Severe cervical glandular cell lesions and severe cervical combined lesions: predictive value of the papanicolaou smear

BACKGROUND: The purpose of the current study was to determine the accuracy of routinely screened cervical smears to predict a glandular cell lesion in histologically confirmed cases of cervical adenocarcinoma in situ (AIS), invasive adenocarcinoma (ADCA), adenosquamous carcinoma (ADSQCA), and severe combined glandular and squamous cell lesions. METHODS: Between 1989-2000, a total of 1,141 women with a histologic diagnosis of cervical AIS, ADCA, ADSQCA, and combined lesions (glandular cell lesion with a coexistent squamous cell lesion) were registered in the Dutch National Pathology Archive (PALGA). In 1054 of these 1,141 histologic cases, an additional conventional Papanicolaou (Pap) smear diagnosis was registered from the same patient. Material was evaluated with regard to the accuracy of cytologic diagnosis, the percentage of combined lesions, the mean age of the patients, and the time interval between AIS and ADCA. RESULTS: Of 1,141 registered histologic cases, 57.5% were registered as having an "intraepithelial" lesion, whereas 42.5% were registered as having an "invasive" process. A combined process was diagnosed in 63.2% of cases. From the same patients, a cytologic diagnosis of a severe cervical epithelial lesion was registered in PALGA for 91.2% (n = 961) of 1054 cases. A cytologic registration of a severe glandular cell lesion (with or without a squamous cell component) was made in 547 cases (51.9%). Prediction of a severe glandular cell lesion on the Pap smear was found to be more accurate in cases of histologically confirmed pure glandular cell abnormalities than in cases with a histologic diagnosis of a combined lesion. The cytologic prediction was found to be correct in 75.2% of cases of pure AIS and 47.3% of cases of AIS with coexistent high-grade squamous intraepithelial lesion (HGSIL) (cervical intraepithelial lesion [CIN] type 2 [CIN 2] or CIN 3). The mean ages of the patients with AIS and AIS + HGSIL were 37.3 years and 34 years, respectively, whereas the mean age of the patients with ADCA and ADCA + HGSIL was 41.9 years and 38.1 years, respectively. The interval between the average ages of patients with AIS and ADCA and those with AIS + HGSIL and ADCA + HGSIL was 4.6 years and 4.1 years, respectively. CONCLUSIONS: On the basis of a data search of the PALGA registry, it can be concluded that in a relatively large number of cases a severe cervical glandular cell lesion was not diagnosed on the Pap smear. Furthermore, data demonstrated that the prediction of a glandular abnormality is less accurate in cases of combined squamoglandular cell lesions than in pure glandular cell lesions.     

Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing: a comparative study using simultaneously sampled histology materials

BACKGROUND: In cervical lesions, the overexpression of p16 is reported to be closely associated with high-risk human papillomavirus (HPV) infection. The objective of the current study was to confirm the usefulness of liquid-based cervical specimens for p16 staining as well as tissue sections. METHODS: A total of 98 patients with cervical lesions were entered into the current study. After the cytologic examination using liquid-based cervical smears, the same slides were immunostained for p16 and were compared with slides of simultaneously obtained, immunohistologically stained tissue sections. Moreover, the status of the HPV infection was examined by polymerase chain reaction using residual cytologic samples. RESULTS: Using liquid-based Pap smears, 98 cases were diagnosed as atypical squamous cells of undetermined significance (38 cases), low-grade squamous intraepithelial lesion (12 cases), high-grade squamous intraepithelial lesion (HSIL) (33 cases), and invasive carcinoma (15 cases). The concordance rate between the cytologic and histologic diagnoses was found to be higher in high-grade lesions compared with low-grade lesions. Immunohistochemistry revealed that all HSIL and invasive carcinoma cases contained p16-positive cells in the liquid-based Pap smears and diffuse p16 staining was observed in all high-grade lesions with greater than CIN Grade 3 cervical intraepithelial neoplasia except for two adenocarcinoma cases. Of the 98 cases, 60 were found to be positive for high-risk HPV and 55 of these 60 HPV-positive cases were found to be p16 positive on cytologic examination. There were 16 cases that demonstrated marked discrepancies between the cytologic and histologic diagnoses. CONCLUSIONS: The results of the current study confirmed that the immunohistochemical detection of p16 was more sensitive and specific than HPV status in cervical lesions using a liquid-based method as well as tissue samples, suggesting that p16 should be used as a satisfactory biomarker for the primary screening of cervical cytology.     

Use of p63 for distinction of glandular versus squamous lesions in cervicovaginal specimens

BACKGROUND: Differentiating primary glandular from high-grade squamous intraepithelial lesions (HSIL) that involve endocervical glands is not an uncommon diagnostic problem in liquid-based gynecological cytology. Squamous and atypical glandular cell lesions may show similar cytomorphologic features. The aim of this study was to evaluate the use of p63 as a marker of basal and/or squamous cell derivation in this differential diagnosis. METHODS: Of 59,257 liquid-based cervicovaginal specimens collected over a 3-year period, 149 were diagnosed as atypical glandular cells of uncertain significance (AGUS) or adenocarcinoma and had histological follow-up. Ten cases (8AGUS and 2 adenocarcinomas) were proven to be high-grade dysplasia on cervical biopsies and the remaining cases represented glandular pathology. Slides from discrepant cases were stained with p63 antibody. In addition, the authors stained 25 control cases (10 adenocarcinomas, 10 HSIL, and 5 negative cervicovaginal specimens). RESULTS: In all 10 discrepant cases, the abnormal groups originally interpreted as glandular in origin showed a homogeneous strong nuclear staining for p63 that indicated their squamous origin. Nuclei of isolated HSIL cells and basal cells from atrophic smears were also positive for p63. Benign and malignant glandular cells were uniformly negative. Isolated metaplastic, intermediate, and superficial squamous cells were likewise negative for this antibody. CONCLUSIONS: p63 is a useful immunocytochemical marker for differentiating primary glandular pathology from HSIL in cervicovaginal specimens. It also detects isolated HSIL cells ("litigation cells"). This antibody is not expressed in AGUS, adenocarcinoma, or normal glandular cells. p63 stains basal cells and may be a diagnostic pitfall in atrophic cervicovaginal specimens.     

Atypical glandular cells of undetermined significance: clinically significant lesions and means of patient follow-up

BACKGROUND: The clinical significance of atypical glandular cells of undetermined significance (AGUS) remains poorly understood, and patient management is not standardized. The authors evaluated the rate, qualification, and follow-up (FU) findings of AGUS patients. METHODS: Computerized records from the authors' institution were searched from April 1992 to December 1997 for diagnoses of AGUS. Results of cytologic and histologic FU were evaluated up to 48 months of FU. Clinically significant lesions were defined as squamous intraepithelial lesion (SIL), endometrial pathology of hyperplasia or higher, adenocarcinoma in situ (AIS), or invasive adenocarcinoma. RESULTS: AGUS was diagnosed in 92 of 87,632 patients (0.11%). FU data were available from 69 patients, consisting of smears and/or surgical pathology specimens from the cervix, endometrium, or ovary. Forty patients had FU smears only, 13 had histologic FU only, and 16 had both. Seventeen patients (25%; 15 patients with unqualified AGUS and 2 patients with "favor endometrial origin" according to the Bethesda System of AGUS subclassification) had clinically significant lesions: high grade SIL (n = 8 patients), low grade SIL (n = 2 patients), endometrial lesion (n = 5 patients), AIS (n = 1 patient), and invasive cervical adenocarcinoma (n = 1 patient). It is noteworthy that 4 patients with carcinoma (3 patients with AIS and 1 patient with invasive carcinoma) were diagnosed after a long FU (36-48 months). The remaining 13 lesions were detected at first FU (1-24 months). Six lesions were detected on FU smear, whereas 15 were detected histologically (4 lesions were detected in both). CONCLUSIONS: AGUS is associated with clinically significant lesions in 25% of patients who are followed. Most of the lesions were high grade and were detected histologically. Moreover, 4 of 17 lesions were detected after a FU period ranging from 36 months to 48 months. The role of qualifying AGUS needs further study. Cancer (Cancer Cytopathol) Copyright 2000 American Cancer Society.     

Comparative sensitivities of ThinPrep and Papanicolaou smear for adenocarcinoma in situ (AIS) and combined AIS/high-grade squamous intraepithelial lesion (HSIL): comparison with HSIL

BACKGROUND: Despite the historic belief that cytologic screening offers little protection against cervical adenocarcinoma (CAC), there is emerging evidence that, by detecting the precursor lesion, adenocarcinoma in situ (AIS), cervical screening may reduce the incidence of CAC as it has for cervical squamous carcinoma. Because liquid-based cytology is fast replacing the conventional Papanicolaou smear (PS), it is important to establish that it is at least as effective in detecting AIS. METHODS: The authors calculated the sensitivities of PS and ThinPrep (TP) for 100 women with histologic AIS (from 160 PS slides and 60 TP slides), for 94 women with AIS+high-grade squamous intraepithelial lesion (HSIL) (from 151 PS slides and 50 TP slides), and for 558 women with HSIL (from 788 PS slides and 383 TP slides). All smears were taken up to 36 months before the histologic diagnosis. RESULTS: In no category was there a significant difference between PS sensitivity and TP sensitivity. The HSIL category had a significantly higher overall sensitivity than the other categories. However, when sensitivity was defined as cytologic detection of high-grade disease, there was no difference between any of the categories. For the detection of a high-grade glandular lesion, the presence of a concurrent histologic HSIL was associated with reduced sensitivity for the detection of AIS. CONCLUSIONS: The current results indicated that it may prove possible for cervical screening, with either PS or TP, to reduce the incidence of CAC.     

Differential expression of cyclin-dependent kinase inhibitors and apoptosis-related proteins in endocervical lesions

The development of neoplasia is associated with abnormalities of cell cycle control and apoptosis. In this study, a panel of cyclin-dependent kinase inhibitors (CDKIs) and apoptosis-related proteins (p16, p21, p53, Bcl2 and hsp27) was analysed by immunohistochemistry in 91 glandular cervical lesions. A significant increase in p21 and p53 expression occurred from normal cervix (n=11) through endometriosis/tubo-endometrioid metaplasia (TEM) (n=19) and cervical glandular intraepithelial neoplasia (CGIN)/adenocarcinoma in situ (AIS) (n=33) to invasive adenocarcinoma (n=28). p16 showed diffuse strong expression in CGIN/AIS and invasive adenocarcinoma compared with focal expression in some TEM/endometriosis lesions and no expression in normal cervix. Bcl2 was highly expressed in TEM/endometriosis compared with CGIN/AIS and adenocarcinoma. p16 immunostaining discriminated accurately between neoplastic and non-neoplastic cervical lesions, provided that diffuse strong positivity was present. Similarly, diffuse expression of Bcl2 distinguished endometriosis/TEM from CGIN/AIS. These data demonstrate that analysis of CDKIs and apoptosis-related proteins provides useful information in the diagnostic assessment of glandular lesions of the cervix.     

Adenocarcinoma in situ of the cervix

BACKGROUND: The current study examines 1) the sensitivity of detection and 2) sampling and screening/diagnostic error in the cytologic diagnosis of adenocarcinoma in situ (AIS) of the cervix. The data were taken from public and private sector screening laboratories reporting 25,000 and 80,000 smears, respectively, each year. METHODS: The study group was comprised of women with a biopsy diagnosis of AIS or AIS combined with a high-grade squamous intraepithelial lesion (HSIL) who were accessioned by the Western Australian Cervical Cytology Registry (WACCR) between 1993-1998. Cervical smears reported by the Western Australia Centre for Pathology and Medical Research (PathCentre) or Western Diagnostic Pathology (WDP) in the 36 months before the index biopsy was obtained were retrieved. A true measure of the sensitivity of detection could not be determined because to the authors' knowledge the exact prevalence of disease is unknown at present. For the current study, sensitivity was defined as the percentage of smears reported as demonstrating a possible or definite high-grade epithelial abnormality (HGEA), either glandular or squamous. Sampling error was defined as the percentage of smears found to have no HGEA on review. Screening/diagnostic error was defined as the percentage of smears in which HGEA was not diagnosed initially but review demonstrated possible or definite HGEA. Sensitivity also was calculated for a randomly selected control group of biopsy proven cases of Grade 3 cervical intraepithelial neoplasia (CIN 3) accessioned at the WACCR in 1999. RESULTS: For biopsy findings of AIS alone, the diagnostic "sensitivity" of a single smear was 47.6% for the PathCentre and 54.3% for WDP. Nearly all the abnormalities were reported as glandular. The sampling and screening/diagnostic errors were 47.6% and 4.8%, respectively, for the PathCentre and 33.3% and 12.3%, respectively, for WDP. The results from the PathCentre were better for AIS plus HSIL than for AIS alone, but the results from WDP were similar for both groups. For the CIN 3 control cases, the "sensitivity" of a single smear was 42.5%. CONCLUSIONS: To the authors' knowledge epidemiologic studies published to date have not demonstrated a benefit from screening for precursors of cervical adenocarcinoma. However, in the study laboratories as in many others, reasonable expertise in diagnosing AIS has been acquired only within the last 10-15 years, which may be too short a period in which to demonstrate a significant effect. The results of the current study provide some encouraging baseline data regarding the sensitivity of the Papanicolaou smear in detecting AIS. Further improvements in sampling and cytodiagnosis may be possible.     

Comparative sensitivities of ThinPrep and Papanicolaou smear for adenocarcinoma in situ (AIS) and combined AIS/high‐grade squamous intraepithelial lesion (HSIL): Comparison with HSIL

BACKGROUND.

Despite the historic belief that cytologic screening offers little protection against cervical adenocarcinoma (CAC), there is emerging evidence that, by detecting the precursor lesion, adenocarcinoma in situ (AIS), cervical screening may reduce the incidence of CAC as it has for cervical squamous carcinoma. Because liquid‐based cytology is fast replacing the conventional Papanicolaou smear (PS), it is important to establish that it is at least as effective in detecting AIS.

METHODS.

The authors calculated the sensitivities of PS and ThinPrep (TP) for 100 women with histologic AIS (from 160 PS slides and 60 TP slides), for 94 women with AIS+high‐grade squamous intraepithelial lesion (HSIL) (from 151 PS slides and 50 TP slides), and for 558 women with HSIL (from 788 PS slides and 383 TP slides). All smears were taken up to 36 months before the histologic diagnosis.

RESULTS.

In no category was there a significant difference between PS sensitivity and TP sensitivity. The HSIL category had a significantly higher overall sensitivity than the other categories. However, when sensitivity was defined as cytologic detection of high‐grade disease, there was no difference between any of the categories. For the detection of a high‐grade glandular lesion, the presence of a concurrent histologic HSIL was associated with reduced sensitivity for the detection of AIS.

CONCLUSIONS.

The current results indicated that it may prove possible for cervical screening, with either PS or TP, to reduce the incidence of CAC. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

The histologic diagnosis of adenocarcinoma in situ and related lesions of the cervix uteri. Adenocarcinoma in situ

Seventy-two cases of in situ adenocarcinoma (AIS) of the cervix were reviewed. Forty-five cases had associated cervical intraepithelial neoplasia and 20 cases had changes of wart virus infection. Five cases had associated microinvasive squamous cell carcinoma and one cases showed frankly invasive squamous cell carcinoma (SCC). Of the 72 cases, 41 showed an endocervical type of AIS and three cases an endometrioid type. There was no case of pure intestinal type AIS. Twenty-eight cases showed a mixed pattern. Architectural patterns characterized by tunnel clusters, cribriform glands, glandular budding and papillary formations were assessed. Most cases showed varying combinations of these patterns but in ten cases significant changes were absent. Both cellular apoptosis and mitotic activity were seen in varying degrees in all cases of AIS. The significance of these and other features of AIS are discussed as well as the conditions involved in the differential diagnosis.     

Can Adenocarcinoma in situ of the Uterine Cervix be Predicted before Cervical Conization?

This study was undertaken to determine the effectiveness of the Papanicolaou (Pap) smear, colposcopicallydirectedbiopsy (CDB), and endocervical curettage (ECC) in preconization detection of adenocarcinoma in situ (AIS)of the uterine cervix. Women, whose cervical conization specimens contained adenocarcinoma in situ without anyassociated invasive lesion at Chiang Mai University Hospital between March 1998 and March 2006, were reviewed.During the study period, fifty-one women who matched the study inclusion were identified. Glandular abnormalitywas detected by Pap smears in 22 women (43.1%). Among 29 women with squamous lesions on Pap smears, 9additional glandular abnormalities were detected on CDB and/or ECC. In total, glandular abnormality was suspectedin 31 women (60.8%) preoperatively. According to the histological type of AIS, glandular abnormality suspectedfrom preoperative evaluation was noted in 20 women (70.4%) who had pure AIS. Among women with mixed AIS/HSIL, only 12 women (50.0%) had preoperative evaluation suggesting glandular abnormality. These data demonstratethat the sensitivity of combining Pap smear, CDB and/or ECC in detecting glandular lesions before conizationcontaining AIS appears to be suboptimal. Further study concerning the improvement of detecting AIS before conizationis warranted to select the most appropriate diagnostic conization method for such lesions.     

Adenocarcinoma in situ of the uterine cervix: screening and diagnostic errors in Papanicolaou smears

BACKGROUND: Little attention has been given to the reasons for failure to detect adenocarcinoma in situ (AIS) of the uterine cervix in Papanicolaou (Pap) smears. In the current study, the authors examined a series of screening or diagnostic errors in cases in which the final histologic diagnosis was either AIS or AIS combined with a high-grade squamous intraepithelial lesion (AIS + HSIL). METHODS: Smears obtained in the 3 years before histologically proven AIS or AIS + HSIL was diagnosed and within a specified 6-year period (1993-1998) were reviewed and reclassified. All were conventional Pap smears. The smears studied were those with a review diagnosis of possible or definite high-grade epithelial abnormality that initially were reported by a cytotechnologist to be negative (screening error) or that were reported by a pathologist to be negative, unsatisfactory, or indicative of a low-grade epithelial abnormality (diagnostic error). A semiquantitative, blinded assessment of the frequency of cytologic criteria for the diagnosis of AIS was made for smears with erroneous diagnoses compared with a series of smears that yielded true-positive findings. RESULTS: Sampling errors, which were defined as cases in which smears did not have sufficient evidence for a diagnosis of possible or definite AIS or HSIL on review, accounted for 35.1% and 36% of all smears from patients with a biopsy diagnosis of AIS and patients with a biopsy diagnosis of AIS + HSIL, respectively. With regard to AIS, there were 3 screening errors and 5 diagnostic errors, accounting for 10.4% of 77 smears. Minimal, poorly preserved material was evident in four smears, including three smears with only one sheet of abnormal glandular cells. In four other smears, there was a moderate amount of adequately preserved glandular material, mainly in large sheets, with varying degrees of crowding and hyperchromasia. With regard to AIS + HSIL, there were 6 screening errors and 6 diagnostic errors, accounting for 13.5% of 89 smears. In those smears, there generally was a moderate amount of abnormal material in the form of crowded groups of suboptimally preserved, hyperchromatic squamous cells. Only two of those smears yielded findings of possible abnormal glandular cells. Only 3 of 20 errors occurred in smears that were examined during the last 3 years of the study. In the semiquantitative assessment, smears with erroneous findings were shown to contain far less abnormal material than true-positive smears and to exhibit a corresponding paucity of diagnostic criteria. CONCLUSIONS: Sampling errors were the main cause of false-negative reports in cases of AIS and AIS + HSIL. The primary factors that contributed to screening or diagnostic errors in AIS were minimal, poorly preserved abnormal material and an overly conservative approach to the assessment of unusual large sheets or aggregates of glandular cells. With regard to AIS + HSIL, most laboratory errors were related to the presence of crowded groups of squamous epithelial cells. There were fewer errors in the last 3 years of the study, raising the possibility of improvement over time.     

Pathology of cervical cancer

Squamous cell carcinoma is the most common malignant cervical tumor, but the incidence of adenocarcinomas has been rising during the past few decades. This article discusses the epidemiology and pathogenesis of the squamous cell carcinoma, its clinical and histologic features, including microinvasive carcinoma, its histologic grade, and variant tumors. The prognostic impact of these features and the differential diagnosis are also covered. The second portion of this article is devoted to the glandular tumors of the cervix, including adenocarcinoma in situ and invasive adenocarcinoma and its variants. The differential diagnosis of these tumors with tumor like glandular lesions is given special attention. Finally, less common malignant cervical tumors are covered, with an emphasis being placed on their significance.     

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.     

Assessment of reflex human papillomavirus DNA testing in patients with atypical endocervical cells on cervical cytology

BACKGROUND: Reflex human papillomavirus (HPV) testing for atypical squamous cells of undetermined significance (ASC-US) has improved the sensitivity and specificity in detecting high-grade squamous dysplasia (cervical intraepithelial neoplasia [CIN]2+). However, to the authors' knowledge there are no guidelines for performing reflex HPV testing in women with atypical endocervical cells (AEC) before colposcopy. This report is of a 5-year experience with reflex HPV testing in women with AEC and assessment of the potential role of reflex HPV testing in guiding subsequent colposcopy-directed cervical biopsy/curettage in a large tertiary care hospital setting. METHODS: All AEC cases cytologically diagnosed from July 2001 to June 2006 were retrieved from the Cleveland Clinic database. The histopathologic diagnoses and the results of HPV testing using the Hybrid Capture 2 (HC-II) method were reviewed. The most severe histopathologic diagnosis was recorded. RESULTS: Of a total 332,470 Papanicolaou (Pap) tests performed, 317 cases of AEC had histopathologic follow-up and reflex testing for high-risk HPV. Histopathologic examination of the 64 HPV-positive AEC cases revealed 18 cases of endocervical adenocarcinoma in situ/adenocarcinoma (AIS+) and 22 cases of CIN2+. Among 253 of the HPV-negative AEC women, AIS+ was found in only 3 cases and CIN2+ in 1 case. Cervical AIS+ was found in 28% of the HPV-positive AEC patients and in only 0.9% of the HPV-negative patients (P<.0001). When the significant glandular (AIS+) and squamous (CIN2+) lesions were combined, 62.5% of the lesions were detected in HPV-positive AEC cases compared with 1.6% in the HPV-negative AEC cases (P<.0001). CONCLUSIONS: Because of a high sensitivity (91.0%) and high specificity (91.2%) in detecting significant cervical lesions, reflex HPV testing for cytologic diagnosis of AEC appears to be a useful ancillary tool in the selection of high-risk patients for colposcopy.     

The utility of p16INK4a and Ki-67 staining on cell blocks prepared from residual thin-layer cervicovaginal material

BACKGROUND: Cell blocks can be prepared from residual thin-layer cervicovaginal (ThinPrep) material and can be used in immunohistochemical staining assays for p16INK4a and Ki-67, which are surrogate markers related to human papillomavirus infection and cell proliferation, respectively. The objectives of the current study were 1) to investigate the feasibility and the role of cell block preparations in identifying significant neoplastic and preneoplastic lesions of the uterine cervix and 2) to assess the feasibility of using p16INK4a and Ki-67 immunohistochemical staining patterns on cell blocks to identify significant preneoplastic cervical lesions. METHODS: Cervicovaginal cytology specimens from 85 patients were analyzed. Cytologic diagnoses based on ThinPrep Papanicolaou test results were as follows: squamous cell carcinoma was diagnosed in 3 specimens, high-grade squamous intraepithelial lesions (HSIL) were diagnosed in 27 specimens, low-grade squamous intraepithelial lesions (LSIL) were diagnosed in 20 specimens, and atypical squamous cells of uncertain significance (ASCUS) were diagnosed in 11 specimens. Diagnoses of negativity for intraepithelial lesions or malignancy (NILM) were made in 24 specimens. Cell block sections were stained with hematoxylin and eosin and were immunostained with antibodies against p16INK4a protein and Ki-67 antigen. RESULTS: The cytomorphologic diagnoses made using cell block preparations were as follows: SCC in 2 specimens, HSIL in 20 specimens, LSIL in 30 specimens, NILM in 32 specimens, and no diagnosis in 1 specimen. In 62 cases (73%), the diagnoses made using cell block preparations were in agreement with the ThinPrep diagnoses. Immunostaining of cell blocks for p16INK4a and Ki-67 exhibited a statistically significant association (P < 0.05) with the presence of significant lesions on either cell block or ThinPrep analysis. CONCLUSIONS: To the authors' knowledge, p16INK4a has not been analyzed previously in ThinPrep cell blocks, and the correlation between Ki-67 expression and cell block diagnoses also has not been reported previously. The current results indicate that cell blocks prepared from residual ThinPrep material represent an additional reliable diagnostic tool in the evaluation of cervical samples. Furthermore, immunohistochemical studies may be helpful in differentiating significant preneoplastic changes from other cervical lesions, such as atrophy.     

Expression of MN/CA9 protein in Papanicolaou smears containing atypical glandular cells of undetermined significance is a diagnostic biomarker of cervical dysplasia and neoplasia

BACKGROUND: Despite the enormous impact that Papanicolaou (Pap) smear screening has had on the incidence of cervical carcinoma in developed countries, there is still an unacceptably high frequency of occurrence of this cancer. In part, this is due to human error associated with cytologic diagnoses of Pap smears. Also, the use of new sampling devices, such as the cytobrush, has increased the complexity of diagnosing benign and neoplastic cervical cytology. This is particularly apparent in the diagnosis of atypical glandular cells of undetermined significance (AGUS). Approximately 40% of AGUS diagnoses have a corresponding significant lesion at biopsy follow-up, and 60% do not. There is clearly a need for an adjunct to cytologic diagnosis that can readily identify AGUS smears that are diagnostic of significant lesions. The authors have identified the MN/CA9 antigen as a strong candidate for an adjunct biomarker. METHODS: A total of 245 Pap smears of all AGUS diagnostic categories with histologic confirmation were studied. The median age of the patients was 39 years. The Bethesda system classification (AGUS-favor reactive, AGUS-not otherwise specified, and AGUS-favor neoplastic) was used. All of the Pap smears were decolorized and immunostained with monoclonal antibody to MN/CA9 antigen by the immunoperoxidase technique. The results of MN/CA9 immunoreactivity were correlated with the histologic data in a semiblinded fashion. RESULTS: The follow-up biopsies showed that a high percentage (70%) of patients had low and high grade cervical intraepithelial neoplasia lesions, respectively (CIN I and CIN II or III). Clinically significant lesions-adenocarcinoma in situ/carcinoma (AIS/CA) and CIN II or III-were found in 50% of the cases. Among these, 11% were AIS/CA. In the three subcategories of AGUS diagnosis, the AGUS-not otherwise specified showed the broadest range of lesions in the follow-up biopsies. Three patterns of MN/CA9 immunoreactivity were observed in the Pap smears: 1) atypical cells, 2) normal endocervical cells only, and 3) all cells negative. All Pap smears that were MN/CA9 positive were histologically confirmed to be clinically significant lesions or CIN I; in addition, there were a very small number (n = 12) of cases of atypia. None of the benign lesions showed MN/CA9 expression in the corresponding Pap smears. Furthermore, the pattern of atypical cell immunostaining identified all cases with significant lesions (AIS/CA and CIN II or III) in the cervices. Conversely, the majority of CIN I cases (82%) and all cases of atypia showed positive immunostaining restricted to normal endocervical cells only. CONCLUSIONS: There is a clear association between MN/CA9 immunostaining of atypical cells and the presence of significant lesions in the cervix. Similarly, there is a clear association between lack of expression of MN/CA9 and the absence of cervical lesions. However, the screen does not allow discrimination between CIN I and atypia. The authors also found that, based on the combined patterns of morphology and immunostaining, they are able to discriminate between AIS and CIN II or III in AGUS Pap smear diagnoses. Thus, expression of the MN/CA9 antigen is indeed a discriminator of significant lesions in AGUS Pap smear diagnoses.     

"See and treat" approach is appropriate in women with high-grade lesions on either cervical cytology or colposcopy

This study was undertaken to evaluate the overtreatment rate of women with abnormal cervical cytology undergoing colposcopy followed by loop electrosurgical excision procedure (LEEP), the so-called "see and treat" approach. Overtreatment was defined as LEEP specimens containing cervical intraepithelial neoplasia (CIN) 1 or less. In this study, medical records of 192 women with abnormal Pap smears undergoing the "see and treat" approach in Chiang Mai University Hospital between October 2008 and October 2010 were reviewed. The preceding Pap smears were as follows: 124 (64.6%) with high-grade squamous intraepithelial lesion (HSIL); 35 (18.2%) with atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H); 20 (10.4%) with low-grade squamous intraepithelial lesion (LSIL); 9 (4.7%) with squamous cell carcinoma (SCCA); and 4 (2.1%) with atypical squamous cells of undetermined significance (ASC-US). Histologic results obtained from loop electrosurgical excision procedure (LEEP) were as follows: CIN 2-3, 106 (55.2%); invasive cancer, 41 (21.4%); CIN 1, 15 (7.8%); adenocarcinoma in situ (AIS), 1 (0.5%); and no lesion, 29 (15.1%). Overall, 22.9% of LEEP specimens contained CIN 1 or less. Significant predictors for overtreatment were type of preceding smears and colposcopic impression. If the "see and treat" approach was strictly carried out in women who had either smears or colposcopic findings revealing high-grade disease, the overtreatment rate was only 7%. Hemorrhagic complication was 6.2% and all could be treated at an outpatient department. In conclusion, the overtreatment rate of the "see and treat" approach in women with various degree of abnormal Pap smears is 23% which would be diminished to the acceptable rate of lower that 10% if strictly performed in those with either smears or colposcopic impressions revealing high-grade abnormality. Peri-operative LEEP complications were mild and acceptable.     

Clinical significance of atypical glandular cells of undetermined significance in postmenopausal women

BACKGROUND: Glandular atypia in Papanicolaou (Pap) smears from postmenopausal women is encountered frequently. This finding can be the result of artifactual alterations such as drying artifacts and inflammatory changes or may represent a squamous or glandular, preneoplastic or neoplastic process. Therefore, it is important to determine the clinical implication of a diagnosis of atypical glandular cells of undetermined significance (AGUS) in postmenopausal patients. METHODS: A total of 30,036 Pap smears were obtained from postmenopausal women between 1995 and 1997. Among these smears, 154 (0.51%) had a diagnosis of AGUS. Follow-up was available for 133 patients (86.4%); 110 patients (82.7%) had histologic follow-up (including cervical biopsy, endocervical [EC] curettage, and/or endometrial [EM] biopsy) and 23 patients (17.3%) had repeat smears. RESULTS: Thirty-six of 110 patients (32.7%) were found to have a clinically significant lesion (defined as a preneoplastic or neoplastic, glandular or squamous lesion) on subsequent histologic follow-up. Nineteen patients (53%) had glandular lesions (15 EM adenocarcinoma [ACA] cases, 2 EC ACA cases, 1 EC adenocarcinoma is situ case, and 1 EM hyperplasia case). Seventeen patients (47%) had a squamous intraepithelial lesion (SIL) (6 cases of low-grade SIL, 9 cases of high-grade [HGIL], and 2 cases of squamous cell carcinoma). Among those patients with repeat Pap smears, five patients had persistent AGUS/atypical squamous cells of undetermined significance and one patient had an SIL. CONCLUSIONS: The incidence of AGUS among postmenopausal patients was similar to that of the general population (0.51% vs. 0.56%; P > 0.05). A significant percentage of these patients were found to have a clinically significant lesion on subsequent follow-up. Furthermore, a majority of these lesions were ACA (53%) or HGSIL (26%). The findings of the current study strongly suggest the need for the close follow-up of postmenopausal patients with a diagnosis of AGUS. Cancer (Cancer Cytopathol) Copyright 2001 American Cancer Society.     

ThinPrep versus conventional Papanicolaou smear in the cytologic follow-up of women with equivocal cervical smears

BACKGROUND: The purpose of the current study was to compare the efficacy of liquid-based cytology and conventional smears in the cytologic follow-up of cases with "atypical squamous cells, cannot exclude a high-grade lesion" (ASC-H) or "atypical glandular cells" (AGC). METHODS: Cytologic follow-up was performed on 214 cases with ASC-H/AGC diagnosis an conventional smears using either ThinPrep (n = 100) or conventional Papanicoloau (Pap) tests (n = 114). Results were then compared with further histologic and/or cytologic follow-up. RESULTS: Repetition on conventional smears enabled a definite diagnosis (within normal limits [WNL], squamous intraepithelial lesion [SIL] or carcinoma) in 58 cases (50.9%). ASC/AGC was confirmed in 50 cases (43.9%), and 6 of the smears (5.3%) were inadequate. WNL, SIL, or carcinoma was diagnosed in 82 (82.0%) cases by following the patients with ThinPrep cytology, whereas ASC or AGC was confirmed in 18 cases (18.0%). No inadequate specimens were found. A diagnosis of SIL or greater (SIL +) was confirmed histologically in 11 of 11 (100.0%) conventional smears and in 31 of 34 (91.2%) ThinPrep specimens. Of the 87 WNL specimens, 9 (8 conventional smears and 1 ThinPrep specimen) developed a histologically confirmed SIL during further follow-up. Specimen adequacy was significantly better in the ThinPrep specimens compared with conventional smears. CONCLUSIONS: Because of better specimen adequacy, ThinPrep cervical cytology appears to significantly reduce the occurrence of ASC/AGC compared with conventional Pap smears.