Agreement Between Endocervical Brush and Endocervical Curettage in Patients Undergoing Repeat Endocervical Sampling
Meredith J. Alston MD David W. Doo MD Sara E. Mazzoni MD MPH Elaine H. Stickrath MD
Denver Health Medical Center University of Colorado Department of Obstetrics and Gynecology Background
• Women with abnormal Pap tests referred for colposcopy frequently require sampling of the endocervix • ASCCP deems both the endocervical brush (ECB) and the endocervical currette (ECC) appropriate means of collecting endocervical samples (1) • Both have advantages and disadvantages, and it is unclear if one modality is superior Background
• ECB has good sensitivity for endocervical lesions, it has poor specificity, ranging from 26- 38%2,3 • ECC has an excellent negative predictive value of 99.4% in women who had a satisfactory colposcopy • ECB is better tolerated by the patient, but runs the risk of contamination from the ectocervix • ECC is less likely to obtain an adequate sample Background
• The results from the endocervical sample may influence clinical management after colposcopy. • Certain treatment options for high grade squamous intraepithelial neoplasia are available only to women with negative endocervical sampling. ▫ Ablative techniques ▫ Expectant management Background
• Over concerns related to potential complications of excisional treatments, as well as over- treatment, there has been a push to re-introduce ablative techniques and, in appropriate clinical circumstances, expectant management, into the routine treatment of patients with cervical cancer precursors (12). Background
• At our institution, it is our concern that due to the possibility of contamination from the ectocervix, a positive ECB may not represent a true positive endocervical sample. • We do not use a sleeve • Positive ECBs return for ECC if otherwise a candidate for ablative therapy or expectant management Objective
• To describe the agreement between these two modalities of endocervical sampling. • Aid clinicians in: ▫ counseling of patients ▫ interpretation of results ▫ selection of an endocervical sampling method in varied clinical scenarios Methods
• IRB approval was obtained through the Colorado Multiple Institutional Review Board
• Retrospective cohort study
• April 1, 2013-June 15, 201
• ECB and returned for ECC Methods
• ECB sampling results ▫ “Low-grade” LSIL ASCUS ▫ “High-grade” HSIL ASC-H • ECC results: negative, LSIL, and HSIL according to LAST terminology(13). Methods • Demographics: ▫ Age ▫ Gravidity ▫ Parity ▫ Insurance ▫ primary language ▫ Contraception ▫ menopausal status ▫ Weight ▫ current drug or tobacco use ▫ history of prior treatment for dysplasia (including type of treatment) Methods • REDCap • Percent agreement between ECB and ECC were calculated based on “low-grade” and “high-grade” classifications • Chi-square and student’s t-test were used to determine differences in dichotomous and continuous variables • Multivariate analyses, using logistic regression modeling, were used to compare outcome measures among the groups • Statistical tests were considered significant at P<0.05. Table 1. Patient Demographics and Clinical Characteristics Mean Age (years) 33.9 ± 10.3 Gravidity 2.27 ± 1.8 Results Parity 1.8 ± 1.5 Primary Language English 56 (70.9%) Spanish 20 (25.3%) Other 3 (3.8%) Insurance Yes 56 (70.9%) No 23 (29.1%) Contraception Method Condoms 7 (8.9%) Depo Provera 4 (5.1%) Implanon/Nexplanon 6 (7.6%) IUD 19 (24.1%) OCPs/Patch/Ring 6 (7.6%) Menopause 7 (8.9%) Sterilization 6 (7.6%) Tobacco Use Yes 14 (17.7%) No 65 (82.3%) Drug Use Yes 2 (2.5%) No 77 (97.5%) History of Prior Treatment Yes 4 (5.1%) No 57 (72.2%) Not Documented 18 (22.8%)
Results Results
Table 2. Demographic and Clinical Predictors of Agreement Between ECB and ECC Variable Agreement No Agreement P Value n=8 n=71 Mean Age (years) 44.3 ± 13.3 32.7 ± 9.3 0.049 Mean Parity 1.5 ± 1.1 1.9 ± 1.6 0.38 Mean weight (pounds) 169 ± 36 156 ± 39 0.37 Primary Language English 5 (62.5%) 51 (71.8%) 0.59 Insured 6 (75.0%) 50 (70.4%) 0.78 Progestin Only Contraception 1 (12.5%) 22 (31.0%) 0.24 Estrogen Contraception 0 6 (8.5%) 1 Menopause 3 (37.5%) 4 (5.6%) 0.02 IUD 0 14 (19.7%) 0.07 Tobacco 2 (25.0%) 12 (16.9%) 0.59 Drugs 0 2 (2.8%) 1 Prior Excision 2 (25.0%) 1 (1.4%) 0.03 Atrophy 1 (12.5%) 7 (9.9%) 1 IUD = Intrauterine Device Discussion
• There is poor agreement between ECB and ECC results for both low-grade (7.4%) and high-grade (16%) dysplasia at the time of colposcopy in our patient population using an unsleeved cytobrush. Discussion
• Although the ASCCP recommends either cytobrush or curettage for evaluation of the endocervix(15), there has been a significant amount of controversy over which is the preferred method. • Previous studies that have compared the relative sensitivities and specificities of the two methods have produced a wide range of results. Discussion
• Our data suggests that ECB collected at the time of colposcopy overestimates the presence of endocervical disease when compared to ECC. We suspect that this may be in a large part due to atypical ectocervical cells adhering to the brush at the time of ECB and thus giving false positive results. Discussion
• In our patient population, given the poor agreement between the two modalities, we have elected to perform endocervical sampling with ECC in those patients who may be candidates for expectant management or ablative therapies. References
• 1. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain JM, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis. 2012 Jul;16(3):175–204. • 2. Holmstrom S. A prospective randomized comparison of the endocervical brush and endocervical curette. Obstet Gynecol. 2002 Apr;99(4):S4. • 3. Mogensen ST, Bak M, Dueholm M, Frost L, Knoblauch NO, Praest J, et al. Cytobrush and endocervical curettage in the diagnosis of dysplasia and malignancy of the uterine cervix. Acta Obstet Gynecol Scand. 1997 Jan;76(1):69–73. • 4. Boardman LA, Meinz H, Steinhoff MM, Heber WW, Blume J. A randomized trial of the sleeved cytobrush and the endocervical curette. Obstet Gynecol. 2003 Mar;101(3):426–30. • 5. Weitzman GA, Korhonen MO, Reeves KO, Irwin JF, Carter TS, Kaufman RH. Endocervical brush cytology. An alternative to endocervical curettage? J Reprod Med. 1988 Aug;33(8):677–83. • 6. Andersen W, Frierson H, Barber S, Tabbarah S, Taylor P, Underwood P. Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal. Am J Obstet Gynecol. 1988 Sep;159(3):702–7. • 7. Klam S, Arseneau J, Mansour N, Franco E, Ferenczy A. Comparison of endocervical curettage and endocervical brushing. Obstet Gynecol. 2000 Jul;96(1):90–4. • 8. Dunn TS, Stevens-Simon C, Moeller LD, Miekle S. Comparing endocervical curettage and endocervical brush at colposcopy. J Low Genit Tract Dis. 2000 Apr;4(2):76–8. • 9. Hoffman MS, Sterghos S, Gordy LW, Gunasekaran S, Cavanagh D. Evaluation of the cervical canal with the endocervical brush. Obstet Gynecol. 1993 Oct;82(4 Pt 1):573–7. • 10. Gosewehr JA, Julian TM, O’Connell BJ. Improving the Cytobrush as an aid in the evaluation of the abnormal Papanicolaou test. Obstet Gynecol. 1991 Sep;78(3 Pt 1):440–3. • 11. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet Lond Engl. 2006 Feb 11;367(9509):489–98. • 12. Khan MJ, Smith-McCune KK. Treatment of cervical precancers: back to basics. Obstet Gynecol. 2014 Jun;123(6):1339–43. • 13. Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: Background and Consensus Recommendations From the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012 Jul;16(3):205–42. • 14. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377–81. • 15. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S1–27. • Thank you! Are Women With Abnormal Pap Smears Being Discharged from Colposcopy Too Soon?
Rachel Kupets MD, MSc, Anna Kone PHD, Julia Gao, Li Wang
Ontario Cervical Screening Program, Cancer Care Ontario Verbal Disclosure
•No Disclosures Introduction
• Research has found that more than half of women referred for abnormal cervical cytology are exited from colposcopy with out undergoing treatment
• Concern that lesions may have been missed in untreated women who may continue to be at elevated risk of developing cervical cancer
• Mcredie et al. published that 50% of women with untreated CIN III progressed into invasive cancer
• Concern whether colposcopy has adequately excluded high grade cervical dysplasia
Kupets, R et al, J Obstet Gynaecol Can. 2014 Dec;36(12):1079-84. McCredie MR, et al Lancet Oncol. 2008 May;9(5):425-34. doi: 10.1016/S1470-2045(08)70103-7 Objective
• To determine the subsequent cervical cancer risk of women discharged from colposcopic care with out treatment as compared to those who under go treatment
• To determine if any clinical factors or colposcopic practices were associated with cervical cancer risk Setting and Study Design
• This study is carried out in the province of Ontario, Canada which has 4.3 million screen eligible women aged 21-69
• Given the universal health care, all residents have a unique health care number which allows for linkage of multiple data bases which reflect health care utilization and cervical smear results
• This study is a population based retrospective cohort design carried out with the use of administrative data Methods
• Cytobase: Pap smear results;
• RPDB: age, socioeconomic characteristics;
• CHDB: services provided by physicians;
• OCR: cancer registry; and
• PIMS: cancer information Methods • Study Cohort: women with a first time cytologic abnormality between 2007-2010 who were referred to colposcopy with one year of pap. No prior history of abnormal pap, colposcopy or treatment for dysplasia or cancer in 3 years prior • Colposcopic episode end: no activity for 14 months • Cohort followed until 2015 • Treatment status was determined with in colposopic episode and cancer incidence was determined post episode Methods
• Logistic Regression assessed impact of colposcopic care, patient factors and screening post discharge on subsequent cervical cancer risk
• Results are stratified by initial cytology diagnosis Characteristics of Women in the Cohort, by Initial Cytology % of Women Exiting After an Initial Colposcopy and No Treatment, by Initial Cytology and Women’s Characteristics Percentage of Women with Treatment During Episode, by Characteristics Percentage of Women with Cancer After Episode, by Characteristics What impacts Risk of Cervical Cancer After Exit? High grade Initial Cytology What Impacts Risk of Cervical Cancer After Exit? Low grade Initial Cytology Conclusions • This study represents a cohort of 56,703 women who initiated a colposcopic episode of care between 2007- 2010 • Women referred to colposcopy for a high grade pap smear and are discharged with out treatment are at elevated risk of cervical cancer; 1.1% vs. 0.3% for those who under go treatment • Mean time to the development of cervical cancer in this group was 588 days +/- 689 days (1-2609) post exit from colposcopy • Women referred for a low grade dysplasia who are discharged with out treatment are NOT at elevated risk Conclusions • Currently due to the fragmented screening program in many jurisdictions in the US and Canada, there is not an integrated cervical cancer screening program which allows women to transition easily between screening, colposcopy, surveillance and back to screening again • This study raises the importance of the establishing an adequate number of evaluations per colposcopic episode and having strategies of stratifying risk for women in whom a lesion is not detected • Proper exit strategies from colposcopy need to be established for treated and untreated women • Appropriate recommendations need to be provided by colposcopists regarding follow up , frequency of screening post colposcopy to primary care physicians and women Thank You
To my co-authors
This Study was initiate and supported by Cancer Care Ontario. We gratefully acknowledge the support of the Ministry of Health and Long-Term Care. The views expressed in this study are those of Cancer Care Ontario and do not necessarily reflect those of the Ontario Ministry of Health and Long-Term Care or the Government of Ontario. Folate Receptor-Mediated Staining Solution (FRDTM) For Detecting CIN2+
Yun Zhao MD Department of Gynecology Peking University People’s Hospital Estimated cervical cancer incidence worldwide, 2012
effective screening, early diagnosis and treatment for pre- cancer and early cancer is imperative. Source: Comprehensive Cervical Cancer Control, A guide to essential practice, WHO 2014 What’s FRD? Folate Receptor-Mediated Staining Solution (FRDTM ) is designed for rapid visualization of the cervical neoplastic epithelia to early detect abnormal lesions (CIN2+). Test results are determined immediately (within 60 sec) after staining of the entire cervical epithelia. FRDTM is capable of detecting abnormal lesions of both squamous and column epithelia. Characteristics of Tumor Cells
Folate receptors over-expressed on tumor cell membranes [1,2] Reactive oxygen species (ROS) accumulated in tumor cells [3,4] . High demand for iron [5-7] : 2+ 3+ - Fe +H2O2→Fe +OH +·OH How to detect cervical lessions?
Conjugates binds to folate receptor and trigger endocytosis. Oxidation reaction. Reaction product exits. Reference
[1] Zhao XB, Lee RJ. Tumor-selective targeted delivery of genes and antisen seo ligo deoxyribonuc leo tides via the folate receptor [J].Adv Drug Deliv Rev,2004,56(8):191-193 [2] Reddy JA, Allagadda Vm, Leamon CP. Targeting therapeutic and imaging agents to folate receptor positive tumors [J].Current Pham Biotech,2005,6,131-150 [3]Goncalves TL, Erthal F, Corte CL, et al. (2005) Involvement of oxidative stress in the pre-malignant and malignant states of cervical cancer in women. Clin Biochem 38: 1071-1075 [4] Beevi SS, Rasheed MH, Geetha A ,et al. (2007) Evidence of oxidative and nitrosative stress in patients with cervical squamous cell carcinoma. Clin Chim Acta 375: 119-123 [5] Canto MI, Setrakian S, Willis J, et al, Methylene blue-directed biopsies improve detection intestinal metaplasia and dysplasia in Barrett’s esophagus [J].Gastrointest Endosc, 000,5:560 [6]Link EM, Blower PJ,Costa DC, et al, Early detection of melanoma metastases with radioiodinated methylene blue[J].Eur J Nuclear Med, 1998,25(9):1322 [7]Kakhlon O,Cabantchik Z . The labile iron pool: characterization, measurement, and participation in cellular processes. Free Radic Biol Med,2002,33(8):1037-1046
FRD test procedure
1.Dip to get solution 2.Smear on the cervix 3.Observe color change FRD Staining Test Multi-center study in the Beijing
Cervical cancer screening
Cytology HR-HPV
NILM ≥ASCUS + -
FRD staining
Colposcopy
Histopathology FRD Staining Test Multi-center study in the Beijing Cytology and HPV test: Patients underwent routine cervical cancer screening. FRD cervical staining: Patients who were returning for evaluation based on an abnormal cervical cytology result and/or HPV results, underwent FRD staining test before they refer to colposcopy. Colposcopy: Colposcopy was performed on patients who had a cytology result of ASCUS or greater, and/or had a positive high-risk HPV result. Biopy: directed or random multiple biopsies and endocervical curettage (ECC) * The multi-center study was approved by the ethical committee of Peking University People’s Hospital, which played the leading role in directing this research. Shaanxi GaoYuan in-vitro diagnostic reagents Co., Ltd only donated FRD staining solution and trained. The excluded standard : Pregnant before examination. Acute inflammation of cervix and/or vaginitis. Women with total hysterectomy. Cervical surgeries, including the conization of cervix, ablative therapy. Patients who has been diagnosed as CIN2+. 1,504 women, aged 20 – 76(Mean 40.29± 10.17 )
Age Case number 20-29 214( 14.23%) 30-39 562( 37.37%) 40-49 409( 27.19%) 50-65 309( 20.55%) >65 10( 0.66%) Total 1504 Results
Histologic Diagnosis Case Number（%） NILM 503( 33.44%)
CIN1 440( 29.26%)
CIN2 254( 16.89%)
CIN3 257( 17.09%)
SCC 50( 3.32%) Total 1504 Sensitivity, Specificity, Positive Prediction Value (PPV), Negative Prediction Value (NPV) of Cytology ( ≥ASCUS), High-Risk HPV, and FRD staining for CIN2+ (n =1504)
Characteristic Cytology HPV FRD Coincidence rate, 48.87 (46.34-51.40) 45.01（42.50-47.53） 66.62 (64.24-69.01) %(95%CI) KAPPA, %(95%CI) 8.77 (5.06-12.48) 8.20（5.90-10.49） 34.59 (30.16-39.03) Sensitivity, %(95%CI) 80.39 (77.11-83.68) 95.54（93.84-97.25） 77.72 (74.27-81.16)
Specificity, %(95%CI) 30.12 (27.19-33.04) 14.95（12.68-17.23） 60.02 (56.89-63.15)
PPV, %(95%CI) 40.63 (37.74-43.52) 40.06（37.43-42.69） 53.63 (50.20-57.06)
NPV, %(95%CI) 72.08 (67.65-76.51) 84.94（79.50-90.38） 81.91 (79.04-84.78)
PLR, (95%CI) 1.15(1.08-1.22) 1.12（1.09-1.16） 1.94(1.78-2.13) NLR, (95%CI) 0.65(0.54-0.79) 0.30（0.20-0.45） 0.37(0.32-0.44) Sensitivity, Specificity, Positive Prediction Value (PPV), Negative Prediction Value (NPV) of Cytology ( ≥ASCUS), High-Risk HPV, and FRD staining for CIN3+ (n =1504)
Characteristic Cytology HPV FRD Coincidence rate, 39.96 (37.48-42.44) 29.72（27.41-32.03） 60.90（58.44-63.37） %(95%CI) KAPPA, %(95%CI) 6.31 (3.76-8.86) 3.80（2.43-5.18） 25.39（21.75-29.03）
Sensitivity, %(95%CI) 83.71 (79.58-87.84) 95.77（93.51-98.02） 86.64（82.84-90.45） Specificity, %(95%CI) 28.74 (26.17-31.30) 12.78（10.89-14.67） 54.30（51.48-57.12）
PPV, %(95%CI) 23.15 (20.67-25.63) 21.97（19.75-24.19） 32.72（29.49-35.94）
NPV, %(95%CI) 87.31 (84.02-90.60) 92.17（88.08-96.26） 94.07（92.31-95.83）
PLR, (95%CI) 1.17(1.11-1.25) 1.10（1.06-1.13） 1.90（1.76-2.05）
NLR, (95%CI) 0.57(0.43-0.74) 0.33（0.19-0.58） 0.25（0.18-0.33） The Results of FRD and Histologic Diagnosis by Cytologic Negative
Histologic Diagnosis
FRD NILM CIN1 CIN2 CIN3 SCC Total - 114( 63.69%) 67( 63.81%) 26( 43.33%) 10( 21.28%) 0( 0.00%) 217( 55.08%)
+ 65( 36.31%) 38( 36.19%) 34( 56.67%) 37( 78.72%) 3(100.00%) 177( 44.92%)
Total 179 105 60 47 3 394 • FRD staining Association with Different Age Groups for the Detection of CIN2+
FRD Characteristic 20-29 30-39 40-49 50-65 Coincidence rate, 65.42（59.05-71.79） 62.99（59.00-66.98） 65.77（61.17-70.37） 75.08（70.26-79.90） %(95%CI)
KAPPA, %(95%CI) 31.65（19.82-43.49） 27.65（20.18-35.13） 33.70（25.38-42.01） 50.12（40.85-59.39）
Sensitivity, %(95%CI) 75.34（65.45-85.23） 73.42（67.61-79.23） 79.87（73.43-86.30） 84.68（77.98-91.38）
Specificity, %(95%CI) 60.28（52.21-68.36） 56.18（50.90-61.45） 57.69（51.69-63.70） 69.70（63.30-76.10）
PPV, %(95%CI) 49.55（40.25-58.85） 52.24（46.70-57.79） 51.97（45.49-58.44） 61.04（53.34-68.74）
NPV, %(95%CI) 82.52（75.19-89.86） 76.40（71.14-81.66） 83.33（77.89-88.78） 89.03（84.11-93.95）
PLR, (95%CI) 1.90（1.49-2.42） 1.68（1.45-1.94） 1.89（1.60-2.22） 2.79（2.23-3.50）
NLR, (95%CI) 0.41（0.27-0.62） 0.47（0.37-0.60） 0.35（0.25-0.49） 0.22（0.14-0.34） • Cytology (≥ASCUS) Association with Different Age Groups for the Detection of CIN2+ Cytology Characteristic 20-29 30-39 40-49 50-65 Coincidence rate, 43.93（37.28-50.57） 48.40（44.27-52.53） 47.43（42.59- 54.37（48.82-59.92） %(95%CI) 52.27） KAPPA, %(95%CI) 2.35（-7.32-12.02） 6.63（0.45-12.82） 6.69（-0.44-13.82） 19.00（11.15-26.84）
Sensitivity, 75.34（65.45-85.23） 79.73（74.44-85.02） 78.52（71.93- 87.39（81.21-93.56） %(95%CI) 85.12） Specificity, 27.66（20.28-35.04） 27.94（23.17-32.71） 29.62（24.07- 35.86（29.18-42.54） %(95%CI) 35.17） PPV, %(95%CI) 35.03（27.57-42.49） 41.94（37.23-46.65） 39.00（33.48- 43.30（36.81-49.79） 44.52） NPV, %(95%CI) 68.42（56.35-80.49） 67.86（60.12-75.59） 70.64（62.09- 83.53（75.64-91.41） 79.19） PLR, (95%CI) 1.04（0.88-1.23） 1.11（1.01-1.22） 1.12（0.99-1.25） 1.36（1.20-1.55）
NLR, (95%CI) 0.89（0.55-1.44） 0.73（0.53-0.99） 0.73（0.51-1.04） 0.35（0.21-0.59） Conclusion 1
Another way for cervical lesion detecting
FRD has a clinical sensitivity of 86.64% and a specificity of 54.30% for detection of lessions(CIN3+) Conclusion 2 FRD Staining-Rapid and intuitive visual results
1 minute Conclusion 3
FRD Staining-Full fill entire cervix
During the procedure, the two cotton swab will cover the entire cervix including the ecto and endocervix Visualization of FRD Staining Acknowledgments We thank all 13 research centers for providing their study data, and the center names and experts in charge of each center were as follows: Peking University People's Hospital (Lihui Wei); Chinese PLA General Hospital (Yali Li); Beijing Anzhen Hospital, Capital Medical University (Bin Li); Beijing Chao-Yang Hospital (Zhenyu Zhang); Beijing Tian Tan Hospital, Capital Medical University (Limin Feng); Fu Xing Hospital, Capital Medical University (Ailuan Lai) Xuanwu Hospital, Capital Medical University (Fengying Wang) Beijing Hospital (Qiubo Lv) Beijing Obstetrics and Gynecology Hospital, Capital Medical University (Dan Lu) Peking University Third Hospital (Hongyan Guo) Beijing Tongren Hospital, Capital Medical University (Jianjun Zhai) Peking Union Medical College Hospital (Yang Xiang) Beijing Shijitan Hospital, CMU (Hongxia Li) Thanks for your interest and attention ! p16 expression in colposcopy-directed and random cervical biopsies of CIN 2 and CIN 3
Cynthia Arvizo, MD April 14, 2016 Cleveland Clinic Colposcopy training focuses on sampling visible lesions POI micro-biopsy protocol
• Designed by Belinson et al to standardize colposcopy and reduce verification bias in clinical trials • First employed in a large population based study in 1997 - Shanxi Province Cervical Cancer Screening Study (SPOCCS I) POI micro-biopsy protocol
1. Divide cervix into 4 quadrants and evaluate by quadrant 2. Biopsy abnormal lesions 3. Biopsy all negative quadrants at the squamocolumnar junction 4. Perform ECC Colposcopy Instruments
POI micro-biopsy instrument
Tischler biopsy forceps Ongoing debate
• Should we biopsy more than what we see? (random biopsies in negative quadrants)
• Do positive biopsies of nonvisible lesions even matter? Sensitivity of Colposcopy for CIN2+
Sensitivity Massad et al 2003 56% Pretorius et al 2004 57.1% Gage et al 2006 69.9%
One additional random biopsy can detect up to 20% more CIN 2 or greater*
Massad, et al. Gynecologic Oncology, 89(3), 424–8. Pretorius et al. Am J Obstet Gynecol. Aug;191(2):430-4., 191(2), 430–434 Gage el al. Obstetrics and Gynecology, 108(2), 264–72. *Huh et al. Obstetrics and Gynecology, 124(4), 670–8. Ongoing debate
• Should we biopsy more than what we see?
• Do positive biopsies of nonvisible lesions even matter? Random biopsies of CIN 2 and 3 are thinner than targeted biopsies
600
500
400
300 COLPO IMP NORMAL COLPO IMP HIGH 200
100 Average Thickness (microns) Average
0 NORMAL CIN 1 CIN 2 CIN 3
Yang B, el al. Gynecol Oncol. 2008;110(1):32-36. p16 overexpression is associated with progression to CIN3
http://www.nature.com/bjc/journal/v112/n6/fig_tab/bjc201559f1.html
Virchows Arch. 2004;445(6):616-620. Hypothesis p16 expression of colposcopy-directed and random biopsies of CIN 2 and CIN 3 is similar Study specimens
• Tissue blocks from patients with CIN 2 or greater were identified from SHENCCAST II database – 10,000 patient population based clinical trial conducted in China that evaluated self sampling and three HPV testing technologies Study design
• Selected biopsies were re-cut and stained for p16 • Diffuse overexpression of p16 was considered “p16 positive” • Pathologist blinded to initial colposcopic interpretation and whether biopsies were directed or random Results of biopsies showing CIN 2 89 patients with CIN2 21 patients without and complete data CIN2 on recut
10 patients with new CIN3 on recut
3 patients without 55 patients diagnosed CIN2 on IHC slides with CIN2 on recut
220 individual biopsies
94 Normal 50 CIN1 76 CIN2 p16 positivity of colposcopy-directed and random biopsies of CIN 2 is similar
p16 positive (%) p16 negative (%) Total Colpo-directed 46 (86.8) 7 (13.2) 53 Random 19 (82.6) 4 (17.4) 23 Total 65 11 76
Chi square p = 0.73 Results of biopsies showing CIN 3 138 patients with complete data 11 patients CIN3 on ECC only 2 patients cancer only 125 patients (no CIN3) included
500 individual biopsies recut and reviewed
155 Normal 79 CIN1 21 CIN2 232 CIN3 9 Cancer 2 AIS
2 insufficient tissue p16 positivity of colposcopy-directed and random biopsies of CIN 3 is similar
p16 positive (%) p16 negative (%) Total Colpo-directed 168 (97.7) 4 (2.3) 172 Random 55 (91.7) 5 (8.3) 60 Total 223 9 232
Fisher’s exact p=0.052 Random lesions of CIN 3 involve less quadrants
No. quadrants Colpo-directed Random Both 1 24 20 0 2 22 1 10 3 16 1 8 4 6 0 8 Conclusions
• Should we biopsy more than what we see? – Additional biopsies increase detection of CIN 2 or greater • Do positive biopsies of nonvisible lesions even matter? – Colposcopy-directed and random biopsies similarly overexpress p16, suggesting they have similar biology and both should be part of colposcopy protocols Acknowledgments
Qing Chen, MD; Chun Wang, MD; Bin Yang, MD, PhD; Robert G. Pretorius, MD; Ruifang Wu, MD, Guixiang Wang, MD; Jerome L. Belinson, MD Office Hysteroscopy In The Diagnosis Of Endocervical Intra-epithelial Neoplasia
Ahmad Sameer Sanad Minia Maternity University Hospital Egypt Cervical glandular intraepithelial neoplasia (CGIN) is considered as a precursor for adenocarcinoma in-situ (AIS) and subsequently invasive cervical adenocarcinoma.
The diagnosis of CGIN faces many challenges at both clinical and pathological level. The lesion may present high in the cervical canal so it may not be seen during colposcopic examination Aim of the Study
The aim of this study is to evaluate the role of office hysteroscopy in diagnosis of CGIN in patients with CIN Patients & Methods
This study was an observational cross-sectional study involving 124 patients with abnormal Pap smear or positive VIA in the period between May 2013 and Nov 2014.
The study was approved by scientific ethical committee of the Department of Ob & Gyn, Minia University in Jan 2013. And from the Institutional Review Board of the Faculty of Medicine; Minia University in Feb 2013. Patients & Methods
The inclusion criteria of the study were Age > 18 years, Negative pregnancy test and Positive PAP smear or positive VIA Patients & Methods
The inclusion criteria of the study were Age > 18 years, Negative pregnancy test and Positive PAP smear or positive VIA Patients & Methods
Exclusion Criteria Current cervicitis or PID. Current uterine bleeding. Evidence of invasive cervical lesions with naked eye or colposcopic examination The study procedure:
The study was conducted through 3 steps
Colposcopy and colposcopy-directed cervical biopsies using (1DL Leisegang Colposcopy with Optic-2 Med Inc Germany). Punch biopsies were taken from any suspicious region. The study procedure:
Cervical hysteroscopy: 3-mm continuous-flow office hysteroscopy with an operative channel.
The light intensity used was as low as possible.
The outer sheath was connected to infusion pump that allowed distension of the uterus with fluid medium 0.9% saline. The study procedure:
Vaginoscopic approach.
Distension of the endocervix was obtained using an irrigation-suction electronic device (Hystromat; Karl Storz).
When the external uterine orifice was visualized, the irrigation of saline was stopped and a syringe with 5 mL of 5% acetic acid was connected to the inflow channel of the hysteroscopy. The study procedure:
A panoramic view of the ectocervix, the transformation zone and the endocervix was noticed for the changes induced by the application of the acetic acid.
The anterior and posterior walls of the endocervix were carefully examined
The lateral walls were examined while gently rotating the tip of the scope within the endocervix, following the principles of an open oblique vision.
Longitudinal crests of the endocervical mucosa were seen protruding into the cavity as the plicae palmatae.
Secondary oblique branching of the mucosa appeared as a tree and constituted the arbor vitae The study procedure:
Once an epithelial lesion was suspected, magnify the image on the monitor.
During the examination a biopsy was performed using 5Fr- grasping forceps with teeth.
The endocervical mucosa was evaluated for both vascularization, and morphology.
The procedure was completed with hysteroscopic examination of the uterine cavity Grading of results
1. Positive if there was: atypical TZ, acetowhite epithelium appeared as sharp, distinct, well defined and dense, mosaicism, punctuation, iodine positivity and atypical vessels,
2. Presence of benign lesion as mucous polyp, adenomatous polyp, masses, immature metaplasia.
3. Negative if there was normal cervix that remained pale and pink in color.
4. Doubt results and the tests were repeated one week later Results
Distribution of the patients according to results of referral cytology
Referral Percentage Cytology Number of patients (n=124)
LSIL 94 75.8% HSIL 22 17.7% AGC 5 4% SIL+AGC 3 2.5% Results
Distribution of the patients according to results of colposcopy and histopathology
Colposcopy & histopathology Number of patients Percentage
No lesion 74 59% Benign lesion (n=25) - Cervicitis 6 4.8% - Metaplasia 19 15.3%
Pre-malignant lesion (n=25) - CIN I 15 12.1% - CIN II 7 5.6% - CIN III 5 4 % Total 124 Results
Distribution of the patients according to hysteroscopic findings of the endocervix Hysteroscopic findings of the No. of patients Percentage endocervix No lesion 97 78.2%
Benign lesions: - Mucinous polyp 8 6.5% - Adenomatous polyp 7 5.7% - Metaplasia 3 2.4% Atypical lesions: (n=9) 7.3% - Acetowhite epithelium 4 - Punctation 3 - Mosaicism 2 Total 124 Results
Results of hysteroscopy in comparison with the results of biopsy
Hysteroscopic findings Biopsy of the endocervix Negative biopsy Positive biopsy
No Lesions (n=97) 97 0 Benign lesion (n=18) 17 1
Atypical lesion (n=9) 3 6
Total (n=124) 117 7 Results
Diagnostic performance of hysteroscopy in detecting endocervical lesions
95% confidence % interval Sensitivity (SE) 86 0.773 - 0.996
Specificity (SP) 98 0.963 - 0.994
Positive predictive value (PPV) 67 0.576 - 0.848 Negative predictive value (NPV) 99 0.984 - 0.999 Diagnostic accuracy (DA) 97.1 0.959 - 0.987 Positive likelihood ratio (LR+) 43 39.63 – 46.35 Negative likelihood ratio (LR-) 0.14 0.128 – 0.167 In conclusion
Hysteroscopy appears to be a safe and effective diagnostic tool that can help to increase the detection of CGIN. We recommend office hysteroscopy to be done in all cases with abnormal cervical cytology or positive VIA referred for colposcopic examination