Negative Colposcopy Research Articles

Management of borderline change in endocervical cells: a more dependable approach.

Background:There are limited data and guidance from the UK on borderline nuclear change in endocervical cells (BNCs). The objective of this study is to determine the clinical outcome of women with BNCs, to determine the accuracy of colposcopy and propose a more robust management algorithm.Methods:This is a retrospective review of all BNC referrals between January 2006 and December 2011 at the Northumbria Healthcare Trust. Histological diagnosis was based on high-grade histology (CIN 2 or worse). Any high-grade histology in the first year of follow-up was included in the final diagnosis.Results:Of the 9001 new referrals, 167 women had BNCs. Thirty-seven (22%) were diagnosed with high-grade histology on initial assessment. Sixty women had satisfactory and negative colposcopy, out of which 7 (12%) were detected with high-grade histology/cytology in the first year of follow-up. Overall, 50 high-grade histology (30%), including two invasive carcinomas were detected.Conclusions:Current follow-up of BNCs relies heavily on colposcopic assessment. A significant proportion of women with negative colposcopy was found to have high-grade histology in the first year of follow-up. We propose a more robust management algorithm to lower the probability of missed high-grade histology in this subgroup of women.

Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN but only weakly with its severity.

This study was performed to evaluate the prognostic significance of human papillomavirus (HPV) viral load, expressed in relative light units (RLUs), in patients with atypical squamous cells of undetermined significance (ASC-US) cytology. A total of 349 ASC-US cases with HPV infection, detected using Hybrid Capture 2, were diagnosed histologically. A colposcopically directed punch biopsy was performed on acetowhite areas. Endocervical curettage biopsy and random cervical punch biopsy in four quadrants were performed in unsatisfactory colposcopy cases. In negative colposcopy cases, random cervical punch biopsy in four quadrants was performed. Case with no cervical intraepithelial neoplasia (CIN), CIN1 and CIN2+ (CIN2/CIN3) accounted for 162, 135 and 52 cases, respectively. The mean age showed no difference among the three groups (P=0.510). There was a significant correlation between RLU values and the presence of CIN (P<0.001), but less so with its severity: the median RLU values for negative, CIN1 and CIN2+ cases were 42.68, 146.45 and 156.43, respectively, with widely overlapping confidence intervals. The cut-off values of RLU to detect CIN1+ and CIN2+ were 6.73 and 45.64, respectively. The HPV viral load in ASC-US cases showed a significant correlation with the presence of CIN and less so with its severity, and showed large overlap of viral loads between grades of CIN. In ASC-US cases, RLU was not an accurate predictor of immediate high-grade CIN.

Cervicoscopy and Microcolposcopy in the Evaluation of Squamo Columnar Junction and Cervical Canal in LSIL Patients with Inadequate or Negative Colposcopy

Objective: The present study evaluated indications' validity of cervicoscopic and microcolposcopic examination in LSIL patients with unsatisfactory or negative colposcopy. Matherial and methods: In the cervico-vaginal pathology unit of the "San Giovanni Calibita Fatebenefratelli" University of Rome "Tor Vergata", 119 patients with a positive cervical cytology (LSIL), were submitted to the exam for the following two indications: 1) unsatisfactory colposcopy 37 (31.1%); 2) negative colposcopy 82 (68.9%).Results: Cervicoscopy allowed the SCJ visualization in 115 (9.6%) patients. In 4 patients 3.4%, the SCJ visualization was not possible due to cervical stenosis. Cervicoscopy without staining, revealed endocervical squamous columnar junction in 33 (28.7%) patients. The blue dye in panoramic view detected endocervical SCJ in 41 (35.7%), out of 115 patients (&gt;5 mm in 34 (29.6%) patients and &gt;10 mm in 7 (6.1%)). Conclusions: Cervicoscopic examination revealed 7.8% of CIN2-3 in LSIL patients with inadequate or negative colposcopy. In patients with negative colposcopy the percentage of undiagnosed lesions inside the cervical canal was very low. The blue dye added sensitivity to the exam.

Hr-HPV testing in the follow-up of women with cytological abnormalities and negative colposcopy

Background:The follow-up after abnormal Pap smear and negative colposcopy is not clearly defined. This study aimed at investigating the role of hr-HPV testing in the management of abnormal Pap test and negative colposcopy for Cervical Intraepithelial Neoplasia grade 2 or worse (CIN2+).Methods:The study enroled 1029 women with abnormal screening cytology (years 2006–2010) and negative colposcopy for CIN2+, which subsequently performed a hr-HPV test. Incident CIN2+ lesions were identified through linkage with cancer registry, hospital discharge records, neoplastic pathology reports and the archive of screening programme (2006–2011).Results:During the follow-up, the cohort developed 133 CIN2+ lesions; only one among hr-HPV-negative women. The probability of developing CIN2+ on follow-up time was 0.44% (95% confidence interval (CI) 0.1–3.1) and 41.8% (95% CI 31.8–53.5) for hr-HPV-negative women and hr-HPV-positive women, respectively. A woman with a positive hr-HPV test had about 105 times higher probability of developing a CIN2+ lesion than a woman with a negative hr-HPV test (hazard ratio (HR)=104.5, 95% CI 14.5–755.1), adjusted for index Pap test result, age and cervix squamocolumnar junction visualisation.Conclusion:Our results confirm that hr-HPV testing is able to select the real group of women at risk of developing CIN2+ lesions in the follow-up of abnormal cytology and first negative colposcopy.

Prognostic value of p16‐INK4A protein in women with negative or CIN1 histology result: A follow‐up study

P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity.

Prognostic Value of HPV E6/E7 mRNA Assay in Women with Negative Colposcopy or CIN1 Histology Result: A Follow-Up Study

Pap test, and especially HPV DNA test, identify a large group of women who do not have any clinically relevant lesions, i.e., CIN2+ (Cervical Intraepithelial Neoplasia grade 2 or worse), but who are at greater risk of getting lesions in the future. The follow up of these women needs new biomarkers with prognostic value. The objective of this study is to evaluate the prognostic value of E6/E7 mRNA over-expression assay (PreTect HPV-Proofer, Norchip) for 5 HR-HPV types (16, 18, 31, 33, and 45) for progression to CIN2+ after a negative colposcopy. This prospective study, conducted at four Italian centres, enrolled 673 women with either a negative colposcopy or a negative or CIN1 histology. The clinical end-point was histological confirmation of CIN2+. Women were classified at baseline according to mRNA results and managed according to local colposcopy protocols. At least one conclusive follow-up test was obtained for 347 women (25 months average lapse since recruitment, range 5–74). Only seven CIN2+ were detected during follow up, three among the 82 women positive for mRNA at baseline, two among the 250 negative (Fisher exact test, p = 0.02), and two among the 12 with an invalid test. Absolute CIN2+ risk was 6.7/1,000 person/years in the whole cohort. The absolute CIN2+ risk was 18.4/1,000 person/years and 3.6/1,000 person/years in mRNA-positive and mRNA-negative women, respectively. In conclusion, E6/E7 mRNA over-expression appears to be a good candidate as a prognostic biomarker to manage HR-HPV DNA-positive women with negative colposcopy or histology, particularly in order to decrease follow-up intensity in those who are negative.

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial

Background:Cervical screening identifies many women with low-grade abnormalities. In vitro and in vivo studies have shown that diindolylmethane (DIM) could potentially halt (cervical) carcinogenesis. We report on a randomised controlled trial of the effect of DIM in women with low-grade cervical cytological abnormalities.Methods:We conducted a pragmatic double-blind, randomised controlled trial of 150 mg DIM (from BioResponse DIM) or placebo daily for 6 months in women with newly diagnosed, low-grade cytological abnormalities. Randomisation was in the ratio 2 (DIM) to 1 (placebo). All women were invited for colposcopy at 6 months with biopsy of any abnormality.Results:Of the 551 randomised women available for analysis, 9% on DIM and 12% on placebo had cervical intraepithelial neoplasia-2 (CIN2) or worse after 6-month supplementation (risk ratio (RR) 0.7 (95% confidence interval (CI): 0.4–1.2)), whereas 4.6% and 5.1%, respectively, had CIN3 or worse (RR 0.9 (95% CI: 0.4–2.0)). A total of 27.3% of women on DIM and 34.3% on placebo had no sign of disease (negative cytology, colposcopy and human papilloma virus (HPV) tests) at 6 months (RR 0.8 (95% CI: 0.6–1.0)). Of those HPV-positive at baseline, 69% (114 out of 166) of the DIM group were positive at 6 months compared with 61% (43 out of 71) of the placebo group: RR 1.1 (95% CI: 0.9–1.4). Diindolylmethane supplementation was well tolerated.Conclusion:The results suggest that short-term DIM supplementation (150 mg day−1) is well tolerated, but is unlikely to have an effect on cytology or HPV infection. Uncertainty remains regarding its effect on CIN2+.

Single negative colposcopy: is it enough to rule out high-grade disease?

It has been proposed that women who have a negative colposcopic examination or who have no cervical intraepithelial neoplasia (CIN) on colposcopic biopsy can be safely returned to routine screening with the next visit being three or five years later. We present data regarding 551 women who had colposcopy in Wales for a low-grade cytological abnormality and who were followed through Cervical Screening Wales for subsequent CIN. Of 436 women declared CIN free initially, 26 (6.0%) had high-grade CIN diagnosed on follow-up. We suggest that additional screening at an interval of less than three years should be offered to women with a negative colposcopy or a biopsy without CIN.

Use of HC2 to triage women with borderline and mild dyskaryosis in the UK

To investigate the feasibility and efficiency of a nationwide rollout of human papillomavirus (HPV)-based triage for cervical cytology results of borderline (BD) or mild dyskaryosis (MD) in the UK, a study at six sentinel sites including more than 10 000 women aged 25–64 was conducted in a real life setting (Kelly et al, 2011). The applied triage test was the Hybrid Capture-2 assay (HC2, Qiagen, GmbH, Hilden, Germany), which detects DNA of 13 high-risk (hr) HPV types. The cut-off chosen for a positive HPV test was ⩾2 RLU/PC (relative light units/positive control), which is lower than what was used in a previous pilot study (⩾3 RLU/PC), but higher than what is widely used in Europe and the US (⩾1 RLU/PC). All HPV-positive women were referred for colposcopy involving biopsies from visually abnormal areas of the cervical epithelium. HPV-negative women and HPV-positive women with negative colposcopy or histology findings were returned to the usual screening schedule. A histological result of CIN1 (cervical intraepithelial neoplasia of grade 1) resulted in a follow-up cytology 12 months later, whereas CIN2 or worse lesions (CIN2+) were treated. Outcomes were the referral rate to colposcopy (or rate of HPV-positivity) and the yield of underlying CIN2+ or CIN3+ among referred women (positive predictive value (PPV)). To evaluate the heterogeneity of HPV prevalence and PPV for cervical disease, several covariates were addressed, including age of the woman, type of liquid-cytology (SurePath (BD, TriPath Imaging inc., Burlington, NC, USA) or ThinPrep (Hologic Inc., Marlborough, MA, USA)) and laboratory site. Below, we summarize the results of the six sentinel studies and include them into previously published meta-analyses on the same topic (Arbyn et al, 2005; Arbyn et al, 2006; Arbyn et al, 2009).

Subsequent risks for cervical precancer and cancer in women with low-grade squamous intraepithelial lesions unconfirmed by colposcopy-directed biopsy: results from a multicenter, prospective, cohort study

To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.

Incidence of cervical intraepithelial neoplasia grade 2 or worse in colposcopy‐negative/human papillomavirus‐positive women with low‐grade cytological abnormalities

To determine the risk of incident high-grade cervical intraepithelial neoplasia (CIN) in human papillomavirus (HPV) -positive women with low-grade cytological abnormalities who had a satisfactory normal colposcopy. A retrospective follow-up study within the NHS HPV/LBC pilot studies. The NHS Cervical Screening Programme in England. A total of 1063 HPV-positive women with borderline or mild dyskaryosis who were negative at colposcopy from three sites within the NHS HPV/liquid-based cytology (LBC) pilot studies. HPV triage took place in 2001/02. In 2009 all information on additional management on HPV-positive/colposcopy-negative women was requested. The rate of disease following a negative colposcopy was calculated, and survival analysis was used to determine whether the grade of referral cytology impacted on risk of subsequent disease. Results were compared with those in women from the same population who had not been HPV triaged. Incident CIN2 or worse during follow up. Of 1063 eligible women 965 had documented follow up. The cumulative rate of CIN2+ at 3 years in these women was 4.4% (95% CI 4.0-7.0%); the median time from normal colposcopy to final result was 27 months. There was no significant increase in the risk of future disease associated with age or initial cytology result. The rate of subsequent high-grade CIN among colposcopically negative triaged women was sufficiently low to justify return to routine recall.

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

p16INK4a as a diagnostic marker of a cervical intraepithelial neoplasia of grade 2+ (CIN2+) in atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytological samples has been analyzed, but has not yet been included in clinical routine practice. One hundred and ninety-one patients with an abnormal Pap test (84 ASC-US and 107 LSILs) who underwent colposcopy were selected for this study. At enrollment, 96 patients (Group 1) had a positive colposcopy and therefore underwent a cervical biopsy, while 95 (Group 2) had a negative colposcopy and were followed up for up to 1 year. Both groups were tested for p16INK4a using immunocytochemical methods, and the p16INK4a results were correlated with histology or follow-up outcome. In Group 1 ASC-US cases, 82% of lesions less than CIN2 were p16INK4a-negative and all CIN2 cases were p16INK4a-positive (p=0.00044). In Group 1 LSIL cases, 71% of lesions less than CIN2 were p16INK4a-negative and 87% of CIN2/3 were p16INK4a-positive (p=0.00033). Seventy-seven percent of Group 2 ASC-US patients with a negative 1-year follow-up (NF-U) were p16INK4a-negative at enrollment, while all patients with positive follow-up (PF-U) were p16INK4a-positive (p=0.00113). In Group 2 LSIL cases, 83% of patients with NF-U were p16INK4a-negative, while 65% of patients with PF-U were p16INK4a-positive at enrollment (p=0.0014). In fact, 39% of the positive p16INK4a LSIL patients had CIN2+ histological lesions. The positive predictive value of p16INK4a for CIN2+ was 50% in ASC-US and 52% in LSIL cases; the negative predictive value was 100 and 94%, respectively. In conclusion, in our patients, a negative p16INK4a appears to be a marker of the absence of CIN3, while a positive p16INK4a can be correlated with the presence of histological CIN2+ found at enrollment or during the subsequent follow-up. Thus, its clinical predictive value is independent from the colposcopic aspect at enrollment.

Tobacco smoking and regression of low‐grade cervical abnormalities

The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0%vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7%vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women.

Analysis of outcome in women with borderline glandular change on cervical cytology

Objective To review the outcome of women presenting with borderline glandular smear on cervical cytology and to investigate correlation between cytology, colposcopy and histology and subsequent smear history. Study design A 5 year retrospective analysis of outcome in all women reported with borderline glandular changes on cytology between 2001 and 2005 at the John Radcliffe Hospital, Oxford, and Cheltenham General Hospital, Gloucestershire, was performed. Cytology, colposcopy, histology and follow-up cytology data at 6, 12 and 24 months after index smear were collated. Results Of 92 women with borderline glandular smears, 56 were referred for colposcopy. This accounts for 0.9% of the total referral (6293) to the colposcopy units. A significant rate of abnormal histology was noted, with CIN 1, 2, 3, CGIN or worse in 20 women (36%) and benign pathology in 18 women (32%). Colposcopy had a sensitivity of 82%, specificity of 39%, negative predictive value of 80% and positive predictive value of 49% in predicting abnormal (premalignant/malignant) histology. Only one woman with normal histology at presentation had subsequent abnormal cytology (1/31), whereas abnormal histology at presentation was strongly associated with subsequent abnormality on follow-up cytology over 24 months (8/21) with a p value = 0.0058. Conclusion Colposcopic examination and biopsy of colposcopically identified abnormalities is reliable, with negative colposcopy having a high negative predictive value. We also recommend thorough colposcopic examination before any invasive investigation as over treatment may impact on the future reproductive outcome [1].

Neither one‐time negative screening tests nor negative colposcopy provides absolute reassurance against cervical cancer

A population sample of 10,049 women living in Guanacaste, Costa Rica, was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993-1994. At the enrollment visit, we applied multiple state-of-the-art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection and treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection and cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (hybrid capture tube test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5-7 years and some up to 11 years. Nonetheless, 16 cases of invasive cervical cancer were diagnosed during follow-up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; 3 of the 6 were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen-positive women. Finally, 3 cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under-screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer.

Value of Normal Colposcopy After an Abnormal Cervical Smear Report

Colposcopy is a secondary screening test used after a cytological specimen is reported as abnormal. A negative or normal colposcopy is not an infrequent outcome, and clinicians need to be aware of the clinical value of a normal and satisfactory colposcopic assessment.To address this problem, the underlying causes need to be fully understood. To this end, we have analyzed a retrospective dataset relating to new referrals to an urban colposcopy service. We have reviewed 1,927 consecutive new colposcopic attendances during a 4-year period (1996-2000). Of these cases, 1,589 (82.4%) had documented satisfactory colposcopy in that the whole transformation zone was identified, and any lesion seen within it was suitable for outpatient-directed biopsy. These cases form the basis of this dataset. Seven hundred seventy-one colposcopies were classified as normal (48%). The presenting smear was atypical squamous cells of undetermined significance (ASCUS) (41.3%), high-grade squamous intraepithelial lesion (HiSIL) (42.2%), low-grade squamous intraepithelial lesion (LoSIL) (13.1%), and unsatisfactory in 3.4%. One hundred five patients (13.6%) eventually underwent loop diathermy excision (loop electrocautery excision procedure). The indications to treat were as follows: a high-grade smear (N=31; 29.5%), a colposcopic suspicion of any cervical intraepithelial neoplasia in the presence of any smear result (N=35; 33%), or a persisting minor cytological abnormality (N=39; 37%). Patients were treated either at their first visit if they had a high-grade smear or up to the 10th visit. Forty-eight (45%) of the treated patients had high-grade disease. No cases of invasive disease were recorded. Normal colposcopy in the presence of a low-grade cervical smear is associated with a very low risk of having or developing high-grade disease. The negative predictive value of normal colposcopy is a valuable clinical utility and underpins the importance of appropriate colposcopic training and the development of competencies that enable the confident exclusion of dysplasia.

A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China

A new test (careHPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2.5 h, to screen women in developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of careHPV as a rapid screening test in two county hospitals in rural China. From May 10 to June 15, 2007, the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new careHPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. Complete data were available for 2388 (94.4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0.0083, the sensitivities and specificities of the careHPV test for a cut-off ratio cut-point of 0.5 relative light units, were 90.0% (95% CI 83.0-97.0) and 84.2% (82.7-85.7), respectively, on cervical specimens, and 81.4% (72.3-90.5) and 82.4% (80.8-83.9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0.0596), compared with 41.4% (29.9-53.0) and 94.5% (93.6-95.4) for VIA (areas under the curve significantly different, p=0.0001 and p=0.0031, for cervical and vaginal-specimen comparisons for the careHPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97.1% (93.2-100) and 85.6% (84.2-87.1), respectively (areas under the curve not significantly different from the careHPV test on cervical specimens, p=0.0163). The careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions.

Host and viral factors in relation to clearance of human papillomavirus infection: A cohort study in Taiwan

Human papillomavirus (HPV) persistence is essential for cervical cancer development. We accrued nested-cohort subjects from a population-based study to investigate the host and viral factors related to outcome of HPV infection. Women (age > or = 30 years old) with HPV-positive but normal cytology and negative colposcopy were invited to participate. After signing informed consent, every participant completed a structured questionnaire and had 6-monthly follow-ups of Pap smear, HPV testing and colposcopy. Total and type-specific HPV clearance rates as well as host and viral factors associated with clearance in 3-year longitudinal follow-up were analyzed. Adjusted hazard ratios (HRs) of progression to > or = cervical intraepithelial neoplasia (CIN) 2 according to baseline HPV of the women with normal cytology were calculated from national registry database. Among the 626 eligible women, 526 (median age 47, 29-75) were enrolled and 412 returned for follow-up at least once. The median follow-up of enrolled subjects was 23 months (range 6.8-39). The 3-year cumulative total HPV clearance rate was 49.0% (95% confidence interval [CI]: 43.3-54.7%). The median 3-year cumulative type-specific HPV clearance rate was 50.0% (range 0-100.0%) with a median time to clearance of 12.4 months (6.4-24.5). Older age was associated with significantly decreased total HPV clearance and decreased type-specific clearance in HPV-18 and -53, while high viral load was associated with decreased total and type-specific clearance. After adjusting confounding variables, the HR of developing > or =CIN2 in baseline HPV-positive women was 34.0-fold (95% CI: 15.5-74.7) as compared to HPV-negative women.

Atypical squamous cells and low squamous intraepithelial lesions in postmenopausal women: Implications for management

Objectives To determine whether the use of local Estrogen Replacement Therapy (ERT) affects the adequacy of colposcopic examination; to distinguish abnormal cervical smears secondary to hypoestrogenism from abnormal cervical smears due to true preneoplastic changes; and to suggest an effective management of atypical squamous cells of undeterminated significance (ASCUS) and low grade squamous intraepithelial lesion (L-SIL) in menopausal women. Study design Two-hundred fifty-four postmenopausal women with abnormal pap smears (L-SIL or ASCUS) underwent colposcopy and HPV DNA testing. All patients with positive colposcopy underwent punch biopsy, and all patients with positive histological findings underwent surgical treatment. Patients with negative colposcopy, both satisfactory [visible Squamo-Columnar Junction (SCJ)] and unsatisfactory, were treated with local estrogenic replacement therapy (ERT) for 3 months, and repeated colposcopy and pap smears. Patients with negative colposcopy and negative pap smears after ERT were included in a 6 months cytological and colposcopic follow-up. Patients with positive colposcopy underwent punch biopsy, if colposcopy was negative and cytology was positive, patients underwent endocervical curettage. Results One-hundred ninety-five had a diagnosis of ASCUS and 59 a diagnosis of L-SIL. At the first colposcopy, 39 patients showed a lesion and had an appropriate treatment. One-hundred eighty-eight in the ASCUS group and 27 in the L-SIL group had a negative colposcopy and were treated with local ERT. At first colposcopic examination, 37 of the 215 negative colposcopies resulted satisfactory and 178 of the 215 resulted unsatisfactory. After local ERT, 130 of the 178 patients had a satisfactory follow-up colposcopy. After ERT, 25 patients of 215 with initial abnormal CVS and negative colposcopy, required appropriate treatment. After ERT, 190 patients of 215 showed negative colposcopy and at cytologic follow-up showed 23 ASCUS and 167 normal CVS. Conclusions A correct diagnosis and an efficient treatment seem to be obtained with a short-time ERT followed by a short-time cytological and colposcopic follow-up. With a single course of local ERT it may be possible to distinguish between benign CVS mimicking atrophy and true preneoplastic changes. Estrogen therapy will often cause enough ectropion of the endocervical cells so that the entire SCJ can be visualized. Moreover, it may reduce the number of endocervical curettage or loop excision or cone procedure for women with inadequate colposcopic examination.

False negative colposcopy is associated with thinner cervical intraepithelial neoplasia 2 and 3

ObjectiveTo assess whether thinner lesion epithelium or lower nuclear density contribute to false negative colposcopy for dysplasia, we determined epithelial thickness and nuclear density and correlated this with the accuracy of colposcopic impression for cervical quadrants with biopsies of normal, CIN 1, CIN 2 and CIN 3. MethodsThe thickness and nuclear density of squamous epithelium of 261 selected cervical biopsies (CIN 2/CIN 3, N=144; Normal/CIN 1, N=117) from the Shanxi Province Cervical Cancer Screening Study (where a colposcopic impression and biopsy were obtained in each cervical quadrant) were measured. Average epithelial thickness was defined as the thinnest area plus the thickest area divided by two. Average nuclear density was defined as the number of nuclei in a 2,500 µm2 grid at the junction of the superficial and intermediate zones plus that at the junction of the intermediate and parabasal zones divided by two. Differences in means were measured by Wilcoxon Rank-Sum Test. Trends among means were measured by a generalized linear mixed model. ResultsMean average epithelial thickness for 33 biopsies of CIN 2/CIN 3 from cervical quadrants with colposcopic impression of normal (184 µm) was less than that of 111 biopsies of CIN 2/CIN 3 from quadrants with colposcopic impressions of low, high, or cancer (321 µm, p<.001). CIN 2/CIN 3 had higher mean average nuclear density (p<.001) and was thinner than normal/CIN 1 (p<.001). ConclusionThe inability of expert colposcopists to visualize some CIN 2/CIN 3 is associated with thinner epithelium.