Managing atypical squamous cells of undetermined significance in Papanicolaou smears

OBJECTIVE: To assess strategies using repeated conventional Pap smear and human papillomavirus (HPV) DNA testing, alone or in combination, for identifying women with concomitant cervical intraepithelial neoplasia 2 and 3 (CIN 2/3) in women with atypical squamous cells of undetermined significance (ASCUS) in their Pap smears. STUDY DESIGN: A total of 360 women cytologically diagnosed with ASCUS were referred for colposcopy and underwent a repeat Pap smear, a biopsy when necessary and HPV testing using three different modes of detection of high-oncogenic-risk HPV types: 1, first-generation Hybrid Capture test (HC-1) (Digene Diagnostics, Gaithersburg, Maryland); 2, second-generation Hybrid Capture test (HC-2); and 3, polymerase chain reaction (PCR). RESULTS: Nineteen patients (5.3%) had histologic CIN 2/3. The sensitivity and specificity of the repeat Pap smear alone for the detection of CIN 2/3 were 73.7% and 62.9%, respectively, when referring all women with a repeat Pap smear using an ASCUS-positive threshold. The proportion of women referred for colposcopy was 39.0%. When HPV testing for high risk was used for identification of women with histologic CIN 2/3, sensitivity and specificity were, respectively, 68.4% and 85.9% for HC-1, 89.5% and 73.9% for HC-2 and 89.5% and 59.0% for PCR. The rate of referral for colposcopy of these three modes of HPV testing was 16.9%, 29.4% and 44.0%, respectively. The sensitivity and specificity for identification of women with concomitant CIN 2/3 using a combination of repeat cytology showing a low grade squamous intraepithelial lesion or high grade squamous intraepithelial lesion and/or a test positive for high-oncogenic-risk HPV group were, respectively, 94.7% and 73.2% when used in combination with HC-2. The referral rate of women for colposcopy of this combined strategy was 30.4%. CONCLUSION: As compared to the strategy using abnormal repeat Pap smear alone, those using high-risk HPV testing with Hybrid Capture showed statistically significantly higher specificities and lower proportions of women with ASCUS referred for colposcopy. In particular, a promising strategy would be to refer for colposcopy only women with repeat Pap smears showing squamous intraepithelial lesion and/or those positive for high-risk HPV detected by Hybrid Capture testing.     

Comparison of three management strategies for patients with atypical squamous cells of undetermined significance, after six months delay: A three-year experience in an Iranian university hospital

Background: A Pap test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5–10% of women with ASCUS harbour serious cervical disease.
Methods: We screened 3619 women, who attended to Mirza Koochak Khan Hospital at Tehran University of Medical Sciences with Pap smears, of whom 100 returned with ASCUS. After six months, each subject underwent a standard cytology (conventional Pap smear), human papillomavirus (HPV) DNA testing (identifying high-risk HPV types with polymerase chain reaction) and colposcopy with multiple cervical biopsies.
Results: Mean age was 44.09 ± 8.6 years. The estimated prevalence of cervical intraepithelial neoplasia (CIN) II or higher was 4%. When histologically verified high-grade lesions (≥ CIN II) were observed, the relative sensitivity of HPV DNA testing was 100% compared with conventional Pap smear, which performed 75% versus 100% relative sensitivity, respectively, using cytological diagnosis high-grade squamous intraepithelial lesion, or low-grade squamous intraepithelial lesion (LSIL) as the cut-off. Negative and positive predictive values (NPV and PPV) of Pap test were 98.9% and 100%. The NPV and PPV of HPV DNA testing were 100%.
Conclusions: Although less complicated than colposcopy, the repeat Pap smear triage algorithm for ASCUS may underdiagnose some women with high-grade CIN, when compared with colposcopy. Considering the high sensitivity of HPV testing, it may be useful as an alternative to the current policy of six-month repeat cytology for women with ASCUS results.     

Follow-up by combined cytology and human papillomavirus testing for patients post-cone biopsy: results of a long-term follow-up

OBJECTIVE: The goal of this study was to evaluate the clinical implications of integrating human papillomavirus (HPV) testing into a long-term follow-up and management protocol for women postconization for high-grade cervical intraepithelial neoplasia (CIN2-3). METHODS: Sixty-seven women were followed-up by Pap smears and HPV type and load testing (mean follow-up, 63 months; range, 50-72). Patients with persistent abnormal cytology on two consecutive smears and those with positive HPV test results (whatever their cytologic findings) were referred for colposcopy-directed biopsy. Patients histologically diagnosed with CIN2-3 and those with high-load HPV (whatever their histologic findings) underwent repeat conization or hysterectomy for residual disease. RESULTS: At follow-up, 29 (43.2%) women had positive cytology or positive HPV results and were referred for colposcopy. Eleven (37.9%) had high-grade cervical intraepithelial neoplasia or high-load HPV results and were further treated by reconization/hysterectomy. The respective positive predictive values of high-load HPV and low-grade squamous intraepithelial lesions were 100 and 60% for any CIN and 90 and 15% for CIN2-3. Only five of nine cases with a final diagnosis of CIN2-3 were originally identified by cytology: the other four were detected only by parallel evaluation by HPV testing. High-load HPV results with normal cytology or low-grade lesions harbored an 80% risk for CIN2-3. CONCLUSIONS: Adding HPV load assessment to the follow-up protocol of women postconization due to CIN2-3 lesions could help detect high-grade residual disease among low-grade lesions and normal cytology cases while concomitantly and safely bestowing the advantage of lowering the rates of colposcopic referrals and surgical procedures.     

Human papillomavirus testing improves the accuracy of colposcopy in detection of cervical intraepithelial neoplasia

To assess the performance of human papillomavirus (HPV) testing and colposcopy in detection of cervical pathology. A series of 389 women referred for colposcopy due to an abnormal Pap smear had cervical swabs analyzed for oncogenic (high-risk [HR]) HPV types using Hybrid Capture II (HC2) assay. Loop electrical excision procedure cone biopsy (88%) or colposcopic biopsy (11%) was used as the gold standard. Of the atypical squamous cells of undetermined significance (ASCUS) smears, 48% were positive for HR HPV, as compared to 76.3% of low-grade squamous intraepithelial lesions (LSIL) smears. HR HPV was detected in 66.7% and 90% of patients with cervical intraepithelial neoplasia (CIN) 1 and CIN2 (or higher), respectively. The sensitivity of the Pap smear using an ASCUS threshold in detecting high-grade CIN was 94.5% (95% confidence intervals (CI): 91-97%) and that of colposcopy 98.5% (95% CI: 95-99%). The respective specificities were 30% (95% CI: 17-28%) and 35.6% (CI: 29-42%). HC2 test had comparable sensitivity, 90% (95% CI: 85-93%), but higher specificity, 54.3% (95% CI: 47-61%). Combining HC2 test with Pap increased specificity, 66.7% and 41.3% for ASCUS and LSIL cutoff, respectively. The minor-abnormality threshold together with HC2 increased specificity of colposcopy with no changes in sensitivity. High viral load (>100 relative light unit/positive control) was associated with significant disease. HPV DNA testing improves the accuracy of colposcopy in the detection of high-grade CIN in women with ASCUS or LSIL smears.     

High-risk HPV DNA detection by Hybrid Capture II. An adjunctive test for mildly abnormal cytologic smears in women > or = 50 years of age

OBJECTIVE: To determine whether high-risk human papillomavirus (HPV) DNA testing could improve the detection of cervical intraepithelial neoplasia (CIN) and cancer in older women (> or = 50 years old) with mildly abnormal results on conventional cytology. STUDY DESIGN: The study was based on 119 patients aged over 50 (median, 62; range, 50-78) referred for colposcopy with Pap smears reported as atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesion (LSIL) from February 1997 to September 1998. The presence of high-risk HPV DNA (including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) was determined with the Hybrid Capture II (Digene, Inc., Silver Spring, Maryland) microplate method. Cytologic examination by Pap smear was based on the Bethesda System and, cervical biopsy was done via colposcopy. RESULTS: High-risk HPV DNA was demonstrated in 75.6% (34/45) of patients with LSIL and 52.7% (39/74) with ASCUS. Those who were HPV positive were significantly more likely to have CIN or cancer (odds ratio, 33.40; 95% confidence interval, 11.89-93.97; P < .0001). The sensitivity of HPV assay for detection of lesions more severe than CIN 2 was 100%, specificity 64.8%, positive predictive value 66.7% and negative predictive value 100%. CONCLUSION: The addition of a high-risk HPV DNA assay to cytologic examination appears to provide excellent sensitivity and negative predictive value for early detection of high grade CIN or cancer in older women with minimally abnormal Pap smears.     

A comparison of the human papillomavirus test and Papanicolaou smear as a second screening method for women with minor cytological abnormalities

BACKGROUND: Of the estimated one million Papanicolaou (pap) smears performed annually in Sweden, about 4% show any degree of abnormality. Approximately, 1% of these cases contain moderate or severe atypia (high-grade squamous intraepithelial lesions) and the rest contain low-grade atypia. Recommendations for the management of minor abnormalities vary in various parts of Sweden. Generally, a second Pap smear is obtained 4-6 months after the first one showing low-grade atypia. The aim of this study is to compare the sensitivity of human papilloma virus (HPV)-DNA testing for the detection of cervical intraepithelial neoplasia (CIN) 2-3 with that of a second Pap smear in women, who had low-grade atypia in their first Pap smear. METHODS: Women with low-grade atypia in the Stockholm area, detected at a population-based cytology screening, were enrolled. A repeat Pap smear, HPV test, and colposcopically directed biopsies were obtained. For the detection of HPV, Hybrid Capture II (HC II) was used. RESULTS: The HPV-DNA test was positive in 66% of the 177 participating women. The sensitivity of the second Pap smear and HPV-DNA test to detect CIN 2-3 was 61 (95% CI = 45-74) and 82% (95% CI = 67-91), respectively. The positive and negative predictive values of HPV testing were 27 (95% CI = 18-35) and 89% (95% CI = 80-97), respectively. CONCLUSIONS: In Sweden, a second Pap smear is often obtained for the follow-up of women with low-grade atypia. The results of our study show that compared to the second Pap smear, HPV testing with HC II is a more sensitive method for detecting high-grade lesions.     

Contribution of human papillomavirus testing by hybrid capture in the triage of women with repeated abnormal pap smears before colposcopy referral

OBJECTIVE: The purpose of this work was to evaluate the ability of testing for high-risk human papillomavirus (HPV) types using the hybrid capture technique to predict the presence of cervical intraepithelial neoplasia (CIN) II,III in patients with repeated atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LGSIL) on Pap smears. METHODS: Hybrid capture testing and tissue biopsy were performed on 503 consecutive women with ASCUS or LGSIL on repeated Pap smears who were referred for colposcopy. RESULTS: A highly significant association (P < 0.0001) was found between a positive test for high-risk HPV types and CIN II,III, with an 87.0% positive predictive value and a 95.7% negative predictive value. In 226 women with ASCUS on repeated Pap smears, a positive test for high-risk HPV types had a 85.7% sensitivity and a 97% specificity for CIN II,III. In 277 patients with LGSIL on repeated Pap smears, a positive test for high-risk HPV types had an 88.2% sensitivity and a 94.7% specificity for CIN I,II. Reserving colposcopy examination for women who were positive for high-risk HPV types would have reduced the number of referrals for colposcopy to 24.6% and maintained a sensitivity of 87.0% for CIN II,III. CONCLUSIONS: A positive hybrid capture test for high-risk HPV types was highly sensitive and specific for the presence of CIN II,III in patients with ASCUS and LGSIL on repeated Pap smears. We believe that improved methodology will eventually enable more selective colposcopy referrals without affecting patient safety among these women.     

改良取样巴氏涂片在人群子宫颈癌筛查中的应用

目的：探讨改良取样巴氏涂片（Pap）在子宫颈癌筛查中的应用价值。方法：对500例30~59岁、3年内未行宫颈癌筛查的妇女行改良Pap、液基细胞学（LCT）和第二代杂交捕获实验（HC-Ⅱ）人乳头瘤病毒（HPV）检测,Pap采用液基细胞学刷取样,2种细胞学取样采用分配样本法。细胞学以无明确诊断意义不典型鳞状细胞（ASCUS）为阳性阈值,对任一细胞学结果或HPV检测阳性的妇女行阴道镜下宫颈多点活检,以病理诊断为金标准,评价2种细胞学方法筛查宫颈癌的价值。结果：宫颈细胞学筛查宫颈上皮内瘤样病变（CIN）Ⅱ以上病变以ASCUS为阳性阈值的筛查效率最高;改良Pap和LCT的筛查效率（ROC曲线下面积比较,Z ＝0.70,P ＞0.05）和不满意率（χ2＝0.343,P =0.558）差异无统计学意义;两种细胞学的诊断完全一致率为86.8%,宫颈癌和宫颈癌前病变级别越高,2种细胞学方法判读结果的一致性越好。结论：改良Pap经济有效,可广泛应用于人群子宫颈癌筛查。     

Human papilloma virus testing in patient follow-up post cone biopsy due to high-grade cervical intraepithelial neoplasia

OBJECTIVE: We evaluated the contribution of the human papilloma virus (HPV) load in planning follow-up and management of women post cone biopsy for high-grade cervical intraepithelial neoplasia (CIN2-3). METHODS: Ninety-six suitable women were followed-up by Pap smears: two consecutive abnormal smears dictated referral for colposcopy-directed biopsy. Before colposcopy, HPV tests determined high-risk HPV DNA type and load (Hybrid Capture System type I). Patients histologically diagnosed with CIN1 or CIN2-3 underwent repeat conization or hysterectomy for residual disease. HPV load was compared to cytology for the detection of residual disease. RESULTS: At follow-up, 20/89 (22.4%) studied women had positive cytology reports of either low- (n = 11) or high-grade (n = 9) squamous intraepithelial lesion (SIL). Colposcopic biopsies diagnosed 9 CIN1 and 8 CIN2-3 cases. Residual disease was corroborated in 16/17 (94.1%) women and the status was readjusted based on cone biopsy/hysterectomy: CIN2-3 in 9 and CIN1 in 7. The positive prediction values for CIN2-3 residual disease with high-grade SIL, CIN2-3 on colposcopic punch biopsy, and high HPV load were 89, 100, and 100%, respectively. For CIN1 residual disease with low-grade SIL, CIN1 on colposcopic punch biopsy, and low and borderline HPV load, they were 54.5, 77.7, and 100%. The HPV load was a more accurate predictor for CIN1 or CIN2-3 on the cervical specimen in cases with low-grade SIL or CIN1 on colposcopic biopsy. CONCLUSIONS: Evaluating HPV loads after a positive cytology report may assist in triaging women post conization biopsy for CIN2-3 to appropriate treatment. Its high positive predictive value, specificity, and sensitivity for CIN1 and CIN2-3 and supplementary information could be especially pertinent for clinical management of low-grade SIL cases.     

Human papillomavirus DNA detection and histological findings in women referred for atypical glandular cells or adenocarcinoma in situ in their Pap smears

OBJECTIVE: To evaluate the association between high-risk human papillomavirus (HPV) DNA detection and histological diagnosis in women referred for atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) at Pap smear. METHODS: In this cross-sectional study, 146 women referred for AGC (124), AGC with high-grade squamous intraepithelial lesion (HSIL) (15), or AIS (7) were tested for HPV DNA using Hybrid Capture II (HC II). All women underwent colposcopic examination, and cervical biopsy was performed for 95 patients. Fifty-one women referred due to AGC with normal colposcopy and normal second Pap smear were scheduled for control visits every 4 months. RESULTS: The overall prevalence of HPV DNA was 38%. HPV DNA was detected in 93% of the women with HSIL associated with AGC and in 71% of women with AIS Pap smear, being significantly higher when compared with the prevalence (29%) in women with AGC alone. Forty-five women (30.8%) had clinically significant histological lesions (CIN 2 or worse). High-risk HPV DNA was detected in only 16% of the women without significant abnormalities in biopsy, in contrast to 96% of those who had CIN 2 or CIN 3 and 75% of women with AIS. Eighty-five percent of women with invasive cervical carcinoma (squamous or adenocarcinoma) tested positive for HPV DNA. HPV DNA detection was significantly associated with histological diagnosis of CIN 2 or worse, with an odds ratio (OR) = 51.8 (95% CI 14.3-199.9). CONCLUSION: HPV DNA detection was strongly associated with the severity of cervical lesion (CIN 2 or worse) in women referred for AGC or AIS in their Pap smear. These data implicate the use of HPV testing in triage of women with AGC Pap smears.     

HPV DNA test and Pap smear in detection of residual and recurrent disease following loop electrosurgical excision procedure of high-grade cervical intraepithelial neoplasia

OBJECTIVE: We compared the performance of cervical cytology and HPV DNA test in detection of residual or recurrent disease following the treatment of cervical intraepithelial neoplasia (CIN) 2/3 with loop electrosurgical excision procedure (LEEP). SUBJECTS AND METHODS: A series of 107 women subjected to LEEP due to histologically confirmed CIN 2/3 between March 2001 and December 2002 were followed-up biannually until January 2004. Follow-up visits consisted of interview and gynecological examination including cervical cytology, hybrid capture II (HCII), and colposcopy. Patients presenting with abnormal colposcopy or high-grade squamous intraepithelial lesion (HSIL) smear were subjected to new excision procedure, and presence of histologically confirmed CIN 2/3 or higher was considered as residual or recurrent disease. Performance indicators were calculated for cytology and HCII assay in detecting residual or recurrent disease. RESULTS: Eleven (10.2%) women showed residual or recurrent disease during the follow-up. Considering HCII and Pap smear as stand-alone tests, both techniques showed similar sensitivity, detecting 100% of CIN 2/3 at the first follow-up visit. At the second follow-up visit, Pap smear showed better specificity and positive predictive value (PPV) than HCII, and both tests had fairly the same high negative predictive value (NPV) and sensitivity. The combined positive HCII and abnormal cytology had the same sensitivity as each of the tests alone, but specificity and PPV were significantly higher than those of single tests. When only one of the tests was positive, the sensitivity and the NPV of the combination remained the same, but its specificity and PPV were lower than that of the combined two positive tests and that of the individual test, at both follow-up visits. CONCLUSIONS: Both tests performed well in detecting residual or recurrent disease after LEEP and combination of the tests did not increase sensitivity of the single tests.     

Usefulness of human papilloma virus testing in the screening of cervical cancer precursor lesions: a retrospective study in 314 cases

OBJECTIVE: To assess the usefulness of human papilloma virus (HPV) typing for predicting pre-malignant and malignant cervical lesions. STUDY DESIGN: 314 women, who underwent colposcopy, biopsies and high and low-risk HPV typing after a confirmed abnormal routine Pap test were studied. HPV-DNAs were typed by using PCR technique. RESULTS: We found a significant increasing rate of high-risk-HPV by the increasing severity of histology, ranging from 40% in negative cases to 86.9% in those with CIN3 lesions. The positive predictive value of high-risk-HPV ranged from 13.3% in patients with atypical squamous cells of undetermined significance (ASCUS) to 29.4% in those with HSIL. By contrast, negative predictive value was 96% in patients with ASCUS, 97.2% in low-grade squamous intraepithelial lesions (LSIL), and 71.4% in high-grade squamous intraepithelial lesions (HSIL). Sensitivity and specificity for detecting CIN2 or CIN3 was 86.0% and 41.3%, respectively. CONCLUSIONS: The high negative predictive value of high-risk HPV testing suggests that HPV negativity could be used for predicting the absence of important cervical lesions, and therefore avoiding unnecessary colposcopy in ASCUS and LSIL cases.     

The evaluation of human papillomavirus DNA testing in primary screening for cervical lesions in a large Japanese population

To examine the utility of human papillomavirus (HPV) DNA testing for the screening of cervical cancer and its precursors, a prospective cohort study was performed in which a total of 8156 women with a median age of 36 years were enrolled. Two smear samples scraped from the uterine cervix were served for Papanicolaou test and HPV DNA testing (Hybrid Capture-II system). HPV-positive samples were further examined for HPV subtype using a DNA microarray chip. Women with cytologic abnormality or those with high-risk HPV DNA were further examined by colposcopy to determine histologic diagnosis. High-risk HPV DNA was detected in 11% of the general population, with higher prevalence of specific types, including 52, 16, 58, 51, 56, and 18. As expected, younger women were likely to have increased frequency of HPV infection. Notably, HPV DNA testing detected all 45 cases of cervical intraepithelial neoplasia (CIN) 3, while cytologic findings were negative in 6 of these cases. It is of particular interest that CIN was commonly associated with multiple HPV types, while invasive cancers had a single type of HPV. In terms of both sensitivity and positive predictive value in detecting the CIN, HPV DNA testing is superior to cytology. However, most importantly, HPV DNA testing in combination with cytology significantly improved the efficacy to CIN screening.     

Does Typing of Human Papillomavirus Assist in the Triage of Women with Repeated Low-Grade, Cervical Cytologic Abnormalities?

Objective.To evaluate the ability of testing for high-risk human papillomavirus (HPV) using the hybrid capture technique to detect cervical intraepithelial neoplasia (CIN) in patients with repeated low-grade cervical cytologic abnormalities and an adequate and normal colposcopy.Methods.Hybrid capture testing and LEETZ were performed on 166 women with repeated low-grade cervical cytologic abnormalities who were referred for colposcopy which was to be adequate and normal.Results.A highly significant correlation (P< 0.0001) was found between a positive test for high-risk HPV types and the finding of CIN II,III. In 67 women with atypical squamous cells of undetermined significance on repeated cytologic studies, a positive test for high-risk HPV types had a sensitivity and specificity of 90 and 96.5%, respectively, for detecting CIN II,III. In 99 patients with low-grade squamous intraepithelial lesions found on repeated cytologic study, a positive test for high-risk HPV types identified all patients as having CIN II,III on cone biopsy (sensitivity, 100%), with a specificity of 86.4%. Restriction of tissue sampling to women who were positive for high-risk HPV types would have reduced the number of tissue samplings performed to 20.4%, while identifying 20 of 21 patients with biopsy-confirmed CIN II,III.Conclusion.A positive hybrid capture test for high-risk HPV types is highly sensitive and specific for detecting CIN II,III in patients with repeated low-grade cervical cytologic abnormalities and an adequate and normal colposcopy and may be used in the triage of these women before performing tissue sampling.     

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.     

Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology

Objective

Testing for human papillomavirus (HPV) has been shown to increase the sensitivity and negative predictive value for detection of high-grade cervical intraepithelial neoplasia (CIN2+), either when used in conjunction with Pap cytology testing or alone. However, there is no satisfying clinical management algorithm for women testing Pap negative/HPV positive. We therefore evaluated the clinical utility of a novel dual biomarker-based approach (p16/Ki-67 Dual-stained cytology) for the identification of CIN2+ in women with Pap negative/HPV positive screening results, without the need to refer all women to immediate colposcopy.

Methods

All women aged ≥ 30 enrolled during 2007/2008 into a regional prospective Pap/HPV co-testing screening pilot project and tested Pap negative, but positive for HPV (n = 425) were included in the analysis. p16/Ki-67 Dual-stained cytology was performed from residual cellular material available from the liquid-based cytology vial collected during the initial Pap/HPV co-testing screening visit. Results were correlated to the presence of CIN2+ confirmed during preliminary follow-up.

Results

p16/Ki-67 Dual-stained cytology tested positive at baseline in 108 out of 425 (25.4%) Pap negative/HPV positive cases. Sensitivity of Dual-stain testing for the detection of biopsy-confirmed CIN2+ during preliminary follow-up within the group of Pap negative/HPV positive women was 91.9% for CIN2+ (34/37 cases), and 96.4% for CIN3+ (27/28 cases). Specificity was 82.1% for CIN2+ on biopsy, and 76.9% for CIN3+, respectively.

Conclusions

Triaging Pap negative/HPV positive screening test results with p16/Ki-67 Dual-stained cytology may identify women with a high probability of underlying CIN2+ and may efficiently complement HPV-based screening programs to prevent cervical cancer.     

High-risk human papillomavirus DNA testing and high-grade cervical intraepithelial lesions

OBJECTIVE: To explore the role of high-risk human papillomavirus (HPV) DNA testing in the improvement of the recognition of cervical cancer and precancerous lesions in women with abnormal cervical cytology. METHODS: A total of 2152 women with abnormal cervical cytology were submitted to both HPV DNA testing and biopsy guided by colposcopy and the results were correlated. RESULTS: Positive rate of high-risk HPV DNA in groups of atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells, cannot exclude high-grade (ASC-H), low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions was 53.7, 53.2, 84.6 and 93.0%, respectively. In each group, the detection rate of grade 2,3 cervical intraepithelial neoplasia (CIN 2,3) or cervical cancer in patients with positive HPV DNA was significantly higher than that with negative HPV DNA (P<0.05). In ASC-US group, the negative predictive value of high-risk HPV DNA testing for detection of CIN 2,3 and cervical cancer was 99.8% and the sensitivity 98%. CONCLUSION: HPV DNA testing is a useful indicator in the management of patients with ASC-US and plays an important role in the evaluation of risk for CIN 2,3 and cervical cancer.     

Human papillomavirus testing as triage for atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions: Sensitivity,specificity, and cost-effectiveness

OBJECTIVE: Our purpose was to evaluate the cost-effectiveness of the use of a Food and Drug Administration–approved human papillomavirus test in triaging patients with Papanicolaou smears showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion for colposcopy compared with an algorithm that used cytologic follow-up.STUDY DESIGN: Four hundred sixty-two women referred to our Colposcopy Clinic with a Papanicolaou smear report of atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion underwent repeat Papanicolaou smear, cervical colposcopy, directed cervical biopsy, and endocervical curettage. In addition, human papillomavirus testing by the Food and Drug Administration–approved HPV Profile (Digene Diagnostics, Silver Spring, Md.) test was done. A comparision of sensitivity, specificity, and cost-effectiveness of an algorithm determining the need for colposcopy on the basis of repeat cytologic testing versus an algorithm that incorporated repeat cytologic testing and human papillomavirus screening was done. The cost-effectiveness of both of these triage algorithms was also compared.RESULTS: As expected, high-risk human papillomavirus deoxyribonucleic acid was detected with greater frequency in relation to increasing severity of cervical intraepithelial neoplasia. In 268 women, the follow-up smear obtained in our clinic was reported as negative. High-risk human papillomavirus types were found in 23.5% of these women. In the human papillomavirus–negative women, 5.9% had grade 2 or 3 cervical intraepithelial neoplasia confirmed on cervical biopsy. In comparison, 20.6% of those with a positive result of the human papillomavirus test had grade 2 or 3 cervical intraepithelial neoplasia on biopsy (p < 0.001). Despite this difference, the sensitivity of a positive result of a high-risk human papillomavirus test in predicting the presence of grade 2 or 3 cervical intraepithelial neoplasia was only 52%. Among the women for whom a follow-up clinic Papanicolaou smear was reported as showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion, there was no difference in the frequency of biopsy-proved grade 2 or 3 cervical intraepithelial neoplasia between those women with a positive human papillomavirus test result and those with a negative test result. Colposcopy would have been recommended for 194 women because of a repeat clinic smear revealing atypical squamous cells of undetermined significance, a low-grade squamous intraepithelial lesion, or a high-grade squamous intraepithelial lesion, and in 21.6% of these women grade 2 or 3 cervical intraepithelial neoplasia was shown on biopsy (sensitivity 63%, specificity 62%). Colposcopy would have been recommended for 180 women because high-risk human papillomavirus or a high-grade squamous intraepithelial lesion was detected at the clinic visit, and in 25% of this group grade 2 or 3 cervical intraepithelial neoplasia was evident on biopsy (sensitivity 67%, specificity 66%). Sensitivity and specificity were virtually identical for the two algorithms, but the cost of human papillomavirus testing was nearly double that of triage based on repeat cytologic testing alone ($692 vs $1246 per case).CONCLUSION: The Food and Drug Administration–approved HPV Profile test is not a cost-effective triage for patients referred with Papanicolaou smears reported as showing atypical squamous cells of undetermined significance or low-grade squamous lesions. (Am J Obstet Gynecol 1997;177:930-6.)     

Performance of Pap smear and human papilloma virus testing in the follow-up of women with cervical intraepithelial neoplasia grade 1 managed conservatively

BACKGROUND: Conservative management (follow-up) of cervical intraepithelial neoplasia grade 1 (CIN1) is acceptable, but evidence on performance of follow-up tools, such as Pap smear and human papilloma virus (HPV) test, is still needed. METHODS: A cohort of 78 women with histologically confirmed CIN1, referred because of atypical squamous cell or low-grade squamous intraepithelial lesion in their Pap smear, was enrolled between August 2000 and September 2002 and was prospectively followed-up at 6 and 12 months, until September 2003. Follow-up examinations included Pap test and Hybrid Capture II (HCII) with high-risk HPV, colposcopy, and cervical biopsies in patients with persistent abnormalities. Odds ratios and performance indicators (with 95% confidence interval) were calculated for HPV and Pap test results in detecting biopsy-confirmed CIN during the follow-up. RESULTS: Thirty-seven (47%) of the women were HPV-positive at baseline. At first follow-up visit, 30 women had persistent CIN1 and one woman progressed to CIN2; 15 patients had CIN1 and one patient CIN2 at the second follow-up visit. Women with persistent CIN1 (or progression) during follow-up had a significantly higher HPV detection rate and abnormal Pap tests, compared to women with regressive disease. Cytology had a far better sensitivity in detecting CIN than HCII at the first follow-up visit (81 versus 52%, respectively), whereas both examinations had equivalent sensitivities at the second follow-up visit (69 and 56%, respectively). Cytology had a superior negative predictive value at the first follow-up visit and better positive predictive value, in addition, at the second visit. CONCLUSIONS: Because cytological abnormalities correlated generally better with the persistence of biopsy-confirmed CIN1 in this follow-up protocol, HCII test is the second-hand option to Pap test, but the use of both Pap and HCII together seems an unnecessary waste of resources.     

子宫颈上皮内瘤变筛查方法的综合评价

目的　对宫颈上皮内瘤变 (CIN)筛查方法即宫颈涂片自动检测系统 (papnetcytologycomputertechnology ,CCT)和新柏氏程控超薄细胞检测系统 (thinpreppaptest,TPT)两种细胞学检查方法进行综合评价。方法　对因细胞学检查异常而行阴道镜下多点活组织检查 (活检 )及病理检查的 374例患者的临床资料进行回顾性分析。结果　细胞学检查诊断为炎症者 9 1% ,低度鳞状上皮内瘤变(LSIL) 4 3 3% ,高度鳞状上皮内瘤变 (HSIL) 2 0 3% ,可疑癌 1 9% ;经阴道镜下多点活检及病理检查 ,诊断为炎症者增加到 5 3 5 % ,CINⅠ减少到 17 9% ,CINⅡ、CINⅢ、原位癌占 2 5 4 % ,可疑早期浸润癌和浸润癌增加到 3 2 %。 2 5 4 %的细胞学不能明确诊断意义的不典型鳞状上皮病变中 ,5 2 6 % (5 0 /95 )为炎症或未见异常 ,4 7 4 % (45 /95 )为CINⅠ以上的病变。 374例患者中 ,行CCT检查者 188例 ,TPT检查者 186例 ,两种细胞学检查结果分别与阴道镜检查结果相比 ,TPT的符合率显著高于CCT(P<0 0 1)。细胞学检查诊断为LSIL及以下病变的符合率 (79 7% )显著高于诊断为HSIL以及癌变者的符合率 (2 0 3% ) ,两者比较 ,差异有显著性 (P <0 0 1) ,而两种细胞学检查方法间无差别。人乳头状瘤病毒 (HPV)感染的发生率为 34 0 % ,阴道镜检查的