agreement between endocervical brush and endocervical

Agreement Between Endocervical

Brush and Endocervical Curettage in

Patients Undergoing Repeat

Endocervical Sampling

Meredith J. Alston MD David W. Doo MDSara E. Mazzoni MD MPHElaine H. Stickrath MD

Denver Health Medical CenterUniversity of ColoradoDepartment 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 endocervicallesions, 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.

Results

Table 1. Patient Demographics and Clinical Characteristics

Mean Age (years) 33.9 ± 10.3

Gravidity 2.27 ± 1.8

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 n=8

No Agreement n=71

P Value

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. ObstetGynecol. 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 endocervicalcurettage? 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 GenitTract 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. ObstetGynecol. 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. ObstetGynecol. 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

http://www.ncbi.nlm.nih.gov/pubmed/18407790

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 MDDepartment of Gynecology

Peking University People’s Hospital

Source: Comprehensive Cervical Cancer Control, A guide to essential practice, WHO 2014

Estimated cervical cancer incidence worldwide, 2012

effective screening, early diagnosis and treatment for pre-cancer and early cancer is imperative.

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] :

Fe2++H2O2→Fe3++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

3.Observe color change1.Dip to get solution 2.Smear on the cervix

Histopathology

Colposcopy

Cervical cancer screening

Cytology HR-HPV

≥ASCUS +

FRD staining

-NILM

FRD Staining Test Multi-center study in the Beijing

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 number20-29 214( 14.23%)30-39 562( 37.37%)40-49 409( 27.19%)50-65 309( 20.55%)>65 10( 0.66%)

Total 1504

ResultsHistologic 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

Characteristic Cytology HPV FRDCoincidence rate,

%(95%CI)48.87 (46.34-51.40) 45.01（42.50-47.53） 66.62 (64.24-69.01)

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 CIN2+ (n =1504)

Characteristic Cytology HPV FRDCoincidence rate,

%(95%CI)39.96 (37.48-42.44) 29.72（27.41-32.03） 60.90（58.44-63.37）

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）

Sensitivity, Specificity, Positive Prediction Value (PPV), Negative Prediction Value (NPV) of Cytology ( ≥ASCUS), High-Risk HPV, and FRD staining for CIN3+(n =1504)

The Results of FRD and Histologic Diagnosis by Cytologic Negative

FRD

Histologic Diagnosis

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+

Characteristic

FRD

20-29 30-39 40-49 50-65

Coincidence rate, %(95%CI)

65.42（59.05-71.79） 62.99（59.00-66.98） 65.77（61.17-70.37） 75.08（70.26-79.90）

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）

Characteristic

Cytology

20-29 30-39 40-49 50-65

Coincidence rate, %(95%CI)

43.93（37.28-50.57） 48.40（44.27-52.53） 47.43（42.59-52.27）

54.37（48.82-59.92）

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, %(95%CI)

75.34（65.45-85.23） 79.73（74.44-85.02） 78.52（71.93-85.12）

87.39（81.21-93.56）

Specificity, %(95%CI)

27.66（20.28-35.04） 27.94（23.17-32.71） 29.62（24.07-35.17）

35.86（29.18-42.54）

PPV, %(95%CI) 35.03（27.57-42.49） 41.94（37.23-46.65） 39.00（33.48-44.52）

43.30（36.81-49.79）

NPV, %(95%CI) 68.42（56.35-80.49） 67.86（60.12-75.59） 70.64（62.09-79.19）

83.53（75.64-91.41）

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）

• Cytology (≥ASCUS) Association with Different Age Groups for the Detection of CIN2+

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 1

FRD Staining-Rapid and intuitive visual results

1 minute

Conclusion 2

FRD Staining-Full fill entire cervix

During the procedure, the two cotton swab will cover the entire cervix including the ecto and endocervix

Conclusion 3

Visualization of FRD Staining

AcknowledgmentsWe 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 squamocolumnarjunction

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), 430–434Gage 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?


Random biopsies of CIN 2 and 3 are thinner than targeted biopsies

Yang B, el al. Gynecol Oncol. 2008;110(1):32-36.

0

100

200

300

400

500

600

NORMAL CIN 1 CIN 2 CIN 3

Ave

rage

Th

ickn

ess

(mic

ron

s)

COLPO IMP NORMAL

COLPO IMP HIGH

p16 overexpression is associated with progression to CIN3

Virchows Arch. 2004;445(6):616-620.

http://www.nature.com/bjc/journal/v112/n6/fig_tab/bjc201559f1.html

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 colposcopicinterpretation and whether biopsies were directed or random

Results of biopsies showing CIN 2

89 patients with CIN2 and complete data

55 patients diagnosed with CIN2 on recut

94 Normal 50 CIN1 76 CIN2

220 individual biopsies

21 patients without CIN2 on recut

10 patients with new CIN3 on recut

3 patients without CIN2 on IHC slides

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

p16 positivity of colposcopy-directed and random biopsies of CIN 2 is similar

Results of biopsies showing CIN 3

138 patients with complete data

11 patients CIN3 on ECC only

500 individual biopsiesrecut and reviewed

2 insufficient tissue

155 Normal 79 CIN1 21 CIN2 232 CIN3 9 Cancer 2 AIS

125 patients included

2 patients cancer only (no CIN3)

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


– 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 EndocervicalIntra-epithelial Neoplasia

Ahmad Sameer SanadMinia Maternity University Hospital

Egypt

Cervical glandular intraepithelial neoplasia (CGIN) isconsidered as a precursor for adenocarcinoma in-situ(AIS) and subsequently invasive cervicaladenocarcinoma.

The diagnosis of CGIN faces many challenges at bothclinical and pathological level. The lesion may presenthigh in the cervical canal so it may not be seen duringcolposcopic 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 studyinvolving 124 patients with abnormal Pap smear orpositive VIA in the period between May 2013 and Nov2014.

The study was approved by scientific ethical committeeof the Department of Ob & Gyn, Minia University in Jan2013. And from the Institutional Review Board of theFaculty 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

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.

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.


Vaginoscopic approach.

Distension of the endocervix was obtained using anirrigation-suction electronic device (Hystromat; Karl Storz).

When the external uterine orifice was visualized, theirrigation of saline was stopped and a syringe with 5 mL of5% acetic acid was connected to the inflow channel of thehysteroscopy.


A panoramic view of the ectocervix, the transformation zone and the endocervixwas 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 withinthe endocervix, following the principles of an open oblique vision.

Longitudinal crests of the endocervical mucosa were seen protruding into thecavity as the plicae palmatae.

Secondary oblique branching of the mucosa appeared as a tree and constitutedthe arbor vitae


Once an epithelial lesion was suspected, magnify the imageon the monitor.

During the examination a biopsy was performed using 5Fr-grasping forceps with teeth.

The endocervical mucosa was evaluated for bothvascularization, and morphology.

The procedure was completed with hysteroscopicexamination of the uterine cavity


Grading of results

1. Positive if there was: atypical TZ, acetowhite epitheliumappeared as sharp, distinct, well defined and dense,mosaicism, punctuation, iodine positivity and atypicalvessels,

2. Presence of benign lesion as mucous polyp, adenomatouspolyp, masses, immature metaplasia.

3. Negative if there was normal cervix that remained pale andpink 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 Cytology Number of patients

(n=124)

Percentage

LSIL 94 75.8%HSIL 22 17.7%AGC 5 4%SIL+AGC 3 2.5%

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- Metaplasia

619

4.8%15.3%

Pre-malignant lesion (n=25)- CIN I- CIN II- CIN III

1575

12.1%5.6%4 %

Total 124

Results

Distribution of the patients according to hysteroscopic findings of the endocervix

Hysteroscopic findings of the endocervix

No. of patients Percentage

No lesion 97 78.2%

Benign lesions:- Mucinous polyp- Adenomatous polyp- Metaplasia

873

6.5%5.7%2.4%

Atypical lesions: (n=9)- Acetowhite epithelium- Punctation- Mosaicism

432

7.3%

Total 124

Results

Results of hysteroscopy in comparison with the results of biopsy

Hysteroscopic findings of the endocervix

Biopsy

Negative biopsy Positive biopsy

No Lesions (n=97) 97 0Benign 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 - 0.996Specificity (SP) 98 0.963 - 0.994Positive predictive value (PPV) 67 0.576 - 0.848Negative predictive value (NPV) 99 0.984 - 0.999Diagnostic accuracy (DA) 97.1 0.959 - 0.987Positive likelihood ratio (LR+) 43 39.63 – 46.35Negative likelihood ratio (LR-) 0.14 0.128 – 0.167

Results

In conclusion

Hysteroscopy appears to be a safe and effectivediagnostic tool that can help to increase the detectionof CGIN. We recommend office hysteroscopy to bedone in all cases with abnormal cervical cytology orpositive VIA referred for colposcopic examination

agreement between endocervical brush and endocervical

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