1. 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

2. 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

3. Conflict of Interest
None with vendors of cytology equipment/testing

4. My editorial in 1999
Has anything changed?

5. 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

6. 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

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

8. AGUS Reporting Rates and Follow-up data )(1992-2000 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

9. 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

10. Recent AGC Reporting Rates and Outcomes on Follow-up 2006 and Later
Study/
year
Number of Paps
AGC%
AIS %
HSIL %
LSIL %
All ca %
EMH %
Schantz P 2006 (pooled from 26 studies)
2,389,206
0.29
2.85
11.1
8.5
5.2
1.3
Zhao C 2009
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

11. AGC Reporting Rates: College of American Pathologists Benchmarking Data
Pap test Type
5th percentile
25th percentile
50th percentile
75th percentile
90th percentile
Conventional (%)
0.1
0.3
0.8
ThinPrep(%)
0.7
SurePath (%)
0.2
0.4
0.9
From Diagnostic Pathology Cytopathology ed Mody DR
Amirsys publishing, Manitoba, 2014

12. Relative Distribution of Malignancies in Paps reported as AGC
Study/
year
Sq Ca cx
Adeno, adsqca cx
Others
Endometrial ca
Ovary/
tube
Total ca cases
Schantz P 2006
5.4%
23.6%
6.9%
57.6%
6.4%
203
Zhao C 2009
2.3%
12.4%
N/A
77.2%
9.1% 44
From Diagnostic Pathology Cytopathology ed Mody DR
Amirsys publishing, Manitoba, 2014

13. 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

15. 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%

17. HSIL Vs AIS

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

20. Menstrual Pap test

21. Pro ExC
P16

22. 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

24. 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)

25. HPV Positivity Rates in Percentiles (CAP 2013 Data)
Category
Mean (%)
10th
25th
50th
75th
90th
ASC-US
37.1
11.8
26.4
38.3
47.8
54.7
ASC-H
39.9
1.0
53.8
68.1 79
NILM>30
10.9
2.1
4.4
6.5 11
22.5
AGC
16.5
13.2 27
39.3
CAP survey in Press (Archives of Pathology and Lab Medicine)

26. 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
ASC-US HPV+
Immediate Colposcopy
ASC-US
2.8
6.9
Repeat in 6-12 months
LSIL
0.97 16
LSIL HPV-
0.19
5.1
LSIL HPV +
0.81 19
ASC-H
0.17 35
ASC-H HPV+
0.12 45
ASC-H HPV -
0.051 12
HSIL,AGC,CA,AIS
Schiffman M and Solomon D. N Engl J med 369:24 Dec 12, 2013

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

28. 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

29. 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:
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

30. References….
Mody DR . Agonizing over AGUS Cancer cytopathology 1999;