Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.

Human Papillomavirus and Cervical Cancer

Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through high-risk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16INK4a. Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16INK4a. In line with this hypothesis, we observed marked overexpression of p16INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n = 47) except those associated with low-risk HPV types (n = 7), all CIN II lesions (n = 32), all CIN III lesions (n = 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16INK4a was observed in normal cervical epithelium (n = 42), inflammatory lesions (n = 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n = 7). Dysplastic cells could also be identified in cervical smears using a specific p16INK4a monoclonal antibody. These data demonstrate that p16INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears. © 2001 Wiley-Liss, Inc.

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Purpose To evaluate the accuracy of conventional and new methods of Papanicolaou (Pap) testing when used to detect cervical cancer and its precursors. Data sources Systematic search of English-language literature through October 1999 using MEDLINE, EMBASE, other computerized databases, and hand searching. Study selection All studies that compared Pap testing (conventional methods, computer screening or rescreening, or monolayer cytology) with a concurrent reference standard (histologic examination, colposcopy, or cytology). Data extraction Two reviewers independently reviewed selection criteria and completed 2 x 2 tables for each study. Data synthesis 94 studies of the conventional Pap test and three studies of monolayer cytology met inclusion criteria. No studies of computerized screening were included. Data were organized by cytologic and histologic thresholds used to define disease. For conventional Pap tests, estimates of sensitivity and specificity varied greatly in individual studies. Methodologic quality and frequency of histologic abnormalities also varied greatly between studies. In the 12 studies with the least biased estimates, sensitivity ranged from 30% to 87% and specificity ranged from 86% to 100%. Conclusions Insufficient high-quality data exist to estimate test operating characteristics of new cytologic methods for cervical screening. Future studies of these technologies should apply adequate reference standards. Most studies of the conventional Pap test are severely biased: The best estimates suggest that it is only moderately accurate and does not achieve concurrently high sensitivity and specificity. Cost-effectiveness models of cervical cancer screening should use more conservative estimates of Pap test sensitivity.

Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review.

EACH YEAR APPROXIMATELY 50 million women undergo Papanicolaou testing in the United States. Of these, approximately 3.5 million (7%) are diagnosed with a cytological abnormality requiring additional follow-up or evaluation. Determining which women with cytological abnormalities are at risk for significant cervical disease, performing appropriate diagnostic workups, and treating cancer precursors present a major public health challenge. There are a number of reasons why comprehensive, evidence-based guidelines are needed for the management of women with cervical cytological abnormalities. One reason is that a National Cancer Institute workshop recently revised the criteria used by cytologists to render certain cytological interpretations, as well as the terminology used for reporting cervical cytology results (ie, the Bethesda System). Other reasons include a better understanding of the pathogenesis and natural history of human papillomavirus (HPV) and cervical cancer precursors, and the availability of data from the National Cancer Institute’s randomized Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intraepithelial Lesion (ASCUS/LSIL) Triage Study (ALTS) (D. Solomon, MD, written communication, September 6-8, 2001). Moreover, existing guidelines were developed before sensitive molecular methods for detecting high-risk types of HPV and liquid-based cytology methods became widely available. Data are now available suggesting that these new technologies, when used together, are attractive alternatives to older approaches for managing women with cer-

2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities.

Background Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. Methods Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. Results The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies. Conclusions The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.

/pdf/safety-and-immunogenicity-trial-in-adult-volunteers-of-a-dcpjwy0mfr.pdf

Safety and Immunogenicity Trial in Adult Volunteers of a Human Papillomavirus 16 L1 Virus-Like Particle Vaccine

THE INCIDENCE of and mortality from cervical cancer in the United States have decreased dramatically over the past 40 years, in part because of early diagnosis and treatment of cervical cancer precursor lesions. The success of cervical cytological screening has served as a model for early diagnosis of other types of cancer. Although numerous studies have shown that lack of cytological screening is a major risk factor for the development of invasive cervical cancer, 1-3 it is important to emphasize that none of the screening, diagnostic, or therapeutic techniques used in medicine are perfect. Accordingly, a few women will develop cervical cancer despite adherence to accepted screening protocols . In addition, problems inherent with sampling, interpretation, and effective clinical follow-up preclude total prevention of cervical cancer. In recent years it has become evident that the cost and morbidity associated with the detection and treatment of low-grade cervical lesions have escalated, probably

https://jamanetwork.com/journals/jama/articlepdf/375003/jama_271_23_037.pdf

Interim Guidelines for Management of Abnormal Cervical Cytology

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Interim Guidelines for Management of Abnormal Cervical Cytology