Increased diagnostic accuracy of atypical glandular cells in cervical liquid‐based cytology using cell blocks

E. K. J. Risse, J. P. Holierhoek, E. M. Meijer‐Marres, E. Ouwerkerk‐Noordam and M. E. Boon Increased diagnostic accuracy of atypical glandular cells in cervical liquid‐based cytology using cell blocks Objective: The purpose of this study was to reduce the number of diagnoses of atypical glandular cells (AGC). Residual material from the cervical ThinPrep® samples (Hologic, Marlboruogh, MA, USA) was used for cell blocks (CB) and immunohistochemistry (IHC). Methods: In 2007 there were 87 patients (0.12% of tests) with AGC on liquid‐based cytology (LBC) in the Leiden Cytology and Pathology Laboratory (LCPL) using the Bethesda System 2001 (TBS). CB with IHC was used for 26 of these cases. The vials still containing the brush (Cervex‐Brush^® Combi) were placed in a shaker for 10 minutes to dislodge the material trapped between the bristles. The residual sampling fluid was used to prepare paraffin sections (Shandon Cytoblock^®) stained with Papanicolaou and immunostaining. Results: Four of five cases with AGC not otherwise specified (NOS) were diagnosed with CB/IHC as benign mimics (endometrium, tubal metaplasia, follicular cervicitis, microglandular hyperplasia) and one of four with AGC‐favour neoplasia (FN) (endocervical polyp). In one of five cases with AGC‐NOS and in two of seven with AGC‐FN, CIN3 was found on subsequent histological biopsy. Of six cases diagnosed as adenocarcinoma in situ (AIS) on LBC with CB/IHC the diagnosis was confirmed in four; one was adenocarcinoma and one glandular atypia. Of eight cases diagnosed as adenocarcinoma on cytology and CB/IHC, the diagnosis was confirmed in three. The other five cases were found to be one each of AIS, squamous cell carcinoma, CIN3, CIN2 with glandular atypia, and cervical endometriosis. Conclusions: By reducing the number of benign mimics of AGC, we achieved a high proportion (16/26; 61.5%) of neoplastic or preneoplastic lesions (glandular or squamous) on histological outcome potentially avoiding colposcopy. Histological biopsy verification by the gynaecologist is needed for final diagnosis of AGC‐FN, AIS and adenocarcinoma.     

Atypical glandular cells of undetermined significance on cervical smears. A study with cytohistologic correlation.

OBJECTIVE: The incidence of endocervical adenocarcinoma has increased steadily over the past two decades. Since the Bethesda System was introduced, the diagnosis of atypical glandular cells of undetermined significance (AGUS) has also risen and now accounts for 0.46-1.83% of all cervical (Pap) smears. The purpose of this study was to evaluate the significance of a diagnosis of AGUS using cytohistologic correlation. STUDY DESIGN: A retrospective review of archival material from 1993 through 1996 identified 64 patients who had smears diagnosed as AGUS and had a subsequent surgical biopsy. The smears were reviewed and cytologic features analyzed and correlated with the histologic diagnosis. RESULTS: On biopsy, 3 (5%) of the 64 cases showed endocervical adenocarcinoma in situ (AIS) (1 case with invasive adenocarcinoma also), 14 (22%) had a benign glandular lesion (endocervical polyp, tubal metaplasia, microglandular hyperplasia, reactive changes), 35 (54%) had squamous intraepithelial lesion (SIL) (15 diagnosed on the original smear), and 12 (19%) had no abnormality. Among the cytologic criteria evaluated, feathering (P = .01), palisading (P < .001) and chromatin clearing (P = .002) were shown to have a significant association with the histopathologic diagnosis of AIS/adenocarcinoma. These features were also useful in distinguishing AIS/adenocarcinoma from SIL and benign glandular changes from AIS/adenocarcinoma but not benign/reactive glandular changes from SIL. CONCLUSION: A diagnosis of AGUS correlated with a clinically significant lesion in the majority of cases. Squamous dysplasia (SIL) was the most common lesion identified. The presence of feathering, nuclear palisading and chromatin clearing increased the likelihood of a histologic diagnosis of AIS/adenocarcinoma.     

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.     

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.     

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.     

Atypical glandular cells of undetermined significance in cervical smears after conization. Cytologic features differentiating them from adenocarcinoma in situ

OBJECTIVE: To evaluate the cytologic features of atypical glandular cells of undetermined significance (AGUS) smears following conization through a comparison with adenocarcinoma in situ (AIS) smears. STUDY DESIGN: Fifty cervical smears, diagnosed as AGUS based on groups of crowded glandular cells that raised the possibility of AIS, from 38 patients who had conization and 24 AIS smears, histologically confirmed, from 17 patients were reviewed. Subsequent follow-up biopsies or hysterectomies in 38 patients were evaluated. RESULTS: Nuclear atypia was a more reliable feature than architectural structure in differentiating postcone effect from AIS on cytology. The predominant cytologic features of the postcone smears were crowded glandular cells with a high nuclear/cytoplasmic ratio and relatively small, hyperchromatic nuclei with rather finely granular and uniformly dispersed chromatin, less distinct nuclear membranes, less frequent mitosis and presence of endometrial-type stromal cells in the background. The architecture of the crowded cells in the postcone smears was sometimes similar to that of AIS. No AIS or high grade squamous intraepithelial lesion histology was encountered in follow-up biopsies or hysterectomy specimens. CONCLUSION: The cytologic features distinguishing AGUS from AIS may be helpful in identifying the postcone effect. Since it is important to avoid miscalling the postcone effect as AIS, it is recommended that one check for a previous history of a cone biopsy.     

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.     

Significance of AGUS Pap smears in pregnant and postpartum women

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

Glandular and squamous atypia and intraepithelial lesions in atrophic cervicovaginal smears. One institution's experience

OBJECTIVE: To review the cytologic features and follow-up histologic findings in atrophic cervicovaginal smears with the diagnoses of glandular or squamous atypia or intraepithelial lesion. STUDY DESIGN: A total of 228 cases were included in the study. The selection criteria included: age > 48 years and a diagnosis of either atypical glandular cells (AGC) (51 cases), cellular changes suggestive of human papillomavirus (HPV) infection (S/O HPV, 97 cases), low grade squamous intraepithelial lesion (LSIL) (60 cases) or high grade squamous intraepithelial lesion (HSIL) (20 cases). Follow-up biopsy information was available for 103 cases (45%). RESULTS: From the AGC group, 35 (69%) cases had tissue studies; 14 (40%) cases showed glandular lesions; 5 (14%) showed squamous intraepithelial lesion (SIL) and atypical cells. Follow-up information was available for 32 (33%) cases classified as S/O HPV; significant lesions (glandular/squamous) were found in 11 (34%). In the LSIL category, 22 (37%) cases had follow-up; 16 (73%) showed SIL. In the HSIL category, 14 cases (70%) underwent biopsy, and all showed SIL (four LSIL and nine HSIL) or squamous cell carcinoma. CONCLUSION: Even though atrophy-related epithelial changes often pose diagnostic difficulties in the interpretation of postmenopausal smears, application of reproducible and established cytologic criteria in diagnosing SIL and/or glandular lesions can improve diagnostic accuracy and result in selection of patients for follow-up tissue studies.     

Interlaboratory reproducibility of atypical glandular cells of undetermined significance: a national survey

OBJECTIVE: The aim of this study was to evaluate the inter-laboratory reproducibility for atypical glandular cells (AGC) (The Bethesda System (TBS) 2001) of the laboratories involved in the screening programmes in Italy. METHODS: A set of 35 selected slides were circulated among 167 laboratories involved in local population-based cervical screening programmes. Each laboratory provided one single diagnosis per smear. The smears were read blind to the original diagnosis and to the diagnoses provided by other laboratories. A 'majority' diagnosis was defined for each case and assumed as the reference standard. The diagnosis provided from each laboratory was compared with the majority diagnosis. RESULTS: According to the majority report the 35 slides in the set were classified as negative in nine cases, AGC in eight, adenocarcinoma in eight, and squamous lesion or squamous + glandular lesion in 10. The crude agreement between all pairs of laboratories was 49.43%. K-values were 0.46, 0.21, 0.34, 0.36 and 0.32 for negative, AGC/AIS (adenocarcinoma in situ of endocervix), AdenoCa, Sq/Sq + Gl and all reporting categories respectively. Concordance according to overall K was moderate to substantial in 77% of the participating laboratories. CONCLUSIONS: The present study shows that the AGC category is not easily reproducible. The data confirmed the importance, in a screening scenario, of AGC/AIS diagnoses, but also presented difficulties in differentiating between the two diagnoses. In addition to the results obtained from the circulation of the slides, laboratories which had annually a low number of cervical smears were able to gain experience focused on particular morphological pictures.     

Follow-up study of atypical glandular cells in gynecologic cytology using conventional Pap smears and liquid-based preparations: impact of the Bethesda System 2001

OBJECTIVE: This study evaluated the impact of the Bethesda System (TBS) 2001 in reporting of atypical glandular cells (AGC) when using conventional Pap smears (CS) and liquid-based cytology preparations (LBC). STUDY DESIGN: Follow-up information for all atypical glandular cells of undetermined significance (AGUS)/ AGC cases encountered in Queen Mary Hospital from July 2000 to June 2004 was analyzed. The difference in percentages associated with certain end points when using different reporting systems and preparation methods were compared. The age trends and time interval between cytologic diagnosis and detection of positive end points were studied. RESULTS: More than half of these cases turned out to be "negative." The majority with "negative" end points belonged to the "not otherwise specified" (NOS) groups (including atypical endometrial cells) in TBS 2001. The connotation of "favor neoplastic" carried a high positive predictive value for significant lesions. Most of the significant outcomes were discovered within the subsequent 6 months. A decreased reporting of "AGC, NOS" and an increased reporting of "atypical endocervical cells, NOS" were noted when using LBC. CONCLUSION: Subcategorization of AGC in TBS 2001 according to cellular origin and risk of malignancy, which is further enhanced by application of LBC, is useful.     

Clinical significance of atypical glandular cells by the 2001 Bethesda System in cytohistologic correlation

OBJECTIVE: To evaluate incidence, cytology findings and pathology outcome of atypical glandular cells (AGC) in Pap smears according to the 2001 Bethesda criteria. STUDY DESIGN: From 103,073 consecutive Pap smears, 113 (0.1%) AGC cases were identified. Of these, 91 (80%) had adequate histologic evaluation included in this study. RESULTS: Abnormal histology findings were seen in 38 patients (42%). Final pathology results revealed 14 endometrial adenocarcinomas, 5 endocervical adenocarcinomas, 1 cervical squamous cell carcinoma, 1 endometrial stromal sarcoma, 6 other malignancies, 4 endocervical adenocarcinomas in situ, 4 cases ofendometrial complex byperplasia, 1 case of endocervical glandular dysplasia and 2 cases of cervical intraepithelial neoplasia 3 with glandular involvement. Women with AGC, favor neoplasia, were more likely to have significant pathology than those with AGC, not otherwise specified, 74% vs. 33% (p = 0.002). Some characteristic background cytologic findings were also noticed in most cases of endometrial, fallopian tube and endocervical adenocarcinoma. CONCLUSION: A diagnosis of AGC is more clinically significant by the 2001 Bethesda System, especially the "AGC, favor neoplastic" category. Some background cytologic features are important because they are indicators of malignancy.     

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.     

Clinical impact of atypical squamous cells of undetermined significance. A cytohistologic comparison

OBJECTIVE: To assess the percentage of squamous intraepithelial lesions (SILs) in the atypical squamous cells of undetermined significance (ASCUS) cytologic diagnosis. STUDY DESIGN: From January 1994 to December 1995, 421 cervical Pap smears with a diagnosis of ASCUS were followed with cervical biopsies within three months. The ASCUS cytologic diagnosis was correlated with the histologic findings and stratified according to age group, previous abnormal history and cell type of ASCUS (squamoid vs. metaplastic). RESULTS: Histologic diagnosis showed that of ASCUS diagnoses, 13% were normal, 34% were reactive, 4.8% were atypical, 43% were low grade SIL, 4% were high grade SIL, 1% were carcinoma in situ, and none were invasive lesions. The patients in the youngest group, up to 25 years, demonstrated the highest percentage of SIL. Patients with a previous abnormal gynecologic history showed a higher percentage of SIL than those without an abnormal history. SILs were observed in 51.5% of squamoid ASCUS and 36.5% of metaplastic ASCUS. CONCLUSION: Forty-eight percent of females having an ASCUS diagnosis on Pap smears had SIL and thus a preneoplastic lesion. The highest percentage of SIL was found in females 25 years and younger. Our findings suggest that an ASCUS diagnosis warrants ongoing follow-up.     

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

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

Glandular lesions of the cervix on thin-layer Pap tests. Validity of cytologic criteria used in identifying significant lesions

OBJECTIVE: To determine the cytologic features that are most helpful in characterizing significant glandular lesions of the cervix observed on the ThinPrep (TP) Pap test (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) and to compare these features with those published for conventional smears. STUDY DESIGN: Thirty-nine TP preparations with cytologic evidence of glandular lesions of the cervix and histologic and/or clinical correlation were studied. These lesions included (1) 11 cases of benign/reactive conditions; (2) 10 cases of adenocarcinoma in situ (AIS), of which 1 had both AIS and carcinoma in situ; (3) 1 case of invasive adenocarcinoma; (4) 15 cases of squamous intraepithelial lesions and squamous cell carcinoma, including 4 with glandular involvement, and (5) 2 cases of adenosquamous cell carcinoma. These cases were reviewed by the first author without knowledge of the histologic diagnosis. Twenty-five previously published cytologic criteria were used to evaluate glandular cells on TP slides. Statistical analysis was performed using Fisher's exact test to determine the significance of the features studied. RESULTS: All glandular lesions had cytologic features on TP similar to those previously described on conventional smears. However, TP slides demonstrated enhanced nuclear features but less-preserved architectural patterns. Reactive lesions showed minimal overlapping without hyperchromasia or mitotic figures and with normal nuclear/cytoplasmic ratios. AIS and invasive adenocarcinoma cases had similar features. Increased cellularity and overcrowding were prominent, whereas feathering, rosettes and cell strips were present but subtle. CONCLUSION: Glandular lesions of the cervix on TP slides shared many of the characteristic features reported for conventional smears. However, nuclear details were more pronounced in TP slides, while architectural patterns, although present, were relatively subtle.     

Carcinoma In Situ of the Uterine Cervix—A Review of Some Present Clinical Problems

The vaginal smear reveals a spectrum of borderline lesions of the uterine cervix. This spectrum is the source of new clinical problems involving both the recognition and treatment of these various entities. A review of the literature of the past decade indicates that vaginal smears should be obtained regularly every year or two in all women beginning at the onset of sexual activity, but the initial smear may be falsely negative in 10 to 30 percent of cases. When patients have abnormal smears, the precise diagnosis can be established more accurately by cold-knife conization than by multiple punch biopsy.While hysterectomy has been considered “definitive treatment,” late recurrence in the vagina occurs in 1.24 percent of patients so treated. A compilation of 1,100 patients with carcinoma in situ of the cervix treated by conization and follow-up smear reveals that in over 90 percent the disease was controlled by the cone alone, and the remainder by repeat cone or hysterectomy.Precise definition is required in treatment decisions concerning micro-invasive lesions, but these may be well treated by non-radical measures. In almost 500 patients so treated, no death occurred from therapy or tumor metastasis.When carcinoma in situ is found during pregnancy, a coexisting invasive carcinoma must be excluded by appropriate conization or punch biopsy and definitive therapy completed after vaginal delivery.     

Clinical value of repeat Pap smear at the time of colposcopy

OBJECTIVE: To determine the clinical value of a repeat (second) Pap smear at the time of colposcopy in the management of patients with recent cytologic abnormalities. STUDY DESIGN: A study of paired Pap smears and their corresponding cervical biopsies during a two-year period, commencing in June 1996, was undertaken. Pap smears and cervical biopsies from 614 patients were evaluated in the Department of Pathology, Royal Darwin Hospital, Northern Territory, Australia. To maintain uniformity, the cytologic and histologic findings were assessed according to the Bethesda System. RESULTS: The original (first) Pap smears included 288 high grade and 326 low grade lesions. The second smears showed 200 high grade, 221 low grade, 167 normal and 26 unsatisfactory cases. Punch biopsies revealed 242 high grade, 300 low grade and 72 inflammatory/reactive lesions. The changes noted in the second Pap smears and in the punch biopsies in the group originally diagnosed as having high grade disease were generally less advanced. The second Pap smears and corresponding cervical punch biopsies showed more advanced changes in the group originally diagnosed as having low grade disease. Removal of part of the abnormal epithelium during the first Pap smear and the desire of the colposcopist not to damage the surface epithelium prior to performing a cervical biopsy may account for some of these findings. Sampling errors and morphological misinterpretation may explain some of the findings. CONCLUSION: In the second smears, new cases of high grade abnormality were discovered mainly in patients with low grade changes on the first smears. Therefore, a second Pap smear at the time of colposcopy is justifiable in the group with low grade changes on the first smear.     

Borderline nuclear change; can a subgroup be identified which is suspicious of high‐grade cervical intraepithelial neoplasia,i.e. CIN 2 or worse?

Borderline nuclear change; can a subgroup be identified which is suspicious of high‐grade cervical intraepithelial neoplasia, i.e. CIN 2 or worse? Only 10% of first borderline smears are associated with a histological high‐grade (HG) abnormality, i.e. CIN 2,3, invasive malignancy or glandular neoplasia on subsequent investigation. The advantages of highlighting this subgroup are obvious but is this possible? From 1996 and 1997, 242 borderline smears with histological follow‐up were examined by two independent experienced observers (observer 1 and 2) without prior knowledge of further investigation results. For each smear a profile of nuclear details was produced, also noting the type of cell mainly affected by the process; then the observers were asked to assess the degree of worry of HG disease for each smear i.e. whether the smear fell into group 1 borderline changes indicative of low‐grade (normal, inflammatory, CIN1/HPV) disease (BL/LG) or group 2 difficult borderline smear, HG disease (CIN 2,3, invasive neoplasia or glandular neoplasia) cannot be excluded (BL/HG). Observer 1 selected a group of BL/HG with a PPV for HG disease of 38%, with observer 2 having a PPV of 50%; this compared with the overall laboratory HG disease PPV for borderline smears of 14%. Both observers found the most useful criterion to be the increase in nuclear:cytoplasmic ratio. Our results show that it is possible to separate a small group of borderline smears which should be classified as ‘borderline/high grade lesion difficult to exclude’ (BL/HG). Both observers had some success in arriving at this classification although their method of selecting out this group was quite different.     

Triage of Atypical Glandular Cell by SOX1 and POU4F3 Methylation: A Taiwanese Gynecologic Oncology Group (TGOG) Study

Introduction

Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC) are detected on Pap smear with unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures.

Methods

We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed “AGC not otherwise specified” (AGC-NOS) were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR) was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3⁺ and endometrial complex hyperplasia.

Results

In 55 patients with AGC, the sensitivity for methylated (^m) SOX1^m, PAX1 ^m, ZNF582^m,PTPRR^m, AJAP1^m, HS3ST2^m, and POU4F3^m for detecting CIN3⁺ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions.

Conclusion

Methylated (^m) SOX1^m and POU4F3^m could be new methylation biomarkers for detection of CIN3⁺ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1^m / POU4F3^m, colposcopy, cervical conization or endometrial sampling should be considered.