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
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
Conflict of Interest None with vendors of cytology equipment/testing
My editorial in 1999 Has anything changed?
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
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
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)
AGUS Reporting Rates and Follow-up data )(1992-2000 publications) Study # of Pap smears AGUS rate (%) SIL (%) AIS (%) EMH (%) CA (%) Goff 1992 21930 0.46 39.7 7.9 3.2 3.2 Nasu 1993 34384 1.8 43.7 3.3 N/A 4.0 Taylor 1993 17000 0.18 37 N/A N/A N/A Kennedy 1996 68368 0.20 9.1 3.9 N/A N/A Zweizig 1997 46804 0.27 21.2 1.2 11.8 9.4 Eddy 1997 177715 0.63 27 1.9 1.1 6.0 Duska 1998 120338 0.17 26 N/A N/A 8.2 Veljovich 1998 84442 0.53 22.6 2.5 2.5 4 CAP 1996 survey N/A 0.35 26.7 N/A N/A N/A Jones 1996 414521 N/A 39.6 5.8 N/A 5.8 Mody (unpubl) 36000 0.4 27 5 N/A 5 Soofer 2000 87632 0.11 19.2 1.9 9.6 1.9 Ronnett 1999 46009 0.5 15.4 3.6 N/A <1 AIS-Adenocarcinoma in situ; SIL Squamous intraepithelial lesion; EMH endometrial hyperplasia; CA carcinoma
AGUS Reporting Rates and Follow- up(%) Study Rate SIL AIS EMH CA Goff92.46 40 8 3.2 3.2 Zweiz97.27 21 1.2 11.8 9.4 Eddy97.6 27 1.9 1.1 6 Veljo98.5 22.6 2.5 2.5 4 CAP96.35 27 BCM96.4 27 5 5 Davey D, Woodhouse S, Styler P, Stasny J and Mody D. Arch Pathol and Lab Med 124(2):203-211, 2000
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 % 2,389,206 0.29 2.85 11.1 8.5 5.2 1.3 247131 0.41 2.4 6.2 16.5 6.7 1.2 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
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 0 0 0.1 0.3 0.8 ThinPrep(%) 0 0.1 0.1 0.1 0.7 SurePath (%) 0 0.1 0.2 0.4 0.9 90 th percentile From Diagnostic Pathology Cytopathology ed Mody DR Amirsys publishing, Manitoba, 2014
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% 203 2.3% 12.4% N/A 77.2% 9.1% 44 Total ca cases From Diagnostic Pathology Cytopathology ed Mody DR Amirsys publishing, Manitoba, 2014
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
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 0.2-0.4% 0.01%
HSIL Vs AIS
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
Menstrual Pap test
P16 Pro ExC
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
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)
HPV Positivity Rates in Percentiles (CAP 2013 Data) Category Mean (%) 10 th 25 th 50 th 75 th 90th ASC-US 37.1 11.8 26.4 38.3 47.8 54.7 ASC-H 39.9 0 1.0 53.8 68.1 79 NILM>30 10.9 2.1 4.4 6.5 11 22.5 AGC 16.5 0 0 13.2 27 39.3 CAP survey in Press (Archives of Pathology and Lab Medicine)
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 - 92 0.27 Repeat screen in 5 yrs HPV+/Pap- 3.6 10 Repeat in 6-12 mos Pap - 96 0.68 Repeat screen in 3 yrs ASC-US HPV- 1.8 1.1 Repeat screen in 3 yrs ASC-US HPV+ 1.1 1.8 Immediate Colposcopy ASC-US 2.8 6.9 Repeat in 6-12 months LSIL 0.97 16 Repeat in 6-12 months LSIL HPV- 0.19 5.1 Repeat in 6-12 months LSIL HPV + 0.81 19 Immediate Colposcopy ASC-H 0.17 35 Immediate Colposcopy ASC-H HPV+ 0.12 45 Immediate Colposcopy ASC-H HPV - 0.051 12 Immediate Colposcopy HSIL,AGC,CA,AIS Immediate Colposcopy Schiffman M and Solomon D. N Engl J med 369:24 Dec 12, 2013
AGC follow-up and HPV Typing ZhaoC, Florea, Austin RA. Arch Pathol lab med 134;2010
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
References. Mody DR. Glandular Cell Abnormalities in Mody Diagnostic Pathology Cytopathology. Amirsys Publishing Inc. 2014: Part 1, section 4, 2-28. 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, 2015:193-240. 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, 2010. 134(1): p. 103-8.
References. Mody DR. Agonizing over AGUS Cancer cytopathology 1999;87 243-44