Pap smears in women with endometrial carcinoma

OBJECTIVE: To correlate Pap smear findings with the histology of endometrial carcinoma and stage of the disease. STUDY DESIGN: Between 1995 and 1998, 76 women with endometrial carcinoma, having had Pap smears done within two to three months of hysterectomy at Memorial Sloan-Kettering Cancer Center, formed the basis for this study. All Pap smears and histologic sections were reviewed. RESULTS: Thirty-four patients had normal Pap smears (45%), and 42 had abnormal ones (55%). The mean age of the two groups was 65.1 and 65.2 years, respectively. Histologic subtypes included 44 International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid adenocarcinoma (low grade) and 32 high grade carcinomas, including 19 FIGO grade 2 or 3 endometrioid adenocarcinomas, 5 papillary serous carcinomas (PSC), 2 clear cell carcinomas (CC), 1 adenosquamous carcinoma, 3 endometrioid adenocarcinomas mixed with PSC and 2 endometrioid adenocarcinomas mixed with CC. The proportions of patients with low and high grade tumors with abnormal Pap smears were 43% (19/44) and 72% (23/32), respectively (P=.01). The proportions of patients with abnormal Pap smears and no myometrial invasion, invasion of <50% and >50% myometrial thickness were 40% (8/20), 62% (26/42) and 57% (8/14), respectively (P =.27). Vascular invasion was identified in 56% (9/16) of patients with abnormal Pap smears and in 55% (33/60) of patients with normal ones (P = .93). The proportions of patients having abnormal Pap smears with stage I and stages II, III or IV disease were 48% (30/62) and 86% (12/14), respectively (P =.01). CONCLUSION: Although the Pap smear is not a sensitive screening test for endometrial cancer and a negative Pap smear does not rule it out, this study revealed that abnormal Pap smears are significantly associated with high grade of tumor and stage II-IV endometrial carcinoma. However, they are not associated with patient age, depth of myometrial invasion or vascular invasion.     

Outcomes of pregnant patients with Pap smears classified as atypical glandular cells

J. Slama, P. Freitag, P. Dundr, J. Duskova, D. Fischerova, M. Zikan, I. Pinkavova and D. Cibula
Outcomes of pregnant patients with Pap smears classified as atypical glandular cells Objectives: The incidence of cervical cancers increases with age. Due to the trend of increasing age of first pregnancy, abnormal Pap smears including those classified as atypical glandular cells (AGC) are being found more often in early pregnancy. Once invasive cancer is excluded, conservative management of squamous intraepithelial lesions (SIL) in pregnancy is considered safe; however, optimal management of AGC is not well established. The aim of our study was to evaluate the outcome of patients with AGC diagnosed from smears during pregnancy. Methods: The study included 17 patients referred to us in early pregnancy with Pap smears reported as AGC: 11 not otherwise specified (AGC‐NOS), five favour neoplasia (AGC‐FN) and one adenocarcinoma in situ (AIS). Thirty‐one with high‐grade SIL (HSIL) Pap smears confirmed on punch biopsy in early pregnancy comprised a control group. Human papillomavirus (HPV) positivity was found in seven patients with persistent AGC‐NOS (including all four who had CIN3 postpartum). All the women were initially examined by expert colposcopy and those with AGC‐FN or AIS smears also by transrectal ultrasound to exclude invasive endocervical cancer. Follow‐up controls were carried out every 8–12 weeks and, if there were no signs of progression, revaluation was scheduled 6–8 weeks after delivery. Results: The mean age of the women was 31.4 years. Conization in one patient in the study group was performed in the 16th week of pregnancy due to colposcopic signs of microinvasive squamous cell cancer confirmed on histology. Progression to invasive cancer was not found in any of the other 16 patients in the study group or in the control group. Cervical intraepithelial neoplasia or AIS was confirmed postpartum by conization or punch biopsy in 47.1% (8/17) of patients in the study group and, in 77.4% (24/31) of patients in the control group. Conclusions: Conservative management of women with AGC in pregnancy is safe where invasive cancer is excluded. As histological verification of glandular pre‐cancerous lesions by punch biopsy is not reliable and the postpartum regression rate cannot be determined precisely, conization should be performed in all cases with AGC‐FN or AIS. Triage of persistent AGC‐NOS with HPV testing is useful in distinguishing significant underlying lesions.     

Benign cellular changes in Pap smears. Causes and significance

OBJECTIVE: We reviewed consecutive cases classified as benign cellular changes (BCC) over a four-month period. STUDY DESIGN: Cases classified as BCC were retrieved from the cytology files. A search was carried out to identify the previous Pap smears and concomitant cervical biopsies. RESULTS: One thousand one hundred three cases (23% of our gynecologic smears) were classified as BCC. Ninety-two patients (8.3%) underwent concurrent cervical biopsies. Specific infections accounted for 8% of BCC cases; reactive changes accounted for 92%. Of the biopsy specimens, 8.3% had no significant pathologic change. The most common biopsy diagnoses were cervicitis (31.5%), immature squamous metaplasia (16.3%) and reserve cell hyperplasia (10.8%). Miscellaneous benign diagnoses accounted for 21.7%. Cervical intraepithelial neoplasia (CIN) 1/human papillomavirus (HPV) was present in 14% of cases. All patients with biopsy diagnoses of CIN 1 had at least two previous abnormal Pap smears. Previous biopsy reports were available for review in 127 (12%) of the 1,103 patients. Of these 127 cases, 53.5% had a previous diagnosis of CIN/HPV; 9.4% had invasive carcinoma. A benign diagnosis was reported in 36.5%. CONCLUSION: The majority of BCC cases are due to reactive and inflammatory processes. In patients with a previous history of CIN, BCC may be of some significance. In patients with no significant prior cervical abnormalities, a Pap smear classified as BCC represents a reactive process.     

Significance of AGUS Pap smears in pregnant and postpartum women

OBJECTIVE: To study the clinical significance of atypical glandular cells of undertermined significance (AGUS) in pregnant and postpartum women. STUDY DESIGN: We evaluated 35 women who were pregnant (30) or within three months postpartum (5) and had a cytologic diagnosis of AGUS. Twenty-seven (77%) patients had follow-up: 17 (63%) patients underwent colposcopic examination and biopsy, and 10 (37%) had repeat Pap smears. Eight patients were lost to follow-up. RESULTS: Five (29.4%) patients had a squamous intraepithelial lesion (SIL), including three high grade and two low grade, on subsequent biopsy. The remaining (70.6%) patients had benign pathology, which included 5 chronic cervicitis, 4 endocervical and/or endometrial polyps, 2 Arias-Stella reaction and 1 microglandular hyperplasia. Among the patients with repeat Pap smears, two had persistent AGUS/atypical squamous cells of undetermined significance, the remaining cases were within normal limits. CONCLUSION: Pregnancy-related changes may present with glandular atypia. In addition, about one-third of pregnant and postpartum women with a diagnosis of AGUS had SIL on subsequent biopsy; that rate is similar to that in nonpregnant women. Therefore, pregnant women with a cytologic diagnosis of AGUS should be followed closely.     

Accuracy of a slide profiler for endocervical cell detection in no-further-review conventional Pap smears

OBJECTIVE: To evaluate the reliability of the Focal-Point slide profiler (TriPath Care Technologies, Burlington, North Carolina, U.S.A.) in determing the absence of endocervical cells in conventional Pap smear slides. STUDY DESIGN: A consecutive series of conventional Pap smears, designated by FocalPoint as requiring no further review (NFR) and as lacking endocervical cells, was manually screened to determine the true presence or absence of endocervical cells. These results were compared to those obtained by FocalPoint. RESULTS: From January 1, 2000, to December 31, 2001, FocalPoint indicated that 797 NFR slides did not contain endocervical cells. In contrast, manual screening revealed that 504/797 (63.2%) did contain endocervical cells. CONCLUSION: The reliability of a negative FocalPoint determination for endocervical cells is limited. Manual screening of NFR slides designated by the instrument as lacking endocervical cells appears to be necessary.     

Utility of the in situ detection of HPV in Pap smears diagnosed as within normal limits.

OBJECTIVE: To determine the clinical significance in normal Pap smears of HPV detection as determined by Hybrid Capture (HC) and in situ hybridization analyses. STUDY DESIGN: We studied 135 consecutive Pap smears as well as 46 other smears from high-risk patients each initially diagnosed as within normal limits. RESULTS: The 135 "normal" Pap smears were rescreened, and 6 (4%) where found to be either ASCUS or SIL. In the remaining 129 cases, HPV DNA was detected in 0% and 9%, respectively, using in situ hybridization and HC I. Upon rescreening the high-risk patients, nine (20%) were reclassified as having SIL/ASCUS; each was in situ hybridization positive, and eight were HC positive; six (67%) of these women developed SIL on follow-up. In the 37 Pap smears in high-risk women still within normal limits after manual rescreening, HPV was detected in 2% by in situ hybridization and 46% by HC; 6% of the HC-positive women developed SIL on follow-up. CONCLUSION: In situ hybridization rarely detects HPV in Pap smears diagnosed as within normal limits after manual rescreening. In situ hybridization is very effective in detecting rare, atypical cells in Pap smears diagnosed as within normal limits and, in a high-risk population, is predictive of SIL on clinical follow-up.     

Extrauterine malignancies. Role of Pap smears in diagnosis and management.

OBJECTIVE: To further elucidate the cytologic manifestations of extrauterine malignancies, to evaluate their possible distinction from primary cervical malignancies and to analyze their clinical significance and role in staging. STUDY DESIGN: Papanicolaou (Pap) smears in 33 cases with abnormal cells originating in histologically proven extrauterine carcinomas were evaluated. These cases came from the files of the Medical College of Pennsylvania and Lankenau Hospitals. RESULTS: Ovary, gastrointestinal tract and breast were the three most frequent primary sites, accounting for 28 of the 33 cases (85%). The histologic types encountered were adenocarcinoma, 29 cases (88%); mucoepidermoid carcinoma, 1 (3%); small cell carcinoma, 1 (3%); cloacogenic carcinoma and large cell lymphoma, 1 (3%). The following diagnoses were rendered at the time of initial evaluation: adenocarcinoma consistent with metastasis, 21 cases; carcinoma, primary versus metastatic, 2; adenocarcinoma, suspicious for endometrial primary, 2; suspicious for carcinoma, 1; and atypical glandular cells, 7. CONCLUSION: The yield for positive Pap smear diagnoses in extrauterine malignancies is best in patients with an established diagnosis of a primary neoplasm. The degree of tumor differentiation and extent of tumor involvement did not appear to correlate with diagnostic yield. There appeared to be no statistically significant association of tumor diathesis with primary versus metastatic carcinoma and presence or absence of documented local involvement of the endometrium, cervix or vagina. Therefore, while Pap smears can serve as a diagnostic tool in the evaluation of extrauterine malignancies, they are best utilized as an adjunct to tumor staging and patient management.     

Ultrastructure of Endosymbiotic Chlorella in a Vorticella

SYNOPSIS Observations were made on the ultrastructure of a species of Vorticella containing endosymbiotic Chlorella. The Vorticella , which were collected from nature, bore conspicuous tubercles of irregular size and distribution on the pellicle. Each endosymbiotic algal cell was located in a separate vacuole and possessed a cell wall and cup-shaped chloroplast with a large pyrenoid. The pyrenoid was bisected by thylakoids and surrounded by starch plates. No dividing or degenerating algal cells were observed.     

P16(INK4a) immunocytochemistry in liquid-based cytology samples in equivocal Pap smears: added value in management of women with equivocal Pap smear

OBJECTIVE: To test whether p1l6(INK4a) immunocytochemistry (ICC) in liquid-based cytology (LBC) is useful with colposcopy in abnormal Pap smears. STUDY DESIGN: A series of 248 women with abnormal Pap smear were analyzed for oncogenic (HR) human papillomavirus (HPV) types using the Hybrid Capture II assay and for p16(INK4a) expression using ICC on cervical samples in PreservCyt liquid media. Colposcopic and loop electrosurgical excision procedure (LEEP) cone biopsy were the gold standard. RESULTS: p16(INK4a) ICC did best as predictor of high-grade squamous intraepithelial lesion, with OR 12.18 (2.72-54.57) (p = 0.0001), showing 88.2% sensitivity (SE), 61.9% specificity (SP), 14.6% positive predictive value (PPV) and 98.6% negative predictive value (NPV). In sorting discrepant cases, p16(INK4a) ICC results in 100% SE and 100% NPV in detecting cervical intraepithelial neoplasia (CIN) 2 lesions among Pap+/biopsy- women. In atypical squamous cells undetermined significance (ASCUS) cytology, adding p16(INK4a) ICC improves specificity of colposcopy from 27.3% to 81.8% and PPV from 42.8% to 71.4%. Best performance is obtained with p16(INK4a) ICC and colposcopy: 83.3% SE, 81.8% SP, 71.4% PPV and 90.0% NPV. CONCLUSION p16(INK4a) is useful in sorting clinically relevant discrepant cases, and p16(INK4a) ICC significantly improves SP and PPV of colposcopy in management of ASCUS cytology.     

Detection of false negative Pap smears by rapid reviewing. A metaanalysis

OBJECTIVE: To explore the diagnostic validity of rapid reviewing (RR) as a quality control method in cytologic laboratories. STUDY DESIGN: Fourteen studies dealing with the detection of false negative Pap smears by RR were included in a metaanalysis. RESULTS: The overall additional yield of positive slides, expressed as the percentage of all reviewed slides, is: 0.18% (95% confidence interval [CI]: .14-.21) for all cytologic abnormalities; 0.07% (CI: .05-.09) for squamous intraepithelial lesions (SIL) and 0.02% (CI: .01-.03) for high grade SIL. The false negative rate of primary screening, evaluated by RR, was 2.0% (CI: 1.5-2.6) for all cytologic abnormalities and 1.4% (CI: .8-2.1) for high grade SIL. The specificity of rapid rescreening was estimated as 97.2% (CI: 96.4-98.1). The positive predictive value of suspicion at RR is about 8.8%. Seven references contained historical data on full rescreening of a random sample of slides reported originally as negative. The results were also pooled and compared with RR. Complete rescreening is more sensitive, but if applied on only 10% of the negative workload, it would yield, on average, 4.7 times fewer extra positives, 5.6 times fewer SIL and 7.9 times fewer high grade SIL in comparison with RR of all sides. CONCLUSION: RR of all smears initially reported as nonpositive is a more effective and a fortiori a more cost effective quality control method in comparison with full rescreening of a 10% random sample.     

Comparison of Carnoy's solution and 96% ethyl alcohol fixation in bloody Pap smears

OBJECTIVE: To compare 2 methods of fixation in bloody Pap smears with Carnoy's solution and 96% ethyl alcohol. STUDY DESIGN: After observation of contact bleeding, 2 samples were prepared from cervical cells with conventional Pap smear. One sample was fixed in 96% ethyl alcohol and another sample was fixed in Carnoy's solution. RESULTS: Of 450 slides, 410 were selected for study. In study of cell adequacy, diagnosis of squamous cells and glandular cells was better in Carnoy's-fixed slides. Blood contamination of slides was reduced in Carnoy's-fixed slides (13.85% vs. 49.51%), and clearance of slides was increased in Carnoy's-fixed slides. Diagnosis of inflammatory cells and pathogenic microorganisms in was increased in Carnoy's-fixed slides, but no difference was seen in diagnosis of epithelial cell and glandular cell abnormalities. CONCLUSION: Carnoy's solution can be used as an effective fixative in bloody smears in conventional Pap tests.     

Clinical significance of a cytologic diagnosis of atypical glandular cells, favor endometrial origin, in Pap smears

OBJECTIVE: To evaluate the significance of a diagnosis of atypical glandular cells, favor endometrial origin (AGC-EM), using cytohistologic correlation. STUDY DESIGN: A retrospective search identified 90 cervicovaginal smears (vaginal pool) with a diagnosis of AGC-EM, in 2 tertiary care medical centers between January 1998 and December 2002. RESULTS: Forty-six (51%) were conventional preparations and 44 (49%) were liquid-based monolayers (SurePath, TriPath Imaging Inc., Burlington, North Carolina, U.S.A.). Follow-up biopsies were available in 55 of 90 (61%) cases, 15 of 90 (17%) cases had cytology follow-up, and 20 of 90 (22%) were lost to follow-up. The patients ranged in age from 30 to 86 years (mean, 56); 56 of 90 (62%) were > 50 years. Among the patients who underwent biopsy, 22 (40%) had a clinically significant lesion, including 10 (18%) endometrial adenocarcinomas, 8 (15%) endometrial hyperplasias and 4 (7%) high grade squamous intraepithelial lesion/squamous cell carcinoma, nonkeratinizing type. The remaining 33 patients had benign histology, including benign endometrium, endometrial polyp, tubal metaplasia, cystic endometrial atrophy and cervical microglandular hyperplasia. Of the patients with cytologic follow-up, 2 had Pap smears showing atypical squamous cells of undetermined significance, while the remainder had negative results. CONCLUSION: In our study population, 40% (22 of 55) of women who underwent biopsy following a diagnosis of AGC-EM had significant uterine lesions, with the majority of the lesions endometrial in origin. Patients with a diagnosis of AGC-EM, especially those > 50, should be followed closely, and endometrial sampling should be included in their initial workup.     

Reduced alcohol use in the staining of Pap smears: a satisfactory low-cost protocol for cervical cancer screening

OBJECTIVE: To describe a low-cost Papanicolaou staining procedure that can be applied to conventional and monolayer gynecologic preparations. STUDY DESIGN: The amount of alcohol consumed in the procedure, which normally accounts for > 80% of the cost of processing, was reduced drastically by (1) using only 1 modified cytoplasmic counterstain (EA type), thereby (2) reducing the number of alcohol rinses by over half Orange-G dye is omitted. RESULTS: The resultant effect of the modified staining protocol is quite satisfactory and attractive to screening eyes: nuclear details are sharp and crisp, while the cytoplasm contains transparent differential staining with blue-green and pink. CONCLUSION: A reduction in the cost of staining should encourage cervical cancer screening, especially in developing countries, where cost is a limiting factor, thus making it possible for more women to be screened without increasing the cost of the program.     

Value of histiocyte detection in Pap smears for predicting endometrial pathology. An institutional experience

OBJECTIVE: To determine the clinical implications of the finding of histiocytes in Pap smears in 1 patient population. STUDY DESIGN: The medical records and Pap smears which the presence of histiocytes was mentioned in the diagnosis between August 1996 and August 2001 were reviewed in conjunction with follow-up surgical findings. The positive predictive value (PPV) for significant endometrial pathology for the isolated finding of histiocytes on Pap smear was determined. RESULTS: Of the 238,225 women screened over a 60-month period, 325 were reported to have histiocytes in their Pap smears. Of them, 238 (73.2%) had subsequent endometrial sampling, hysterectomy or both, and follow-up Pap smears. Two hundred seven smears (87%) failed to disclose endometrial pathology. Thirty-one cases (13%) resulted in significant histopathologic findings, including 12 uterine malignancies, 8 endocervical polyps, 7 endometrial polyps, 2 submucosal leiomyomata, 1 simple hyperplasia without atypia and 1 case of tamoxifen-related changes. Upon review of the clinical records, 58% (18/31) of those patients had other significant clinical and/or cytologic findings. Five of the 18 patients (27.8%) had associated postmenopausal bleeding, 11 had additional abnormal Pap smear findings (atypical glandular cells, 6/18, or 33.3%; endometrial cells, 5/18, or 27.8%), and another 2 had both postmenopausal bleeding and atypical glandular cells (2/18, or 11.1%). The PPV for significant uterine pathology for women with the isolated finding of histiocytes on a Pap smear was 5.5% and 60% with additional clinical and/or Pap smear findings. The PPV for endometrial cancer was 1.3% in women with the isolated finding of histiocytes on a Pap smear but 20% for women with histiocytes and additional clinical/or Pap smear findings. CONCLUSION: Based on the findings of this study and recently published data, we conclude that the isolated finding of increased histiocytes in the absence of postmenopausal bleeding, endometrial cells or atypical glandular cells on a Pap smear is a poor indicator of uterine disease.     

Accuracy of liquid-based Pap tests: comparison of concurrent liquid-based tests and cervical biopsies on 782 women with previously abnormal Pap smears

OBJECTIVE: To evaluate the diagnostic performance of a liquid-based Pap test, the ThinPrep Pap test (TP) (Cytyc Corp., Boxborough, Massachusetts, U.S.A.), by comparing concurrent TP and cervical biopsy results on 782 patients who were referred for colposcopy because of previously abnormal conventional Pap smears (CPs). STUDY DESIGN: The ability of TP diagnoses of atypical cells of undetermined significance (ASC-US) and squamous intraepithelial lesions (SILs) to predict biopsy diagnoses of cervical intraepithelial neoplasia (CIN) was analyzed using chi2 and McNemar tests. RESULTS: The rate of agreement between diagnoses of SIL by TP and CIN by biopsy was 74.7%. ASC-US accounted for 16.0% of TP diagnoses. ASC-US had biopsy diagnoses of CIN 1 in 60% and CIN 2/3 in 12.8% of cases. For TP diagnosis of low grade SIL, biopsy diagnoses of CIN 2/3 were found in 13.5% of cases. For TP diagnoses of ASC-US and higher, the proportions of TP and cervical biopsies in comparable diagnostic categories were statistically significant (p < 0.001), with TP having sensitivity of 89.4% and positive predictive value of 89.7% for the detection of CIN. The false positive rate for TP was 8.1%, but rescreening confirmed the presence of abnormal cells in 51 of 63 (81.0%) cases of ASC-US or higher having negative biopsies. TP had a false negative rate of 8.3% and negative predictive value of 61.3%. Rescreening showed that most (77.6%) of the false negative TP specimens failed to have abnormal cells on the slides. CONCLUSION: For patients having previously detected cervical abnormalities by CP, concurrent TP demonstrated the following: (1) that it has high diagnostic accuracy for SIL, (2) that ASC-US was diagnostically equivalent to LSIL, and (3) that false negative TP for SIL can be attributed primarily to sampling rather than cytotechnologists' screening errors.