Biomedical subjects

A T Lorincz

Publications and source records attributed to A T Lorincz.

At least 19 recordsLinked to original sources

PubMed2006

Cross-sectional comparison of an automated hybrid capture 2 assay and the consensus GP5+/6+ PCR method in a population-based cervical screening program.

In this cross-sectional study, clinical performances of the hybrid capture 2 assay using an automated instrument (i.e., rapid capture system) (hc2-RCS) and the high-risk human papillomavirus GP5+/6+ PCR-enzyme immunoassay (EIA) test were compared using cervical scrape specimens from 8,132 women that participated in a population-based screening trial. The hc2-RCS test scored significantly more samples positive (6.8%) than the GP5+/6+ PCR-EIA (4.8%) (P < 0.0005). This could be attributed largely to a higher positivity rate by the hc2-RCS test for women with cytologically normal, borderline, or mild dyskaryosis. A receiver operator characteristics analysis of the semiquantitative hc2-RCS results in relation to different cytology categories revealed that these differences are owing to differences in assay thresholds. For women classified as having moderate dyskaryosis or worse who also had underlying histologically confirmed cervical intraepithelial neoplasia grade 3 or cervical cancer (> or =CIN3), the hc2-RCS scored 97% (31/32) of samples positive, versus 91% (29/32) by GP5+/6+ PCR-EIA. However, this difference was not significant (P = 0.25). After increasing the hc2-RCS cutoff from 1.0 to 2.0 relative light units/cutoff value of the HPV16 calibrator (RLU/CO), no additional CIN3 lesions were missed by hc2-RCS, but the number of test-positive women with normal, borderline, or mild dyskaryosis was significantly decreased (P < 0.0005). However, at this RLU/CO, the difference in test positivity between hc2-RCS and the GP5+/6+ PCR-EIA was still significant (P = 0.02). The use of an RLU/CO value of 3.0 revealed no significant difference between hc2-RCS and GP5+/6+ PCR-EIA results, and equal numbers of smears classified as > or =CIN3 (i.e., 29/32) were detected by both methods. In summary, both assays perform very well for the detection of >or =CIN3 in a population-based cervical screening setting. However, adjustment of the hc2-RCS threshold to an RLU/CO value of 2.0 or 3.0 seems to produce an improved balance between the clinical sensitivity and specificity for > or =CIN3 in population-based cervical screening.

Automation↗

PubMed2003

Epidemiologic correlates of antibody response to human papillomavirus among women at low risk of cervical cancer.

A population at low risk for developing cervical cancer in Southern Brazil was studied to identify the main determinants of serological response to human papillomavirus (HPV). Enzyme-linked immunosorbent assay tests were performed in 976 women to detect serum IgG antibodies against HPV 16 L1 virus-like particles (VLPs) and HPVs 16, 18, 6 and 11 L1 VLPs as a mixture of antigens. Women with four or more sexual partners were more likely to be seropositive than women with one partner (HPV 16 serology odds ratio [OR]=3.06, 95% confidence interval [CI]: 2.0-4.8; HPV 6/11/16/18 serology OR=4.64, 95% CI: 3.0-7.2). HPV DNA and both serological responses were associated. Those positives to HPV 16 serology were twice as likely to have a cytological diagnosis of squamous intraepithelial lesions (SILs) than seronegatives (OR=2.07; 95% CI: 1.0-4.5, and OR=1.73; 95% CI: 0.8-3.8). Seropositivity to HPV 16 and HPV 6/11/16/18 antigens seem to be better markers of past sexual activity than current HPV infection, and humoral response to HPV 16 or HPV 6/11/16/18 may not be a strong indicator of cervical lesions in populations at low risk for cervical lesions.

Adolescent↗

PubMed2001

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica.

We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case-control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (P(trend)= 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1-6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16-0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (>/=3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women.

Adolescent↗

PubMed2001

Cervical HPV DNA detection as a predictor of a recurrent SIL diagnosis among untreated women.

OBJECTIVES: This study was conducted to test whether patient history of untreated cervical intraepithelial neoplasia (CIN) 1 or low-grade squamous intraepithelial lesions (LGSIL) modifies the interpretation of a positive HPV DNA result with regards to subsequent squamous intraepithelial lesions (SIL). METHODS: Seventy-three women with recurrent SIL were compared to 105 controls who remain cytologically normal during follow up. Cervical samples collected at enrollment were assayed for HPV DNA in the subject and control groups. RESULTS: Women with and without a history of LGSIL who tested positive for HPV DNA were at a similarly increased risk of having (recurrent) LGSIL as compared to controls. However, in women with a history of LGSIL, HPV DNA appeared to be less predictive for high-grade squamous intraepithelial lesions (HGSIL) than in women without a history of disease. CONCLUSIONS: Past history of untreated CIN1 or LGSIL does not modify the predictive value of a positive HPV DNA test for subsequent LGSIL. The observed difference of the predictive value of a positive HPV DNA test for the risk of recurrent HSIL compared to incident HSIL should be pursued.

Journal Article↗

PubMed2000

Comparison of human papillomavirus DNA testing and repeat Papanicolaou test in women with low-grade cervical cytologic abnormalities: a randomized trial. HPV Effectiveness in Lowgrade Paps (HELP) Study No. 1 Group.

BACKGROUND: Results of cervical cytology screening showing atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) indicate risk for high-grade cervical intraepithelial neoplasia (CIN 2 or 3). In a community-based randomized trial we compared the test performance of human papillomavirus (HPV) DNA testing with that of 6-month repeat Papanicolaou (Pap) test in detecting histologically confirmed CIN 2 or 3. METHODS: We randomly assigned 212 women aged 16-50 years with ASCUS or LSIL on cervical cytology screening to undergo either immediate HPV DNA testing or a repeat Pap test in 6 months. Cervical swabs for the HPV DNA testing and the Pap smears were obtained by their family physicians. We tested the swabs for oncogenic HPV using the Hybrid Capture II assay (Digene Corp., Beltsville, Md.). Community-based pathologists examined the Pap smears. All women were referred for colposcopy by their family physicians. Two gynecological pathologists assessed the histology findings. We calculated test performance in women who completed the trial using CIN 2 or 3 as the reference standard. RESULTS: A total of 159 women completed the study. Compared with HPV DNA testing, which detected 87.5% (7/8) of the cases of CIN 2 or 3, repeat Pap smear showing high-grade intraepithelial neoplasia (HSIL) detected 11.1% (1/9) of cases (p = 0.004), and repeat Pap smear showing ASCUS, LSIL or HSIL detected 55.6% (5/9) (p = 0.16). Corresponding specificities were 50.6%, 95.2% (p = 0.002) and 55.6% (p = 0.61). Loss to follow-up was 17.1% in the HPV test group and 32.7% in the repeat Pap group (p = 0.009). Given the 7 cases of CIN 2 or 3 detected by HPV testing and the 5 cases detected by the repeat Pap smear, the incremental cost of HPV testing was calculated to be $3003 per additional case of CIN identified. INTERPRETATION: HPV DNA testing was more costly but was associated with significantly less loss to follow-up. It may detect more cases of CIN 2 or 3 in women with low-grade cytologic abnormalities.

Adolescent↗

PubMed2000

Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions.

BACKGROUND: Certain types of human papillomavirus (HPV) in cervical samples are strongly associated with squamous intraepithelial lesions (SIL) and invasive cervical carcinoma. We determined and compared the test characteristics of testing for HPV with samples obtained by patients and with samples obtained by their physicians. METHODS: In a consecutive series of women referred to a colposcopy clinic at a teaching hospital because of abnormalities on cervical cytologic screening, 200 agreed to collect vulvar, vaginal and urine samples for HPV testing. The physician then collected cervical samples for HPV testing, and colposcopy, with biopsy as indicated, was performed. Presence of HPV was evaluated using the hybrid capture II assay (Digene Corp., Silver Spring, Md.) with a probe cocktail for 13 carcinogenic types. Cervical specimens were also tested for HPV by polymerase chain reaction and hybridization with type-specific probes. Cervical smears for cytologic examination were obtained from all women. RESULTS: High-grade lesions (high-grade squamous intraepithelial lesions [HSIL], equivalent to cervical intraepithelial neoplasia [CIN] grade 2 or 3, and adenocarcinoma) were found in 58 (29.0%) of the 200 women. Carcinogenic types of HPV were detected in the self-collected vaginal samples of 50 (86.2%) of these 58 women, in the self-collected vulvar samples of 36 (62.1%) and in the self-collected urine samples of 26 (44.8%). Carcinogenic types of HPV were detected in the cervical samples collected by physicians for 57 (98.3%) of these 58 women. The remaining 142 women (71.0%) had normal findings or low-grade squamous intraepithelial lesions (LSIL, CIN grade 1). Test results were negative or noncarcinogenic types of HPV were detected in the self-collected vaginal samples of 76 (53.5%) of these 142 women, in the self-collected vulvar samples of 89 (62.7%) and in the self-collected urine samples of 99 (69.7%). The sensitivity for self-collected samples ranged from 44.8% to 86.2%, and the specificity from 53.5% to 69.7%. For the samples collected by physicians, the sensitivity was 98.3% and the specificity 52.1%. The self-sampling methods were generally acceptable to the women: 98.4% of respondents (126/128) deemed urine sampling acceptable, 92.9% (118/127) found vulvar sampling acceptable, and 88.2% (112/127) found vaginal sampling acceptable. INTERPRETATION: Self-collection of samples for HPV testing was acceptable to women attending a colposcopy clinic for investigation of suspected cervical lesions and shows sufficient sensitivity to warrant further evaluation as a screening test for cervical cancer prevention programs.

Adenocarcinoma↗

PubMed2000

HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica.

CONTEXT: Human papillomaviruses (HPVs) are known to cause most cervical cancer worldwide, but the utility of HPV DNA testing in cervical cancer prevention has not been determined. OBJECTIVE: To provide comprehensive data on the screening performance of HPV testing for the most common carcinogenic types, at different levels of analytic sensitivity. DESIGN: Laboratory analysis conducted during 1993-1995, using 3 cytologic techniques and cervicography, followed by colposcopic examination of women with any abnormal cervical finding, to detect all high-grade intraepithelial lesions and cancer (reference standard of clinically significant disease). The HPV testing was performed subsequently with masking regarding clinical findings. SETTING: Guanacaste Province, Costa Rica, a region with a high age-adjusted incidence of cervical cancer. PARTICIPANTS: Of 11742 randomly selected women, 8554 nonpregnant, sexually active women without hysterectomies underwent initial HPV DNA testing using the original Hybrid Capture Tube test; a stratified subsample of 1119 specimens was retested using the more analytically sensitive second generation assay, the Hybrid Capture II test. MAIN OUTCOME MEASURES: Receiver operating characteristic analysis of detection of cervical high-grade intraepithelial lesions and cancer by HPV DNA testing based on different cut points of positivity. RESULTS: An analytic sensitivity of 1.0 pg/mL using the second generation assay would have permitted detection of 88.4% of 138 high-grade lesions and cancers (all 12 cancers were HPV-positive), with colposcopic referral of 12.3% of women. Papanicolaou testing using atypical squamous cells of undetermined significance as a cut point for referral resulted in 77.7% sensitivity and 94.2% specificity, with 6.9% referred. Specificity of the second generation assay for positivity for high-grade lesions and cancer was 89.0%, with 33.8% of remaining HPV DNA-positive subjects having low-grade or equivocal microscopically evident lesions. The higher detection threshold of 10 pg/mL used with the original assay had a sensitivity of 74.8% and a specificity of 93.4%. Lower levels of detection with the second generation assay (<1 pg/mL) proved clinically nonspecific without gains in diagnostic sensitivity. CONCLUSIONS: In this study population, a cut point of 1.0 pg/mL using the second generation assay permitted sensitive detection of cervical high-grade lesions and cancer, yielding an apparently optimal trade-off between high sensitivity and reasonable specificity for this test. The test will perform best in settings in which sensitive detection of high-grade lesions and cancer is paramount. Because HPV prevalence varies by population, HPV testing positive predictive value for detection of high-grade lesions and cancer will vary accordingly, with implications for utility relative to other cervical cancer screening methods.

Adult↗

PubMed1999

Utility of liquid-based cytology for cervical carcinoma screening: results of a population-based study conducted in a region of Costa Rica with a high incidence of cervical carcinoma.

BACKGROUND: In a study using a split-sample design, liquid-based cytology (ThinPrep Processor, Cytyc Corporation, Boxborough, MA) was compared with the conventional Papanicolaou (Pap) smear in Guanacaste, Costa Rica. The study provides the first population-based comparison of the ThinPrep screening technology and includes "gold standard" measures of diagnostic accuracy. METHODS: The population-based study was performed among over 8000 women residing in a Costa Rican province with a high incidence of cervical carcinoma. Conventional smears were prepared and diagnosed in Costa Rica, while the residual material on the sampling device was collected into a liquid preservative and shipped to the U.S., where ThinPrep cytologic slides were prepared and diagnosed. Cytologic diagnoses based on the two techniques, categorized according to the Bethesda System, were compared with a "gold standard" final case diagnosis for each patient, also based on Bethesda terminology, that reflected an integrated interpretation of all available data, including cytology, histology, and cervicography. Results were also compared with the results of HPV DNA detection (Hybrid Capture, Digene Corporation, Silver Spring, MD). RESULTS: ASCUS was the threshold for colposcopy referral. There were significantly more women referred according to this threshold with the ThinPrep slide (12.7%) than with the conventional smear (6.7%, P<0.001). Compared with the final case diagnosis, referral by ThinPrep slides detected 92.9% of cases with high grade squamous intraepithelial lesions (HSIL) and 100% of carcinoma cases. Smears detected 77.8% of HSIL and 90.9% of carcinomas. Thus, ThinPrep cytology was significantly more sensitive in the detection of HSIL and cancer (McNemar test, P<0.001). Adjudication of cases in which the ThinPrep and smear diagnoses disagreed, using the final case diagnoses and the HPV DNA test results as reference standards, suggested that the ThinPrep method was detecting additional true SIL as opposed to false-positives. CONCLUSIONS: In a population-based study of high risk women, ThinPrep cytology demonstrated significantly increased sensitivity for detecting HSIL and carcinoma, with a concurrent significant increase in colposcopy referrals.

Cervix Uteri↗

PubMed1999

Collection devices for human papillomavirus.

BACKGROUND: Human papillomavirus (HPV) testing has relied to date on samples collected by experienced health professionals. Self-administered testing devices could allow HPV testing to occur in large-scale epidemiologic studies of primary care screening populations. The purpose of this study is to determine whether a self-collection device for cervicovaginal HPV infection could be developed. METHODS: A prospective randomized trial of a consecutive sampling of 93 women, 18 years or older, receiving routine cervical cancer screening and colposcopy in the urban gynecologic clinics in Philadelphia, Pennsylvania, were randomized into 2 arms. Women in arm 1 used a self-administered tampon before the physician-directed swabs of the cervix; in arm 2, women underwent the physician-directed swab testing before using the self-administered tampon. The concordance of HPV DNA positivity between sampling methods detected by a Hybrid Capture HPV tube test for both low- and high-risk types of HPV was the main outcome measure. RESULTS: The concordance rate (ie, women whose cultures were classified as negative on both tests or positive on both tests) for arms 1 and 2 were similar: 78.3% and 80.9%, respectively. CONCLUSIONS: The tampon was equivalent to the physician-directed swab in HPV detection and suggests its feasibility in long-term primary care studies of screening populations.

Adolescent↗

PubMed1998

Performance of a semiautomated Papanicolaou smear screening system: results of a population-based study conducted in Guanacaste, Costa Rica.

BACKGROUND: Automated cytology devices have utility in quality assurance applications, but the effectiveness of these devices in primary screening is unknown. METHODS: Enrollment smears obtained from 7323 women participating in a population-based study sponsored by the National Cancer Institute were screened manually in Costa Rica and then evaluated independently in the U.S. with the PAPNET system (Neuromedical Systems, Inc., Suffern, NY), a semiautomated, neural network-based device. Smears with abnormal PAPNET images were microscopically rescreened and then diagnosed by a U.S. cytopathologist. ThinPrep slides (Cytyc Corporation, Boxborough, MA), prepared from rinses of the cytologic sampler, and cervigrams (National Testing Laboratories, Fenton, MO) were also evaluated. Women with any abnormal cytologic diagnosis or a positive cervigram were referred for colposcopy with biopsy and definitive therapy if indicated. RESULTS: Based on the U.S. cytotechnologist's review of the PAPNET images, 1017 (13.9%) of 7323 smears were selected for manual screening, resulting in the selection of 492 (6.7%) possibly abnormal slides for referral to the U.S. pathologist. Ultimately, 312 smears (4.3% of the total) were diagnosed as containing squamous cells of undetermined significance or a more severe abnormality (> or =ASCUS), resulting, hypothetically, in the referral of 66.5% of women with a final diagnosis of a squamous intraepithelial lesion or a more severe abnormality (> or =SIL) and 86.0% of patients with > or =high grade SIL. Conventional microscopic screening performed in Costa Rica resulted in the hypothetical referral of 6.5% of patients with > or =ASCUS for colposcopy, including 69.5% of patients with > or =SIL and 79.8% of those with > or =high grade SIL. CONCLUSIONS: In this study, PAPNET-assisted cytologic screening accurately identified smears obtained from women with high grade SIL or carcinoma. Determination of the clinical cost-effectiveness of PAPNET-assisted screening in routine practice awaits future study.

Cohort Studies↗

PubMed1998

Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy?

BACKGROUND: The purpose of this study was to determine the efficacy of a repeat Papanicolaou (Pap) smear and the Hybrid Capture tube-based (HCT) HPV DNA test for detecting cervical intraepithelial neoplasia (CIN) grade 2 or 3 in women with recent atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap smear reports. METHODS: Women with a recent Pap smear report of ASCUS (n = 169) or LSIL (n = 110) had a repeat Pap smear, sampling of the cervix for HCT HPV DNA assay and a colposcopy examination. Data were evaluated using three different triage thresholds for colposcopy examination: a repeat Pap smear of persistent ASCUS or more severe dysplasia, a finding of persistent LSIL or more severe dysplasia, and a carcinogenic HPV test result. RESULTS: The sensitivity, specificity, and positive and negative predictive values for detecting CIN 2/3 were 70%, 45%, 7%, and 96% for a repeat Pap smear using an ASCUS-positive threshold and 20%, 86%, 8%, and 94% for a repeat Pap smear using an LSIL-positive threshold, respectively, when women with an initial ASCUS Pap smear were considered. HPV testing for carcinogenic viruses alone or in combination with a repeat Pap smear (using ASCUS as a positive threshold) yielded results of 50%, 67%, 9%, and 96%, respectively, and 70%, 37%, 7%, and 95%, respectively, for detecting CIN 2/3. In women with an initial LSIL Pap smear, respective values for detecting CIN 2/3 by a repeat Pap smear with an ASCUS threshold were 92%, 26%, 14%, and 96%, and for an LSIL threshold 23%, 64%, 8%, and 86%, respectively. Hybrid Capture HPV testing alone or in combination with a repeat Pap smear yielded 69%, 43%, 14%, and 91%, respectively, and 100%, 21%, 14%, and 100%, respectively. CONCLUSIONS: A Pap smear triage threshold restricted to LSIL or more severe dysplasia for women with prior ASCUS or LSIL Pap smear results was clearly ineffective for detecting high-grade cervical precancerous lesions. In contrast, when the repeat Pap smear triage threshold was expanded to include persistent ASCUS as abnormal, 83% of the women with CIN 2/3 were detected. Detection of carcinogenic HPV DNA using the HCT test was almost as sensitive for detecting CIN 2/3 as a solitary repeat Pap smear using an ASCUS or more severe positive threshold. Combining the HPV test with a repeat Pap smear did not significantly improve the sensitivity of cytology for detecting high-grade CIN. This study suggests that women with ASCUS and particularly LSIL Pap smears should be referred for a colposcopy examination until better triage methods become available.

Adult↗

PubMed1998

Comparison of two tests for detecting carcinogenic HPV in women with Papanicolaou smear reports of ASCUS and LSIL.

BACKGROUND: The detection of cancer-associated types of human papillomavirus (HPV) in cervical specimens predicts the presence and future development of cervical intraepithelial neoplasia (CIN). The purposes of this study were (1) to determine the efficacy of a second-generation assay by hybrid capture (HC II) to detect carcinogenic HPV from residual cervical cells of a liquid-based cervical cytologic specimen, and (2) to compare the performance of this second-generation test with the first-generation hybrid capture (HCT) HPV test of material from direct cervical sampling to detect CIN in women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap) smear reports. METHODS: Women with a recent Pap smear report of ASCUS or LSIL had a sampling of the cervix using either an Ayre's spatula and cytobrush or an Accellon device sampling for liquid-based cytologic system HC II HPV testing, followed by a Dacron swab sampling of the cervix for standard HCT HPV testing of the paired specimens. All women received colposcopy examinations including cervical biopsy and endocervical curettage, when indicated, to determine criterion standards for comparison. RESULTS: Paired swabs and liquid-based cervical specimens from 242 women were available for testing by standard HCT and the newer HC II HPV DNA assays. The sensitivity, specificity, and positive and negative predictive values for detecting CIN grade 2 or 3 (CIN 2/3) were 61.9%, 57.0%, 12.0%, and 94.0%, respectively, for the HCT test, and 90.5%, 29.4%, 10.9%, and 97.0%, respectively, for the liquid-based cytology HC II assay. When only women with an initial ASCUS Pap smear report were considered, the HC II test results were 88.9%, 40.3%, 9.1%, and 98.2%, respectively. CONCLUSIONS: Testing for lower genital tract carcinogenic HPV DNA using a cervical cytology liquid transport media residual sample is clinically feasible. The new HC II microplate HPV test achieved a greater test sensitivity for detecting carcinogenic HPV and correspondingly of CIN 2/3 compared with the currently available first-generation HC HPV test. Use of a liquid-based cervical cytology system combined with intermediate triage by HC II testing of residual cells for carcinogenic HPV alone may help to efficiently identify CIN 2/3 in women who have a prior screening Pap smear report of ASCUS.

Adult↗

PubMed1998

Human leukocyte antigen class I/II alleles and development of human papillomavirus-related cervical neoplasia: results from a case-control study conducted in the United States.

The host immune response to human papillomaviruses (HPVs) is believed to be an important determinant of progression of HPV-associated cervical neoplasia. Human leukocyte antigens (HLAs) are important in the presentation of foreign antigens to the immune system. Previous studies have suggested a possible association between HLA and cervical neoplasia, but the specific alleles found to be associated with disease have varied between studies. To further evaluate this issue, we conducted a nested case-control study within a 24,000-woman cohort study in the United States. A total of 711 women were selected for the study: 141 women diagnosed with high-grade squamous intraepithelial lesions (HSILs) of the cervix; 202 women diagnosed with low-grade SILs (LSILs); 166 women with no history of cervical neoplasia, but evidence of HPV-16 infection; and 202 women with no history of cervical abnormalities and who were HPV negative during follow-up as part of our cohort. Cervicovaginal lavage samples collected from participants were used for HPV testing by L1 consensus primer PCR and the Hybrid Capture tube test methods. DNA extracted from these same lavage samples were used for PCR-based HLA genotyping. Our results suggest a positive association between HLA B7 and HLA DQB1*0302 and disease. A negative association with disease was observed for HLA DRB1*1501-DQB1*0602 and DRB1*13. Associations were strongest when analyses were restricted to HPV-16-positive cases as follows. Compared with women who were cytologically normal and HPV negative, HLA B7 was associated with a 1.5-fold increased risk of HPV/LSIL [95% confidence interval (CI) = 0.95-2.5] and a 2.5-fold increased risk of HSIL (95% CI = 1.2-5.1). HLA DQB1*0302 was associated with a 1.5-fold increased risk of HPV/LSIL (95% CI = 0.94-2.4) and a 1.7-fold increased risk of HSIL (95% CI = 0.84-3.5). HLA DRB1*1501-DQB1*0602 was associated with a decreased risk of HSIL [relative risk (RR) = 0.21; 95% CI = 0.07-0.62]. HLA DRB1*13 was associated with a decreased risk of HPV/LSIL (RR = 0.78; 95% CI = 0.51-1.2) and HSIL (RR = 0.63; 95% CI = 0.30-1.3). Individuals who were either homozygous for DQB1*0302 or carriers of both B7 and DQB1*0302 were found to be at highest risk of disease (RR = 4.5, 95% CI = 1.5-14 for HPV/LSIL; and RR = 9.0, 95% CI = 2.4-34 for HSIL). No synergistic effect was observed for the alleles found to be associated with reduced risk of cervical neoplasia. Our findings support previous studies that have found HLA B7 and DQB1*0302 to be positively associated with cervical neoplasia and are consistent with those that have suggested that DRB1*13 is negatively associated with disease, but do not confirm previous assertions that DRB1*1501-DQB1*0602 increases the risk of cervical disease.

Adult↗

PubMed1997

Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing.

BACKGROUND: Several new techniques have been developed to improve the sensitivity of cervical carcinoma screening and reduce equivocal cytologic diagnoses referred to as atypical squamous cells of undetermined significance (ASCUS). This study evaluates the effectiveness of combining two newly introduced diagnostic techniques: preparation of thin-layer cytologic slides from ThinPrep liquid buffer and selected Hybrid Capture testing for human papillomavirus (HPV) DNA. Because HPV DNA detection has been strongly associated with the presence of a cervical carcinoma precursor ("squamous intraepithelial lesion," or SIL), HPV testing might be useful for identifying women with ASCUS who have an underlying SIL. METHODS: Two hundred specimens demonstrating diverse cervical abnormalities were selected from a prospective population-based study of 9174 women conducted in Costa Rica. The entire cohort had been screened with conventional cervical smears; ThinPrep slides made from liquid buffer, PAPNET, a computerized slide reading system; and Cervicography. Patients with any abnormal screening test were referred for colposcopy, punch biopsy, and loop excision of cases with high grade cytologic abnormalities not explained by punch biopsy. For this investigation, the results of ThinPrep cytology and HPV testing alone and in combination were compared with the final diagnoses, with an emphasis on the detection of carcinoma and high grade SIL. RESULTS: The 200 subjects studied included 7 women with a final diagnosis of carcinoma, 44 with high grade SIL, 34 with low grade SIL, 51 with a variety of equivocal diagnoses, and 64 with normal diagnoses. A ThinPrep cytologic diagnosis of SIL or carcinoma was made in 39 (76%) of the 51 women with final diagnoses of high grade SIL or carcinoma. Hybrid Capture testing detected carcinoma-associated types of HPV DNA in 100% of women with carcinoma, 75% with high grade SIL, 62% with low grade SIL, 20% with equivocal final diagnoses, and 12% of normal women. If colposcopy referral had been limited to women with a ThinPrep diagnosis of SIL or a diagnosis of ASCUS associated with the detection of carcinoma-associated HPV DNA from the same vial, 100% of women with carcinoma and 80% with high grade SIL would have been examined. To achieve this high sensitivity in the entire population of 9174 women would have required the referral of about 7% of the population. The combined screening strategy would have performed marginally better than optimized conventional screening with referral of any abnormal cytology (ASCUS and above). CONCLUSIONS: A cervical carcinoma screening technique which uses a single sample for cytopathology and HPV testing to triage equivocal diagnoses may be promising if it proves to be cost-effective.

Carcinoma↗

PubMed1997

Evaluation of PAPNET testing as an ancillary tool to clarify the status of the "atypical" cervical smear.

To assess the utility of the PAPNET system (Neuromedical Systems Inc., Suffern, NY) in clarifying the status of cervical smears showing borderline abnormalities, we analyzed the results of five cytotechnologists who reclassified 200 "atypical" smears by evaluating PAPNET images only. The interobserver agreement (reliability) of the PAPNET reviewers was computed, and their readings were compared with three standards: the consensus diagnosis of five pathologists who used light microscopy, the detection of cancer-associated human papillomavirus DNA by Southern analysis, and the correlation with diagnoses of biopsy specimens obtained during passive follow-up. The PAPNET reviewers classified 18 to 65% of cases as normal, 25 to 42% as equivocal, and 10 to 55% as abnormal. Unanimous interobserver agreement was achieved in only 24 (13%) cases. Four of the five PAPNET reviewers agreed moderately well with the results of the pathology reference panel. In four of the five PAPNET reviews, classification of cases as abnormal was strongly correlated with the detection of cancer-associated types of human papillomavirus. Consensus PAPNET results of abnormal were predictive of abnormal histologic findings at follow-up. Theoretically, if colposcopy had been performed on all of the women with equivocal or abnormal PAPNET results (based on the consensus of the panel), as much as 95% of biopsy-confirmed lesions could have been detected, but 79% of women would have been referred. Restriction of colposcopy referral to women with definitely abnormal PAPNET readings would have reduced referrals to 31%, but the sensitivity of the triage would have dropped to 51% of biopsy-confirmed lesions.

Biopsy↗

PubMed1997

Immune activation in cervical neoplasia: cross-sectional association between plasma soluble interleukin 2 receptor levels and disease.

In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL-2R levels were found to increase with increasing disease severity (Ptrend = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among LSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as > or = 450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (Ptrend = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (Ptrend = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2-mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

Adolescent↗

PubMed1996

Interleukin 2 production in vitro by peripheral lymphocytes in response to human papillomavirus-derived peptides: correlation with cervical pathology.

Human papillomavirus (HPV) is believed to be the major cause of cervical cancer. To investigate whether a cellular immune response, especially a T helper type 1 response, is related to the natural defense against HPV-related cervical lesions, the interleukin 2 response of peripheral blood lymphocytes in vitro to overlapping peptides from HPV-16 E6 and E7 oncoproteins was compared with the degree of cervical cytological abnormality among 140 women in a cross-sectional study. We compared 66 women diagnosed with low-grade squamous intraepithelial lesions (LSIL), 21 with high-grade squamous intraepithelial lesions (HSIL), and 28 with invasive cervical cancer with 25 women who were cytologically normal but previously HPV-16 DNA positive. The fraction showing strong interleukin 2 production against HPV-16 peptides was greatest among cytologically normal women (35%) and declined with increasing disease severity [LSIL] (20%), HSIL, (17%), and cancer patients (7%); X2 test P for the trend = 0.02], whereas the responses against a recall influenza antigen were not significantly different among groups. Our finding suggests that a T helper lymphocyte type 1 response to HPV antigens is associated with disease status. This result may reflect a targeted effect of the disease on immune function or a protective effect of the immune response against disease progression.

Adolescent↗

PubMed1996

Epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 virus-like particles in cervical HPV-16 DNA-positive and-negative women.

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested.

Antibodies, Viral↗