Cervical acid phosphatase: a biomarker of cervical dysplasia and a potential surrogate endpoint for colposcopy. (65/413)

BACKGROUND: In 2000, cervical acid phosphatase (CAP) has been recently described as a biomarker labeling abnormal squamous cells on Pap smears (USPTO #6,143,512). The enzyme activity is presented as a red, granular deposit on a modified Papanicolaou background. This unique property was utilized for development of MarkPap technology intended for cervical cancer screening. MATERIAL/PATIENTS & METHODS: We conduct a multicenter, random assignment, assessor blinded, 2-group (test and control), split-sample designed clinical trial on 1,500 subject/specimens to assess safety and efficacy of the new test, in comparison with the control, for cervical cancer screening in standard Pap test environment. Safety is measured with frequency, severity and relation of adverse events. Efficacy is measured with primary endpoints (portion of positive/abnormal specimens detected, and the false negative rate). At the end of the follow-up period (two years) when the study will be completed, other efficacy endpoints such as accuracy (sensitivity/specificity) and predictive values will be added to the method evaluation. Here we present in interim analysis. RESULTS: In April 2003, the recruitment was completed and the first twelve hundred cases have been evaluated. There was no serious or related adverse event in both groups. Minor, unrelated adverse events were rare and insignificantly distributed in both groups. PRIMARY ENDPOINTS: A: Portion of positive/abnormal specimens detected: Pe (new test) = 0.166, Ps (Pap control): 0.082; Ps' (ACS reported value for US in year 2000): 0.07. Pe >/= Ps + delta, for delta = 0.5Ps. B. False negative rate: Pe = 0.05, Ps' = 0.10. Confidence intervals: 95% CI: Test [0.148-0.193], Pap control [0.068-0.098]. OR = 2.26. chi2 = 40.69101 is greater than the critical value of 3.841 (P < 0.01). CONCLUSION: We concluded that CAP had added to visibility of Pap test and has enabled cytoscreeners to significantly improve the detection of positive/abnormal specimens and reduce false negative rate. We discuss this unique property of CAP with emphasis on using it as a surrogate endpoint for colposcopy and eventual removal of a cervical lesion that, if untreated, could progress into cancer.  (+info)

Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. (66/413)

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.  (+info)

Why is high grade squamous intraepithelial neoplasia under-diagnosed on cytology in a quarter of cases? Analysis of smear characteristics in discrepant cases. (67/413)

BACKGROUND: The accuracy of cervical cytology has been questioned due to high false negative rate. In order to improve the sensitivity of cytology it is prudent to analyze the factors which hamper with the diagnosis of high grade lesions. AIMS: To study the cyto-histologic agreement in High grade squamous intraepithelial lesions (HSIL) of uterine cervix and to analyze the smear characteristics in discrepant cases. SETTINGS AND DESIGN: Cervical smears of 100 histology proven cases of Cervical intraepithelial neoplasia III (CIN III) were retrieved and reviewed to study cyto-histologic agreement in the diagnosis of high grade lesions. The discrepant smears, undercalled on cytology, were further analyzed to determine the reasons for misinterpretations. Statistical analysis was performed to find out any significant factors for discrepancies. RESULTS: Cytology was able to correctly identify 74 HSILs while in 26 cases a diagnosis of Low grade squamous intraepithelial lesions (LSIL) or below was given. On review, 16 of these non correlating cases could be reclassified as HSIL on cytology while in 10 the diagnosis of LSIL or less persisted. 12/16 (75%) discrepant cases, reclassified as HSIL represented interpretive errors. Sampling errors (7/10) and air drying (5/10) were more frequent in under diagnosed cases. The statistical analysis did not yield any significant differences in the two review groups. CONCLUSION: 26% of HSIL cases were underdiagnosed on cervical smears. The major confounding factors responsible for under interpretation on cytology included air drying artifacts and metaplastic maturation of abnormal cells.  (+info)

Correlation of colposcopic anogenital findings and overall assessment of child sexual abuse: prospective study. (68/413)

OBJECTIVE: To examine the relationship between colposcopic anogenital findings and overall assessment of sexual abuse. DESIGN: Prospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: Seventy-seven children (mean age, 6.5 years; range, 6 months-16 years) referred consecutively for sexual abuse evaluation between July 1999 and June 2002 were included. MAIN OUTCOME MEASURES: Colposcopic anogenital findings (categorised as normal, non-specific, concerning for abuse, or clearly abnormal) were correlated with the overall assessment of likelihood of abuse (classified as no evidence of abuse, possible abuse, probable abuse, or definite abuse). The sensitivity and specificity of clearly abnormal findings in detecting definite abuse were computed, and the diagnostic impact of colposcopy findings were expressed as likelihood ratios. RESULTS: Anogenital findings were normal in 45% of patients, non-specific in 29%, concerning for abuse in 13%, and clearly abnormal in 13%. Seven of the 16 confirmed cases of sexual abuse had normal or non-specific findings. Overall assessment showed that 46% of all patients had no evidence of abuse, 20% had cases of possible abuse, 13% had cases of probable abuse, and 21% had cases of definite abuse. The sensitivity and specificity of abnormal anogenital findings in detecting definite abuse were 56.3% and 98.4%, respectively. Colposcopy showed a fair correlation with the overall assessment of abuse (weighted kappa, 0.245). The diagnostic impact of normal, non-specific, concerning, and clearly abnormal findings in terms of likelihood ratios were 0.23, 1.12, 0.00, and 34.30, respectively. CONCLUSIONS: Anogenital findings are often normal or non-specific in sexual abuse. In general, colposcopy examination findings do not directly reflect the final diagnosis. A category-4 finding on colposcopy is very helpful in confirming definite abuse, whereas other findings do not rule out the diagnosis.  (+info)

Triage with human papillomavirus testing of women with cytologic abnormalities prompting referral for colposcopy assessment. (69/413)

BACKGROUND: The current study was conducted to evaluate the cost-effectiveness of triaging for colposcopy using human papillomavirus (HPV) testing. METHODS: HPV tests were performed in a consecutive series of women who were referred for colposcopy for persistent atypical squamous cells of undetermined significance (ASCUS)-favor reactive (n = 35 women), ASCUS-favor squamous epithelial lesion (n = 164 women), atypical glandular cells of undetermined significance (n = 74 women), low-grade squamous epithelial lesion (n = 161 women), or high-grade squamous epithelial lesion (n = 78 women). The cost effectiveness of triaging women with ASCUS results using HPV testing was determined compared with the current protocol. RESULTS: The sensitivity of HPV testing for cervical intraepithelial neoplasia > Grade 2 was very high. Cost analysis showed a moderate increase in cost with the addition of HPV triage. CONCLUSIONS: Because HPV testing is highly sensitive, it may be useful as an alternative to the current policy of 6-month repeat cytology for women with ASCUS.  (+info)

Low-dose topical delivery of all-trans retinoic acid for cervical intraepithelial neoplasia II and III. (70/413)

OBJECTIVE: The objective of this study was to determine an effective dose for all-trans retinoic acid (atRA) delivered with a cervical cap and sponge for 4 days to women with cervical intraepithelial neoplasia (CIN) II/III. METHODS: Study participants made up of 175 women with biopsy-proven CIN II/III were randomized to four consecutive days of atRA at one of three doses (0.16%, 0.28%, and 0.36%) or placebo. All subjects underwent a repeat colposcopy evaluation and biopsy of the cervix at 12 weeks. RESULTS: The study participants mean ages were 27.6 years. The racial distribution was 63% Caucasian, 27% African American, and 8% other. Among participants, 93% were human papillomavirus-positive at baseline with 68% positive for high-risk types. The disease response at 12 weeks to atRA or placebo was not significantly different (P = 0.49) among the four dose groups. Participants with CIN II at baseline were more likely to be free of disease at 12 weeks than participants with CIN III at baseline (P = 0.003). There were no reported systemic adverse events related to drug or placebo exposure and only mild local self-reported and clinician-detected toxicities. CONCLUSION: Lower concentrations of atRA applied with a cervical cap for 4 days were no more effective than placebo. However, the rate of histologic regression in biopsied CIN II/III patients was high even over a short time interval, and emphasizes the importance of having a placebo arm and an adequate sample size.  (+info)

Colposcopic proficiency-disease spectrum in a single family practice colposcopists' clinic. (71/413)

PURPOSE: We sought to assess colposcopic proficiency in a family practice teaching clinic. METHODS: Subjects were a prospective cohort of women age 13 to 68 who were colposcopy clinic attendees from 1991 to 2002. Data recorded on each subject included demographic variables, sexual history, history of sexually transmitted diseases, reason for referral to colposcopy, Pap smear results, colposcopic impression, colposcopic biopsy results, and diagnoses. The Kappa statistic was used to measure agreement between clinical colposcopic assessment and biopsy results. RESULTS: Eight hundred twenty-six patients were enrolled. Compared to biopsy, colposcopic impression overall correctly predicted normal cervical biopsy in 55.8% (95% CI: 45.8%, 65.8%) of cases, and predicted abnormal biopsy 84.9% (95% CI: 81.6%, 88.1%) of the time. Colposcopic impression of low-grade squamous intraepithelial lesion (LSIL) correctly predicted LSIL on biopsy in 64.6% of cases, and correctly predicted the absence of LSIL 74.2% of the time. Colposcopic impression of high-grade squamous intraepithelial lesion (HSIL) correctly predicted biopsy results of HSIL in 70.05% of cases (Kappa = 0.544, P<.0001). There was a 12.7% error rate in discriminating normal from LSIL (Kappa -.258, with P<.0001). CONCLUSION: Family physicians perform colposcopy with good correlation between colposcopic impression and subsequent histology.  (+info)

New cervical cancer screening strategy: combined Pap and HPV testing. (72/413)

Our strategy for cervical cancer screeing is being revolutionized by our new understanding of how human papillomavirus (HPV) contributes to carcinogenesis and the natural history of cervical cancer. The American Cancer Society and the American College of Obstetricians and Gynecologists now recommend combined HPV and Papanicolaou (Pap) testing for cervical cancer screening in women age 30 or older. However, although incorporation of HPV DNA testing into primary screening provides clear benefits, it also raises new questions.  (+info)