Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women

OBJECTIVE: To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. STUDY DESIGN: From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. RESULTS: Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. CONCLUSION: Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.     

Polymorphism of Ag(+)-NORs in cervical smears from women with cervical cancer

OBJECTIVE: To evaluate Ag(+)-stained (Ag(+)-NOR) polymorphism in four groups of patients with various grades of cervical lesions and in a control group. STUDY DESIGN: Forty-five women were selected, diagnosed and classified on the bases of the Pap smear and colposcopy/biopsy at Hospital de Ginecologia y Obstetricia del Instituto Mexicano del Seguro Social in Monterrey, Mexico. Five categories were considered: (1) inflammatory, (2) low grade squamous intraepithelial lesions (LSILs), (3) high grade squamous intraepithelial lesions (HSILs), (4) invasive cervical cancer, and (5) normal. The cervical smears were stained by the Ag(+)-NOR method. One hundred cells per slide were counted and classified according to the polymorphism of Ag(+)-NOR dots: typical (spherical) and atypical (large, kidney shaped and clustered). The four shapes of Ag(+)-NORs were quantified by percentage and transformed using the arcsine root procedure. RESULTS: Statistical analysis showed a significant decrease in spherical shape according to neoplastic development. The three atypical shapes showed a significant increase in patients with HSIL and invasive carcinoma in respect to LSIL. Principal components analysis grouped the data at five locations in the plane formed by the first two principal components according to the diagnosis. CONCLUSION: These findings suggest the potential diagnostic and prognostic value of the determination of Ag(+)-NOR polymorphism in cervical cytology studies.     

Actinomyces-like organisms in cervical smears from women using intrauterine contraceptive devices.

Cervical smears from 293 users of intrauterine contraceptive devices attending family planning clinics in East Fife, Dundee, and Angus were stained by Papanicolaou and Gram''s methods and examined for actinomyces-like organisms. Of the 128 women using plastic devices, 40 gave smears positive for these organisms. In contrast only two positive smears were obtained from the 165 women using devices containing copper and none from a control group of 300 women taking oral contraceptives. Colonisation was more common in women whose plastic devices had been in situ for over two years. Correlations between the presence of these organisms and recorded incidences of pain and both clinical and cytological evidence of inflammation of the lower genital tract were highly significant (p = 0.00001, p < 0.00001, and p < 0.00001 respectively). The results suggest that plastic intrauterine contraceptive devices predispose to colonisation by actinomyces-like organisms, particularly after long-term use. Hence if the apparently bacteriostatic action of copper devices is confirmed these should probably be more widely used.     

Review of cervical smears from 76 women with invasive cervical cancer: cytological findings and medicolegal implications

OBJECTIVE: To review cervical smears from 76 women which were taken prior to the diagnosis of invasive cervical cancer and to determine the appropriateness of the cytology reports issued on the smears. METHODS: Cervical smears, clinical records, cervical smear history and cytology reports from 76 women with invasive cervical cancer were reviewed. After microscopic review of the cervical smears, the cases were divided into two groups: Group 1 comprised 50 women who were found to have had at least one false-negative (F/N) smear report prior to the diagnosis of invasive cervical cancer. Group 2 comprised 26 women for whom no evidence of F/N reporting was found. RESULTS: A total of 209 cervical smears from the 50 women in group 1 were available for review (range 2-12 smears per woman); 100 of the 209 smears were considered to have been reported appropriately. Ninety-seven smears which had been reported originally as negative or inadequate were found, on review, to contain numerous severely dyskaryotic cells and were reclassified as F/N smears. All of the 50 women had at least one F/N smear and 29 had two or more. Twelve smears from eight women contained only a few (<200 severely dyskaryotic cells). Forty women developed invasive squamous carcinoma and 10 developed invasive adenocarcinoma. The stage at diagnosis ranged from 1A to stage 4. Seventy-one smears from the 24 women in group 2 were available for review (range 1-15 smears per woman). In two cases included in group 2, no smears were provided for review as the smears had been lost or mislaid. Review of the 71 smears confirmed the accuracy of the original cytological classification of the smear. Nineteen women were diagnosed with squamous cancer, two microinvasive cancer, one glassy cell, two adenocarcinomas, and one with adenosquamous carcinoma. One women was found to have an embryonal rhabdomyosarcoma of the corpus uteri involving the cervix. DISCUSSION/CONCLUSION: The medicolegal implications are discussed in the light of the above findings. Evidence of breach of duty of care was presented in all 50 cases in group I although causation was not established in every case. There was no evidence of failure of duty of care in terms of the standard of the cervical cytology reports issued or standard of clinical management in 17 of the 26 cases in group 2. However, in seven of the 26 cases in group 2, clinical management of the case was substandard due to failure to investigate symptoms of irregular bleeding regardless of a negative cytology report (two cases), failure to act upon a suspicious smear report or consecutive inadequate smear reports (two cases), failure of follow-up after treatment of CIN3 (two cases) and histological misdiagnosis (one case).     

Actinomyces in cervical smears of women using intrauterine contraceptive devices

Cervical smears from 1,784 women who attended the family planning clinics of the Institute for Research in Reproduction were examined for the presence of Actinomyces-like organisms. Among 815 intrauterine contraceptive device (IUD) users, the repeat smears from 57 women were positive for Actinomyces-like organisms, giving a prevalence rate of 6.99%. Immunofluorescent staining using specific antisera confirmed the presence of A. israelii in all 57 women. Forty IUD users whose smears were positive for Actinomyces-like organisms underwent bacteriologic culture studies; A. israelii was isolated in 23 of these cases. The clinical findings at the time of smear collection in the 57 IUD users were within normal limits. The initial cervical smears of all IUD users and both the initial and repeat smears of all nonusers were negative for Actinomyces-like organisms. The data indicate that prolonged use (greater than 2 years) of an inert or copper intrauterine device promotes the overgrowth of Actinomyces in the vagina and that this can be detected by routine cervical cytology.     

The effect of tamoxifen on cervical squamous maturation in Papanicolaou stained cervical smears of post-menopausal women

Using cervical smears obtained as part of routine gynaecological examinations, a retrospective study of the effects of the drug tamoxifen on squamous epithelial maturation of the cervix of post-menopausal women being treated for advanced breast cancer was made. The degree of squamous epithelial maturation was quantitated by using the Maturation Index and the Maturation Value. Although tamoxifen is a synthetic, non-steroidal compound classified as anti-oestrogenic, the findings indicate that this drug commonly produces a level of squamous maturation indicative of oestrogenic stimulation in Papanicolaou stained cervical smears from post-menopausal patients receiving this drug. Knowledge of the oestrogenic effect of tamoxifen in the cervix can obviate clinical concern about endometrial carcinoma.     

Significance of histiocytes on otherwise-normal cervical smears from postmenopausal women. A retrospective study of 108 cases

OBJECTIVE: To evaluate the significance of histiocytes on normal cervical smears from postmenopausal women and correlate them with endometrial pathology. STUDY DESIGN: Histiocytes were classified into three types. The clinical history was obtained from cytologic and surgical reports. RESULTS: Among 108 cervical smears, 13 had large, foamy histiocytes (type A), 88 had histiocytes resembling superficial endometrial stromal cells (type B), and 7 had variably sized histiocytes alone or in association with inflammatory or multinucleated cells (type C). Endometrial pathology was identified in 13 patients (12.0%): 4/13 with type A histiocytes (2 endometrial adenocarcinomas, 2 endometrial polyps), 8/88 with type B histiocytes (8 endometrial polyps) and 1/7 with type C histiocytes (endometrial polyp). Among 70 patients with no clinical indications for endometrial sampling except for the presence of histiocytes, 4 demonstrated endometrial pathology (all endometrial polyps). In contrast, endometrial pathology was identified in 9/38 with clinical indications for endometrial sampling. Among the 13 patients with endometrial pathology, 9 had a significant clinical history (sensitivity of 69.2%), and 4 had histiocytes as the only indication for endometrial biopsy (sensitivity of 30.8%). CONCLUSION: A significant clinical history is more predictive of endometrial pathology and outweighs the significance of histiocytes as an indication for endometrial biopsy.     

Nuclear grooves in intermediate cells in cervical smears

One thousand cervical smears from women who took part in a hospital-based screening programme for early detection of cervical cancer were studied for the presence of nuclear grooves. Grooved nuclei were frequently detected in intermediate cells in all phases of the menstrual cycle, although their frequency of occurrence was slightly lower in the luteal and premenstrual phases. The mean number of nuclear grooves varied from 3.6 to 4.2 in different phases of the menstrual cycle. The differences, however, were not statistically significant. The presence of nuclear grooves in cervical cells appears to be a nonspecific finding at present.     

Five-year follow-up of women with borderline and mildly dyskaryotic cervical smears

This study investigated the 5-year follow-up status of women with cervical smears showing borderline nuclear changes (BNC) or mild dyskaryosis and the effect of koilocytosis on the outcome. Thirteen per cent of women with cervical smears showing BNC had high-grade cervical intraepithelial neoplasia (CIN). In contrast, 28% of women with cervical smears showing mild dyskaryosis had high-grade CIN. The presence of koilocytosis (24% for borderline smears and 34% for mild dyskaryotic smears) did not appear to influence the risk of developing high-grade CIN. Our results suggest that the simultaneous implementation of the British Society for Clinical Cytology proposed terminology and the colposcopy guidelines from the British Society for Colposcopy and Cervical Pathology could have an impact on colposcopy services.     

Progression of abnormal MIB-1 staining patterns of reserve cells in cervical smears from women ultimately developing high grade squamous intraepithelial lesions

OBJECTIVE: To assess, in a longitudinal study in women diagnosed with high grade squamous epithelial lesion (HSIL), the progression over time of proliferative activity in reserve cells using population screening cervical cytology specimens. STUDY DESIGN: Twenty consecutive, unselected patients with HSIL lesions were part of the national cervical screening program. From the archives, for each patient, the last prior normal population screening smear was included in the study. Concurrent sets of cervical smears from 80 age-matched women without pathology formed the controls. The original slides were stained using MIB-1 monoclonal antibody. The fraction of MIB-1-positive reserve cells was assessed using systematic random sampling and running progressive means assessment to ensure a sufficient sample size. RESULTS: The proliferation fraction in reserve cells of HSIL patients was significantly raised (mean, 65.0%; range, 53.5-94.1%; p < 0.01) as compared with that in concurrent controls (mean, 12.8%; range, 1.9-45.4%). Prior smears from HSIL patients, although without morphologic abnormalities, had abnormally high proliferation fractions (mean, 59.1%; range, 1.0-94.7%), significantly raised over those from concurrent controls (mean, 9.4%; range CONCLUSION: In population-based cervical smear screening, HSIL patients already have abnormally raised proliferation fractions of reserve cells, even without morphologic changes in squamous cells, 1-5 (mean, 3.6) years prior to diagnosis.     

Usefulness of AgNOR technique and CEA expression in atypical metaplastic cells from cervical smears

OBJECTIVE: To evaluate the proliferating capacity of atypical metaplastic cells in cervical smears by AgNOR technique and image analysis and investigate the probable relation with squamous intraepithelial lesions (SIL) using immunocytochemical assay for carcinoembryonic antigen (CEA). STUDY DESIGN: Eight cervical smears were stained with Papanicolaou stain for diagnosis of atypical metaplastic cells. After removal of the stain the smears were processed with a silver colloidal solution and the AgNOR area determined by image cytometry. Differences in the mean AgNOR protein area between reactive metaplastic cells and controls were tested by Student's t test. The CEA was investigated by immunocytochemical staining in smears with atypical metaplastic cells and smears from high-grade squamous intraepithelial lesions (HSIL). RESULTS: The mean AgNOR areas from atypical metaplastic cells (4.55, 6.66, 4.68, 5.30, 4.97, 6.20, 6.28, and 7.35) were significantly greater those that of intermediate metaplastic cells and cells from low-grade squamous intraepithelial lesions (LSIL) (0.77, 0.99, and 0.82, respectively). The atypical metaplastic cells showed values of mean AgNOR area intermediate between that of basal cells (3.28) and HSIL cells (7.73) or neoplastic cells (16.12). The CEA was strongly expressed by the atypical metaplastic cells. CONCLUSION: The expression of CEA in the atypical metaplastic cells underlies the probable relation to SIL. Although the organizer region areas raised high values, it would be necessary to use a greater number of cases to define whether the AgNOR area is indicative of the proliferative activity of the atypical metaplastic cells.     

Canonical analysis of cells in normal and abnormal cervical smears

Over 4,000 cells from 105 normal and 96 abnormal uterine cervical scrapes were prepared according to the UCLA monolayer procedure, stained by a routine Papanicolaou method and visually classified by two cytopathologists and a technologist into seven classes: parabasal, metaplastic, mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ and invasive carcinoma. Canonical analysis was used to correlate effects-coded class membership variables with 23 cell features derived from digital image analysis. In general, nuclear texture measures derived from linear combinations of run-length correlations along with features derived from a Markov transitional probability matrix provided the best predictors of cell class. After cells were divided into benign (moderate dysplasia or less) and malignant (severe dysplasia or worse) groups, discriminant analysis correctly classified 84% of the benign cells and 91% of the malignant cells.     

An audit of cervical smears reported to contain atypical glandular cells

The terminology and classification system for the reporting of cervical smears is currently under review. However, evidence on which to base the reporting of atypical cervical glandular cells is lacking. This audit of glandular atypia reporting in cervical smears provides evidence to support a three-tier sub-classification system for cervical glandular atypia. The three sub-classifications are distinct with respect to their positive predictive values and to the cell type of the abnormality as confirmed by histology and therefore relate to further clinical investigation.     

Cost analysis of PAPNET-assisted vs. conventional Pap smear evaluation in primary screening of cervical smears

OBJECTIVE: To assess the difference in costs between PAPNET-assisted and conventional microscopy of cervical smears when used as a primary screening tool. STUDY DESIGN: We performed time measurements of the initial screening of smears by four cytotechnologists in one laboratory. Time was measured in 816 conventionally screened smears and in 614 smears with PAPNET-assisted screening. Data were collected on the components of initial screening, clerical activities and other activities in the total work time of cytotechnologists in the routine situation and on resource requirements for both techniques. RESULTS: PAPNET saved an average of 22% on initial screening time per smear. Due to costs of processing and additional equipment, the costs of PAPNET-assisted screening were estimated to be $2.85 (and at least $1.79) higher per smear than conventional microscopy. The difference in costs is sensitive to the rate of time saving, the possibility of saving on quality control procedures and the component of the initial screening time in the total work time of cytotechnologists. CONCLUSION: Although PAPNET is time saving as compared with conventional microscopy, the associated reduction in personnel costs is outweighed by the costs of scanning the slides and additional equipment. This conclusion holds under a variety of assumptions. Using PAPNET instead of conventional microscopy as a primary screening tool will make cervical cancer screening less cost-effective unless the costs of PAPNET are considerably reduced and its sensitivity and/or specificity are considerably improved.