3/3/2014 NEW ERA OF THE CERVICAL PAP SMEAR TESTING. Objectives

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1 Yasmin Elshenawy, M.D Outpatient Cytopathology Center Johnson city, TN NEW ERA OF THE CERVICAL PAP SMEAR TESTING Disclosure Statement of Financial Interest I am Yasmin Elshenawy, MD DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. Objectives History and epidemiology of the PAP test HPV and its relation to cervical cancer Understand differenet laboratory screening methods New age cutoffs guidelines for PAP screening Update on management guidelines of squamous cervical lesions 1

2 History GEORGE PAPANICOLAOU ( ) At Cornell Hospital, NY women patients were required to take a routine vaginal smear Dr. Herbert Traut Ob/Gyn collaborated with Dr. Papanicolaou to validate the diagnostic potential of the vaginal smear This diagnostic procedure was named the Pap test Epidemiology Cervical Cancer was the #1 Cancer Killer of Women Now Ranks #13 in the USA 12,000 new cases & more than 4000 deaths in % of squamous CA of the cervix contains DNA from high risk types of HPV (HR HPV) American Cancer Society, Atlanta GA 2013 HPV & Cervical Cancer HPV recognized as the underlying cause of cervical cancer since 1996 NIH Consensus Conference on Cervical Cancer 1996 World Health Organization/European Research Organization on Genital Infection and Neoplasia 1996 Munoz, N. et al. HPV in the etiology of human cancer. Vaccine 24S3 2006;24S3:

3 Pathophysiology Family Papillomaviridae 55 nm in diameter 100 HPV have been characterized, >40 identified in the genital tract Non enveloped viruses, DS DNA genome Integrated in premalignant lesions with tumor DNA Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: Unresolved issues. Nat Rev Cancer. 2007;7:11 22 E6 binds with p53 (blocks apoptosis) E7 binds to retinoblastoma gene (Rb gene) Both cause unrestricted cell proliferation and blockage of apoptosis Common HPV Types and their effects Low risk HPV 6,11 40, 42, 43, 44, 54, 61, 70, 72, 81 Lead to Benign cervical changes Genital warts Munoz et al. N Engl J Med. 2003;348:518. 3

4 Common HPV Types and their effects High risk HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Lead to Precancer cervical changes Cervical cancer Anal and other cancers Munoz et al. N Engl J Med. 2003;348:518 Purpose of the PAP test 1) Detect cervical cancer at an early stage 2) Detect and remove high grade lesions, so prevent potential cervical cancer HSIL on cytology has PPV of 70% for CIN 2 or more Up to 8% will have cancer (higher in older women) Limited by: 1. Small lesions 2. Inaccessible location 3. Poor sampling of lesion 4. Few abnormal cells on the slide 5. Inflammation or blood obscuring cell visualization Cibas; Cytology: Diagnostic Principles and Clinical Correlates, 3 rd edition

5 PAP test is Most successful cancer screening Most expensive cancer screening How to obtain optimum specimen? Cibas, Cytology: Diagnostic Principles and Clinical Correlates 3 rd edition 2009 Types of smears Liquid base Smear Conventional Smear 5

6 Examples of liquid base preparations Liquid based cytology techniques FDA approved ThinPrep Filtration and collection of vacuum packed cells on a membrane and transferring to the glass slide Surepath Centrifugation and sedimentation through a density gradient Cibas: Cytology: Diagnostic Principles and Clinical Correlates, 3 rd edition 2009 Advantages of Liquid base Smaller area to screen, Less mistakes Uniform thickness of the smear Less obscuring muscus and blood Ability to perform HPV DNA and other molecular test 6

7 Automated PAP screening 1998 FDA approved Auto PAP screen: FocalPoint Slide Profiler 2002 use for Surepath 2003 Use for ThinPrep imaging system Regulation of the cytology Laboratory Cibas ; Cytology: Diagnostic Principles and Clinical Correlates, Expert Consult 7

8 In the lab we use SquamousCell Lesions Atypical squamous cells of undetermined significance (ASC US) cannot exclude HSIL (ASC H) Low grade squamous intraepithelial lesion (LSIL) mild dysplasia/cin I High grade squamous intraepithelial lesion (HSIL) CIN2/CIN3/CIS Squamous cell carcinoma NEW ERA with advances in cervical cancer prevention Evidence based cytology screening intervals Cytology technology: liquid based cytology (LBC) Adjunctive test modalities: HPV DNA testing Primary prevention through HPV vaccination, first vaccine hit the market in

9 Evidence based cytology screening intervals Cibas:Cytology: Diagnostic Principles and Clinical Correlates, 3 rd edition 2009 Consensus Conference 2012 American Society of Colposcopy and Cervical Pathology (ASCCP) American Cancer Society American Society of Clinical of Pathology (ASCP) Age Screening Changes Triple A Guideline: ACS, ASCCP, American Society for Clinical Pathology CA Cancer J CLIN March 2012 Age Screening < 21 No Screening Cytology alone every 3 years Preferred: Cytology + HPV every 5 years* OR Acceptable: Cytology alone every 3 years* > 65 No screening, following adequate neg prior screens After total hysterectomy No screening, if no history of CIN2+ in the past 20 years of cervical cancer ever If cytology result is negative or ASCUS + HPV negative 9

10 Age Screening Changes U.S. Preventive Services Task Force (USPSTF) Cervical Cytology Guidelines March 2012 Criteria Grade Recommendation Cytology only, 21 to 65 years old A Every 3 years Cytology + HPV co testing, years old A Every 5 years Women under 21 years old D Avoid screening Age 65 with adequate prior screening and not high risk D Avoid screening Total hysterectomy; benign disease D Avoid screening HPV testing, alone or in combination, < 30 years old D Avoid screening Beware high risk populations, do not follow the guidelines. 1. History of cervical cancer 2. Exposed in utero to diethylstilbestrol (DES) 3. Immune compromised patient (eg, infection with human immunodeficiency virus). HPV Molecular Test Hybrid Capture 2 HPV DNA test GOLD standard Cervista HPV HR test HR HPV DNA based screening assays Cervista HPV 16/18 test HR HPV DNA based genotyping assay, is approved for reflex testing of patients with positive high risk HPV Cervista test results Cobas 4800 HPV test HR HPV DNA based PCR Screening assay with capability for concurrent genotyping for HPV 16 and HPV 18 by real time PCR Aptima HPV assay Detection of E6 and E7 mrna Cox JT, Castle PE, Behrens CM, ey al: Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: Am J Obstet Gynecol 10

11 Role of High risk HPV DNA testing in screening An adjunct to cytology screening in women 30 to 65 years An option for follow up years with ASC US Saslow D, Solomon D, Lawson HW 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. Am J Clin Pathol 2012; 137: HPV test as primary Screening Tool? Strong NPV for HPV test but lack specificity Still unclear =how to follow up on HPV + Harms undefined Lack of US clinical trials results Whitlock EP, Vesco KK, Eder M,etal. Liquid based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med Nov 15;155(10):687 97, W

12 Management changes: Adequacy: Transformation zone (EC/TZ) No (EC/TZ) :Prior recommendation was repeat in 1 year Reasoning was that most CIN/SIL/cancer occurs at (EC/TZ) zone New longitudinal studies fail to show that women with no EC/TZ are at increased risk Can you test for HPV with no TZ? Yes, You can Provides independent information More sensitive in detecting early endocervical adenocarcinoma Preferred in women ages 30 65, repeat in 5 years if both are negative Negative PAP 12

13 Management changes for NILM Management changes: Unsatisfactory Pap Tests Insufficient squamous cells or >75% obscured With liquid based Paps, most related to in adequate squamous cells With conventional smears: blood, mucus and thicker material Specimen Adequacy management Unsatisfactory Pap: repeat in 2 4 months Repeated unsatisfactory results : Proceed to colposcopy Treat specific cause of inflammation or atrophy HPV testing not recommended, Why? Positive HPV/unsat Pap cotest: Still results in more patient work up anyway Negative HPV result not helpful if no cellular control 13

14 LSIL, how to diagnose? Enlarged nuclei 3x size of nucleus of intermediate cell Hyperchromasia No nucleoli Binucleation is more common than multinucleation Koilocytes Management of LSIL Management of LSIL 14

15 HSIL, how to diagnose? Nuclei exhibit asymmetrical 3 D clusters High nuclear irregularities High N/C ratio Management of HSIL ASCUS, how to diagnose? Nuclear changes are more marked than reactive, less than LSIL Nucleus is 2.5 3x size of intermediate cell nucleus 15

16 Management of ASCUS Management of ASCUS 21 24yrs At last Being Rarely or Never Screened is the major contributing factor to most cervical cancer deaths today 16

17 THANK YOU QUESTIONS? 17