Cytology suggestive of glandular neoplasia: outcomes and suggested management

Eighty-three cases having a cervical smear result showing abnormal glandular cells were identified and matched up with the diagnostic histology result. Thirty-four (41.0%) were associated with malignancy and 26 (31.3%) with a cervical intraepithelial lesion without invasion. Thirty-eight (45.8%) had conditions of the cervix as follows: 12 cases had invasive disease of the cervix; nine (10.8%) adenocarcinoma of cervix and three (3.6%) squamous carcinoma of cervix. Nineteen (22.9%) had cervical intraepithelial neoplasia (CIN/SIL) alone and seven (8.4%) had cervical glandular intraepithelial neoplasia (CGIN) +/- CIN. There were 16 (19.3%) cases with malignancies of the uterine corpus and six (7.2%) had a malignancy arising from another primary site. Twenty-three (27.7%) had no malignant or pre-malignant condition. The risk of malignancy was related to age and ranged from 18.2% in those under 35 years to 67.9% in those 55 years and over. A protocol for the management of these cases is described.     

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

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

An audit of liquid‐based cervical cytology screening samples (ThinPrep and SurePath) reported as glandular neoplasia

S. A. Thiryayi, J. Marshall and D. N. Rana
An audit of liquid‐based cervical cytology screening samples (ThinPrep and SurePath) reported as glandular neoplasia Objectives: The aims of this study were to assess the number of cases diagnosed as glandular neoplasia (national report code 6) of cervical (6A) and non‐cervical (6B) types on ThinPrep (TP) and SurePath (SP) liquid‐based cytology (LBC) samples and to calculate the positive predictive value (PPV) of these diagnoses for significant glandular and/or squamous pathology for local audit and as a contribution to national data on glandular neoplasia. Methods: A computerized search identified all screening LBC samples reported as glandular neoplasia during the 24‐month period from January 2006 to December 2007. Corresponding histology samples were identified, with a minimum follow‐up period of 6 months for each case. Results: A total of 70 samples, representing 70 patients, were reported as glandular neoplasia, 39 TP (55.7%) and 31 SP (44.3%), with 46 samples (31 TP, 15 SP) reported as 6A and 24 samples (eight TP, 16 SP) as 6B. PPV of glandular neoplasia was calculated for a biopsy diagnosis of cervical glandular intraepithelial neoplasia/adenocarcinoma and/or cervical intraepithelial neoplasia (CIN) 2 or worse. The PPV of 6A was 100% for both TP and SP. The PPV of 6B for adenocarcinoma was 62.5% for TP and 66.7% for SP. The combined PPV for 6A + 6B was 92.3% for TP, 83.3% for SP and 88.4% combined. The overall pick‐up rates for the two methods were significantly different (TP 0.031%, SP 0.052%; P = 0.014). Histology showed only CIN3 with endocervical crypt involvement in nine TP cases and one SP case.     

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.     

The inadequate smear: does it matter?

The objective of this study was to quantify the incidence of underlying cervical intraepithelial neoplasia (CIN) among women referred for colposcopy with three consecutive inadequate smears. The design was a retrospective cohort study analysing data from a regional colposcopy database at Cervical Screening Wales. Women who were referred to all the colposcopy clinics in Wales with three consecutive inadequate smears, the third inadequate smear being taken between 1 April 2001 and 31 March 2002 constituted the study population. The results of the fourth smear taken at the colposcopy clinic after three consecutive inadequate smears, the worst biopsy results from any of the subsequent colposcopies and the relationship between the result of the fourth smear taken at colposcopy clinic and any histology result were the main outcome measures. The accuracy of the colposcopic opinion was also examined. Of the 433 women identified as having been referred because of three consecutive inadequate smears, 302 were linked to either a subsequent smear and/or a biopsy result. An adequate smear result was available for 85% of these women when the smear was taken in the colposcopy clinic; 77% were reported as negative and 8% were abnormal. Of the 347 women seen in the colposcopy clinic, high-grade CIN was seen in 3% and low-grade lesion in 8%. The sensitivity and specificity of the fourth inadequate smear test in predicting underlying CIN were 15% and 84% respectively, with a positive predictive value of 8%. The sensitivity and specificity of colposcopy in predicting histological CIN among patients with three inadequate smears was 70% and 49%, respectively, and the positive predictive value was 44%. This study raises the question as to whether three consecutive inadequate smears should be considered as an indication for colposcopy, or merely for a further smear to be taken in circumstances where there is a greater likelihood getting an adequate result.     

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

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

Endocervical glandular cell abnormalities in conventional cervical smears: evaluation of the performance of cytomorphological criteria and HPV testing in predicting neoplasia

Objective:  To analyse the correlation between cytomorphological criteria in smears with atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) and human papillomavirus (HPV) reflex test results with different neoplastic histological diagnoses, particularly to distinguish between glandular and squamous neoplasia.
Methods:  A series of 155 women with glandular abnormalities in their conventional cervical smears was included: 106 with AGC, 35 with AGC associated with high-grade squamous intraepithelial lesion (HSIL) and 14 with AIS. Two reviewers evaluated 35 cytomorphological criteria and hybrid capture II (HCII) was performed in all cases. Colposcopy was carried out in all cases and biopsy in 126/155. For statistical purposes, predictive values and odds ratio (OR) were calculated, followed by chi-square automatic interaction detection.
Results:  Histology detected 56 cases of squamous and 17 of glandular intraepithelial or invasive neoplasia. Predictive values of the papillary groups and feathering criteria for glandular neoplasia were, respectively, 80.0% and 73.3%. Feathering was the criterion with the highest OR for distinguishing glandular from squamous neoplasia and also for distinguishing between glandular and non-neoplastic diagnosis. Rosettes and pseudostratified strips did not perform as well. Multivariant Classification and Regression Trees analysis identified feathering as the best criterion for distinguishing between glandular, squamous and non-neoplastic diagnoses regardless of HPV status.
Conclusions:  Feathering was the best criterion for predicting glandular neoplasia.     

Assessment of the Accuracy of Cytology In Women Referred For Colposcopy and Biopsy: the Results of a 1 Year Audit

The results of weekly colposcopy review meetings have been audited for 1 year and cases where there was a discrepancy between the referral cervical smear and the initial colposcopy biopsy have been analysed. New referrals (n = 476) for colposcopy were studied. In the final outcome 80% of 326 women referred for moderate or severe dyskaryosis were found to have cervical intraepithelial neoplasia (CIN) grade II or III or invasive carcinoma. Three women found to have invasive carcinoma had been referred for severely dyskaryotic smears. Twenty women were referred for smears with cell changes suggesting glandular neoplasia: five were found to have adenocarcinoma in situ, whereas eight had CIN and seven had negative biopsies. The results justify the referral policy and demonstrate the need for further investigation when initial colposcopic biopsies are negative.     

Outcomes of cervical liquid-based cytology suggesting a glandular abnormality

Objective: To ascertain the positive predictive value of both ?glandular neoplasia (national standard code 6) and borderline change (national standard code 8) in glandular cells in liquid‐based cervical cytology specimens in Cardiff and Vale NHS Trust and to outline the histological outcomes of these cases. Method: Eighty‐nine liquid‐based (Surepath?) cervical cytology cases were retrospectively identified from a 2‐year period (January 2005 to December 2006) and correlated with histopathological diagnoses. Results: Initial punch biopsy histology revealed 18 cases (21%) of cervical glandular intraepithelial neoplasia (CGIN). A further nine cases (10%) of CGIN were identified following local excision or hysterectomy. Ten cases of invasive malignancy were identified: four endocervical adenocarcinomas (all node negative, TNM stage T1b1), five endometrial adenocarcinomas and one squamous cell carcinoma. There were 10 with high‐grade cervical intraepithelial neoplasia (CIN) alone. Women diagnosed with endometrial malignancy presented later with an average age of 64.6 years compared with 34.9 years for endocervical lesions. Taking high‐grade CIN or worse as a positive outcome, the overall positive predictive value (PPV) of glandular abnormalities on cytology (both code 6 and 8) was 58.1% [95% confidence interval (CI) 47.8, 68.4]. PPV for borderline change in glandular cells alone was 24.1% (95% CI 8.5, 39.6) and for ?glandular neoplasia alone 75.4% (95% CI 64.3, 86.5). Conclusion: With our interpretation of the classification, women with cytological diagnoses of glandular neoplasia of the cervix should initially be investigated by local resection rather than punch biopsy, and those with borderline change in glandular cells with repeat cytology.     

The Cervex: an ectocervical brush sampler

The performance of a new ectocervical brush sampler--the Cervex--was compared with the Ayre spatula in 280 paired cervical smears. The Cervex smears were superior in quality of spread, transformation zone sampling in all degrees of cervical patency and in detection of histologically proven epithelial abnormalities, with a false negative rate of 10.9% compared with 20% for the Ayre. Improvement in predictive value was noted in atrophic samples, with increased cellularity and transformation zone representation. Difficulty has been encountered in obtaining adequate samples from the older woman and from those with iatrogenic scarring of the cervix. Although two-sampler techniques may be used, submission of high quality pan-cervical material from a single sampler onto one slide is economically and organizationally attractive. The Cervex seems capable of producing such samples and deserves further evaluation for routine screening.     

How predictive is a cervical smear suggesting glandular neoplasia?

The prevalence of endocervical adenocarcinoma and its precursors has increased, in part due to increased diagnostic awareness of these lesions. To date, limited information has been published regarding the predictive value of glandular abnormalities in cervical smears. This study details the histological follow up of 418 cervical smears showing glandular abnormality, reported in our department over a six year period from 1993 to 1998. Histological follow up was available for 395 of the 418 smears (94.50%). The overall positive predictive value (PPV) for this group of smears was 72.66% for either significant glandular or squamous pathology (at least low grade cervical glandular intraepithelial neoplasia or CIN2 on follow up biopsy), and 55.70% for significant glandular pathology alone. Examination of subcategories of abnormal glandular smear showed that the PPV increased with the degree of abnormality reported within the smears.     

An audit of cervical smears reported to contain atypical glandular cells

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

Glandular prediction: the pride and the prejudice

For the cytologist and clinician alike, glandular lesions pose possibly the greatest challenge in cervical screening. Worldwide, with increasing confidence in cytological prediction, terminology is evolving. In the UK, with the adoption of liquid based methods, the technical aspects of cervical cytology are being addressed, it is now time to standardise our terminology in glandular reporting. Consideration of the cytological complexity, clinical needs and international protocols is essential in this endeavour.     

Clinicopathological significance of borderline nuclear change – high grade dyskaryosis not excluded

During a recent discussion on classification of cervical cytology, the introduction of a 'Borderline Nuclear Change - High Grade Dyskaryosis Not Excluded' (BNCH) category was proposed. BNCH cases diagnosed prospectively were retrieved from laboratory records. Questionnaires were sent to referring practitioners regarding clinicopathological outcome. Cytopathological features resulting in the BNCH classification were recorded on slide review. A total of 103 reports on conventional cervical smears diagnosed as BNCH from 1999 to 2002 were retrieved, comprising 0.096% of 107 634 smears. Of 86/103 cases with clinical follow-up, CIN2 or worse was present in 30 (35%); 15 (17%) showed a borderline/low-grade abnormality and 41 (48%) were negative. No individual cytopathological feature was predictive of high-grade disease on follow-up. The yield of high-grade abnormalities on follow-up of BNCH supports the introduction of this terminology.     

Cervical intraepithelial neoplasia grade III (CIN III) and invasive cervical carcinoma: the yawning gap revisited and the treatment of risk

In a 3-year study of the population of Southampton and south-west Hampshire there were 10 times as many cases of CIN III compared with invasive squamous carcinoma (700 compared with 70). The peak incidence of CIN III per 1000 screened women years was in those aged 25-29 years, which was 20 years earlier than the peak incidence of invasive cervical cancer per 1000 women years at risk. Ninety percent of CIN III was diagnosed in women under 50 years. There were 14 cases of cervical glandular intraepithelial neoplasia grade III (CGIN III), three coexisting with CIN III, all in women aged under 50 years: the gap between intraepithelial and invasive lesions was not seen for glandular neoplasia. Although referral was for at least moderate dyskaryosis in 86.8% of women with CIN III or CGIN III, most had been screened previously, either having had mild abnormalities requiring repeat cytology (39.8%) or negative cytology (34.5%). Only 12 women aged > or = 50 years had previous negative cytology: 21.4% compared with 35.6% of women aged < 50 years (P = 0.034). The results of this study suggest that the best opportunity for preventing invasive squamous cell carcinoma lies in screening women aged 20-39 years when the incidence of CIN III in the screened population is highest and before the peak incidence of invasive disease. The results also indicate the importance of repeated screening and follow up of minor cytological abnormalities in the detection of CIN III. The benefit of screening must be regarded as a treatment of risk, since it is almost certain that a high proportion of CIN III regresses or persists unchanged.     

The number of dyskaryotic cells on an initial ThinPrep® cervical sample showing mild dyskaryosis has predictive value

OBJECTIVES: Recent National Health Service Cervical Screening Programme (NHSCSP) guidelines suggest referral for colposcopy following an initial result of mild dyskaryosis. The aim of this study was to investigate if the number of dyskaryotic cells counted on an initial ThinPrep cervical sample showing mild dyskaryosis has predictive value. METHODS: Cases of mild dyskaryosis on ThinPrep cervical samples from 2002 were retrieved from the cytology department records of St Luke's Hospital. A total of 123 sequential cases with a first-time result of mild dyskaryosis on ThinPrep slides with follow-up cytology available in the same institution were identified. While blinded to outcome, the number of dyskaryotic cells was counted in each case. Follow-up colposcopy/histology information was retrieved where indicated. The number of dyskaryotic cells counted on each slide was collated with outcome data. RESULTS: Of the 123 cases, six women were lost to follow-up. Seventy-three had a negative outcome, 27 had a low-grade outcome and 17 had a high-grade outcome. Only one of 17 high-grade outcome cases had < or = 15 dyskaryotic cells on the initial slide. The distribution of women with a negative/low-grade outcome and those with a high-grade outcome with >15 and < or = 15 dyskaryotic cells on the initial slide was tested using a chi-square test (P = 0.008). The negative predictive value for a high-grade outcome when < or = 15 dyskaryotic cells were present on the initial slide was 97.7%. CONCLUSION: The number of dyskaryotic cells on ThinPrep slides showing mild cervical dyskaryosis has predictive value. The number of dyskaryotic cells may be used to select women suitable for cytological rather than colposcopic follow-up.     

Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid‐based cervical cytology

K. Chummun, M. Fitzpatrick, P. Lenehan, P. Boylan, E. Mooney and G. Flannelly
Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid‐based cervical cytology Background: In 2008, the management of women in Ireland with atypical glandular cells changed to immediate referral to colposcopy. The optimal management of these women is unclear. A balance between the detection of occult disease and overtreatment is required. Methods: Our study aim was to document the experience of this policy at the National Maternity Hospital, Dublin. Information from the computerized data management system was analysed with the statistical package SPSS. Results: In 2009, 156 women attended colposcopy following a single atypical glandular cell diagnosis on liquid‐based cytology. The mean age was 41 years. Thirty (19.2%) women had abnormal vaginal bleeding, 31 (19.9%) were smokers and 34 (21.8%) had received previous treatment. The colposcopy was satisfactory in 125 (80.1%) and unsatisfactory in 31 (19.9%). Cervical histology was available for 146 (93.6%) women: 57 excisional procedures and 89 diagnostic biopsies. Abnormal histology was detected in 46 women (31.5%). Four women (2.7%) had invasive cancer, five (3.4%) had adenocarcinoma in situ, 21 (14.4%) had cervical intraepithelial neoplasia (CIN) grade 2 or 3 and 16 (11.0%) had CIN1. No abnormality was detected in 100 women (68.5%), including 35 (61.4%) of those who had undergone excisional procedures. The colposcopic impression in this group was unsatisfactory in 10 women (28.6%), glandular abnormalities in six (17.1%), high‐ and low‐grade changes in 12 (34.2%) and six (17.1%) women, respectively, and normal in one (2.9%). The findings were essentially negative in the remaining 10 women: overall, 30 (19.2%) of the 156 women referred to colposcopy had at least CIN2. Conclusion: This study confirmed significant levels of high‐grade disease in women referred to colposcopy with atypical glandular cells on cytology. Concerns about undetected endocervical disease resulted in high levels of negative excisional biopsies. Alternative strategies, including endometrial sampling, human papillomavirus testing and discussion at clinicopathological meeting, should be considered.     

Atypical glandular cells in cervical smears: histological correlation and a suggested plan of management based on age of the patient in a low-resource setting

Objectives:  To perform an audit of all smears reported as atypical glandular cells (AGC) using the Bethesda system (TBS) 2001.
Methods:  A total of 18 376 cervical smears were screened from January 2005 to June 2007, of which 65 cases were reported as AGC. Follow-up histology was available in 31 cases (47.7%), in whom a detailed cytological/histological correlation was carried out.
Results:  AGC constituted 0.35% of all Pap smears. Follow-up histology was normal or benign in 20 cases, whereas a squamous or glandular abnormality was seen in 11 cases. Squamous abnormalities included one case each of cervical intraepithelial neoplasia (CIN)1, CIN2 and CIN3 and five cases of squamous cell carcinoma. All glandular epithelial abnormalities were endometrial in origin and included two endometrial adenocarcinomas and one uterine serous carcinoma. Neither in situ nor invasive adenocarcinoma of the endocervix was observed. Review of smears and reclassification as AGC, not otherwise specified and favour neoplasia revealed a higher proportion of abnormality in the latter group, reaffirming the utility of subtyping. The median age of women with AGC was 41 years. The outcome was analysed with respect to the median age. In women aged equal or more than 40 years, AGC reflected a high-grade squamous or glandular epithelial abnormality in 50% of cases compared with none in those less than 40 years old ( P  = 0.010).
Conclusion:  The age of the woman as well as the subtype of atypical glandular cells influences outcome and hence must be taken into consideration while formulating an acceptable management strategy in these women in a low-resource setting.     

Clinical relevance of human papillomavirus testing in cytopathology

Cancer of the uterine cervix is the second most common cancer in women worldwide. Currently, cervical screening is based on cytology alone. Because infection with high-risk human papillomavirus types (hrHPVs) is a necessary cause of cervical cancer, it has been postulated that screening might become more efficient when it is based on combined cytology and hrHPV testing. In this review we will discuss the advantages of added HPV tests in cervical cancer screening, as a quality control for false-negative smears, in triage of women with equivocal smears, in follow-up of women treated for CIN3 or cervical cancer and for the detection of cervical adenocarcinoma.