BACKGROUND: Little is known in human immunodeficiency virus (HIV)-positive women about how the combination of plasma HIV RNA level and CD4+ T-cell count is associated with the natural history of human papillomavirus (HPV) infection or about HPV reactivation--whether it occurs and with what frequency in HIV-positive women. METHODS: HIV-positive (n = 1848) and -negative (n = 514) women were assessed at semiannual visits (total person-years = 5661) for cervicovaginal HPV with polymerase chain reaction assays and for squamous intraepithelial lesions (SILs) by Pap smear. We studied the prevalent detection of HPV and SILs with generalized estimating equations and the incident detection and persistence of HPV and SILs with multivariable Cox models. All statistical tests were two-sided. RESULTS: We observed a strong interaction between the associations of CD4+ and plasma HIV RNA strata with both prevalent (P(interaction) = .002) and incident (P(interaction) = .001) detection of HPV. Indeed, the hazard ratio for incident HPV detection peaked between 4.0 and 5.0, with either a CD4+ count of less than 200 cells per mm3 or an HIV RNA level of more than 100,000 copies per mL. Although incident HPV detection in all women was associated with the number of recent sex partners (P(trend)<.001), 22% of sexually inactive HIV-positive women with a CD4+ count of less than 200 cells/mm3 also had at least one incidentally detected HPV type. The association between CD4+/HIV RNA strata and HPV persistence was statistically significantly smaller (P<.001) than for incident HPV detection. SIL prevalence, incident detection, and persistence had similar associations with CD4+/HIV RNA strata as HPV (above). CONCLUSION: In HIV-positive women, plasma HIV RNA level and CD4+ count in combination appear to have a strong and statistically interactive association with incident detection of HPV, some of which may reflect HPV reactivation (e.g., in sexually inactive women). The more moderate association between HIV coinfection and HPV persistence could partly explain why cervical cancer rates have not reached more epidemic proportions in HIV-positive women.

Br J Cancer. 2005 May 9;92(9):1794-9.

Human papillomavirus infection in women who develop high-grade cervical intraepithelial neoplasia or cervical cancer: a case-control study in the UK.

Grainge MJ, Seth R, Coupland C, Guo L, Rittman T, Vryenhoef P, Johnson J, Jenkins D, Neal KR. Division of Epidemiology and Public Health, School of Community Health Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK. matthew.

Human papillomavirus (HPV) testing might identify older women who could be withdrawn from the cervical screening programme, or require less frequent screening. A case-control study using the United Kingdom cervical screening population was set up to help address this issue. Cases comprised 575 women who developed cervical intraepithelial neoplasia (CIN) grade 2 or worse over a 13-year period following a cytologically normal baseline smear, and were stratified by age group ('under 20', '20-39' and 40 years or over). Controls (n=601) were women who remained disease free over this interval and were the same age on average as cases. DNA was extracted from the baseline smears and tested for HPV by PCR using GP5+/6+ consensus primers. HPV+ samples were tested for HPV types 16 and 18 using specific PCR primers. In all, 27.0% of cases tested positive for HPV at baseline, compared with 15.4% of controls (odds ratio (OR)=2.00; 95% confidence interval (CI), 1.50-2.68). Among women aged 40 years or over, the OR for HPV 16 was 8.95 (95% CI, 2.63-30.4). These results support the need for further cervical screening of HPV- older women, as many of the cases were HPV- at baseline.

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