Progression curves for endometrial lesions

OBJECTIVE: To derive a numeric measure for the progression of endometrial lesions as a baseline study for an eventual assessment of chemopreventive intervention efficacy. STUDY DESIGN: Tissue sections from normal endometrium at the proliferative and secretory phase, simple hyperplasia, atypical hyperplasia from cases free of concomitant adenocarcinoma and adenocarcinoma of the endometrium were recorded at high spatial resolution. Six cases from each diagnostic category were chosen as "typical," and 60 epithelial nuclei were randomly selected for measurement for each case. Discriminant analyses were carried out to derive a direction of progressive change in feature space and to correct the progression curve for the presence of cells not expressing progressive change among the random sample of nuclei. RESULTS: A well-conditioned progression curve was derived based on the mean discriminant function scores for each diagnostic category and the mean nuclear abnormality of the nuclei in each category, as expressed by their deviation in feature values from normal reference nuclei. The lesion signatures showed a clear trend toward extension into the range of higher nuclear abnormalities with increasing progression. There was an indication that abnormal endometrial lesions may comprise cases with distinctly different degrees of nuclear abnormality. CONCLUSION: A numeric assessment of lesion progression for endometrial lesions, based on karyometric measurements, is possible. The data suggest that additional analysis may provide further characterizing information for individual lesions.     

Diverse glandular pathologies coexist with high-grade squamous intraepithelial lesion in cyto-histological review of atypical glandular cells on ThinPrep specimens

Objective: To identify in cytology, high‐grade squamous intraepithelial lesions with endocervical glandular extension in cases previously diagnosed as atypical glandular cells (AGC), analyse possible reasons for the diagnostic pitfall and document the frequency of glandular pathology coexisting with high‐grade cervical intraepithelial lesion in histology. Methods: Thirty‐nine ThinPrep® cervical smear (Pap) tests reported as AGC of undetermined significance and showing high‐grade lesions on histology [cervical intraepithelial neoplasia (CIN) 2 or 3, endometrial or extrauterine adenocarcinoma] were reviewed retrospectively to identify the cases of high‐grade squamous intraepithelial lesion with endocervical glandular extension, using the Bethesda 2001 system. Cyto‐histological correlation was performed. Results: A high frequency of diverse glandular pathologies coexisted with high‐grade cervical intraepithelial lesions on histology. This included endocervical glandular extension in 63%, benign glandular pathology in 33% and pre‐neoplastic or malignant glandular pathology (endocervical glandular dysplasia, adenocarcinoma in situ and metastatic breast carcinoma) in 17% cases. On cytology, the sensitivity was 40%, specificity was 80% and positive predictive value was 86% for endocervical gland extension in high‐grade squamous intraepithelial lesions. Conclusions: Special efforts to recognize endocervical glandular extension in high‐grade squamous intraepithelial lesions and glandular neoplasia coexisting with squamous intraepithelial lesions from the heterogeneous category of AGC can contribute to increasing the diagnostic accuracy. The identification of endocervical glandular extension on cervical cytology would alert the gynaecologist to perform a thorough assessment of the endocervix during colposcopy. This could also help to decide on the need to perform deeper conization rather than loop electrosurgical excision procedure to ensure negative margins when colposcopic biopsy shows CIN 2 or 3.     

The role of cervical cytology and colposcopy in detecting cervical glandular neoplasia

Objective:  To determine the role of cervical cytology and colposcopy in the management of endocervical neoplasia.
Setting:  Colposcopy unit and cytology laboratory in a teaching hospital.
Sample:  Group 1 included 184 smears showing endocervical glandular neoplasia from 129 patients and group 2 included 101 patients with histology showing endocervical abnormalities in a 6-year period (1993–1998). Follow-up of 6–11 years to 2004 was available.
Methods:  Group 1 were identified from the cytology computer records. Group 2 were identified from histology records on the cytology database and a record of histology cases kept for audit purposes. The clinical records were examined retrospectively.
Results:  The positive predictive value (PPV) of abnormal endocervical cells in smears was 81.1% for significant glandular/squamous [cervical glandular intraepithelial neoplasia (CGIN)/cervical intraepithelial neoplasia grade2 (CIN2 or worse)] lesions. The PPV of colposcopy was 93.5% for significant glandular/squamous lesions of the cervix. The postcolposcopy probability of a significant lesion when colposcopy was normal was 87.5%. The sensitivity of colposcopy in detecting endocervical lesions was 9.8%. The sensitivity of cervical smears in detecting a significant endocervical abnormality (CGIN or worse) was 66.3%. The false negative rate for cytology of endocervical glandular lesions was 4.0%.
Conclusions:  Endocervical glandular neoplasia detected on cytology is predictive of significant cervical pathology even when colposcopy is normal, which supports excisional biopsy in the primary assessment of these smears. The high concomitant squamous abnormality rate justifies the use of colposcopy to direct biopsies from the ectocervix. Cervical cytology is the only current screening method for cervical glandular abnormalities but sensitivity is poor.     

AgNOR counts in cervical smears under normal and other cytopathologic conditions

OBJECTIVE: To investigate the diagnostic value of AgNOR counts in cervical smears in the process of cervical carcinogenesis and in discriminating the different grades of squamous intraepithelial lesion (SIL). STUDY DESIGN: Silver nitrate staining for AgNOR counts was performed in 50 cervical smears of cytologically diagnosed normal, inflammatory, low grade SIL (LSIL) (mild dysplasia), high grade SIL (HSIL) (moderate and severe dysplasia) and squamous cell carcinoma. The smears were derived from the ongoing routine outpatient cytology screening at Queen Mary's Hospital, Lucknow, India. RESULTS: In normal and inflammatory smears, the number of AgNOR dots varied from 1 to 2, in mild dysplasia from 2 to 4, in moderate dysplasia from 4 to 6 and in severe dysplasia from 6 to 8. Frank cervical carcinoma cases revealed 8-10 dots. Thus, a progressive increase in AgNOR counts was observed when the severity of pathologic lesions increased. Statistical analysis revealed a significant difference in AgNOR counts between normal and inflammatory smears, but it was highly significant between inflammatory and LSIL cases, between LSIL and HSIL, and between severe dysplasia and frank malignancy. CONCLUSION: This study underscored the diagnostic importance of AgNOR counts, especially in discriminating between LSIL and HSIL of the cervix. Another study is under way to assess the potentiality of AgNOR counts as tumor markers in cervical carcinogenesis.     

Karyometry of infiltrating breast lesions

OBJECTIVE: To characterize nuclei from well-differentiated, moderately differentiated and poorly differentiated lesions of invasive breast cancer by karyometry and to test the hypothesis that these diagnostic categories form homogeneous sets. STUDY DESIGN: Histopathologic sections from 6 cases of well-differentiated, 11 cases of moderately differentiated and 17 cases of poorly differentiated ductal carcinomas were digitally recorded. From each case 100 nuclei were segmented and analyzed by karyometry. A discriminant analysis was performed, and nuclear and lesion signatures were computed. The nonsupervised learning algorithm P-index was applied. A progression curve per diagnostic category based on mean nuclear abnormality and a discriminant function score was derived. RESULTS: The well-differentiated lesions formed a homogeneous set, but both the moderately and poorly differentiated lesions showed 2 significantly different subpopulations with nuclei of substantially different nuclear abnormality and progression. CONCLUSION: The visual histopathologic diagnostic assessment of these lesions was based on an evaluation of both tissue architectural criteria and nuclear criteria. Here, only the pattern of nuclear chromatin was evaluated. Cases belonging to the same diagnostic category as assessed by their differentiation may be further characterized by the extent to which the nuclei deviate from normal. There was substantial case-to-case heterogeneity in these invasive lesions.     

Sensitivity of the Pap test in detecting high grade lesions: what should be the acceptable cytologic threshold for colposcopic referral?

OBJECTIVE: To devise an optimal cytology threshold for colposcopy referral in resource-limited settings. STUDY DESIGN: Four hundred seventy-two symptomatic women 20-60 years old were screened by both cytology and colposcopy. Onsite biopsy was taken if lesions grade 1 or above were detected on colposcopy. Women found to have cervical intraepithelial neoplasia (CIN) 2 and above lesions on histopathology were stratified according to their cytologic diagnosis (atypical squamous cells of undetermined significance [ASCUS]+ threshold, low grade squamous intraepithelial lesion [LSIL]+ threshold, and high grade squamous intraepithelial lesion [HSIL]+ threshold). The comparative sensitivity, specificity and predictive values in each group were calculated, taking biopsy as the gold standard. RESULTS: The sensitivity of LSIL + cytology to detect CIN 2+ lesions was 91.5% (referral load, 30.7%). While the sensitivity of ASCUS+ cytology threshold was almost the same (92.3%), the referral load was much higher (42.2%). With HSIL+ cytology threshold, though the referral load was reduced substantially (21.9%), the sensitivity also decreased, to 81.5%. CONCLUSION: The results indicate that in order to achieve high sensitivity, the LSIL cytology threshold appears to be optimum for colposcopic referrals.     

Cervical squamous intraepithelial lesions and associated cervical infections in an HIV‐positive population in Rural Mpumalanga,South Africa

P. J. Swanepoel, P. Michelow, R. Du Plessis, I. G. Proudfoot, G. A. Tarr, S. L. Bockel, C. J. Swanepoel
Cervical squamous intraepithelial lesions and associated cervical infections in an HIV‐positive population in Rural Mpumalanga, South Africa Background: The incidences of genital human papillomavirus (HPV) infection, associated squamous intraepithelial lesions and cervical squamous cell carcinoma are significantly increased in HIV‐positive women. The role of other cervicovaginal infections in the acquisition of the HPV infection, cervical carcinogenesis and genital HIV infection remains largely speculative. Methods: A retrospective study was conducted including 1087 HIV‐positive women in rural Mpumalanga province, South Africa, for the period 1 May 2009 to 31 August 2010. For each patient, the age at first presentation, cervical cytological diagnosis, subsequent follow‐up cytology and histology, and microscopically visible infections (including endemic Bilharzia) were tabulated and statistically analysed. Results: The prevalence of low‐grade squamous intraepithelial lesion (LSIL), high‐grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, atypical squamous cells of undetermined significance (ASC‐US) and atypical squamous cells, cannot exclude HSIL (ASC‐H) in the study population were 22.1%, 30.9%, 0.6%, 13.5% and 4.0%, respectively. LSIL, HSIL and squamous cell carcinoma were diagnosed, respectively, at the average ages of 35.7, 37.9 and 37.2 years. Four patients with cervical intraepithelial neoplasia grade 1 (CIN1), 32 with CIN2/CIN3 and two with cervical squamous cell carcinoma were also diagnosed with Bilharzia. Of the other infections only bacterial vaginosis had a positive statistical correlation with HPV‐induced cervical abnormalities (LSIL, HSIL or squamous cell carcinoma). Conclusion: This study confirms the high prevalence of progressive HPV‐associated cervical disease in a rural Southern African HIV‐positive population, which is at least equal to or worse than in other African HIV‐positive studies. The high incidence of Bilharzia infection in those cases that underwent cervical cone excision suggests a possible relationship with progressive HPV disease and cervical carcinogenesis. Bacterial vaginosis (perhaps in combination with Bilharzia) may compromise the normal barriers against HPV and HIV infection.     

Observer variation in histopathological diagnosis and grading of cervical intraepithelial neoplasia.

To assess the variability among histopathologists in diagnosing and grading cervical intraepithelial neoplasia eight experienced histopathologists based at different hospitals examined the same set of 100 consecutive colposcopic cervical biopsy specimens and assigned them into one of six diagnostic categories. These were normal squamous epithelium, non-neoplastic squamous proliferations, cervical intraepithelial neoplasia grades I, II, and III, and other. The histopathologists were given currently accepted criteria for diagnosing and grading cervical intraepithelial neoplasia and asked to mark their degree of confidence about their decision on a visual linear analogue scale provided. The degree of agreement between the histopathologists was characterised by kappa statistics, which showed an overall poor agreement (unweighted kappa 0.358). Agreement between observers was excellent for invasive lesions, moderately good for cervical intraepithelial neoplasia grade III, and poor for cervical intraepithelial neoplasia grades I and II (unweighted kappa 0.832, 0.496, 0.172, and 0.175, respectively); the kappa value for all grades of cervical intraepithelial neoplasia taken together was 0.660. The most important source of disagreement lay in the distinction of reactive squamous proliferations from cervical intraepithelial neoplasia grade I. The histopathologists were confident in diagnosing cervical intraepithelial neoplasia grade III and invasive carcinoma (other) but not as confident in diagnosing cervical intraepithelial neoplasia grades I and II and glandular atypia (other). Experienced histopathologists show considerable interobserver variability in grading cervical intraepithelial neoplasia and more importantly in distinguishing between reactive squamous proliferations and cervical intraepithelial neoplasia grade I. It is suggested that the three grade division of cervical intraepithelial neoplasia should be abandoned and a borderline category introduced that entails follow up without treatment.     

Evaluation of p16INK4a in cervical lesion of premenopausal and postmenopausal women

Pap smears of postmenopausal women are often misdiagnosed because of the difficulty in distinguishing atrophic epithelial cells groups only by morphological criteria. In this study we investigated the diagnostic application of immunocytochemical staining of p16INK4a on conventional Pap smear. A total of 137 cervical specimens were enrolled in this study, of which 77 and 60 cervical smears were taken from premenopausal and postmenopausal women, respectively. Two cervical smears were taken simultaneously in 68 women, one for conventional cytology and the other for immunostaining. Additional 69 cervical smears were taken from the archive, decolorized and then used for immunostaining. In premenopausal women 1 out of 14 (7.1%) with negative cytology, 7 out of 24 (29.2%) with low grade squamous intra-epithelial lesion (LSIL), all 35 (100%) with high grade squamous intraepithelial lesion (HSIL) and all 4 (100%) with squamous cell carcinoma (confirmed by histopathology) had positive staining to p16INK4a. In postmenopausal women p16INK4a positivity was observed in 4 out of 7 (57.1%) cases of LSIL, 12 out of 14 (85.7%) cases of HSIL and all 4 out of 5 (80%) different cases of carcinoma (1 cervical adenosquamous carcinoma and 3 cervical squamous cell carcinoma in situ confirmed by histopathology), but none of 34 smears with normal cytology. Twenty smears with normal cytology chosen for the negative control in this study were from the group of postmenopausal women and were as expected negative for p16INK4a immunostaining. In the group of postmenopausal women, 16 out of 60 (26.7%) cases the cytological diagnosis was established on the basis of pl6lNK4a immunostaining as being HSIL. From our preliminary study on a limited number of samples, we can however conclude that pl6INK4a immunostaining is a very useful tool for cytological diagnosis enabling to distinguish HSIL from normal, reactive or inflammatory changes.     

Karyometry in Barrett's esophagus

OBJECTIVE: To derive a progression curve for lesions in Barrett's esophagus based on karyometric features. STUDY DESIGN: High-resolution imagery of 900 nuclei from normal gastric tissue, Barrett's metaplasia, Barrett's high grade dysplasia and adenocarcinoma of the esophagus was recorded. Karyometric features were computed, and nuclear signatures and lesion signatures for these lesions were derived. A progression curve was defined. RESULTS: Esophageal lesions were distinctly different from the normal gastric fundus tissue, with nuclei from Barrett's metaplasia deviating from normal almost as much as nuclei from high grade dysplasia and adenocarcinoma. There was considerable case-to-case variability and overlap between lesions histologically assigned to different diagnostic categories. CONCLUSION: The karyometric data suggest that Barrett's metaplasia is a more developed lesion than previously assumed.     

Glandular and squamous atypia and intraepithelial lesions in atrophic cervicovaginal smears. One institution's experience

OBJECTIVE: To review the cytologic features and follow-up histologic findings in atrophic cervicovaginal smears with the diagnoses of glandular or squamous atypia or intraepithelial lesion. STUDY DESIGN: A total of 228 cases were included in the study. The selection criteria included: age > 48 years and a diagnosis of either atypical glandular cells (AGC) (51 cases), cellular changes suggestive of human papillomavirus (HPV) infection (S/O HPV, 97 cases), low grade squamous intraepithelial lesion (LSIL) (60 cases) or high grade squamous intraepithelial lesion (HSIL) (20 cases). Follow-up biopsy information was available for 103 cases (45%). RESULTS: From the AGC group, 35 (69%) cases had tissue studies; 14 (40%) cases showed glandular lesions; 5 (14%) showed squamous intraepithelial lesion (SIL) and atypical cells. Follow-up information was available for 32 (33%) cases classified as S/O HPV; significant lesions (glandular/squamous) were found in 11 (34%). In the LSIL category, 22 (37%) cases had follow-up; 16 (73%) showed SIL. In the HSIL category, 14 cases (70%) underwent biopsy, and all showed SIL (four LSIL and nine HSIL) or squamous cell carcinoma. CONCLUSION: Even though atrophy-related epithelial changes often pose diagnostic difficulties in the interpretation of postmenopausal smears, application of reproducible and established cytologic criteria in diagnosing SIL and/or glandular lesions can improve diagnostic accuracy and result in selection of patients for follow-up tissue studies.     

Relative accuracy of cervical and anal cytology for detection of high grade lesions by colposcope guided biopsy: a cut-point meta-analytic comparison

Background

We recently reported, using a receiver operating characteristic area metric, the first meta-analytic comparison of the relative accuracy of cervical and anal cytology in detecting moderate or severe histopathologic lesions by magnification directed punch biopsy. The aim of the present research was to meta-analytically examine cut-point specific operating characteristics (sensitivity, specificity) of cervical and anal cytology in detecting high grade squamous intraepithelial lesion (HSIL) histopathology by colposcope directed punch biopsy.

Methodology/Principal Findings

The primary eligibility requirement was availability of tabulated cytology (normal, atypical cells of unclear significance [ASCUS], low grade squamous intraepithelial lesion, HSIL or atypical squamous cells cannot rule out high grade [ASC-H]) and biopsy (Conclusions/SignificanceUsing a cytology cut-point of HSIL or ASC-H, anal cytology is less sensitive but comparably specific to cervical cytology. However, using a cut-point of ASCUS, differences in accuracy were of borderline significance.     

Exploratory analysis of quantitative histopathology of cervical intraepithelial neoplasia: objectivity, reproducibility, malignancy-associated changes, and human papillomavirus.

BACKGROUND: As part of a project to evaluate emerging optical technologies for cervical neoplasia, our group is performing quantitative histopathological analyses of biopsy specimens from 1,190 patients. Objectives in the interim analysis are (a) quantitatively assessing progression of the neoplastic process of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesions (SIL), (b) detecting malignancy-associated changes (MACs), and (c) phenotypically measuring human papillomavirus (HPV) detected by DNA testing. METHODS: The diagnostic region of interest (ROI) from immediately adjacent sections were imaged, and the basal lamina and surface of the superficial layer were delimited. Nonoverlapping quantitatively stained nuclei were selected from 1,190 samples with histopathological characteristics of normal (929), koilocytosis (130), CIN 1 (40), CIN 2 (23), and CIN 3/carcinoma in situ (CIS) (68). A fully automatic procedure located and recorded the center of every nucleus in the region of interest (ROI). We used linear discriminant analysis to assess the changes between normal and CIN 3/CIS. RESULTS: Scores computed from the cell-by cell features and the clinical grade of CIN/SIL were highly correlated, as were those of the architectural features and the clinical grade of CIN/SIL. We found even higher correlations between a combination of cell-by-cell and architectural scores, and clinical grade. Using these scores, we found MACs in the normal biopsy specimens from patients with high-grade CIN/SIL. Furthermore, the same scores correlated with the molecular detection of HPV. CONCLUSIONS: Quantitative histopathology can be used in large clinical trials as an objective and reproducible measure of CIN/SIL. Detectable phenotypic changes correlate well with CIN/SIL neoplastic progression. It can also be used to infer the presence of CIN/SIL (MACs) and molecular changes associated with increased risk of cancer development (high-risk HPV).     

Interobserver and intraobserver variability in the cytologic diagnosis of normal and abnormal metaplastic squamous cells in pap smears

OBJECTIVE: Interoberver variability has important implications for patient care, diagnostic error and medical litigation. In the management of any cervical epithelial abnormality, its biologic significance as well as diagnostic reproducibility is very important. Interobserver variability has not been measured adequately for metaplastic squamous lesions. We analyzed interobserver and intraobserver variability and diagnostic accuracy in the diagnosis of dysplastic metaplastic cells. STUDY DESIGN: Sixty Pap smears from patients with abnormalities of metaplastic squamous cells of varying severity were selected from the files of Lankenau Hospital, Wynnewood, Pennsylvania, U.S.A., diagnosed between 1990 and 1996. These were reviewed by four observers with different levels of cytology experience. Each of the observers blindly and independently reviewed all Pap smears. Tabulated results were analyzed to determine interobserver and intraobserver variability and diagnostic accuracy. RESULTS: Statistically significant interobserver reproducibility was found between both inexperienced observers as well as between observers 1 (experienced) and 3 (inexperienced) and between observers 2 (experienced) and 4 (inexperienced). The observed degree of agreement between both experienced observers (1 and 2) reflected random rating rather than reproducibility. There was no difference in interobserver reproducibility in low vs. high grade lesions. Intraobserver reproducibility had no significant correlation with experience of the observer. The sensitivity ranged from 0.69 to 0.97 (mean, 0.79), while the specificity ranged from 0.09 to 0.46 (mean, 0.30). Mean diagnostic accuracy was better in benign and low grade squamous intraepithelial lesions in comparison to high grade squamous intraepithelial lesions. CONCLUSION: There was good interobserver agreement in classifying squamous metaplastic lesions. The agreement did not correlate with grade of dysplasia or experience of the cytopathologists. These findings should be considered in making treatment, quality assurance and legal decisions. A larger study is indicated to study interobserver and intraobserver variability and define cytologic criteria for lesions of metaplastic squamous cells.     

Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology

A. Talaat, D. Brinkmann, J. Dhundee, Y. Hana, J. Bevan, R. Irvine, S. Bailey and R. Woolas
Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology Objective: To review the risk of pre‐invasive and invasive gynaecological pathology in women referred with cervical cytology reporting ?glandular neoplasia. Methods: Review of the case notes of all women referred with cervical cytology reported as ?glandular neoplasia between January 1999 and December 2008 at two UK hospitals: Portsmouth Hospitals NHS Trust and Queen Mary’s Hospital Sidcup. The category of ‘borderline nuclear change in endocervical cells’, result code 8 according to the national health service cancer screening programme (NHSCSP), was excluded from the study. Results: A total of 200 women were identified using the hospitals’ pathology computer systems. Invasive carcinoma was found in 48 women (24%): 28 endocervical adenocarcinomas, eight squamous cell carcinomas (SCC), ten endometrial and two ovarian adenocarcinomas. Pre‐invasive neoplasia was found in 115 (57.5%), including 14 cervical glandular intraepithelial neoplasia (CGIN), 31 cervical intraepithelial neoplasia (CIN) grade 2/3 and 70 concomitant CGIN and CIN2/3. CIN1/HPV was found in 25, simple endometrial hyperplasia in three and no histological abnormality in three. Thirty‐four (70.8%) of 48 invasive carcinomas (of which 23 were endocervical adenocarcinomas) were in asymptomatic women investigated for abnormal cytology. Fourteen of 34 (41.4%) of those with ?glandular neoplasia thought to be endometrial were CGIN or CIN2/3. Colposcopic appearances were normal in 47.6% of women with pure cervical glandular neoplasia (adenocarcinoma or CGIN) compared with 12.8% with squamous cell lesions (CIN2/3 or SCC): P = 0.0001. Thus, colposcopy was more sensitive for detecting squamous cell abnormalities than their glandular counterparts. Although cervical adenocarcinomas are less amenable to prevention by screening than cervical SCC, in our study cervical cytology predominantly detected these abnormalities at their early asymptomatic stages. Conclusion: At least CIN2 was found in 81.5% in women referred with cervical cytology reporting ?glandular neoplasia. A thorough evaluation of the whole genital tract is needed if colposcopy is negative.     

ASCUS, mature metaplastic type. Cytologic diagnosis and follow-up

OBJECTIVE: To study the cytologic criteria for follow-up of mature metaplastic cells within the atypical squamous cells of undetermined significance (ASCUS) category. STUDY DESIGN: Squamous epithelial abnormalities between January 1994 and June 1997 at our institution totaled 2,632 and included squamous carcinoma (1), high grade squamous intraepithelial lesions (278), low grade squamous intraepithelial lesions (875) and ASCUS (1,478). From the ASCUS group, 134 (9.06%) were metaplastic; 89 were selected for review. Criteria for case selection were follow-up with tissue biopsy or at least two Pap smears and no previous epithelial abnormality. Patients ranged from 27 to 70 years of age. Parameters tabulated included number of abnormal cells per slide, their architecture, cell size, shape, cytoplasmic hue and texture, nuclear size and contour, chromatin pattern and nucleoli. Additionally, specimens were reviewed for hormonal status and inflammation. The findings were correlated with follow-up data. RESULTS: Cells generally appeared single or in loose, monolayered sheets of three to seven cells per group. The cells were well demarcated, polygonal or oval and ranged from 11 to 30 microns with cyanophilic or eosinophilic thickened cytoplasm. The round to oval nuclei with slight irregularity showed a minimally increased nuclear/cytoplasmic ratio with stippled chromatin. Upon review, 69 smears were confirmed as ASCUS-M. Follow-up revealed 42 with benign findings, 9 with persistent ASCUS/ASCUS-M and 18 with low grade squamous intraepithelial lesions. CONCLUSION: In mature metaplastic cells with minimal atypia in patients with no previous or concurrent dysplasia, the follow-up details were similar to those described for ASCUS-superficial/immediate squamous cells. These patients could be followed conservatively.     

Conventional Pap smear and liquid-based cytology as screening tools in low-resource settings in Latin America: experience of the Latin American screening study

OBJECTIVE: To evaluate the performance of the conventional Pap test and liquid-based cytology (LBC) in an ongoing multicenter trial testing optional screening tools (cytology, screening colposcopy, visual inspection with acetic acid, visual inspection with Lugol's Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, S?o Paulo, Brazil) conventional and self-sampling), for cervical cancer in Brazil and Argentina. STUDY DESIGN: A cohort of 12,107 women attending four clinics (Campinas, S?o Paulo, Porto Alegre, Buenos Aires) were randomized into the 8 diagnostic arms. Women testing positive with any of the tests were referred for colposcopy, and cervical biopsies were used as the gold standard to assess performance characteristics of the diagnostic tests. Conventional Pap smears were sampled by all clinics (n = 10,240), and LBC (Autocyte PREP, [TriPath Imaging, Burlington, North Carolina, U.S.A.], n=320, and DNA-Citoliq [Digene Brazil], n =1,346) was performed by 1 of the clinics. RESULTS: Conventional Pap smears showed no squamous intraepithelial lesions (normal) in 8,946 (87.4%) and LBC in 1,373 (82.4%). Using high grade squamous intraepithelial lesions (HSIL) as the cutoff, Pap smears predicted high grade (cervical intraepithelial neoplasia [CIN] 3) with OR 63.0 (95% CI, 36.90-107.70), standard error (SE) 59%, SP 97.8%, positive predictive value (PPV) 68.1% and negative predictive value (NPV) 96.7%. The same figures for Autocyte PREP were: OR 9.0 (95% CI, 2.43-33.24), sensitivity (SE) 33.3%, specificity (SP) 100%, PPV 100% and negative PV (NPV) 88.8%. DNA-Citoliq detected CIN 3 as follows: OR 11.8 (95% CI 2.60-53.26), SE 40.0%, SP 94.6%, PPV 40.0% and NPV 94.6%. Lowering the cutoff to low grade squamous intraepithelial lesions increased SE and NPV but compromised SP and PPV. The detection rates for high grade lesions after an atypical squamous cells of undetermined significance diagnosis were similar with the 3 techniques. In our settings, the 3 methods of cervical cytology were slightly different in performance. The conventional Pap smear had the highest SE, while Autocyte PREP had 100% SP and PPV in detecting CIN3 with the HSIL cutoff. All 3 tests had lower SE but higher SP as compared to HCII.     

European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1

The current paper presents the first part of Chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to manage women with abnormal cervical cytology. Throughout this article the Bethesda system is used for cervical cytology terminology, as the European guidelines have recommended that all systems should at least be translated into that terminology while cervical intraepithelial neoplasia (CIN) is used for histological biopsies (Cytopathology 2007; 18 :213–9). A woman with a high‐grade cytological lesion, a repeated low‐grade lesion or with an equivocal cytology result and a positive human papillomavirus (HPV) test should be referred for colposcopy. The role of the colposcopist is to identify the source of the abnormal cells and to make an informed decision as to whether or not any treatment is required. If a patient requires treatment the colposcopist will decide which is the most appropriate method of treatment for each individual woman. The colposcopist should also organize appropriate follow‐up for each woman seen. Reflex testing for high‐risk HPV types of women with atypical squamous cells (ASC) of undetermined significance with referral for colposcopy of women who test positive is a first option. Repeat cytology is a second possibility. Direct referral to a gynaecologist should be restricted to special circumstances. Follow‐up of low‐grade squamous intraepithelial lesion is more difficult because currently there is no evidence to support any method of management as being optimal; repeat cytology and colposcopy are options, but HPV testing is not sufficiently selective, unless for older women. Women with high‐grade squamous intraepithelial lesion (HSIL) or atypical squamous cells, cannot exclude HSIL (ASC‐H) should be referred without triage. Women with glandular lesions require particular attention. In a subsequent issue of Cytopathology, the second part of Chapter 6 will be presented, with recommendations for management and treatment of histologically confirmed intraepithelial neoplasia and guidance for follow‐up of special cases such as women who are pregnant, postmenopausal or immunocompromised.     

Cytological aspects of uterine cervical adenocarcinoma, adenosquamous carcinoma and combined adenocarcinoma-squamous carcinoma: appraisal of diagnostic criteria for in situ versus invasive lesions

Cytological aspects of uterine cervical adenocarcinoma, adenosquamous carcinoma and combined adenocarcinoma-squamous carcinoma: appraisal of diagnostic criteria for in situ versus invasive lesions
This paper reports the cytological findings based on air-dried smears in a retrospective series of 143 cases of endocervical adenocarcinoma, combined adenocarcinoma-squamous carcinoma and adenosquamous carcinoma drawn from the files of the BC Cancer Registry. Cervical cytology smears were available before biopsy in 131 patients, but in 18 cases the cytology showed no abnormality. Malignant changes or high-grade atypia of glandular and/or squamous cells (defined as moderate or severe dyskaryosis) were detected in 103 cases. In 46 cases, only a high-grade squamous abnormality was detected. Low-grade glandular and/or squamous lesions were detected in nine cases and one showed atypical endometrial-type glands. The cervical smears of 64 cases were reviewed in detail to determine the important cytomorphological criteria of in situ and invasive adenocarcinoma in air-dried smears, the technique used for preparing PAP smears in British Columbia. Endocervical cells were absent in four cases. Numerous (>10) groups of glandular cells were present in 51 cases. Important clues to the diagnosis of adenocarcinoma included crowding of nuclei, stratification of nuclei, loss of polarity, syncytial balls and papillary groups of glandular cells, nuclear enlargement, nuclear pleomorphism, and the presence of free-lying atypical glandular cells. Nuclear hyperchromatism, chromatin pattern, nuclear borders, nuclear membranes, and numbers and morphology of nucleoli were not helpful criteria in our material. Criteria enabling reliable distinction between in situ and invasive adenocarcinoma and/or mixed adenocarcinoma-squamous carcinoma could not be established.     

Test characteristics of various screening modalities for cervical cancer: a feasibility study to develop an alternative strategy for resource-limited settings

OBJECTIVE: To determine test characteristics - sensitivity, specificity, positive and negative predictive values - of different screening modalities to detect cervical precancerous and cancerous lesions in order to devise an effective alternative strategy for cervical cancer screening in resource-poor settings. METHODS: A total of 472 women presenting with nonspecific gynecologic symptoms were screened by cytology, visual inspection with acetic acid application (VIA), VIA with magnification (VIAM) and human papillomavirus (HPV)-DNA testing. Colposcopic examination was performed in all and on-site biopsy was taken if any grade I and above lesion was detected on colposcopy (230). On histopathological examination, 105 showed cervical intraepithelial neoplasia II and above lesions. Sensitivity, specificity and predictive values for each test were calculated taking colposcopy and or directed biopsy as the gold standard. Comparisons were made with cytology in order to assess the feasibility of alternative strategies in resource-poor settings. RESULTS: VIA was less sensitive (86.7% versus 91.4%) but more specific (90.7% versus 86.6%) than cytology at low grade squamous intraepithelial lesion (LSIL) threshold but the difference was not statistically significant (P > 0.01). HPV testing improved the sensitivity over cytology (97.1% versus 91.4%) but there was a nonsignificant loss of specificity (84.2% versus 86.6%). Results of VIAM were more or less similar to VIA. CONCLUSION: VIA can be used as a mass screening tool for cervical cancer in resource-poor settings.