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Mark Schiffman

Publications and source records attributed to Mark Schiffman.

At least 73 records · Page 4Linked to original sources
PubMed2004

A case-control study of risk factors for invasive cervical cancer among U.S. women exposed to oncogenic types of human papillomavirus.

Oncogenic human papillomavirus (HPV) infections, the necessary cause of most cervical cancers, are common and usually clear within 1 to 2 years. Identifying cofactors that lead to cancer among HPV-infected women has depended mainly on case-control studies defining HPV by DNA testing. DNA testing assesses only current infection; thus, concerns about residual confounding remain. To assess cofactors, we used seropositivity to five oncogenic HPV types as a marker of past exposure and confined our analysis to seropositive controls compared with cancer cases. Study subjects had participated in a multicenter U.S. case-control study conducted in the early 1980s. The detailed questionnaire and stored sera for 235 cases of squamous carcinoma and 486 controls motivated the reanalysis. We measured antibodies to HPV types 16, 18, 31, 45, and 52. Independent, significant predictors of seropositivity among controls included numbers of sexual partners, Black race, and oral contraceptive use. Condom use was protective. Among HPV-exposed women, Papanicolaou screening, Black race, and yeast infection were significantly associated with reduced cancer risk. Current smoking was associated with a 2-fold increase in risk; there were independent, significant trends of increased risk with numbers of cigarettes smoked (P for trend = 0.003) and years of smoking (P for trend = 0.01). Other significant predictors of increased risk included low education and income and history of nonspecific genital infection. Unlike recent HPV DNA-based investigations, based on the use of HPV-seropositive controls in this study, oral contraceptive use was unrelated to the risk of cervical cancer and multiparity was only weakly related to risk. It is particularly worth considering further why studies of different designs are inconsistent regarding the effect of oral contraceptive use.

Adult↗
PubMed2003

Stability of archived liquid-based cervical cytologic specimens.

BACKGROUND: Exfoliated cervical cell specimens collected in PreservCyt, a methanol-based medium used in ThinPrep liquid-based cytology, have been archived in epidemiologic studies. However, long-term DNA stability and cytologic stability of these biospecimens have not been evaluated. METHODS: Cervical specimens were collected into PreservCyt from participants in a natural history study of human papillomavirus (HPV) infection and cervical carcinoma in Guanacaste, Costa Rica (1993-2000), and stored at ambient temperatures. Thirty specimens classified as low-grade squamous intraepithelial lesions by liquid-based cytology were randomly chosen from each collection year (except for 1994) and selectively assessed for molecular and cytologic stability. Specimens were tested in 2001 for 1) HPV DNA by the Hybrid Capture 2 test, 2) beta-globin DNA by polymerase chain reaction amplification of multiple length fragments (268, 610, and 1327 bp), and 3) nuclear preservation by visual inspection of newly made liquid-based cytology slides. All testing was done masked to year of collection. Associations of stability and storage time were evaluated using standard contingency tables and chi-square tests for trend. RESULTS: Human papillomavirus DNA, as detected by the Hybrid Capture 2 test, was unaffected by storage time. Stability of beta-globin DNA (P(Trend) < 0.0001) and nuclear preservation (P(Trend) < 0.0001) declined with increasing storage time. Approximately 15% of specimens could not be amplified for any beta-globin DNA fragment after 5 years of storage (collected in 1996). In addition, cytology slides made from 41% specimens were rated as marginal (32%) or unsatisfactory (9%) after 8 years of storage (collected in 1993). CONCLUSIONS: Cervical specimens archived in PreservCyt underwent partial DNA and cytologic degradation after several years of storage. Methodologic studies to optimize long-term storage of cervical cells for epidemiologic studies of cervical carcinoma are needed.

Adult↗
PubMed2003

Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis.

BACKGROUND: Annual Pap smear screening has been favored over less frequent screening in the United States to minimize the risk of cervical cancer. We evaluated whether simultaneous screening with a Pap test and human papillomavirus (HPV) testing is useful for assessing the risk for cervical intraepithelial neoplasia (CIN) 3 or cervical cancer. METHODS: We enrolled 23 702 subjects in a study of HPV infection at Kaiser Permanente, Northwest Division, Portland, OR. Data were analyzed for 20 810 volunteers who were at least 16 years old (mean = 35.9 years) with satisfactory baseline Pap tests and suitable samples for HPV testing. Women were followed for up to 122 months (from April 1, 1989, to June 30, 1999) to determine the risk for histopathologically confirmed CIN3 or cancer. RESULTS: Among 171 women with CIN3 or cancer diagnosed over 122 months, 123 (71.9%, 95% confidence interval [CI] = 65.2% to 78.7%) had baseline Pap results of atypical squamous cells or worse and/or a positive HPV test, including 102 (86.4%, 95% CI = 80.3% to 92.6%) of the 118 cases diagnosed within the first 45 months of follow-up. During this 45-month period, the cumulative incidence of CIN3 or cancer was 4.54% (95% CI = 3.61% to 5.46%) among women with a Pap test result of atypical squamous cells or worse, positive HPV tests, or both compared with 0.16% (95% CI = 0.08% to 0.24%) among women with negative Pap and HPV tests. Age, screening behavior, a history of cervical cancer precursors, and a history of treatment for CIN minimally affected results. CONCLUSIONS: Negative baseline Pap and HPV tests were associated with a low risk for CIN3 or cancer in the subsequent 45 months, largely because a negative HPV test was associated with a decreased risk of cervical neoplasia. Negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, whereas positive results identify a relatively small subgroup that requires more frequent surveillance.

Adolescent↗
PubMed2003

Correlates of IL-10 and IL-12 concentrations in cervical secretions.

Interindividual variations in host immune responses to HPV infection are thought to be important determinants of viral persistence and progression to cervical intraepithelial neoplasia and cancer. However, few studies have measured local immune markers at the site of infection (e.g., the cervical mucosa). We sought to determine biologic correlates of IL-10 and IL-12 concentrations in cervical secretions. Cervical secretions were passively collected using a WeckCel sponge from 247 women participating in a natural history study of human papillomavirus infection as part of an immunologic ancillary study. IL-10 and IL-12 concentrations were determined using standard ELISA assays. In general, IL-10 and IL-12 levels were significantly intercorrelated (Pearson's correlation coefficient = 0.6) but had somewhat different determinants. Significant increases (P < 0.05) in IL-10 concentrations were observed for nonovulatory phases of the menstrual cycle, postmenopausal status, recent use of oral contraceptives (OC), low secretion volume, macrolevels of heme contamination, and high vaginal pH. Increasing IL-10 levels were also observed among smokers, women with increasing numbers of lifetime sex partners, and women who report having less frequent sex (less than once per week), however, these results were not statistically significant. Significantly higher IL-12 concentrations were observed among recent OC users, women with low secretion volume, and women with a high vaginal pH. There was a non-statistically significant observation of increasing IL-12 levels among nonsmokers, women with increasing numbers of lifetime and recent pregnancies, and increasing levels of heme contamination. We failed to observe a significant association between HPV and IL-10 or IL-12 levels in this crosssectional sample. Future analyses of cervical cytokine levels and HPV infection should control for the inherent variation of local cytokine levels due to hormonal influences, hemoglobin contamination, pH, and cervical secretion volume differences.

Adult↗
PubMed2003

Postcolposcopy management strategies for women referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: a two-year prospective study.

OBJECTIVE: This study was undertaken to compare postcolposcopy management strategies for women referred for low-grade squamous intraepithelial lesions (LSIL) or oncogenic human papillomavirus (HPV) DNA-positive atypical squamous cells of undetermined significance (ASCUS), with cervical intraepithelial neoplasia (CIN) grade 1 or less found at initial colposcopy. STUDY DESIGN: A 2-year prospective follow-up of 1539 women was designed to assess the percentage sensitivity of different postcolposcopy management strategies to detect subsequent CIN grade 2 or 3 and percentage referral to repeat colposcopy. RESULTS: HPV testing at 12 months was sensitive (92.2%) for detection of CIN grade 2 or 3 with a referral rate to repeat colposcopy of 55.0%. Repeat semiannual cytology with referral to colposcopy at an ASCUS threshold demonstrated similar sensitivity (88.0%) but with a higher rate of referral to colposcopy (63.6%). Combining cytology and HPV testing did not increase sensitivity and hurt specificity. Baseline viral load and colposcopic impression were not helpful. CONCLUSION: The most efficient test for identifying women with CIN grade 2 or 3 after colposcopy might be an HPV test alone at 12 months.

Adolescent↗
PubMed2003

Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy.

OBJECTIVE: The purpose of this study was to determine the risk of cumulative cervical intraepithelial neoplasia (CIN) grade 2 or 3 according to initial colposcopy and directed biopsy results among women with low-grade squamous intraepithelial lesions (LSIL) or human papillomavirus (HPV) DNA positive atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: A 2-year follow-up of 897 cases of LSIL and 1193 cases of HPV DNA positive ASCUS from the ASCUS/LSIL Triage Study was used to simulate American Society for Colposcopy and Cervical Pathology Consensus Conference recommendations. Women with CIN grade 1 or less were followed up for 2 years by semiannual cytologic examination, with universal exit colposcopy. The clinical end point was a cumulative clinical center histologic diagnosis of CIN grade 2 or 3. RESULTS: The cumulative risk of CIN grade 2 or 3 was equivalent for LSIL (27.6%) and HPV positive ASCUS (26.7%). After excluding the women with a diagnosis of CIN grade 2 or 3 at initial colposcopy and directed biopsy (17.9%), the remaining women were at nearly identical risk for subsequent CIN grade 2 or 3 regardless of initial colposcopy result (completely negative colposcopy-11.3%; negative colposcopically directed biopsy-11.7%; and CIN grade 1 biopsy-13.0%). CONCLUSION: LSIL and HPV positive ASCUS are clinically equivalent. Initial colposcopic detection of obviously prevalent CIN grade 2 or 3 reduces risk. However, for the remaining women who have CIN grade 1 or less on colposcopy and directed biopsy, the risk for subsequent CIN grade 2 or 3 (whether missed, prevalent, or truly incident) is approximately 12% over 2 years. This risk does not vary meaningfully by initial distinction of histologic CIN grade 1 from negative colposcopy and biopsy.

Adolescent↗
PubMed2003

Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia.

This chapter suggests promising areas of future epidemiologic research on human papillomavirus (HPV) and anogenital cancer, organized around our understanding of cervical carcinogenesis. The major steps in cervical carcinogenesis include HPV infection, HPV persistence over a certain period of time, progression to precancer, and invasion. Backward steps include clearance of HPV infection and regression of precancer. Additional studies of incident HPV infections among virgins initiating sexual activity could clarify the earliest aspects of transmission and immune response. Research on older women and their male partners should focus on understanding the determinants of varying age-specific HPV prevalence curves and underlying dynamics of viral persistence, clearance, and latency. It will be particularly important for epidemiologists to define HPV persistence rigorously in order to guide clinical management and vaccine trials. Intensive longitudinal studies that collect visual, microscopic (cytologic and histologic), and molecular data will be needed to understand the fate of individual HPV infections and to clarify whether multiple, concurrent infections act independently on the cervix. Case-control designs will be useful mainly in searching for new biomarkers of risk of progression among HPV-infected women that could then be validated prospectively. Prospective confirmation is also needed for the etiologic cofactors established by case-control studies of invasive cervical cancer. Much of the knowledge about cervical cancer might apply to anal neoplasia. Epidemiologic studies of other genital tumors such as penile neoplasia are still needed, but multicentric groups must place great emphasis on measurement technology, given the difficulty in obtaining reliable comprehensive measurements.

Age Distribution↗
PubMed2003

Why do Black Americans have a higher risk of pancreatic cancer than White Americans?

BACKGROUND: For several decades, the incidence of pancreatic cancer has been 50% to 90% higher among blacks than among whites in the United States. The purpose of this study was to identify risk factors that may contribute to this racial disparity. METHODS: We conducted a population-based case-control study of pancreatic cancer diagnosed in Atlanta (GA), Detroit (MI), and 10 New Jersey counties from August 1986 through April 1989. In-person interviews were exclusively with subjects (526 cases and 2153 population controls), rather than with next of kin. RESULTS: The determinants of the higher incidence of pancreatic cancer among blacks than among whites differed by sex. Among men, established risk factors (, cigarette smoking, long-term diabetes mellitus, family history of pancreatic cancer) account for 46% of the disease in blacks and 37% in whites, potentially explaining all but 6% of the excess risk among blacks. Among women, however, other factors appear to contribute to the racial disparity, notably moderate/heavy alcohol consumption (>7 drinks per week) and elevated body mass index (above the first quartile). When these less accepted risk factors were combined with the established risk factors, 88% of the disease in black women and 47% in white women were explained, potentially accounting for all of the excess risk among blacks in our female study population. CONCLUSIONS: Among men, the established risk factors (mainly cigarette smoking and diabetes mellitus) explain almost the entire black/white disparity in incidence. Among women, however, other factors appear to contribute to the racial disparity, notably moderate/heavy alcohol consumption and elevated body mass index. In the absence of these factors, pancreatic cancer incidence rates among blacks probably would not exceed those among whites of either sex.

Adult↗
PubMed2003

Chlamydia trachomatis, herpes simplex virus 2, and human T-cell lymphotrophic virus type 1 are not associated with grade of cervical neoplasia in Jamaican colposcopy patients.

BACKGROUND: A few recent studies have suggested that other sexually transmitted infections may increase the likelihood of a human papillomavirus (HPV) infection progressing to high-grade cervical neoplasia and cancer. GOAL: The goal was to assess whether exposures to Chlamydia trachomatis, human T-cell lymphotrophic virus type 1 (HTLV-I), and/or human simplex virus type 2 (HSV-2) are greater in colposcopy patients with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) than in patients with low-grade cervical neoplasia (CIN1). STUDY DESIGN: Sequential patients (n=447) attending a colposcopy clinic in Kingston, Jamaica, a country with high cervical cancer rates and high HTLV-I prevalence, were tested for (1) HPV DNA by L1 consensus primer (MY09/11) polymerase chain reaction assays, (2) C trachomatis DNA by ligase chain reaction, (3) C trachomatis antibodies by both microimmunofluorescence and a peptide (VS4) enzyme linked immunosorbent assay (ELISA), (4) HTLV-I antibodies by ELISA confirmed by western blotting, and (5) HSV-2 antibodies by a recombinant HSV-2-specific ELISA. Odds ratios and 95% confidence intervals were estimated with use of multinomial logistic regression models. RESULTS: HPV DNA detection was associated with grade of cervical neoplasia but other evaluated sexually transmitted infections were not. CONCLUSIONS: HTLV-I, C trachomatis, and/or HSV-2 were not associated with severity of cervical neoplasia in Jamaican women.

Adult↗
PubMed2003

Right-sided ectocervical lesions may be associated with false-negative cytology among women with histologic cervical intraepithelial neoplasia 2 or 3.

BACKGROUND: The association between the location of an ectocervical lesion and the sensibility of cytologic screening has not been adequately evaluated. METHODS: We evaluated the proportion of false-negative cytologic interpretations using three independent cytologic interpretations (conventional, PapNet, and ThinPrep) according to lesion location in 111 women with histologic cervical intraepithelial neoplasia 2 or 3 of a population-based study of cervical neoplasia conducted in Guanacaste, Costa Rica. Semiquantitative measures of human papillomavirus viral load were also considered. RESULTS: Lesions on a women's right ectocervix were associated with more frequent false-negative results than lesions on left ectocervix for each of the cytologic methods or when the most severe interpretation was considered (p = .004). Right-sided lesions had nonsignificantly lower viral loads than left-sided lesions (p = .2). CONCLUSIONS: Cervical intraepithelial neoplasia 2 or 3 located on the right side of the cervix may be poorly sampled with broom samplers in some settings, resulting in false-negative cytologic results.

Journal Article↗
PubMed2003

Comparison between prototype hybrid capture 3 and hybrid capture 2 human papillomavirus DNA assays for detection of high-grade cervical intraepithelial neoplasia and cancer.

We compared the performance of a prototype version of the Hybrid Capture 3 (HC3) human papillomavirus (HPV) DNA assay to the current generation Hybrid Capture 2 (HC2) assay, both of which target 13 oncogenic HPV types, for the detection of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) with cervicovaginal lavage specimens collected at enrollment into a 10-year cohort study at Kaiser Permanente (Portland, Oreg.). HC3 results for a risk-stratified sample (n = 4,364) were compared to HC2 results for the entire cohort (n = 20,810) with receiver operating characteristics curves, and the optimal cut points for both tests (relative light units [RLU]/positive control [PC]) for the detection of CIN3+ were determined. Specimens were also tested for HPV16 and HPV18 with separate HC3 type-specific probes. The optimal cut point for detecting CIN3+ was 1.0 RLU/PC for HC2, as previously shown, and was 0.6 RLU/PC for HC3. At the optimal cut points, HC3 and HC2 had similar screening performance characteristics for CIN3+ diagnosed at the enrollment visit. In analyses that included cases CIN3+ at enrollment and those diagnosed during early follow-up, HC3 had nonsignificantly higher sensitivity and equal specificity for the detection of CIN3+ compared to HC2; this increase in sensitivity was primarily the result of increased detection of CIN3+ in women who were 30 years of age or older and were cytologically negative (P = 0.006). We also compared the performance of the hybrid capture tests to MY09/11 L1 consensus primer PCR results (n = 1,247). HC3 was less likely than HC2 to test positive for specimens that tested positive by PCR for any untargeted types (P < 0.001). HC3 was less likely than HC2 to test positive for untargeted PCR-detected single infections with HPV53 (P = 0.001) and HPV66 (P = 0.01). There was good agreement between test positivity by PCR and by single type-specific HC3 probes for HPV16 (kappa = 0.76; 95% confidence interval [CI] = 0.71 to 0.82) and for HPV18 (kappa = 0.73; 95% CI = 0.68 to 0.79). In conclusion, we suggest that HC3 (>/=0.6 RLU/PC) may be slightly more sensitive than and equally specific test as HC2 (>/=1.0 RLU/PC) for the detection of CIN3+ over the duration of typical screening intervals.

Cross Reactions↗
PubMed2003

Human papillomavirus: epidemiology and public health.

Approximately 15 types of human papillomavirus (HPV) infection cause virtually all cases of cervical cancer. Human papillomavirus 16 is the major type, accounting for approximately 50% of cases. The major steps of cervical carcinogenesis include HPV infection, viral persistence and progression to precancer (as opposed to viral clearance), and invasion. Human papillomavirus is the most common sexually transmitted infection. However, most HPV infections become undetectable by even sensitive HPV DNA testing within 1 to 2 years. The prevalence of infection peaks at young ages and declines thereafter, perhaps as the result of HPV type-specific acquired immunity. Most HPV infections are neither microscopically evident nor visible, making HPV DNA detection the diagnostic reference standard. Poorly defined immunologic factors are the major determinants of viral outcome. Smoking, multiparity, and long-term oral contraceptive use increase the risk of persistence and progression. Other sexually transmitted infections (eg, Chlamydia trachomatis), chronic inflammation, and nutritional factors might also play a role. Overt, long-term viral persistence in the absence of precancer is uncommon. New prevention strategies can be derived from the evolving knowledge of HPV carcinogenesis. Human papillomavirus vaccination is the ultimate prevention strategy, and large-scale trials are already underway. In the meantime, HPV DNA diagnostics are more sensitive although less specific than cytology, permitting a consideration of lengthened screening intervals. In terms of public health education, clinicians and patients will need to shift discussions of the mildly abnormal Papanicolaou test to consideration of HPV infection as a common sexually transmitted infection that rarely causes cervical cancer.

Carrier State↗
PubMed2003

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

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.

Carcinoma, Squamous Cell↗
PubMed2003

Histopathologic extent of cervical intraepithelial neoplasia 3 lesions in the atypical squamous cells of undetermined significance low-grade squamous intraepithelial lesion triage study: implications for subject safety and lead-time bias.

Cervical intraepithelial neoplasia 3 (CIN3) is the precursor of mostsquamous carcinomas and serves as a surrogate end point. However, small CIN3 lesions are rarely associated with concurrent invasion. We hypothesized that aggressive follow-up for cytology of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) leads predominantly to detection of smaller CIN3 lesions than those usually associated with cancer. We assessed this hypothesis in a masked histopathologic review of 330 CIN3 lesions in the ASCUS LSILTriage Study, focusing on ASCUS referrals. ASCUS referrals underwent randomized management [colposcopy for repeat cytology of high-grade squamous intraepithelial lesion (HSIL), colposcopy for oncogenic human papillomavirus (HPV) detection or repeat HSIL, or immediate colposcopy]; then all were followed with repeat cytology for 2 years, followed by colposcopy and aggressive treatment. We assessed all CIN3 lesions qualitatively and measured 39 of them. CIN3 lesions were overwhelmingly small. Compared with enrollment, lesions found at follow-up or exit involved fewer tissue fragments (P < 0.01) and showed less diffuse gland involvement (P = 0.03). CIN3 lesions found postenrollment after HPV testing involved the fewest tissue fragments [versus immediate colposcopy (P = 0.04) or repeat cytology of HSIL (P = 0.02)], and none showed diffuse gland involvement. The median distal-proximal length was 6.5 mm (median replacement of total epithelium = 5%) in the 39 measured cases. We conclude that CIN3 lesions underlying ASCUS or LSIL generally lack features associated with invasion, particularly if managed using HPV testing, suggesting that aggressive management leads to early detection of CIN3 but probably prevents relatively few cancers in screened populations.

Adult↗
PubMed2003

A comparison between real-time polymerase chain reaction and hybrid capture 2 for human papillomavirus DNA quantitation.

Studies investigating human papillomavirus (HPV) viral load as a risk factor in the development of squamous intraepithelial lesions (SILs) and cancer have often yielded conflicting results. These studies used a variety of HPV viral quantitation assays [including the commercially available hybrid capture 2 (HC 2) assay], which differ in their ability to account for differences in cervical cell collection, linear dynamic range of viral load quantitation, and determination of type-specific versus cumulative viral load measures. HPV-16 and HPV-18 viral quantitation using real-time PCR assays were performed to determine whether type-specific viral load measurements that adjust for specimen cellularity result in a different association between viral load and prevalent SIL and cancer, compared with HC 2 quantitation (which does not adjust for cellularity or multiple infections). In general, HPV-16 viral load as measured by real-time PCR increased linearly with increasing grade of SIL while HPV-18 measured using similar techniques increased through low-grade SIL (LSIL), with HPV-18 viral load among high-grade SIL and cancers near the level of cytologically normal women. HC 2 viral load, using the clinical 1.0 pg/ml cut point, differentiated cytologically normal women from women with any level of cytological abnormality (normal versus >/=LSIL) but did not change as lesion severity increased. There was no evidence for plateau of HC 2 at high copy numbers, nor was significant variability in total specimen cellularity observed. However, cumulative viral load measurements by HC 2, in the presence of multiple coinfections, overestimated type-specific viral load. Multiple infections were more common among women with no (32%) or LSIL (51%) [versus 23% in high-grade SIL/cancer], partially explaining the lack of a dose response using a cumulative HC2 viral load measure. The nonrandom distribution of multiple infections by case-control status and the apparent differential effect of viral load by genotype warrant caution when using HC 2 measurements to infer viral load associations with SIL and cancer.

Carcinoma, Squamous Cell↗
PubMed2003

A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer.

Increased understanding of human papillomavirus (HPV) infection as the central cause of cervical cancer has permitted the development of improved screening techniques. To evaluate their usefulness, we evaluated the performance of multiple screening methods concurrently in a large population-based cohort of >8500 nonvirginal women without hysterectomies, whom we followed prospectively in a high-risk region of Latin America. Using Youden's index as a measure of the trade-off between sensitivity and specificity, we estimated the performances of a visual screening method (cervicography), conventional cytology, liquid-based cytology (ThinPrep), and DNA testing for 13 oncogenic HPV types. The reference standard of disease was neoplasia > or = cervical intraepithelial neoplasia grade 3 (CIN 3), defined as histologically confirmed CIN 3 detected within 2 years of enrollment (n=90) or invasive cancer detected within 7 years (n=20). We analyzed each technique alone and in paired combinations (n=112 possible strategies), and evaluated the significance of differences between strategies using a paired Z test that equally weighted sensitivity and specificity. As a single test, either liquid-based cytology or HPV DNA testing was significantly more accurate than conventional cytology or cervicography. Paired tests incorporating either liquid-based cytology or HPV DNA testing were not substantially more accurate than either of those two test strategies alone. However, a possibly useful synergy was observed between the conventional smear and cervicography. Consideration of age or behavioral risk profiles did not alter any of these conclusions. Overall, we conclude that highly accurate screening for cervical cancer and CIN 3 is now technically feasible. The remaining vital issue is to extend improved cervical cancer prevention programs to resource-poor regions.

Adolescent↗