Should women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, receive reflex human papillomavirus-DNA testing?

BACKGROUND: The 2001 American Society for Colposcopy and Cervical Pathology Consensus Guidelines recommend that women who have Papanicolaou (Pap) smears diagnosed as atypical squamous cells (ASC), cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H) should be referred for immediate colposcopic examination. The objective of this pilot study was to evaluate whether reflex human papillomavirus (HPV)-DNA testing performed on smears diagnosed as ASC-H may obviate the need for immediate colposcopic examination. METHODS: All ThinPrep Pap smears that were diagnosed as ASC-H or atypical squamous metaplastic cells (ASMT) between 2001-2003 and that had HPV-DNA testing and subsequent histologic and/or cytologic follow-up were evaluated. Those smears that were diagnosed as ASMT were reviewed and reclassified under the 2001 Bethesda System as either ASC of undetermined significance (ASCUS) or ASC-H. Smears that were diagnosed as ASCUS were excluded from the study. RESULTS: The study included of 48 smears that were diagnosed as ASC-H. All patients with biopsy-proven HSIL had positive high-risk (HR)-HPV results (100% negative predictive value). Approximately 80% of patients with ASC-H who had biopsy-proven, low-grade intraepithelial lesion on follow-up had positive HR-HPV results. Among the patients who had ASC-H with negative follow-up, 50% had positive HR-HPV results, and 50% had negative HR-HPV results. CONCLUSIONS: Among patients with ASC-H, a negative HR-HPV result was found to be an excellent predictor of the absence of HSIL. The results of this pilot study suggested that HPV-DNA testing may serve as a means to better select which patients with ASC-H on Pap smear should undergo colposcopic examination. This approach potentially may reduce medical costs and eliminate the need for routine colposcopic examination among patients with ASC-H Pap smears.     

Identification of progressive cervical epithelial cell abnormalities using DNA image cytometry

BACKGROUND: The objectives of the current study were to compare the capabilities of conventional cervical cytology and of DNA image cytometry (DNA-ICM) in the prediction of progressive or regressive behavior in atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and atypical glandular cells (AGC). METHODS: One hundred ninety-six women with Papanicolaou (Pap) smears that yielded diagnoses of ASC, LSIL, or AGC were included in a prospective cohort study. Slides were classified according to the Bethesda system. DNA-ICM was performed according to the consensus reports of the European Society of Analytical Cellular Pathology. RESULTS: Reference standard verification was available in 108 patients. The rate of DNA aneuploidy in Pap smears increased significantly from cervical intraepithelial neoplasia 1 (CIN1) (54%) and CIN2 (64.3%) to CIN3 or greater (CIN3+) (83.3%) in subsequent biopsies (P < 0.05). Using ASC, LSIL, and AGC as input cytologic diagnoses and >/= CIN2 as the output histologic diagnosis, the positive predictive values (PPVs) for conventional cytology and DNA-ICM were 35.2% and 65.9%, respectively (P < 0.001). The negative predictive value (NPV) of DNA-ICM was 85.0%. When >/= CIN3 was used as the output histologic diagnosis, conventional cytology had a PPV of 22.2%. The PPV and NPV of DNA-ICM were 43.9% and 93.3%, respectively. CONCLUSIONS: The results of the current study confirmed the prognostic validity of DNA image cytometry for differentiation between progressive and regressive lesions in patients with ASC, LSIL, and AGC diagnoses.     

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

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.     

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

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.     

ThinPrep Pap Test: performance and biopsy follow-up in a university hospital.

BACKGROUND: The ThinPrep Pap Test (TP), a liquid-based cervical cytology preparation, was approved for use in the U.S. in 1996. The purpose of this study was to compare TP performance and biopsy follow-up studies with a similar population of high risk patients sampled by conventional Papanicolaou (Pap) smear (CS). METHODS: Diagnostic and specimen adequacy interpretations for 2727 TP direct-to-vial Pap tests from a high risk university hospital practice were compared with 5000 CS preparations from the same physicians taken 1 year previously. Biopsy follow-up studies for the categories of squamous intraepithelial lesion (SIL), carcinoma, and atypical squamous cells of undetermined significance (ASCUS) for each time period and technique were contrasted. RESULTS: The SIL/carcinoma detection rate increased from 7.7% to 10.5% (P < 0.01) and the ASCUS rate decreased from 12.5% to 6.9% (P < 0.01); the percentage of satisfactory but limited specimens decreased from 19.4% to 10.5% (P < 0.01). Low grade SIL cases increased by 57% (P < 0.01) whereas the 26% increase in high grade SIL cases was not statistically significant. Greater than 90% of ungraded SIL, high grade SIL, and carcinoma cases had abnormal biopsies by both the TP and CS methods. The number of biopsy-confirmed high grade dysplasias and carcinomas was similar in the two groups. A low grade SIL detected by TP was less likely to have an abnormal biopsy (70% vs. 85% for CS). Nevertheless, the 57% increase in low grade SIL diagnoses by TP resulted in more TP patients with dysplastic biopsy diagnoses. Follow-up studies for ASCUS cases diagnosed by either TP or CS were similar, and 21-24% of patients eventually were found to have dysplasia. CONCLUSIONS: The TP technique appears to lead to the increased detection of low grade SIL lesions, decreased satisfactory but limited samples, and fewer equivocal specimens. No increase in biopsy-confirmed high grade dysplasias and carcinomas was found. Follow-up studies for the ASCUS category were nearly identical to those for CS.     

Cytology of desmoplastic small round cell tumor

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a high-grade malignant tumor that has a predilection for adolescent males and usually affects the abdominal cavity. The cytology literature regarding DSRCT, including aspirates and ascitic fluid, is limited. To the authors' knowledge, findings in ThinPrep slides have not been described previously. METHODS: Seven cytologic specimens from five patients with histologically confirmed DSRCT were reviewed. Five specimens were fine-needle aspiration biopsies (FNABs), (liver, flank soft tissue, abdomen, and two resected colons [pericolic]) and two specimens were ascitic fluid. Cytologic features were studied in ThinPrep slides and direct smears, which included hematoxylin and eosin, Papanicolaou, and Quik-Dip stains. RESULTS: All specimens showed moderate to high cellularity. The tumor cells were arranged singly and in clusters. The cells demonstrated high nuclear/cytoplasmic ratios, granular chromatin reminiscent of small cell carcinoma, usually inconspicuous nucleoli, smooth to irregular nuclear membranes, and frequent nuclear molding. The cytoplasm was scant to moderate, pale blue, and occasionally vacuolated. Pseudorosettes were observed in six specimens. One ThinPrep slide and the direct smears contained cells with perinuclear, cytoplasmic densities. Stromal fragments were present in the direct smears but were uncommon in ThinPrep. Three specimens were diagnosed as being consistent with DSRCT. Two specimens were diagnosed as malignant small cell tumor. Molecular studies performed on histologic material in four cases confirmed the presence of the diagnostic translocation, t(11;22)(p13;q12). CONCLUSIONS: DSRCT may be diagnosed accurately in cytology specimens. Characteristic cytologic features include granular chromatin, smooth to irregular nuclear membranes, nuclear molding, cytoplasmic vacuoles, pseudorosettes, and metachromatic stroma. Cytoplasmic densities may be observed in direct smears and ThinPrep slides.     

A comparison of liquid-based cytology and Pap smear as a screening method for cervical cancer

The implementation of population-based screening for cervical cancer with Pap smear in the early sixties was set to detect and treat precancerous lesions, hopefully preventing a subsequent invasive cervical cancer. Epidemiological data indicate that organized screening has a major impact on morbidity and mortality from cervical cancer. The limited sensitivity of a single smear necessitates repeated smears in organized program. It is suggested that liquid-based cytology improves the sensitivity. The aim of this split-sample study was to compare ThinPrep liquid-based cytology with conventional Pap smear, relying on a laboratory with long-term experience of the latter. In total, 137 women with atypical Pap smear in population-based cervical screening were enrolled for the split-sample study. The performance of both techniques (ThinPrep liquid-based cytology and conventional Pap smear) were compared and validated by a histological follow-up. Women without representative histological biopsy were excluded from the study. Pap smear had sensitivity for detection of CIN2-3 of 47% compared to 66% for liquid-based material. The concordance of the two sampling techniques with the histological diagnosis was 37% and 53%, respectively, this difference being statistically significant. The proportion of reports on atypical squamous cells of undetermined significance (ASCUS) was significantly less in the liquid-based material, 4.3% compared to 8% of the conventional smears. This improved sensitivity in combination with the possibility to perform reflex testing such as HPV DNA or p16 immunocytochemistry without renewed sampling gives ThinPrep a substantial advantage and makes the liquid-based technique interesting.     

The effect of the quality of Papanicolaou smears on the detection of cytologic abnormalities.

BACKGROUND: Controversy continues regarding the relation between the quality of Papanicolaou (Pap) smears, especially the presence of endocervical cells (ECC), with the finding of cytologic abnormalities. METHODS: As part of a study regarding performance feedback on the quality of Pap smears, data from 56,475 Pap smears obtained by 176 participating clinicians over a 20-month period were analyzed to assess the relation between the presence of ECC, the categorization of global specimen adequacy as "satisfactory" or "satisfactory with limitations," and the prevalence of atypia and squamous intraepithelial lesions (SILs). RESULTS: Atypia was less likely to be found in "satisfactory" Pap smears than in "satisfactory with limitations" quality Pap smears (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.5-0.6; P < 0.001), even though the latter could contain ECC. No association was found between satisfactory Pap smears and cytologic abnormalities. Compared with specimens with no ECC, an ECC count of > or = 50 on a slide was associated positively with the detection of atypia (OR, 2.1; 95% CI, 1.8-2.4; P < 0.001) or SILs (OR, 1.7; 95% CI, 1.3-2.2; P < 0.001). A similar relation existed between ECC counts of 25-50 (OR, 1.9; 95% CI, 1.1-2.2; P = 0.01) and the detection of SILs. No relation was found between specimens with < 25 ECC and the presence of atypia or abnormalities. CONCLUSIONS: The global adequacy criterion of "satisfactory" assigned to a Pap smear does not indicate that there is a greater likelihood of detecting cytologic abnormalities compared with lower quality Pap smears. To the authors' knowledge, previous studies regarding the link between ECC in the Pap smear and cytologic abnormalities have not addressed the relevance of how many ECC are needed to maximize the identification of abnormalities. The data from the current study support the value of obtaining at least 25 ECC as a quality indicator of sampling.     

ThinPrep detection of cervical and endometrial adenocarcinoma: a retrospective cohort study

BACKGROUND: The current study was performed to compare the accuracy of the ThinPrep trade mark Papanicoloau (Pap) test with that of the conventionally prepared Pap smear in detecting cervical and endometrial adenocarcinomas. METHODS: The subject group consisted of all ThinPrep cases of atypical glandular cells of undetermined significance (AGCUS) or adenocarcinoma diagnosed between March 1998 and March 2000. Conventional smears collected between January 1996 and January 1998, before laboratory conversion to the ThinPrep system, comprised the control group. Histologic follow-up was obtained. RESULTS: One hundred eighty-six (0.17%) of 112,058 ThinPrep Pap tests were interpreted as AGCUS/adenocarcinomas, compared with 77 (0.09%) of 83,464 conventional smears (P < 0.001). The overall sensitivity of a ThinPrep AGCUS/adenocarcinoma smear in detecting either cervical or endometrial adenocarcinoma was increased (72.0% vs. 41.5%; P < 0.001). The ThinPrep Pap test was more sensitive in detecting endometrial adenocarcinomas (65.2% vs. 38.6%; P = 0.010) and there was a trend for a higher sensitivity in detecting cervical adenocarcinomas (87.1% vs. 55.5%; P = 0.108). CONCLUSION: The ThinPrep Pap test is a more sensitive method of detecting cervical and endometrial adenocarcinomas than the conventional Pap smear.     

Implementation of the Thinprep imaging system in a tertiary military medical center

BACKGROUND:

The ThinPrep Imaging System (TIS) was implemented at Brooke Army Medical Center (BAMC) in February 2006 and has been a crucial part of the ability of the Department of Pathology and Laboratory Services ability to improve efficiency and turnaround times for Papanicolaou (Pap) test reporting. The increased detection rate of squamous abnormalities, specifically high‐grade squamous intraepithelial lesions (HSIL), has been well documented by many studies. In addition, the TIS has increased productivity for many laboratories. The objective of this study was to evaluate the effects of implementing the TIS at BAMC, a tertiary military medical center. Specifically, the following were assessed: 1) whether the detection of squamous abnormalities was increased with the TIS, 2) how the rate of high‐risk human papillomavirus (HR‐HPV) detection in atypical squamous cells (ASC) of undetermined significance (ASC‐US) cases changed (or did not change) before and after implementation of the TIS, and 3) how the TIS influenced productivity.

METHODS:

All gynecologic cytology at BAMC has been collected and processed using the ThinPrep system since 2002. Before February 2006 and before implementation of the TIS, Pap tests were screened manually by the cytotechnologists. Detection rates of squamous abnormalities were compared between the period from February 2005 to December 2005 (manual screening) and the period from February 2006 to December 2006 (image‐assisted screening). Squamous abnormalities included ASC‐US; ASC, cannot rule out HSIL (ASC‐H); low‐grade squamous intraepithelial lesion (LSIL); HSIL; glandular abnormalities; and malignancies (squamous or glandular). In addition, the rates of HR‐HPV‐positive, HR‐HPV‐negative, and HR‐HPV‐quantity not sufficient were compared for the same periods. During both periods, testing for HR‐HPV was performed only on ASC‐US Pap tests. HR‐HPV was tested with Digene Hybrid Capture 2 methodology. Productivity was calculated as the change in average slides screened per hour before and after imager implementation.

RESULTS:

In total, 107,647 Pap tests were analyzed in the 2005 (54,438 Pap tests) and 2006 (53,209 Pap tests) timeframes. Increases in the detection of ASC‐H, atypical glandular cells (AGC), LSIL, and HSIL were statistically significant. The proportion of negative for intraepithelial lesion or malignancy (NILM) and unsatisfactory cases decreased significantly with implementation of the TIS. The ASC to squamous intraepithelial lesion (ASC:SIL) ratio decreased from 1.5 to 1.0 after TIS implementation. Decreases in the ASC‐US HR‐HPV‐positive proportion and increases in the ASC‐US HR‐HPV‐negative proportion after implementation of the TIS were statistically significant. In our laboratory, a 60% increase in productivity was noted with use of the TIS.

CONCLUSIONS:

Implementation of the TIS at BAMC significantly increased the detection of ASC‐H, AGC, LSIL, and HSIL but had no significant impact on the ASC‐US detection rate. Although the ASC‐US rate did not change, both the HR‐HPV‐positive rate and the ASC:SIL ratio decreased. The data from the current study suggested that, at least initially, the use of imager‐directed screening may increase the number of clinically insignificant ASC‐US Pap tests. Cancer (Cancer Cytopathol) 2009. Published 2009 by the American Cancer Society.     

液基细胞学筛查宫颈癌的研究

目的 评价ThinPrep液基细胞学在宫颈癌高发区筛查的准确性。方法 1997年例受检者同时做宫颈脱落细胞液基标本采集和阴道镜活检,用液基标本做薄片细胞学诊断和肿瘤相关人乳头瘤病毒（human papilloma virus,HPV)检测。细胞学诊断采用TBS分级系统,阳性诊断包括意义不明的不典型鳞状细胞（ASCUS）以上病变,诊断结果与阴道活检诊断和肿瘤相关HPV DNA阳性检出率对照。所有检查均双盲进行。结果 ThinPrep液基细胞学检出100％（12／12）的鳞状细胞癌（SCC）;93．2％（69／74）的鳞状上皮内高度病变（HSIL）,其中CIN396．8％（30／31）,CIN90．7％（39／43）;72．4％（92／127）的鳞状上皮内低度病变（LSIL）。SCC和CIN3的分级准确率分别达100％和87．1％。HPVDNA阳性检出率与细胞学分级密切相关,且在细胞学与组织学相同级别基本一致。结论 宫颈液基标本收集方法有利于细胞学和肿瘤相关HPV DNA双重检查。ThinPrep液基细胞学检查敏感性高,尤其是对鳞状上皮内高度病变。     

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

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.     

Atypical squamous cells of undetermined significance in liquid-based cytologic specimens: results of reflex human papillomavirus testing and histologic follow-up in routine practice with comparison of interpretive and probabilistic reporting methods

BACKGROUND: Human papillomavirus (HPV) DNA testing for high-risk types after Papanicolaou (Pap) smear interpretations of atypical squamous cells of undetermined significance (ASCUS) is a sensitive method for identifying women who harbor underlying high-grade squamous intraepithelial lesions (HSIL). To the authors' knowledge, the application of HPV testing to ASCUS smears in routine practice with comparison of probabilistic and interpretive models of cytologic reporting has not been reported. METHODS: HPV DNA testing was performed reflexively on 216 liquid-based Pap smears that initially were interpreted as ASCUS. According to the interpretive model, ASCUS interpretations were modified and reported as either low-grade squamous intraepithelial lesions (LSIL) or squamous intraepithelial lesions (SIL) when HPV positive and as reactive when HPV negative. Using the probabilistic model, ASCUS interpretations were maintained and simply reported with the HPV test result. Histologic follow-up data were obtained. RESULTS: Of the 216 women with ASCUS cytology, 142 (65.7%) were positive for high-risk HPV types. Of the 142 HPV-positive ASCUS smears, 101 (71.1%) were modified to an interpretation of LSIL (96 cases) or SIL (5 cases). Histologic follow-up of 55 of the 101 HPV-positive smears in the interpretive group and 26 of the 41 HPV-positive smears in the probabilistic group yielded similar percentages of lesions (18 lesions [32.7%] and 9 lesions [34.6%], respectively). However, there was a preponderance of low-grade lesions in the interpretive group (89%) but a nearly equal distribution of low-grade and high-grade lesions in the probabilistic group (56% and 44%, respectively); overall, 22% of the lesions were high-grade. Of the 74 HPV-negative ASCUS smears, 71 (96%) were modified to reactive and all 5 with histologic follow-up were judged as negative. CONCLUSIONS: Colposcopy with tissue studies was virtually restricted to HPV-positive cases, regardless of the reporting model used, suggesting that clinicians are basing colposcopy triage on the HPV test result rather than the definitiveness of the cytologic interpretation. This observation, the similar yield of lesions in both groups, and the significant risk of high-grade lesions argue against application of the interpretive model to HPV-tested ASCUS cases.     

Oral contraceptive pills are associated with artifacts in ThinPrep Pap smears that mimic low-grade squamous intraepithelial lesions

BACKGROUND: The authors noted a significant increase in the diagnosis of atypical squamous cells of undetermined significance (ASCUS) in premenopausal women using oral contraceptive pills (OCP) (9%) versus women not on OCP (4%) using ThinPrep Pap smears (P = 0.02). The purpose of this study was to correlate these morphologic changes with human papillomavirus (HPV) DNA detection by in situ hybridization and clinical follow-up. METHODS: Eighty-four ThinPrep Pap smears diagnosed as ASCUS or ASCUS favor low-grade squamous intraepithelial lesions (LGSIL) in young women receiving OCP were studied by HPV in situ hybridization. This information was correlated with colposcopic follow-up and AutoCyte Pap smear results. The authors also studied 80 ThinPreps from young women with a Pap smear diagnosis of unequivocal LGSIL where there was a corresponding biopsy (positive controls) and 40 ThinPreps diagnosed as within normal limits and that rescreened as such (negative controls). RESULTS: The detection rate of HPV DNA by in situ hybridization was 33% (28 of 84) in ASCUS cases versus 90% (72 of 80) for cases of unequivocal LGSIL. A blinded review of the 29 ASCUS Pap smears performed by AutoCyte showed that 66% (19 of 29) were diagnosed as within normal limits. The majority of the cervical biopsies in the women with ASCUS by ThinPrep Pap smears were negative for dysplasia (29 of 39 [74%]) whereas 71 of 80 biopsies (88%) showed dysplasia in women with Pap smears diagnosed as unequivocal LGSIL. The periodic acid-Schiff (PAS) stain demonstrated that many of the cells with halos in the ThinPrep Pap smears that mimicked LGSIL contained glycogen. CONCLUSION: The ThinPrep induces changes that mimic LGSIL in young women on OCP. These artifacts may reflect pressure-induced alteration of glycogen. PAS analysis and, more directly, HPV testing by in situ hybridization can help differentiate this mimicking from actual LGSILs.     

Cervical cytology of atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes

BACKGROUND: The 2001 Bethesda System category of atypical squamous cells (ASC) denotes changes suggestive, but inconclusive for, a squamous intraepithelial lesion (SIL). ASC is subcategorized as: 1) "undetermined significance (ASC-US)," when changes suggest low-grade or indeterminate-grade SIL and 2) "cannot exclude high-grade squamous intraepithelial lesion (ASC-H)," when a cancer precursor is suspected. METHODS: To better define the characteristics of ASC-H, the authors analyzed and compared human papillomavirus (HPV) testing data and outcomes after 2 years for participants in the Atypical Squamous Cells of Undetermined Significance Low-Grade SIL Triage Study (ALTS), a randomized trial of 5060 women. RESULTS: Among women with thin-layer cytology findings of ASC-H, 84% tested positive for HPV, 50% (95% confidence interval [95% CI], 41%-60%) were diagnosed with cervical intraepithelial neoplasia (CIN) type 2+, and 30% (95% CI, 22-39%) were diagnosed with CIN3+. Positive HPV tests and diagnoses of CIN2+ and CIN3+ were found to be more common among women with ASCH compared with those with ASC-US, but the highest frequencies were found to be associated with high-grade SIL. For women age < 35 years with ASC-H, HPV detection exceeded 85%, whereas only 4 of 10 women (40%) age >/=35 years tested positive for HPV (P = 0.009). CONCLUSIONS: A finding of ASC-H seems to confer a substantially higher risk for CIN2+ and CIN3+ than ASC-US. Immediate colposcopy may be the appropriate management for young women with ASC-H, but the utility of HPV testing for managing older women with ASC-H requires additional study.     

Liquid-based cytology versus conventional Papanicolaou smear in an organized screening program : a prospective randomized study

BACKGROUND: The objective of this study was to evaluate whether liquid-based cytology (LBC) can improve high-standard cervical cancer screening cytology further. The primary endpoint was histopathologic high-grade lesions in current and subsequent screening rounds. The secondary endpoints were cytologic diagnosis and inadequate samples. METHODS: Women were randomized to smear taking by conventional Papanicolaou (Pap) smear or LBC according to the time of appointment. Eight thousand eight hundred ten conventional Pap smears and 4674 LBC samples were included. Evaluations of atypical cytology and referral to colposcopy and treatment were performed as routine procedures. Histopathologic diagnoses were retrieved from a regional database 8 months after the study was closed. The mean follow-up was 2 years and 9 months. RESULTS: Inadequate samples were observed in 0.3% of LBC samples versus 0.7% of Pap smears (P = .002). The total fraction of nonbenign diagnoses in cytology was 4.5% versus 3.5%, respectively (P < .001). Histopathologic evaluation was made on 570 patients constituting 4.6% of the LBC samples and 4% of the Pap smears. Forty percent more high-grade lesions were identified as a result of LBC sampling (1.20% vs 0.85%; P = .05). The influence of the sampling method was significant for all variables (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.12-2.28) for high-grade lesions that were identified by histology when adjusting for age and screening unit in a logistic regression model. At the second follow-up 2 years and 1 month later, the OR was decreased only slightly (1.51; 95% CI, 1.13-2.01). CONCLUSIONS: In the ongoing cervical screening program of western Sweden, liquid cytology produced a significantly higher yield of histologic high-grade lesions compared with conventional Pap smears.     

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

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.     

SpinThin, a simple, inexpensive technique for preparation of thin-layer cervical cytology from liquid-based specimens: data on 791 cases

BACKGROUND: Acceptance of liquid-based fixatives for cervical cytology has been limited by the more complex slide-preparation procedures, increased cost, and reports that increased sensitivity has been based largely on comparison with conventional cytology without histologic correlation. Here the authors describe and evaluate a technically simple and relatively inexpensive method (which they call SpinThin) for preparing Cytospin (Shandon Inc., Pittsburgh, PA) cervical cytology slides from samples in liquid fixative using a modified electric toothbrush holder to put the cells in suspension. Results are compared with conventional cytology and histologic biopsy. METHODS: A total of 791 cervical cytology specimens from 2 patient groups at high risk of uterine cervical neoplasia were entered into this study, and a spatula and cytobrush (174 specimens) or cytobroom (617 specimens) were used to collect conventional smears. The collection device with remaining cellular sample was placed in an alcohol-based fixative solution; the cells were put into suspension by a brief burst of vibration using a modified electric toothbrush holder, then cytocentrifuged on a slide and stained with the Papanicolaou technique. RESULTS: Specimen adequacy in SpinThin slides was better than that of conventional cytology smears. However, the prevalence of dysplasia, including atypical squamous cells of undetermined significance (ASCUS-D), in conventional smears and SpinThin slides was the same--27% and 25%, respectively--and excluding ASCUS-D, it was 20% in both. The prevalence of neoplasia (low or high grade squamous intraepithelial lesion, or carcinoma) histologically was 31% in the 647 cases biopsied, and agreement with histology was similar for SpinThin and conventional smears. CONCLUSIONS: Using a simple and relatively inexpensive new technique (Spin-Thin), slides prepared from fluid-based cervical cytology specimens obtained with the cytobrush or cytobroom correlated very well with the corresponding conventional smears within major diagnostic categories, and both correlated well with histology.     

Cytologic findings after fertility-sparing radical trachelectomy

BACKGROUND: Radical trachelectomy is a surgical procedure intended to preserve fertility in patients with early-stage cervical carcinoma in which the cervix is amputated in continuity with the parametrium and upper vagina, thereby sparing the uterus and adnexa. Follow-up is performed with periodic cytology specimens. The objective of the current study was to analyze the cytologic findings after this novel procedure. METHODS: Isthmic and vaginal Papanicolaou-stained ThinPrep cytology specimens taken from patients after radical vaginal and abdominal trachelectomy were reviewed. The specimens were also analyzed for the presence of benign endocervical cells, lower uterine segment glandular cells, endometrial stromal cells, and endometrial cells. The findings were correlated with the original diagnosis and follow-up, which included subsequent cytology specimens and biopsies. RESULTS: Cytology specimens (n = 223) from 44 patients were included in this study. An endometrial component was identified in 131 of the cases (59%). Twenty-eight cases were diagnosed as abnormal in the original cytology examination. Twenty of these cases and 5 additional cases that were diagnosed cytologically as benign had subsequent biopsies. The biopsies confirmed the presence of a lesion in only 4 of 25 biopsies (3 low-grade squamous intraepithelial lesions and 1 adenosquamous carcinoma). All cases diagnosed as atypical glandular cells represented tubal metaplasia, lower uterine segment glandular cells, or endometrial stromal cells. CONCLUSIONS: Cytology specimens after trachelectomy frequently contain glandular cells from the lower uterine segment epithelium or endometrial stromal cells, which can lead to a misdiagnosis of atypical glandular cells of undetermined significance. Tubal metaplasia is also a potential pitfall in these specimens. Pathologists and gynecologic oncologists should be aware of the potential pitfalls in the surveillance of smears after trachelectomy.     

The significance of the Papanicolaou smear diagnosis of low-grade squamous intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion

BACKGROUND: Cervical cytologic specimens that show a low-grade squamous intraepithelial lesion (LSIL) occasionally contain a few cells that are suspicious for, but not diagnostic of, a high-grade squamous intraepithelial lesion (HSIL). In such cases, a diagnosis of LSIL cannot exclude HSIL is rendered. The objective of the current study was to assess the positive predictive value (PPV) for HSIL in follow-up cervical biopsies for these cases. METHODS: One hundred forty-four women with a Papanicolaou (Pap) diagnosis of LSIL cannot exclude HSIL and their follow-up cervical biopsies were reviewed. Results were compared with a control group of 155 women with a Pap diagnosis of LSIL. A subset of biopsies was tested and typed for human papillomavirus (HPV) DNA by polymerase chain reaction amplification using consensus primers followed by restriction fragment length polymorphism analysis. HPVs were scored as low-risk or high-risk types. RESULTS: Women with LSIL cannot exclude HSIL had a higher incidence of HSIL (PPV = 29%) on follow-up cervical biopsy than the control group (PPV = 15%, P < 0.01). In addition, SIL, indeterminate grade was diagnosed in 10% of cervical biopsies in the study group as compared with 4% in controls. Review of Pap smears from the study group showed that there were 3 types of cells suspicious for a high-grade lesion: atypical squamous metaplastic cells (62%), atypical keratinized cells (20%), and dysplastic cells of borderline nuclear-to-cytoplasm ratio (18%). HPV analysis confirmed the presence of high-risk HPV types in the study cases with high-grade cervical biopsies. CONCLUSIONS: Women with a Pap diagnosis of LSIL cannot exclude HSIL appear to be more likely to harbor a high-grade lesion than those diagnosed with LSIL alone. Its use appears warranted. Women with this diagnosis merit appropriate clinical follow-up to exclude HSIL.