[Comparison of conventional PAP smears with thin layer specimen (liquid-based PAP test) and correlation with cytopathological findings with HPV status using the hybrid capture system]

Spital Pflegi-Neumünster, Zürich.

Cervical smears of 554 outpatients of a hospital were examined using a blinded, split sample match pair protocol for which a conventional PAP-smear (CS) was first prepared with Cervex brush and the reminder of the sample was used for the thin-layer-preparation (TLP) according to the manual CytoRich System. The preparations of the two methods were compared with respect to quality and to sensitivity for atypias. In addition the HPV status was determined on the same cell suspension in cases with borderline changes (BLC) and dysplasias including carcinoma using the Hybrid Capture System. The use of TLP reduced the proportion of suboptimal preparations by more than 50% (14.6% vs. 35%) and eliminated the only inadequate preparation registered in CS. The DSP detected more than twice as many dysplasias of all degrees as CS (3.4% vs. 1.4%) and reduced the proportion of BLC to one third (3.2% vs. 9.6%). The percentages of cases positive for high- and intermediate-risk HPV in preparations with BLC, LSIL and HSIL were 17, 62.5% and 100% respectively. The TL-method improves significantly the efficiency of PAP-smears and allows the typing of HPV which is of clinical importance for the management of low grade squamous intraepitelial lesions and borderline changes. The findings speak against the further use of CS for cervical screening.

这种薄层方法比传统巴氏涂片大大提高了效率和通过HPV的分型对LSIL和交界性改变进行重要的临床管理。这个结果表明反对进一步的用传统巴氏涂片进行宫颈癌筛查。

Comment in:

Cancer. 2000 Feb 25;90(1):67-9.

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

Women & Infants Hospital, Brown University, Providence, Rhode Island 02905-2401, USA.

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

结论：在一个人口为基础的高风险妇女的研究中表明ThinPrep细胞学显著提高检测HSIL和癌的敏感性，同时大大增加了阴道镜的推广。

Liquid-based cytology for primary cervical cancer screening: a multi-centre study.

Institut Alfred Fournier, 25 boulevard Saint Jacques, Paris, 75014, France.

The aim of this six-centre, split-sample study was to compare ThinPrep fluid-based cytology to the conventional Papanicolaou smear. Six cytopathology laboratories and 35 gynaecologists participated. 5428 patients met the inclusion criteria (age > 18 years old, intact cervix, informed consent). Each cervical sample was used first to prepare a conventional Pap smear, then the sampling device was rinsed into a PreservCyt vial, and a ThinPrep slide was made. Screening of slide pairs was blinded (n = 5428). All non-negative concordant cases (n = 101), all non-concordant cases (n = 206), and a 5% random sample of concordant negative cases (n = 272) underwent review by one independent pathologist then by the panel of 6 investigators. Initial (blinded) screening results for ThinPrep and conventional smears were correlated. Initial diagnoses were correlated with consensus cytological diagnoses. Differences in disease detection were evaluated using McNemar's test. On initial screening, 29% more ASCUS cases and 39% more low-grade squamous intraepithelial lesions (LSIL) and more severe lesions (LSIL+) were detected on the ThinPrep slides than on the conventional smears (P = 0.001), including 50% more LSIL and 18% more high-grade SIL (HSIL). The ASCUS:SIL ratio was lower for the ThinPrep method (115:132 = 0.87:1) than for the conventional smear method (89:94 = 0.95:1). The same trend was observed for the ASCUS/AGUS:LSIL ratio. Independent and consensus review confirmed 145 LSIL+ diagnoses; of these, 18% more had been detected initially on the ThinPrep slides than on the conventional smears (P = 0.041). The ThinPrep Pap Test is more accurate than the conventional Pap test and has the potential to optimize the effectiveness of primary cervical cancer screening.

ThinPrep实验是比传统巴氏实验更准确和具有做为初次宫颈癌筛查的潜在的高效率。

Does liquid-based technology really improve detection of cervical neoplasia? A prospective, randomized trial comparing the ThinPrep Pap Test with the conventional Pap Test, including follow-up of HSIL cases.

Cytology Laboratory of Jörg H. Obwegeser, Zurich, Switzerland. zylabob@swissonline.ch

OBJECTIVE: To compare the sensitivity, specificity and specimen adequacy of the ThinPrep Pap Test (TP) with the conventional Pap Test (CV) in a low-risk population with subsequent follow-up of HSIL cases. STUDY DESIGN: A prospective, randomized, controlled design was chosen to compare the TP with CV. Cytologic diagnosis and specimen adequacy were evaluated and compared with histology data in high grade squamous intraepithelial lesion (HSIL) cases. Fifteen gynecologists in private practice, all trained in colposcopy, participated in the trial. Cytologic diagnosis, specimen adequacy and follow-up of the cytologic HSIL cases were compared in the two groups. In total, 1,999 patients were included, 997 in the TP group and 1,002 in the CV group. Randomization assignments were designated on cytology case report forms, which were placed in sealed envelopes. Each envelope had a sequential randomization number on the outside to allow tracking and authentication of randomization assignments. RESULTS: Comparison of results between CVs and TPs revealed no statistically significant differences in all diagnostic categories, ranging from "within normal limits" to HSIL. Specimen adequacy, however, was superior with CVs (P < .001). The cytologic diagnosis of HSIL correlated with the histologic diagnosis in 91% of the TP group and 100% of the CV group. CONCLUSION: Because there was no statistically significant difference in sensitivity and specificity of the two techniques, improved detection of cervical abnormalities and better specimen adequacy might not be a consequence of utilizing liquid-based preparations but of a better sampling technique. Removing mucus and cellular debris from the cervical surface with a cellulose swab before sampling cells with a proper sampling device results in the same sensitivity and specimen adequacy and is much less expensive than the liquid-based technique.

结论：因为两种技术在敏感性和特异性上没有显著性的统计学差异。提高了检测宫颈的异常情况和更多样本量可能不是使用液基的结果，而是用了更好的采样技术。在用适当采样工具之前，用纤维素拭子从宫颈表面去除黏液和细胞碎片，得到的结果是同液基技术相同的敏感性和充足的标本量并便宜得多的花费。

Conventional and liquid-based cervicovaginal cytology: a comparison study with clinical and histologic follow-up.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68498-7549, USA. jbaker@unmc.edu

Increased rates of squamous intraepithelial lesion (SIL) diagnosis with liquid-based cervicovaginal cytology (CVC) methods are well documented. This retrospective study compares the ability of the ThinPrep Pap Test (TP) and the conventional Pap smear (CP) to detect biopsy-proven SIL and to exclude nonneoplastic disease. All CVC reports from January 1999 through December 2000 from seven community Family Medicine clinics affiliated with the University of Nebraska were reviewed. For women with at least one CVC diagnosis of epithelial cell abnormality (ECA), follow-up histology, cytology, and clinical data were obtained. Statistical analysis was performed using the chi-square method. SIL was diagnosed in 166 of 3,286 patients by TP (5.1%) and in 169 of 4,872 patients by CP (3.5%) (P < 0.001); 32 of the TP diagnoses (1.0%) and 34 of the CP diagnoses (0.7%) were high-grade SIL (HSIL). Atypical squamous or glandular cells of undetermined significance (ASCUS/AGUS) was the most severe abnormality diagnosed by TP in 218 patients (6.6%) and by CP in 279 patients (5.7%). Follow-up histology data on CVC SIL diagnoses showed evidence of cervical intraepithelial neoplasia in 94 patients screened by TP (2.9%) and in 79 patients screened by CP (1.6%) (P < 0.001); the biopsy diagnoses were CIN 2 or CIN 3 in 34 patients in the TP group (1.0%) and in 28 patients in the CP group (0.6%) (P < 0.025). Follow-up of patients in whom the first ECA CVC diagnosis was ASCUS or AGUS disclosed a positive predictive value for CIN of 22.8% for TP ASCUS/AGUS diagnoses and 11.9% for CP ASCUS/AGUS diagnoses (P < 0.005). In this population, TP was significantly better than CP in detecting biopsy- proven disease and in screening out benign abnormalities.

在这群人中的活检证实病变和良性异常改变检测中，液基细胞学实验大大优于传统涂片。

Histologic follow-up of atypical endocervical cells. Liquid-based, thin-layer preparation vs. conventional Pap smear.

Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio, USA.

OBJECTIVE: To review the histologic findings in patients diagnosed with "atypical glandular cells of uncertain significance, endocervical cell type" (AGUS-EC) by ThinPrep Pap Test (TPPT) or conventional Pap smear (CPS) and to evaluate the clinical value of subclassifying AGUS-EC as "favor reactive" or "favor neoplastic." STUDY DESIGN: All TPPT and CPS diagnosed as AGUS-EC (favor reactive, unspecified and favor neoplastic) from January 1998 through December 1999 and all available histologic follow-up (defined as endocervical curettage, cervical biopsy, cervical conization or hysterectomy obtained within six months of the time of an AGUS-EC diagnosis) were obtained from a computerized database. RESULTS: AGUS-EC was diagnosed in 0.77% of CPS (683 of 88,825) and 0.59% of TPPT (183 of 30,968) (P = NS). There was no statistically significant difference in any of the follow-up histologic diagnoses between the CPS and TPPT groups. The majority of the follow-up biopsies demonstrated benign processes in both groups. Patients with a diagnosis of AGUS-EC "favor neoplastic" had a greater proportion of true glandular pathology as compared with AGUS-EC "unspecified" or "favor reactive" (P < .001). None of the patients with a diagnosis of AGUS-EC "favor reactive" were found to have true glandular pathology; however, a minority of them proved to have squamous pathology. CONCLUSION: In this study there was no difference in CPS and TPPT in regard to the specificity of a diagnosis of AGUS-EC for true glandular pathology. Subclassifying AGUS-EC as "favor reactive" or "favor neoplastic" may provide valuable information for directing patient follow-up.

结论：在这个研究中，通过确诊的腺体病理证实ThinPrep实验同传统巴氏涂片在诊断AGC（颈管来源）的特异性没有差异。AGC（颈管来源）的次分类“AGC倾向反应性”或“倾向肿瘤”为指导病人的后续追踪提供了宝贵的信息。（注：2001版之前的TBS语言都改为2001版的语言）

Conventional pap smear and liquid-based cervical cytology smear: comparison from the same patient.

Cytopathology Unit, Borgo San Lorenzo Hospital, Florence, Italy. conforti@plugit.net

BACKGROUND: The results of blind reading of smears obtained with liquid-based cytology in patients previously screened by conventional cytology were compared. MATERIAL AND METHODS: Cases selected for the study were a consecutive series of 99 subjects undergoing colposcopy within the screening program of the Florence District. The Pap test samples were processed utilizing the Thin Prep 2000 (Cytyc Corporation, Boxborough, MA). The liquid-base cytology smears were randomly admixed and read by seven expert cytologists with more than 15 years of experience in Pap smear reading. For each case, a consensus diagnosis was created and considered as the definitive diagnosis. Cytologic reports in conventional and liquid-based cytology smears were compared by the kappa statistic to evaluate diagnostic agreement. RESULTS: The study showed that the conventional and liquid-based cytology provide comparable cytologic reports and that the latter is not less sensitive than the former in detecting CIN2+ lesions of the cervix. DISCUSSION: Such evidence suggests the feasibility of randomized studies comparing the two methods, which are needed before adopting liquid-based cytology as the current method when screening for cervical cancer.

讨论：这种证据表明了随机研究比较这两种方法的可行性，采用液基细胞学做为宫颈癌筛查的方法之前的研究是必须的。

Positive predictive value of liquid-based and conventional cervical Papanicolaou smears reported as malignant.

Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, USA.

OBJECTIVES: The predictive value of cervical Papanicolaou (Pap) smears reported as "positive for malignancy," especially those obtained by the liquid-based method, has not been adequately assessed. The objectives of this study are to determine the positive predictive value of Papanicolaou smears with features of malignancy, to compare the accuracy of Papanicolaou smears obtained by the liquid-based method to those obtained by the conventional technique in this setting, and to study the factors influencing a false-positive cytologic diagnosis of malignancy. MATERIALS AND METHODS: Pap smears significant for malignant cytology were identified at Fletcher Allen Health Care Hospital in Burlington, VT, from May 1, 1995, to April 30, 2001. A retrospective review of the hospital records and pathology reports was performed documenting patient characteristics, the collection technique, and the final histology. An independent review of the cytology and histology was performed. The positive predictive value and false-positive rate of malignant cytology were calculated for the liquid-based and conventional Pap smear techniques. RESULTS: A total of 472,743 Pap smears were performed during the period specified. One hundred four Pap smears were reported as positive for malignancy, yielding a prevalence rate of 0.02%. A total of 68 patients had paired cytology and histology specimens. Malignant cytology was identified in 36 smears obtained by the liquid-based technique and 32 smears obtained by the conventional technique. A true-positive result, meaning malignant cytology confirmed by the presence of invasive carcinoma on histology, was obtained in 61 of 68 (89.7%) patients. A false-positive result, meaning malignant cytology not confirmed by histology, was obtained in 7 of the 68 (10.3%) patients. The false-positive rate of malignant cytology was 8.4% for the liquid-based technique and 12.5% for the conventional technique. All 7 false-positive smears were diagnosed with high-grade dysplasia by histology. Three of the 7 patients with high-grade dysplasia had previous treatment for dysplasia, one of whom was also pregnant at the time of the smear. CONCLUSIONS: Malignant cervical Papanicolaou smear cytology has a high positive predictive value in the setting of gynecologic and nongynecologic malignancies. Previous treatment for cervical dysplasia or pregnancy may influence the false-positive rate of malignant cytology.

Comment in:

Cancer. 2004 Jun 25;102(3):200; author reply 200-1.

Liquid-based cytology and conventional cervical smears: a comparison study in an Asian screening population.

Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. anycheun@hkucc.hku.hk

BACKGROUND: This study compared the findings of cervical cytology screening by ThinPrep Papanicolaou (Pap) tests (TP) with the findings of screening by conventional cervical smears (CS) in a screening population involving what to the authors' knowledge is the largest sample of ThinPrep Pap tests published to date. METHOD: Data from 191,581 CS that were screened in the period from March 1, 1998 to February 28, 2000 were compared with data from 190,667 TP performed from March 1, 2000 to February 28, 2002 and that were obtained from the same sources. RESULTS: With TP, the unsatisfactory rate was reduced from 0.48% to 0.32%. Fewer cases were considered to be suboptimal (19.12% vs. 12.97%). The detection rates of squamous cell carcinomas, adenocarcinomas, and high-grade squamous intraepithelial lesions (HSIL) were essentially unchanged in the TP group (0.005%, 0.003%, and 0.25%, respectively) compared with the rates for the CS group (0.01%, 0.006%, and 0.25%, respectively). There was an increase in the detection of atypical squamous cells of undetermined significance (ASCUS; 3.74% vs. 3.19%) and low-grade SIL (LSIL; 1.67% vs. 1.01%) with a decrease in the ASCUS-to-LSIL ratio from 3.15 for CS to 2.33 for TP. The detection of atypical glandular cells of undetermined significance (AGUS) increased slightly from 0.07% to 0.09%. The proportion of cells reported to have reactive atypia dropped from 2.71% to 1.48%. Limited biopsy correlation (range, 73.2-76.2%) confirmed the increased sensitivity of TP. More actinomyces (1.07% vs. 0.52%) were detected in TP samples despite of a similar portion of intrauterine-device users. The average primary screening and rapid rescreening time of each slide were reduced from 8 minutes to 4 minutes and from 2 minutes to less than 1 minute, respectively. CONCLUSIONS: The preliminary experience of the authors of the current study appears to support the use of the ThinPrep Pap test to enhance the efficiency of cervical cytology screening.

结论：以作者目前研究的初步经验表明支持用ThinPrep巴氏实验做宫颈细胞学筛查以提高效率。

Cytohistologic correlation rates between conventional Papanicolaou smears and ThinPrep cervical cytology: a comparison.

Cytopathology Division of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. mary.chacho@yale.edu

BACKGROUND: The ThinPrep Papanicolaou (Pap) test, a liquid-based alternative to the long-used conventional Pap smear, received Food and Drug Administration approval in 1996. The current study is a comparison of the accuracy, as assessed by cytohistologic correlation, of conventional versus ThinPrep Pap smears in a hospital setting. METHODS: A retrospective analysis of all patients who underwent Pap smears (conventional and ThinPrep) and pertinent surgical pathology tissue processed in our department over a 1-year period was undertaken. Tissue diagnoses were grouped into broad general categories to correlate with the Bethesda system. The statistical significance of differences between the two types of Pap test results compared with tissue diagnoses was assessed using a chi-square test with 1 degree of freedom and an alpha value of 0.05. RESULTS: Of the 65,421 Pap smears interpreted during the study period, histologic correlation was possible in 1544 patients. Of those diagnosed as negative (644 conventional and 245 ThinPrep Smears), low-grade squamous intraepithelial lesion (LGSIL) (116 conventional and 114 ThinPrep smears), and high-grade squamous intraepithelial lesions (HGSIL) (142 conventional and 131 ThinPrep smears), there was no statistically significant difference found between the correlation rates of conventional and ThinPrep Pap smear results. However, review of all cases of invasive cervical carcinoma identified during this time period showed the ThinPrep to be less consistent in predicting the presence of invasive carcinoma compared with the conventional Pap smear. CONCLUSIONS: Based on cytohistologic correlation evidence, the ThinPrep Pap test may not be more effective in detecting cervical disease, particularly invasive carcinoma, when compared with the conventional Pap smear.

结论：基于细胞组织学相关证据，ThinPrep巴氏实验同传统巴氏涂片比较没有更有效的检测出宫颈病变、特别是浸润癌。