Guest Lecture 8.45–9.30 Monday 15 September 2003 Endocervical Adenocarcinoma and its Precursors

The incidence of malignant and pre‐malignant endocervical glandular lesions is increasing. Part of this is an apparent increase due to a reduction in the number of invasive cervical squamous carcinomas but there is evidence that there is a real increase in malignant and pre‐malignant endocervical glandular lesions. Different terminologies are in use in the UK where the term cervical glandular intraepithelial neoplasia (CGIN) is commonly used and the rest of the world where pre‐malignant lesions are classified as glandular dysplasia and adenocarcinoma in situ (AIS) (WHO classification). It is well established that high‐grade CGIN (AIS in WHO terminology) is a precursor lesion of cervical adenocarcinoma but it is controversial whether a recognizable precursor to high grade CGIN (namely low‐grade CGIN) exists and criteria for diagnosing this are poorly established and poorly reproducible. Most cases of CGIN are of usual or endocervical type but other morphological subtypes described include endometrioid, intestinal, tubal and stratified mucinous intraepithelial lesion (SMILE). The presence of skip lesions and lesions high up the endocervical canal has been overemphasised in CGIN with most cases occurring close to the transformation zone. Treatment is on an individualized basis but local excision with negative margins and close cytological follow‐up may be employed. There is evidence in the literature that early invasive adenocarcinomas behave in a similar fashion to early invasive squamous carcinomas and that, on selected occasions, conservative therapy can be safely undertaken. However, further studies are needed to ascertain the behaviour and natural history of early invasive cervical adenocarcinoma. In 10%–15% of cases it may be impossible to ascertain whether a malignant endocervical glandular lesion is invasive or in situ. There are many benign mimics of CGIN and adenocarcinoma, including tuboendometrial metaplasia (TEM), endometriosis and microglandular hyperplasia (MGH). Although careful morphological examination usually allows confident distinction of these lesions, a panel of immunohistochemical stains including MIB1, bcl2 and p16 may assist.     

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.     

黏蛋白在宫颈腺体病变的表达及意义

目的:研究不同级别宫颈腺体病变组织中黏蛋白MUC2、MUC5AC、MUC6、CD10的表达情况,进而分析其与宫颈腺体病变发生发展的关系。方法:将2005年2月至2012年2月于哈尔滨医科大学附属第二医院妇产科手术切除及活检的宫颈病变患者病理组织183例,根据国际妇产科学联盟(FIGO)标准分为宫颈微腺体增生(MGH)60例;宫颈腺体不典型增生(EGD)57例;宫颈腺癌(ECA)56例,以免疫组化法检测MUC2、MUC5AC、MUC6、CD10的表达情况。结果:MUC2和CD10的阳性细胞比例随着宫颈腺体病变程度级别的增高呈上升趋势(P=0.046),而MUC5AC的表达则随着宫颈腺体病变程度级别的增高呈下降趋势(P0.001);MUC6在三种宫颈病变组织中均呈低表达,不具有显著性差异(P0.05)。结论:黏蛋白表型可以作为评估宫颈腺体病变恶性潜能的有用的标记物。     

The Ca2+-binding S100A2 protein is differentially expressed in epithelial tissue of glandular or squamous origin

It has been previously shown that S100A2 is downregulated in tumor cells. The level of immunohistochemical S100A2 expression was therefore characterized in 424 normal and tumoral (benign and malignant) tissues of various origins, but mostly epithelial (with either glandular, squamous, respiratory or urothelial differentiation). We also investigated whether S100A2 could be co-localized with cytokeratin K14, an intermediate filament protein expressed in basal proliferative keratinocytes. Our data show that S100A2 has a low level of expression in non-epithelial tissue. In epithelial tissue S100A2 expression decreases remarkably in the tumors when compared to the normal specimens, and was correlated with the level of keratin K14. This decrease in S100A2 staining from normal to cancer cases is more pronounced in glandular than in squamous epithelial tissue. In addition, the patterns of S100A2 staining also differ between glandular and squamous tissue. These data suggest distinct functional roles for S100A2 in epithelial tissue of squamous or glandular origins.     

P-cadherin expression predicts clinical outcome in oral squamous cell carcinomas

P-cadherin, a transmembrane molecule similar to E-cadherin involved in the cell-cell adhesion, and catenins form complexes between its cytoplasmic domain and the cytoskeleton. Five cell lines, 108 specimens of oral squamous cell carcinomas (OSCC), 9 metastasis and 10 of normal oral mucosa were examined to evaluate P-cadherin expression and cellular localization by immunohistochemistry and western-blotting. In normal oral mucosa there was a membranous expression only in basal and parabasal layers. 91 cases (84%) showed membranous/cytoplasmic positivity, whereas 17 cases (16%) were negative. In particular, while well-differentiated carcinomas showed P-cadherin upregulation, the protein was homogeneously hypo- or unexpressed in low-differentiated carcinomas. There was a statistically significant correlation between P-cadherin expression and tumour grading: G3 tumours had a lower score than G1-G2 tumours (P<0.05). When analysed for prognostic significance, patients with no P-cadherin expression (score 0) had poorer overall and diseases-free survival rates than the P-cadherin-expressing group (score 1) (P=0.0463 and P=0.0471, respectively). Western blotting analysis of cell lines and tissue samples confirmed immunohistochemical findings. When cell staining pattern of positive cases was examined, 52 cases showed a prevalent membranous pattern, while 39 had a prevalent cytoplasmic pattern. Cases with prevalent cytoplasmic staining showed high rates of lymph node metastases (P>0.05), and regional relapse (P <0.05) and poorer survival rates than the group with prevalent membranous expression (P<0.0001). An absent P-cadherin expression could constitute a hallmark of aggressive biological behaviour in oral squamous cell carcinoma.     

Monoclonal antibodies in the cytodiagnosis of serous effusions

In order to assess the value of immunocytochemical staining as a method of discriminating between benign reactive mesothelial cells and malignant epithelial cells in serous effusions, we have studied the reactions of a panel of commercially available antibodies on cells harvested from 83 pleural and peritoneal fluids and compared the results with the clinical and cytological diagnoses. The antibodies used were raised against cytokeratin (PKK1), epithelial membrane antigen (EMA), carcino-embryonic antigen (CEA), pregnancy specific B1-glycoprotein (SP1) and leucocyte common antigen (LCA). Anti-CEA was positive in 16 of 39 effusions (41%) containing carcinoma cells. Pregnancy specific B1-glycoprotein (SP1) was positive in 33% of the same samples. Mesothelial cells did not stain with these antibodies. Thus anti-CEA and SP1 can be used to discriminate between benign mesothelial and malignant epithelial cells in effusions. Anti-PKK1 stained both benign reactive mesothelial cells and malignant epithelial cells and cannot be used to discriminate between these two cell types. Strong positive staining of malignant cells was noted with anti-EMA. However, as occasional weak staining of mesothelial cells was also noted, strong staining with this antibody may be regarded as suspicious but not conclusive of malignancy.     

Tissue microarrays for testing molecular biomarkers of cervical intraepithelial neoplasia: feasibility study

OBJECTIVE: To test the possibility of creating tissue microarrays of pre-malignant lesions of the cervix. STUDY DESIGN Paraffin-embedded blocks of 240 cervical tissue specimens were sampled. Lesions from benign squamous and glandular epithelium through various grades of cervical intraepithelial neoplasia (CIN) to frank carcinoma of squamous and glandular origin were cored with a 0.6-mm needle and arrayed in 4 tissue blocks. Sections of these blocks were stained with hematoxylineosin (H-E) and evaluated as to adequacy of tissue cores, representativity of the material and correspondence to the original diagnosis. Immunohistochemical staining with p16 and a novel marker C4.8(4/2/#1) was performed. RESULTS: In > 80% of cases sufficient material from the lesion could be obtained. No or inadequate material was seen in 6% of cases. The core sample did not correspond to the original diagnosis in 12% of cases. The reason was mainly a discrepancy in the grade of the CIN. Discrepancies in diagnoses occurred in only premalignant lesions. Immunohistochemical staining could reliably be performed and evaluated on all tissue cores. CONCLUSION: Tissue microarrays of cervical intraepithelial lesions are technically feasible and can be created reliably. The key to success is a careful and repeated comparison of the tissue block with the corresponding H-E section. Tissue microarrays of preinvasive cervical lesions may allow high throughput analysis of emerging molecular biomarkers in cervical carcinogenesis.     

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.     

Prevalence of human papillomavirus type 16 variants in the Federal District, Central Brazil

We report the prevalence of human papillomavirus type 16 (HPV-16) variants in women with cervical lesions from the Federal District, Central Brazil. We analyzed 34 HPV-16 samples, identifying the sequence variations of E6 and L1 genes and correlating variant frequency with disease status. The most prevalent HPV-16 variant was the European (50%), followed by Asian-American (41.2%), African-1 (5.9%), and African-2 (2.9%). European and non-European variants appeared in equal frequencies among the cytological types of lesions - atypical squamous or glandular cells of undetermined significance, cytological alterations suggesting HPV infection, cervical intraepithelial neoplasias, squamous cell carcinoma, and adenocarcinoma.     

Digital image analysis of AgNORs in cervical smears of women with premalignant and malignant lesions of the uterine cervix

We performed a hospital-based, unmatched case-control study to investigate the association between progressive stages of cervical neoplasia and digital analysis of cell proliferation by silver stained nucleolus organizer region associated proteins (AgNORs). We measured cell proliferation levels in the cervical epithelial cells of 10 women with low grade squamous intraepithelial lesions (LG-SIL), eight with high grade squamous intraepithelial lesions (HG-SIL), 11 with cervical cancer (CC) and eight with no cervical lesions (controls) using the AgNORs technique. Cell proliferation was measured by digital image analysis (DIA). DIA revealed increased total areas of AgNORs in HG-SIL and CC compared to LG-SIL and control patients. AgNORs with a kidney or cluster shape exhibited greater areas than those with a spherical or long shape. We propose a cut-off of 118 pixels to differentiate benign (control and LG-SIL) from malignant (HG-SIL and CC) lesions. DIA of AgNORs is a simple and inexpensive method for studying proliferation. The increased total area of AgNORs in malignant lesions provides information regarding cell behavior and may be related to cervical carcinogenesis; however, further validation studies are required to establish its usefulness in cytological analysis.     

Glandular lesions of the cervix—cytological and histological correlation

In this retrospective review we assessed the frequency with which atypical glandular cells in cervical smears predict cervical glandular lesions. Asymptomatic patients ( n =34) with one or more smears showing atypical glandular cells and subsequent histopathological assessment were studied. Independent cytological and histological review was undertaken. Cytological review confirmed atypical glandular cells in 29 cases, 17 of which had coexisting squamous dyskaryosis. Histological review of these 29 cases revealed glandular neoplasia in 13 (45%) and microglandular hyperplasia (MEH) in an additional four (14%). Initial reporting had underestimated the prevalence of glandular neoplasia.     

Glandular lesions of the cervix—cytological and histological correlation

In this retrospective review we assessed the frequency with which atypical glandular cells in cervical smears predict cervical glandular lesions. Asymptomatic patients (n=34) with one or more smears showing atypical glandular cells and subsequent histopathological assessment were studied. Independent cytological and histological review was undertaken. Cytological review confirmed atypical glandular cells in 29 cases, 17 of which had coexisting squamous dyskaryosis. Histological review of these 29 cases revealed glandular neoplasia in 13 (45%) and microglandular hyperplasia (MEH) in an additional four (14%). Initial reporting had underestimated the prevalence of glandular neoplasia.     

Atypical glandular cells: criteria to discriminate benign from neoplastic lesions and squamous from glandular neoplasia

OBJECTIVE: To evaluate the presence of some criteria in cervical smears with atypical glandular cells and their correlation with histological patterns to identify pre-neoplastic and neoplastic lesions. METHODS: Seventy-three women referred with an atypical glandular cell smear, who had undergone conization or hysterectomy, were included in this study. Referral Pap smears were reviewed using the set of 27 cyto-morphological criteria that was correlated with the histological diagnosis. RESULTS: Histological results showed intraepithelial or invasive neoplasia in 35 (48%) cases and benign lesions in 38 (52%) cases. After logistic regression and decision tree analysis an increased nuclear/cytoplasmic ratio and the presence of dyskeratotic cells were strongly associated with intraepithelial or invasive neoplasia and the differential cyto-morphological criteria for glandular lesions were decreased cytoplasm, irregular nuclear membranes and the presence of nucleoli. CONCLUSION: The analysis of individual cyto-morphological criteria can better predict intraepithelial or invasive neoplasia and differentiate glandular from squamous lesions.     

Levels of circulating cell-free serum DNA in benign and malignant breast lesions

PURPOSES OF THE STUDY: We analyzed circulating cell-free DNA in the serum of patients with benign and malignant breast disease and in healthy individuals to determine its diagnostic value. BASIC PROCEDURES: Serum samples were obtained from 50 healthy individuals, 33 patients with malignant breast disease and 32 patients with benign breast disease. Circulatory DNA was extracted from serum samples. Cell-free DNA was quantified by real-time quantitative PCR for the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Tissue samples from patients with malignant and benign breast lesions were histopathologically examined. MAIN FINDINGS: The mean levels of circulating cell-free DNA in serum samples were 41,149 genome equivalents (GE)/mL in patients with malignant disease, 30,826 GE/mL in patients with benign disease, and 13,267 GE/mL in healthy individuals. Healthy individuals had significantly lower levels of cell-free DNA than patients with malignant or benign breast disease (p=0.001, p=0.031). No significant difference was observed between malignant and benign disease. There was a correlation between cell-free DNA levels and tumor size but not with other tumor characteristics. PRINCIPAL CONCLUSION: Our results suggest that levels of circulating cell-free DNA in serum could have diagnostic value to discriminate between healthy individuals and patients with breast lesions but not between patients with malignant and benign breast lesions.     

O-9Uncommon subtypes of borderline nuclear changes: cytological features and predictive value

Introduction:  To establish the significance of cytological features which could predict clinically significant endometrial pathology, and therefore guide reporting practice in cervical samples.
Methods:  A retrospective review of SurePath liquid-based cytology (LBC) cervical samples between 2002 and 2006, obtained at screening and colposcopy. These smears contained normal endometrial cells present at inappropriate times of the menstrual cycle, endometrial cells with atypia (borderline change) and with features suspicious / diagnostic of endometrial carcinoma (glandular neoplasia). False negative and false positive cases detected on subsequent histology were also included. The control group comprised negative samples and a few abnormal smears. All smears were randomly assigned and blinded to menopausal status, age, use of oral contraceptive pill and hormone replacement therapy and presence of intrauterine device. Each smear was reviewed for 16 cytologic criteria and a cytological diagnosis was given for each.
Results:  A total of 219 smears were available for review; 137 were negative, out of which 85 contained normal endometrial cells, 41 contained endometrial cells with atypia, 10 contained endometrial cells with features suggestive of adenocarcinoma and 31 contained endometrial cells with features diagnostic of adenocarcinoma. The feature most associated with benign endometrial cells is top hat with central cell condensation. In contrast, the features associated with malignant endometrial cells are smooth nuclear membrane, pale chromatin, small nucleoli and scalloped borders.
Discussion:  The criteria identified in this study do not definitively define a neoplastic process, but appear to be helpful in individual cases. This study emphasises that endometrial changes should be always interpreted with the relevant clinical information, which would otherwise lead to overdiagnosis in premenopausal women.     

Rapid rescreening of cervical smears as a quality control method in a high-risk population

OBJECTIVE: Cancer of the cervix is one of the commonest cancers in South Africa. Accurate cytological diagnosis is one of the prerequisites for an effective cervical screening programme and requires the implementation of appropriate quality assurance modalities. This study was undertaken to determine if rapid review of reportedly negative cervical smears is a useful internal quality assurance modality in an unscreened population with very high rates of cervical carcinoma. METHOD: Approximately 26% of all cervical smears received at the study institution between 1 January 1998 and 31 December 2003, and initially reported as negative or inadequate, underwent rapid review. RESULTS: A total of 62,866 (26%) cervical smears out of 241,796 reportedly negative or inadequate cervical smears underwent rapid review. An amended report was sent out in 373 (0.59%) of these 62,866 cervical smears. This included 101 cases of high-grade squamous intraepithelial lesion (HSIL) and high-grade atypical squamous cells (ASC-H), 143 low-grade squamous intraepithelial lesions, 54 atypical squamous cells of undetermined significance (ASC-US) and 33 atypical glandular cells that were not reported initially. The false-negative proportion for HSIL and ASC-H (combined) in this study was 5.76%. No squamous cell carcinomas were diagnosed on rapid review but one patient with HSIL/ASC-H on review had squamous cell carcinoma on biopsy. Three cytotechnologists had a lower sensitivity of primary screening and required retraining. CONCLUSIONS: Rapid review is beneficial as an internal quality assurance modality in an unscreened high-risk population and increases the detection of women with significant cervical lesions requiring treatment. The relatively low cost of rapid review compared with other rescreening modalities makes this an attractive option in low resource settings.     

基于免疫组化和癌症基因组图谱数据分析的脾酪氨酸激酶在宫颈癌中的表达研究

摘要 目的：探讨Syk 在宫颈癌中的表达及其临床意义。方法：应用免疫组化检测Syk在宫颈癌、癌前病变(CIN)和相应的正常宫颈组织中的表达。借助R2生物信息平台挖掘Syk在TCGA数据库305例宫颈鳞癌中的mRNA表达及其与预后的关系。结果：免疫组化结果显示,Syk在宫颈癌巢分化较好的中心区表达较强,在分化较低的癌巢周边区表达较弱。Syk 染色主要定位在宫颈癌和正常宫颈组织的细胞质和细胞膜,正常宫颈组织基底细胞无 Syk 表达,8例CIN组织细胞核中可见Syk表达, 但宫颈癌组织细胞核中未见Syk表达。Syk在宫颈癌、CIN和正常宫颈组织中的阳性率分别是76%、54%、40%,三组间的表达差异具有统计学意义（P=0.001）。Syk 在深度浸润和淋巴结转移中表达较强。数据挖掘结果显示,Syk mRNA在305例不同临床分期的宫颈癌中均表达,Syk mRNA高表达组219例,Syk mRNA低表达组73例,其中13例生存数据缺失,Syk高表达组的患者预后较差。结论：Syk在宫颈癌中的表达提示Syk在宫颈癌中具有致癌蛋白的作用,Syk在某些CIN中的核表达可能与更好的预后相关。     

Fractal dimension in aspiration cytology smears of breast and cervical lesions

OBJECTIVE: To standardize the automated measurement of fractal dimension on cytologic smears and compare the fractal dimension of benign and malignant breast cells and cervical lesions on cytologic material to evaluate its role in the discrimination of benign from malignant cells. STUDY DESIGN: We randomly selected fine needle aspiration cytology smears of 42 cases of infiltrating duct carcinoma and 38 cases of fibroadenoma of the breast. Similarly, 16 cervical carcinoma and 20 normal cervical smears were selected for study. Ten cells were selected randomly from each case. Box counting of fractal dimension of malignant and benign cells was achieved with an image cytometer (Leica, Cambridge, England) using Quantimet 600 software (Leica). Then a well-spaced grid with multiple small boxes of a particular pixel length was superimposed on the cell. The dimension of the box was selected as 4, 8 and 16 pixels. With the help of a logical "AND" operation, we counted the number of boxes touching the peripheral margin of the cell nuclei. For each cell, the log-log graph of 1 per box size was plotted against the number of boxes touching the peripheral rim of the cell. The slope of each graph was identified using the least-squares method of regression analysis. RESULTS: The mean fractal dimension of malignant cells was 0.8536 +/- 0.1120 as compared to 0.8403 +/- 0.1115 in benign cell groups. The Mann-Whitney U test showed a significant difference in fractal dimension in these 2 groups (P = .05). The mean fractal dimension of malignant cells from the cervix was 0.8656 +/- 0.1499 as compared to 0.8315 +/- 0.1312 in benign cells. The Mann-Whitney U test showed a significant difference in fractal dimension in these 2 groups (P < .02). CONCLUSION: Fractal dimension may be a helpful adjunctive technique to discriminate between benign and malignant cells.     

Cytological Changes Associated With Tubo-Endometrioid Metaplasia of the Uterine Cervix

Two women who had undergone previous cervical surgery for the treatment of glandular intraepithelial neoplasia (GIN) and cervical intraepithelial neoplasia (CIN), were found to have severely dyskaryotic cells of glandular and metaplastic type in follow-up cervical smears. A third patient was found to have similar abnormal cells in a routine screening smear. All of the patients were subjected to either hysterectomy or cervical conization and in all cases histological examination showed tubo-endometrioid glands in the endocervix, well away from the uterine isthmus, with no associated endometrial stromal tissue. All of the cervical smears were reviewed and cytological features that facilitate the distinction between tubo-endometrioid metaplasia and squamous or glandular dyskaryosis were identified. These features include the smaller size of affected cells, more marked nuclear hyperchromasia, inconspicuous nucleoli, the formation of glandular structures, the lack of discrete squamous dyskaryosis and the absence of the typical 'feathering' noted with GIN. the possibility of tubo-endometrioid metaplasia should be considered when atypical glandular or metaplastic cells are noted in cervical smears, particularly, but not exclusively, in women who have been treated for CIN or GIN. In the presence of these changes clinicians should rebiopsy the cervix before embarking on further unnecessary surgery which may adversely affect fertility and pregnancy, particularly in younger patients.     

Atypical squamous cells of undetermined significance: audit and the impact of potential litigation. Retrospective review of 682 cases

For quality assurance purposes, the frequency of 'abnormal' cytological diagnoses of the non-systematic National Cervical Cancer Screening Programme (NCCSP) was evaluated. In 1999, an unexpected high number of Class (Cl) III cases (i.e. atypical squamous cells of undetermined significance) was reported. The cytological and histological results were reviewed in order to detect a possible cause for this threefold increase. The abnormal Papanicolaou (PAP) smears examined by conventional methods from 1 January 1990 to 31 December 2002 were analysed. The smears of 682 cases diagnosed in 1999 with a Cl III category were reviewed in 2000 and correlated with the available histological diagnoses provided by the Central Department of Pathology. Of the 682 Cl III cases, 176 cases (26.1%) had no follow-up, 314 cases (46.0%) had repeat cytology and 192 cases (28.2%) an histological correlate corresponding to 90 (46.9%) benign lesions, 78 (40.6%) squamous intraepithelial lesions, two (1%) invasive cervical cancers (one squamous and one glandular). Twenty-two Cl III cases (11.5%) were histologically within normal limits. Retrospective smear review confirmed 330 Cl III diagnoses (48.3%), 127 cases (18.6%) were recategorized as Cl IIIG (i.e. atypical glandular cells of undetermined significance), 22 cases (3.2%) as Cl IIID (i.e. mild to moderate dysplasia) and six cases (0.9%) as Cl IVa (i.e. severe dysplasia and/or carcinoma in situ). A total of 197 original Cl III cases had to be reclassified in the Cl II category (28.9%), only two cases showing mild and moderate dysplasia on histology. Thus, 195 cases (28.6%) comprised cytological overdiagnoses. The Cl III category being, by definition, a delicate and often subjective diagnosis, all external influences such as pressure of litigation should be avoided to reduce cytological overdiagnoses as a result of an unnecessary 'fear-factor'.