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.     

Role of human papillomavirus DNA testing in management of women with atypical squamous cells of undetermined significance

To find the sensitivity, specificity, and positive and negative predictive values of the high-risk group human papillomavirus (HPV) DNA testing as a triage tool to detect high-grade squamous intraepithelial lesions (HSILs, ie, cervical intraepithelial neoplasia [CIN] 2 or worse) in women with a cytologic smear showing atypical squamous cells of undetermined significance (ASC-US). All new cases with cytologic smears showing ASC-US that presented in King Chulalongkorn Memorial Hospital from January 2003 to November 2003, excluding known cases of HSILs and pregnancies, were enrolled. Cervical cell samplings were done by cervical cytobrush technique and tested for high-risk group HPV with the Hybrid Capture 2 (HC2) test. All participants were examined under a colposcope. Then cervicographs were taken before colposcopic-directed cervical biopsies were done. Of the 90 ASC-US cases enrolled, the pathologic results were normal in 30.0%, squamous metaplasia in 16.7%, CIN 1 in 37.8%, CIN 2 in 1.1%, CIN 3 in 11.1%, and microinvasive cervical carcinoma in 3.3%. The prevalence of HSILs and the prevalence of high-risk HPV detection were 15.6% and 38.9%, respectively. Using pathologic results from cervical biopsy as the gold standard, the HC2 has the sensitivity, specificity, and positive and negative predictive values of 85.7%, 69.7%, 34.3%, and 96.4%, respectively, to detect HSILs. High-risk group HPV detection can be used as an additional triage test to detect HSILs in women having ASC-US with high sensitivity and negative predictive value.     

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.     

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.     

Atypical squamous cells of undetermined significance in girls and women

OBJECTIVE: To estimate the outcome of adolescents with atypical squamous cells of undetermined significance (ASC-US) on cytology. METHODS: A review of ASC-US cytology in girls and women aged 10-19 years between 1995 and 1999 was performed. The cytologic and histologic follow-up of each patient was evaluated. The outcome was recorded as the most significant (highest grade) subsequent cervical smear or biopsy. RESULTS: Overall, 535 of 7897 (6.8%) cervical cytologic specimens were reported as ASC-US. The study group consisted of 398 patients for whom pathologic follow-up was available. The mean duration of follow-up was 19 months. Follow-up consisted of repeat cytology in 251 (63%) patients and colposcopy with cervical biopsies and/or endocervical curettage in 147 (37%) of the adolescents. Two hundred fifty-three (64%) adolescents had no pathologic abnormalities on follow-up. Persistent ASC-US was identified in 65 (16%), low-grade squamous intraepithelial lesions/cervical intraepithelial neoplasia (CIN) 1 was found in 44 (11%) and high-grade squamous intraepithelial lesions/CIN 2 or 3 occurred in 36 (9%) of the adolescents. No cases of invasive carcinoma were found. CONCLUSIONS: Among adolescents with ASC-US, the rate of squamous intraepithelial lesions/CIN is similar to that of adults. Although the optimal management of ASC-US in adolescents is unknown, these patients warrant close follow-up. LEVEL OF EVIDENCE: III     

Potential hazards of following atypical and low-grade cervical cytology without colposcopy

Objective: To determine the frequency of high-grade cervical intraepithelial neoplasia in patients with atypical and low-grade cervical cytology and to assess the optimal evaluation and follow-up.Methods: Prospective observational study of 367 of 7,651 private patients who had cytologic, virologic, or colposcopic changes suggesting cervical intraepithelial neoplasia or cervical carcinoma. The study was performed to determine the frequency of cervical intraepithelial neoplasia in the various cytologic groups and to assess the effect of testing for human papillomavirus on the sensitivity, specificity, and positive predictive value of these tests.Results: Papanicolaou smears that included all non-negative tests (high- and low-grade squamous intraepithelial lesions and atypical squamous or glandular epithelial cells of undetermined significance) had the maximal sensitivity (89%) for high-grade cervical intraepithelial neoplasia and cancer. The combined cytologic categories of high- and low-grade squamous intraepithelial lesions had a sensitivity of 58%, this was reduced to 24% if only high-grade squamous intraepithelial lesions were considered relevant for additional evaluation. If we had not evaluated the patients with atypical squamous and glandular cells of undetermined significance, we would have missed diagnosing one third of high-grade and one half of low-grade cervical intraepithelial neoplasia. Cervical cytology was false negative in 8% of patients with high-grade and in 14% of those with low-grade cervical intraepithelial neoplasias. High-risk human papillomavirus deoxyribonucleic acid was detected in 40% of women with high-grade and in 24% of those with low-grade grade cervical intraepithelial neoplasias. The positive predictive value of cytology with atypical squamous cells of undetermined significance increased from 5% to 38% for high-grade and from 30 to 85% for high- and low-grade cervical intraepithelial neoplasias in patients with detectable high-risk human papillomavirus deoxyribonucleic acid. Virologic studies produced no significant improvement on these diagnoses in women with high- or low-grade cytology.Conclusions: Because of the poor sensitivity of cytology suggesting high-grade squamous intraepithelial lesions, we recommend that all women with atypical or low-grade cytology be recalled for colposcopy and high-risk human papillomavirus deoxyribonucleic acid testing, if available. Decisions whether to perform a biopsy should be based on the result of colposcopic examination. Performing colposcopy only on those patients who have cytologic high-grade squamous intraepithelial lesions and following those with lower grade cytologic anomalies without colposcopic diagnosis appears inadequate to rule out high-grade cervical intraepithelial neoplasia.     

Colposcopy: the value of HPV testing in clinical practice

The indications for colposcopy have changed recently because of the new Bethesda terminology, the introduction of HPV testing in clinical practice, and the latest consensus guidelines on management of patients with an abnormal cervical cytological test. Colposcopy remains the reference technique to assess patients with abnormal cytological test results, especially those with ASC-H, LSIL, HSIL, and AGC. In women with an ASC-US result, colposcopic examination of only those who test positive for high-risk HPV increases the specificity of the technique. When liquid-based cytology is used, HPV DNA testing is the preferred approach in these women. In primary screening using combined cytology and HPV DNA testing in women over the age of 30, colposcopy is indicated in patients with normal cytology and two HR HPV DNA positive tests performed at a nine month interval. For the follow up of untreated patients with ASC-US/LSIL and CIN I, colposcopy carried out at one year after a single HR HPV DNA positive test is as sensitive as colposcopy after two or three abnormal cytology tests. After excision or conization in patients with high-grade CIN, colposcopy after a single HR HPV DNA positive test is as sensitive as cytology testing and colposcopy at six months. Therapeutic decisions must not be based solely on the results of HPV DNA testing except in specific cases.     

高危型人乳头状瘤病毒DNA检测与细胞学联合检查对子宫颈癌前病变筛查的研究

目的评价高危型人乳头状瘤病毒(HPV)DNA检测联合宫颈细胞学检查对宫颈癌前病变筛查的效果。方法2003年1月至2004年6月,对广东省人民医院妇科门诊5210名妇女进行宫颈癌前病变筛查,采用第二代杂交捕获试验(HC-Ⅱ)检测高危型HPV DNA联合细胞学检查,同时进行阴道镜检查,并以宫颈活检的组织病理学结果为确诊标准。结果受检者平均年龄(34±9)岁,筛查并最后经病理诊断为HPV感染890例,宫颈上皮内瘤变(CIN)Ⅰ级83例,CINⅡ73例,CINⅢ80例,宫颈浸润癌54例,子宫内膜癌5例,阴道上皮内瘤样病变1例,宫颈结核1例。以组织病理学为确诊标准,高危型HPV DNA检测CINⅡ、Ⅲ的敏感度是92·22%,特异度是74·71%,阳性预测值5·19%,阴性预测值99·84%。宫颈细胞学筛查CINⅡ、Ⅲ,以未明确诊断意义的不典型鳞状上皮细胞(ASCUS)为分界点的敏感度、特异度、阳性预测值和阴性预测值分别是90·00%、80·34%、11·94%和99·63%;以低度鳞状上皮内病变(LSIL)为分界点的敏感度、特异度、阳性预测值和阴性预测值分别是70·13%、91·58%、11·11%和99·51%;以高度鳞状上皮内病变(HSIL)为分界点的敏感度、特异度、阳性预测值和阴性预测值分别是48·05%、98·46%、31·90%和99·21%。高危型HPV DNA检测联合细胞学检查筛查CINⅡ、Ⅲ的敏感度、特异度、阳性预测值和阴性预测值分别是98·70%、73·08%、5·21%和100·00%。高危型HPV DNA在不同宫颈病变中的阳性率分别是:宫颈癌85·2%(46/54),CINⅢ92·5%(74/80),CINⅡ86·3%(63/73)和CINⅠ45·8%(38/83)。结论高危型HPV DNA检测在宫颈癌前病变的筛查中有很高的敏感度和阴性预测值,高危型HPV DNA检测联合细胞学检查可使敏感度和阴性预测值有提高,但特异度未能提高。     

冷刀锥切术切缘阴性的重度宫颈鳞状上皮内瘤变患者的预后影响因素分析

目的探讨冷刀锥切术切缘阴性的重度宫颈鳞状上皮内瘤变（HSIL）患者的预后影响因素。方法回顾分析1999年1月至2004年1月间,卫生部北京医院妇产科266例冷刀锥切手术切缘阴性的HSIL患者的临床资料,分析影响预后的因素,并随访治疗结局。其中宫颈上皮内瘤变（CIN）II20例,CIN11246例（包括原位癌82例）;腺体累及者40例,无腺体累及者226例;257例检测高危型人乳头状瘤病毒（HPV）患者中,高危型HPV阳性244例,阴性13例。结果中位数随访时间46个月,总复发率为8．6％（23／266）,无浸润癌发生。CINⅡ患者中1例（5．0％,1／20）复发,CINⅢ患者（不包括原位癌）中9例（5．5％,9／164）复发,而82例原位癌中13例（15．8％,13／82）复发,原位癌与CINⅡ及CINⅢ（不包括原位癌）患者复发率比较,差异均有统计学意义（P〈0．05）。腺体累及者中7例（17．5％,7／40）复发,无腺体累及者中16例（6．0％,16／226）复发,两者比较,差异有统计学意义（P〈0．05）。高危型HPV阳性者中21例（8．6％,21／244）复发,而13例高危型HPV阴性者中无一例复发,两者比较,差异有统计学意义（P〈0．05）。结论冷刀锥切术切缘阴性的HSIL复发率低;病理分级高和腺体受累是影响疗效及预后的因素。     

The current status of HPV DNA testing

Infection with high-risk types of HPV underlies most cases of high-grade cervical intraepithelial neoplasia (CIN) and practically all cases of invasive cervical cancer. Currently, cervical HPV DNA is detected by means of PCR and sandwich capture molecular hybridization methods. Research has focused on the potential role of HPV testing in three conditions: screening for cervical neoplasia, triage of women with low-grade lesions and follow-up after conservative surgical treatment for CIN. Concerning the first condition, HPV testing does not seem to offer an obvious advantage over traditional cytology screening, mainly due to false positive results in younger women with transient HPV infection. A possible exemption to this is the case of middle-aged women and low-resource settings, where the excellent sensitivity of a HPV test is desirable. Although data are controversial regarding low grade lesions, results from randomized studies indicate that HPV testing could be useful in a triage of women with an initial cytological diagnosis of ASCUS, where detection of DNA of a high-risk type should lead to colposcopy. Although there is a lack of randomized controlled trials in this field, data from observational studies indicate that HPV DNA testing after conservative surgical treatment for CIN may be very sensitive and detect early residual and recurrent disease.     

Expanded cytological referral criteria for colposcopy in cervical screening: comparison with human papillomavirus testing

OBJECTIVE: The goal of this study was to investigate whether expanded cytologic referral criteria for colposcopy or the addition of human papillomavirus (HPV) testing on cervical screening could improve the rates of detection of cervical intraepithelial neoplasia (CIN). METHODS: HPV testing by semiquantitative polymerase chain reaction/ELISA was performed in 1000 women who were self-referred for routine Pap smear. They underwent colposcopy following an abnormal smear result or a positive HPV test. As abnormal smear results were considered reports of low- or high-grade squamous intraepithelial lesion, atypical squamous cells of undetermined significance, and even HPV-associated reactive cellular changes (mild koilocytosis, mild dyskeratocytosis, hyperchromatic nuclei, bimultinucleation, and cleared cytoplasm). Loop excision of the transformation zone was performed in women with cytology and colposcopy indicative of CIN, as well as in women with normal cytology but positive HPV test and colposcopic impression of CIN. RESULTS: The Pap test was abnormal in 89% of the cases of CIN 1 (34/38) and 96% of CIN 2/3 (27/28) diagnosed in our population. HPV testing picked up four additional cases of CIN 1 (11%) and one case of CIN 2/3 (4%). Overall the HPV test detected 95% of the cases of CIN 1 (36/38) and 89% of the cases of CIN 2/3 (25/28). CONCLUSION: HPV testing does not appear to add significantly to cytology in terms of positive predictive value or detection rate, if extended cytologic indications for colposcopy are used.     

Immunohistochemical and molecular study of severe cervical dysplasia associated with HPV-83

BACKGROUND: Based on epidemiological data, infections with specific types of HPV can be classified as high-risk (HR), low-risk (LR) or intermediate-risk (IR) HPV depending on the risk of progression to cervical cancer. CASE: A 70-year-old woman consulted for relapse of abnormal cytology with high-grade squamous intraepithelial lesions (HSIL) associated with HPV-83 infection. Histological examination demonstrated high-grade cervical intraepithelial neoplasia (CIN III) with strong and diffuse staining by the P16(INK4a)-specific antibody. CONCLUSION: This patient's intermediate-risk HPV infection (HPV-83) rapidly progressed to severe cervical intraepithelial neoplasia (CIN III) with strong anti-P16(INK4a) immunolabelling. Analysis of the E6 peptide sequence revealed several mutations in one of the two putative zinc finger regions (AA residues 107-135) associated with p53 binding.     

Role of Cervical Cancer Biomarkers p16 and Ki67 in Abnormal Cervical Cytological Smear

IntroductionCervical cancer is the most common cancer in India. Screening for cervical cancer helps in marked reduction of invasive cervical cancers. The low sensitivity of Papanicolaou cytology (Pap smear) and high-risk human papillomavirus (HR-HPV) in excluding high-grade intraepithelial lesion (ASC-H) leads to unnecessary referrals to colposcopy-guided biopsy. The combined cervical cytology screening and HR-HPV have its own limitations and still need further standardization. Using additional biomarkers like staining with p16 and Ki-67 might help in triaging abnormal pap smear.Materials and MethodsA prospective, cross-sectional study was performed over a period of 16 months in the Department of Obstetrics and Gynaecology, in collaboration with Department of Pathology. Study was conducted to know the efficacy of immunostaining with p16/Ki-67 in predicting the presence of significant lesion in cases of mild cytological atypia. PAP smears (conventional and LBC) along with P16, Ki-67 and available biopsies were correlated.ResultsLiquid-based cytology (LBC) was done in 2134 cases, out of which 46 cases showed abnormal cytological findings such as [22 atypical squamous cells of undetermined significance (ASCUS), 3 low-grade squamous intraepithelial lesion (LSIL), 8 atypical squamous cells cannot exclude high-grade lesion (ASC-H), 6 high-grade squamous intraepithelial lesion (HSIL), 5 squamous cell carcinoma (SCC), 2 adenocarcinoma, 1 atypical glandular cells of undetermined significance (AGUS)]. Immunostaining with p16 and Ki-67 was performed on 38 cases of abnormal cytological smears. Out of 38 abnormal cytology cases, 28 cases had shown co-staining for both p16 and Ki-67, suggestive of true HPV infection of the cells. Of the 38 cases, 07/14 ASCUS, 06/06 HSIL, 07/08 ASC-H, 05/05 squamous cell carcinoma and 02/02 adenocarcinoma also showed dual positivity for p16 and Ki-67. One case of AGUS was diagnosed, but the smear was unsatisfactory for immunocytochemical evaluation and excluded from the study. Three cases of LSIL were also diagnosed on cytological evaluation, and 1 of them however showed positivity for p16 and Ki-67 on immunocytochemistry (ICC). In the ASC-US group, the sensitivity and specificity of the immunostaining in diagnosing CIN2 + lesions were 87.51%, and in LSIL group, the sensitivity and specificity of the immunostaining in diagnosing CIN2 + lesions were 100%. p16/Ki-67 positivity also increased with cytological severity which in turn corresponded with histological findings: it reached from 50% in ASC-US to 100% in both HSIL and SCC categories.ConclusionThis immunostaining with p16 and Ki67 can be a useful method in the triaging of the ASC-US and the LSIL group as considering the high sensitivity and specificity values.     

Liquid-based cytology and human papillomavirus testing: A pooled analysis using the data from 13 population-based cervical cancer screening studies from China

Objective

The objective of this study was to evaluate the impact of introducing HR-HPV testing in cytology regarding cervical cancer screening practice.

Methods

A pooled analysis of liquid-based cytology (LBC) and HR-HPV testing using data from 13 population-based cervical cancer screening studies conducted in China was performed. Participants (n = 25,404) received LBC and HR-HPV testing. Women found to be positive on screening were referred for colposcopy and biopsy. The effectiveness of screening strategies that use: LBC with HR-HPV triage for atypical squamous cells of undetermined significance (ASC-US), HR-HPV testing with cytology triage for HPV positive tests, or LBC and HPV cotesting was compared with that of LBC screening alone.

Results

LBC with HR-HPV triage for ASC-US had similar sensitivity compared with LBC alone, but significantly increased specificity for both cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) and CIN3 or worse (CIN3 +) endpoints, and had the best balance between sensitivity and specificity among the strategies. LBC and HR-HPV cotesting had the highest sensitivity and negative predictive value (NPV) and could permit a safe extension of screening intervals. Through the use of an immediate colposcopy threshold of ASC-US or worse for HR-HPV positive women and the use of a raised threshold of low-grade squamous intraepithelial lesion (LSIL) or worse for HR-HPV negative women, LBC and HR-HPV cotesting could provide the same effectiveness as LBC testing with HR-HPV triage for ASC-US at baseline tests.

Conclusions

The results of the current study support the use of the cervical cancer screening guidelines in China.     

Clinical and economic implications of adding HPV tests to the routine cytology follow-up and management of patients with histologically defined cervical intraepithelial neoplasia grade 1

OBJECTIVE: The objective of this study was to evaluate the clinical and economic implications of adding human papillomavirus (HPV) testing to the follow-up and management protocol of women with a histological diagnosis of low-grade cervical intraepithelial neoplasia (CIN1). METHODS: The study cohort consisted of 314 women with histological diagnosis of CIN1 and who met the inclusion criteria. They were followed-up by pap smears and samples for HPV tests that were obtained and analyzed on the first visit after referral. HPV assessment was carried out later. Colposcopy and biopsies were performed when there were two consecutive abnormal pap results or positive HPV tests. Women with any degree of CIN underwent cone biopsies. RESULTS: The positive predictive value (PPV) of low-grade squamous intraepithelial lesion and high-grade squamous epithelial lesion to identify high-grade lesions (CIN2-3) were 48.9 and 95%, respectively. The PPV of low-risk HPV type for CIN1 and that of high-risk HPV type for CIN2-3 were both 97%. Of the 314 study participants, 68 (21.6%) patients were positive for HPV analysis, and 67 of these (98.5%) had either CIN1 or CIN2-3 on the cone biopsy, with an overall PPV of 95%. The cost effectiveness ratio was $1457 per additional case detected by the "HPV approach." CONCLUSIONS: Testing for the presence of high-risk HPV types is both clinically and economically more beneficial than cytology in the follow-up and management of patients with a diagnosis of CIN 1 because of its better sensitivity, specificity, and PPV reports.     

Human papillomavirus infection and cervical disease in human immunodeficiency virus-1-infected women

OBJECTIVE: To report on the natural history of high-risk human papillomavirus (HPV) infection and cervical disease in human immunodeficiency virus (HIV)-1-infected women living in Cape Town, South Africa. METHODS: This was a prospective study of 400 untreated, HIV-1-infected women who underwent high-risk HPV DNA testing, cytology, colposcopy, histology, and CD4 count testing every 6 months for 36 months. Human immunodeficiency virus viral loads and HPV type distribution were determined at entry and after 18 months. RESULTS: Sixty-eight percent of the women were high-risk HPV DNA positive at entry, 35% had a cytologic diagnosis of low-grade squamous intraepithelial lesion (LSIL), and 13% had high-grade squamous intraepithelial lesion (HSIL). There were no cancers. Abnormal cytology and high-risk HPV positivity were strongly correlated with low CD4 counts and high HIV viral loads. The most prevalent types of HPV were HPV-16, -52, -53, -35, and -18. Incident high-risk HPV infection occurred in 22%, and of those infected with high-risk HPV, 94% of infections persisted over an 18-month period, and 6% cleared their infections. Cytologic progression to SIL from normal/atypical squamous cells of undetermined significance cytology occurred in 17% of cases, but only 4% of cases of LSIL progressed to HSIL. CONCLUSION: There is a high level of high-risk HPV infection in HIV-1 infected women, but progression to HSIL over 36 months occurred in the minority of cases. We recommend an initial colposcopy for an abnormal test, and if no high-grade lesion is identified, triennial screening would be appropriate. Human papillomavirus type 16 was the commonest, and HPV-18 was the fifth commonest, suggesting that vaccination against these two types would have a significant effect. LEVEL OF EVIDENCE: II.     

下生殖道感染与子宫颈细胞学异常的相关性研究

Objective?To study the association between abnormal cervical cytology and bacterial vaginosis (BV), vulvovaginal candidiasis(VVC), trichomonas vaginitis(TV), high-risk human papillomavirus(HR-HPV) infection in women attending cervical cancer screening. Methods?The study recruited 3 300 women aged 21 to 64 years of age who participated in cervical cancer screening. Demographic information was collected. Cervical exfoliated cell specimens were collected for liquid-based cytological diagnosis and HR-HPV detection. Reproductive tract secretions specimens were collected for molecular vaginitis diagnostics from women who were diagnosed with negative for intraepithelial lesion or malignancy(NILM) and all HR-HPV positive or ≥atypical squamous cells of undetermined significance(ASC-US). The Logistic multivariate model was used to analyze the risk factors of abnormal cervical cytology. Results?645 women were included in the study, including 408 NILM, 182 ASC-US, 23 low-grade squamous intraepithelial lesion (LSIL), and 32 high-grade squamous intraepithelial lesions (HSIL). The positive rate of HR-HPV (14.7%, 39.0%, 78.3% and 87.5%) increased with the severity of cytology (P<0.001). The prevalence of BV in different cytological diagnosis (34.1%, 49.5%, 60.9% and 43.8%) were significantly different (P<0.001), and the prevalence of BV in ASC-US were significantly higher than that in women with NILM (P<0.05). The prevalence of VVC in different cytological diagnosis (14.2%, 4.9%, 8.7% and 3.1%) was significantly different (P<0.01), and the ASC-US group was significantly lower than the NILM group (P<0.001). There was also a significant difference in the distribution of the prevalence of TV (2.5%, 9.3%, 4.3%, and 6.3%, P<0.01). The prevalence of TV in women with abnormal cytology was higher than that in women with normal cytology(P<0.05). The Logistic analysis showed that HR-HPV infection, BV, TV, VVC, lower level of education, and postmenopause were related to abnormal cervical cytology. Conclusion?HR-HPV infection is the determinant of abnormal cervical cytology. BV, TV, VVC, lower level of education, postmenopause, etc. may associate with abnormal cervical cytology.     

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.     

Human papillomavirus genotyping using HPV DNA chip analysis in Korean women

This study was designed to investigate the genotypes of human papillomavirus (HPV) in Korean women who had abnormal cervical cytology and to evaluate the clinical accuracy of HPV DNA chip analysis for the diagnosis of cervical neoplasia. Liquid-based cytology preparations, HPV DNA chip analysis, and cervical biopsy were performed in 2358 women. High-risk HPV was identified in 23.5% of 1650 histologically confirmed normal samples (including cervicitis and squamous metaplasia) and in 81.8% of 708 samples with cervical intraepithelial neoplasia (CIN) and carcinoma (P<0.01). The major prevalent high-risk HPV genotypes in 381 samples of CIN II/III were HPV-16, -58, -33, and -31, in order of prevalence rate (average overall, 78.0%), and HPV-16, -18, -58, and -33 (average overall, 81.2%) in 133 samples of squamous cell carcinoma (SCC). The infection rate of HPV-16 was significantly higher than that of other high-risk HPV genotypes in all normal, CIN, and SCC cases (P < 0.01) and increased with more advanced squamous cervical lesions (P<0.01). The detection accuracy of high-risk HPV using HPV DNA chip analysis for CIN II or worse was as follows: sensitivity 84% (81-87%), specificity 72% (70-74%), positive predictive value 47% (44-50%), and negative predictive value 94% (92-95%). These results suggest that HPV DNA chip analysis may be a reliable diagnostic tool for the detection of cervical neoplasia and that there are geographic differences in the distribution of high-risk HPV genotypes.