GYN (Glandulars) Still Difficult After All These Years! Dina R Mody, MD Director of Cytology Laboratories and fellowship Program Methodist Hospital

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2 GYN (Glandulars) Still Difficult After All These Years! Dina R Mody, MD Director of Cytology Laboratories and fellowship Program Methodist Hospital and Bioreference Labs (Houston) Department of Pathology and Genomic Medicine Houston Methodist Hospital Professor of Pathology and Laboratory Medicine Weill Medical College of Cornell University

3 Objectives Historical perspective Reporting rates and outcomes then and now Reasons for these outcomes i.e mimics and how to resolve major ones Understand the role of HPV testing and biomarkers as applicable to Glandulars in Cervicovaginal cytology Super abbreviated version as I have only 15 minutes at the end of the day

4 Conflict of Interest None with vendors of cytology equipment/testing

5 My editorial in 1999 Has anything changed?

6 Bethesda 2001 AGUS gone! Confusion with ASCUS AGC Atypical glandular cells AIS free standing entity Things remain the same in 2014 just expanded Endometrial cells to be reported in women 45 yrs or older

7 TBS 2001 and 2014 Negative for Intraepithelial Lesion or Malignancy (NILM) Epithelial Cell Abnormality Squamous (ASC-US, ASC-H, LSIL, HSIL,CA) Glandular (AGC, AIS, Adenocarcinomas) Other Other

8 Epithelial Cell Abnormalities Glandular Cell Atypical Glandular Cells (AGC) Unspecified Favor neoplastic Atypical Endocervical cells Not otherwise specified Favor neoplastic Atypical Endometrial cells Adenocarcinoma in situ (Endocervical) Adenocarcinoma (Endocervical, Endometrial, extrauterine or Not otherwise specified)

9 AGUS Reporting Rates and Follow-up data )( publications) Study # of Pap smears AGUS rate (%) SIL (%) AIS (%) EMH (%) CA (%) Goff Nasu N/A 4.0 Taylor N/A N/A N/A Kennedy N/A N/A Zweizig Eddy Duska N/A N/A 8.2 Veljovich CAP 1996 survey N/A N/A N/A N/A Jones N/A N/A 5.8 Mody (unpubl) N/A 5 Soofer Ronnett N/A <1 AIS-Adenocarcinoma in situ; SIL Squamous intraepithelial lesion; EMH endometrial hyperplasia; CA carcinoma

10 AGUS Reporting Rates and Follow- up(%) Study Rate SIL AIS EMH CA Goff Zweiz Eddy Veljo CAP BCM Davey D, Woodhouse S, Styler P, Stasny J and Mody D. Arch Pathol and Lab Med 124(2): , 2000

11 Recent AGC Reporting Rates and Outcomes on Follow-up 2006 and Later Study/ year Schantz P 2006 (pooled from 26 studies) Zhao C 2009 Number of Paps AGC % AIS % HSIL % LSIL % All ca % EMH % 2,389, AGC-Atypical Glandular cells; AIS-Adenocarcinoma in situ; SIL Squamous intraepithelial lesion; EMH endometrial hyperplasia; CA carcinoma From Diagnostic Pathology Cytopathology ed Mody DR Amirsys publishing, Manitoba, 2014

12 AGC Reporting Rates: College of American Pathologists Benchmarking Data Pap test Type Conventional (%) 5 th percentile 25 th percentile 50 th percentile 75 th percentile ThinPrep(%) SurePath (%) th percentile From Diagnostic Pathology Cytopathology ed Mody DR Amirsys publishing, Manitoba, 2014

13 Relative Distribution of Malignancies in Paps reported as AGC Study/ year Schantz P 2006 Zhao C 2009 Sq Ca cx Adeno, adsqca cx Others Endomet rial ca Ovary/ tube 5.4% 23.6% 6.9% 57.6% 6.4% % 12.4% N/A 77.2% 9.1% 44 Total ca cases From Diagnostic Pathology Cytopathology ed Mody DR Amirsys publishing, Manitoba, 2014

14 Hyperchromatic Crowded Groups (HCGs) AIS* HSIL Adenoca Cx* Squamous ca cx ACA endometrium* Other Carcinomas *If all criteria not met then default is some form of AGC Exodus ball Aggressive endocervical sampl Follicular cervicitis LUS endometrium Tubal metaplasia MGH Atrophy

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16 HSIL Vs AIS Features HSIL AIS Strips & Rosettes Absent Present Gland forms Absent Present Feathering Absent Present Polarity Lost Maintain Nu Shape Round/irreg Oval/cigar Chromatin Coarse Even Cytoplasm Dense Even Background Isolated cells Rare/abs Frequency % 0.01%

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18 HSIL Vs AIS

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20 Squamous vs Adenocarcinomas(Cervical) Squamous Keratinization (if present) Dense cytoplasm Syncytial arrangement Features of HSIL Cell block from Liquid based P40 IHC positive Adenocarcinoma Mucin or delicate cytoplasm Columnar configuration Organoid architectural features Nuclear polarization Cell block P40 negative

21 Menstrual Pap test

22 P16 Pro ExC

23 Mimics of Endometrial Adenocarcinoma/Endometrial AGC Hyperplasia Arias Stella Reaction & Pregnancy Endometrial & Endocervical polyps Cervical Small cell carcinoma IUD changes Fixation & staining artifacts Radiation changes Post menopausal atrophy and bare nuclei

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25 Role of HPV testing in Cervicovaginal cytology Triage ASC-US LSIL Secondary triage Co-testing Women 30 yrs Test of Cure Primary Screening Cobas FDA approved for women 25 yrs (one of 3 options: Pap q3 yrs, co test q 5yrs, HPV q3yrs)

26 HPV Positivity Rates in Percentiles (CAP 2013 Data) Category Mean (%) 10 th 25 th 50 th 75 th 90th ASC-US ASC-H NILM> AGC CAP survey in Press (Archives of Pathology and Lab Medicine)

27 Risk Stratification 5yr Risk of HSIL+ and Suggested Management Based on Test Results Screen Result Frequency % 5 yr Risk of HSIL+ Suggested Management HPV-/Pap Repeat screen in 5 yrs HPV+/Pap Repeat in 6-12 mos Pap Repeat screen in 3 yrs ASC-US HPV Repeat screen in 3 yrs ASC-US HPV Immediate Colposcopy ASC-US Repeat in 6-12 months LSIL Repeat in 6-12 months LSIL HPV Repeat in 6-12 months LSIL HPV Immediate Colposcopy ASC-H Immediate Colposcopy ASC-H HPV Immediate Colposcopy ASC-H HPV Immediate Colposcopy HSIL,AGC,CA,AIS Immediate Colposcopy Schiffman M and Solomon D. N Engl J med 369:24 Dec 12, 2013

28 AGC follow-up and HPV Typing ZhaoC, Florea, Austin RA. Arch Pathol lab med 134;2010

29 HPV testing and Glandulars: Notes. Atypical Glandulars and above are high risk lesions Associated HPV negative results should NOT alter the initial management 25% of AGC cases will test + for HPV 50% of AGC cases which are HPV+ are found to have significant lesions on follow-up( HSIL/AIS/Ca) <5% HPV negative AGC have significant HPV associated lesions HPV negative AGC more likely to have endometrial pathology Please refer to ASCCP.org/guidelines for the most current management guidelines

30 References. Mody DR. Glandular Cell Abnormalities in Mody Diagnostic Pathology Cytopathology. Amirsys Publishing Inc. 2014: Part 1, section 4, Wilbur D, Chhieng D, Guidos B and Mody D in Nayar R and Wilbur D eds. The Bethesda System for Reporting Cervical Cytology New York: Springer-Verlag, 2015: Zhao, C., A. Florea, and R.M. Austin, Clinical utility of adjunctive high-risk human papillomavirus DNA testing in women with Papanicolaou test findings of atypical glandular cells. Arch Pathol Lab Med, (1): p

31 References. Mody DR. Agonizing over AGUS Cancer cytopathology 1999;