High Profile Call Girls Jaipur Vani 8445551418 Independent Escort Service Jaipur
Potpouri Of Asc H Shidham Et Al (Wk#13 Asc Annual Meeting 2008)
1. A potpourri of ASC-H and related interpretations-
Introduction Problem based learning
(Nov 11, 2008, 1.30 to 1.35)
A potpourri of ASC-H and related interpretations-
Problem based learning
P bl b dl i
Vinod B. Shidham, MD, FRCPath, FIAC
Medical College of Wisconsin,
Milwaukee, WI
Mamatha Chivukula , MD
Magee-Womens Hospital of University of Pittsburgh Medical Center,
Pittsburgh, PA
R. Marshall Austin, MD, PhD
Magee-Womens Hospital of University of Pittsburgh Medical Center,
Pittsburgh, PA
A potpourri of ASC-H and related interpretations-
Problem based learning
Educational objectives
Upon conclusion of this presentation, participants will be able to…
1. Describe cytomorphological spectrum of ASC-H.
2. Define LSIL-H with review of literature.
3. Differential diagnosis of hyperchromatic crowded groups.
4. Discuss application of ancillary tests.
1
2. A potpourri of ASC-H and related interpretations-
Problem based learning
A potpourri of ASC-H and related interpretations-
Problem based learning
P bl b dl i
Shidham VB 1.35 to 2.15 (35 minutes + 5 minutes Q/A)
Morphological Evaluation of Twilight Zone in Cervical Cytology.
Chivukula M 2.15 t 1 55
Chi k l M. 2 15 to 1.55 (35 minutes + 5 minutes Q/A)
i t i t
Study cases and application of two-color immunochemistry
Austin RM. 2.55 to 3.30 (30 minutes + 5 minutes Q/A)
Quality Improvement, Ancillary HPV testing, and Medicolegal aspects
2
3. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning http://bethesda2001.cancer.gov/terminology.html Problem based learning
(Nov 11, 2008, 1.35 to 2.15)
Part I
Morphological Evaluation of
Twilight Zone in Cervical Cytology.
Vinod B. Shidham, MD, FRCPath, FIAC
Professor
Executive editor & co-editor-in-chief, CytoJournal (www.cytojournal.com)
Director- Cytopathology Fellowship Training Program & FNA Service
Department of Pathology
Medical College of Wisconsin
9200 W Wisconsin Av,
Milwaukee, WI 53226, USA
vshidham@mcw.edu
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
EPITHELIAL CELL ABNORMALITIES http://nih.techriver.net/
SQUAMOUS CELL
Atypical squamous cells
- of undetermined significance (ASC-US)
- cannot exclude HSIL (ASC-H)
Low grade squamous intraepithelial lesion (LSIL) encompassing: HPV/mild dysplasia/CIN 1
High grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe
dysplasia, CIS/CIN 2 and CIN 3
- with features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma
GLANDULAR CELL
AGUS
Atypical (NOS)
- endocervical cells (NOS or specify in comments)
- endometrial cells (NOS or specify in comments)
- glandular cells (NOS or specify in comments)
Atypical (favor neoplastic)
- endocervical cells, favor neoplastic
- glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
- endocervical, endometrial, extrauterine, and not otherwise specified (NOS)
OTHER MALIGNANT NEOPLASMS: (specify)
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
EPITHELIAL CELL ABNORMALITIES
SQUAMOUS CELL
Atypical squamous cells
- of undetermined significance (ASC-US)
- cannot exclude HSIL (ASC-H)
Low grade squamous intraepithelial lesion (LSIL) encompassing: HPV/mild dysplasia/CIN 1 Atypical squamous cells
High grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe
dysplasia, CIS/CIN 2 and CIN 3
- with features suspicious for invasion (if invasion is suspected)
Squamous cell carcinoma cannot exclude HSIL (ASC-H)
(ASC H)
GLANDULAR CELL
AGUS
Atypical (NOS)
- endocervical cells (NOS or specify in comments)
- endometrial cells (NOS or specify in comments)
- glandular cells (NOS or specify in comments)
Atypical (favor neoplastic)
- endocervical cells, favor neoplastic
- glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
- endocervical, endometrial, extrauterine, and not otherwise specified (NOS)
OTHER MALIGNANT NEOPLASMS: (specify)
1
4. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
ASC-H Problem based learning
Normal vs ASC-H Problem based learning
Source: Source:
http://nih.techriver.net/patientImagesHighRes/6322.jpg?content-type=download http://nih.techriver.net/patientImagesHighRes/5568.jpg?content-type=download
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning
ASC-H Problem based learning
Source:
http://nih.techriver.net/patientImagesHighRes/5866.jpg?content-type=download
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning
ASC-H vs HSIL Problem based learning
Source:
http://nih.techriver.net/patientImagesHighRes/2064.jpg?content-type=download
2
5. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
The literature
correlating different
cytomorphological patterns
with
biopsy results??
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
1. “Checker board” MGH – like pattern
Cytomorphological Patterns of ASC-H.
1. MGH-like
2. Repair like - Dark nuclei
3A. Atrophy-like- with single cells - Smudgy chromatin
- Nucleoli.
Nucleoli
3B At h lik ith
3B. Atrophy-like- with HCG of parabasal cell groups
f b l ll
- Normoblast-like apoptosis
4. ASC-H: NOS confined to the area of nucleus
5. Cyanophilic small atypical parakeratotic cells
6A. HSIL- syncytial
6B. HSIL- Single cell
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
2. “School of fish” Repair – like pattern 3A. Atrophic “ Single-cell” pattern
- Cohesive clusters
-P i t l li
Prominent nucleoli. - Ab d t blue cytoplasm
Abundant bl t l
- Low N/C ratio - Open chromatin
- W/wout nucleoli
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
3
6. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
3B. Atrophic “ Parabasal cell groups” 5. Small Atypical parakeratotic cells
- HCG of small parakeratotic cells
- Sharp angulated cell margins (vs
- HCG of parabasal cells
p round peripheral borders of cells at
- Small dark nuclei periphery of HSIL syncytium)
- Variable, usually scant cytoplasm - Small koilocytes
- Relatively high N/C ratio
- Chromatin may be smudgy
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
6A. “Isolated cell pattern” 6B. “Syncytial cell” pattern
-Groups of atypical cells
- High N/C ratio (without distinct cell borders)
- Hyperchromatic nuclei - Focal single-cell apoptosis
single cell
(with random distribution of apoptotic bodies)
without nucleoli
- Hyperchromatic nuclei
- Coarse chromatin • (without nucleolar prominence)
- Coarse to fine chromatin
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
Cytomorphological Patterns associated with different clinicopathological categories.
Chivukula M, Shidham VB. ASC-H in Pap test- definitive categorization of cytomorphological spectrum.
CytoJournal 2006, 3:14 doi:10.1186/1742-6413-3-14
Free full text is available at: http://www.cytojournal.com/content/3/1/14
PDF at: http://www.cytojournal.com/content/pdf/1742-6413-3-14.pdf
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
4
7. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
1. MGH-like pattern
Shidham VB, Rao RN, Machhi J, Chavan A.
Microglandular Hyperplasia has a cytomorphological spectrum overlappping with Atypical
Squamous Cells- cannot exclude High-grade Squamous Intraepithelial Lesion (ASC-H).
Groups of metaplastic cells arranged in checkerboard like pattern. The dark nuclei may show nucleoli (arrows). (A
& b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained
Diagnostic Cytopathology 2004 ;30:57-61.
section]).
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
2. Repair-like pattern
Shidham et al.
Diagnostic Cytopathology
2004 ;30:57-61. Cohesive groups of cells with ill-defined school of fish pattern with relatively polarized cells with pointed ends
(arrow head) show relatively low N/C ratio. The nuclei show nucleoli (arrows). (a & b- Cervical smear [Papanicolaou
stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]).
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
3A. Atrophy-like pattern 3B. Atrophy-like pattern-
Single cell pattern. HCG 0f Parabasal cell groups
Cohesive hyperchromatic crowded groups of small parabasal cells with high N/C ratio. The nuclei are relatively
Isolated cells with hyperchromatic atypical nuclei with smudgy chromatin). (a & b- Cervical smear [Papanicolaou small and show nucleoli (arrow). (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical
stained SurePath™ Preparation]). biopsy [Hematoxylin-eosin stained section]).
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
5
8. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
4. ASC-H: NOS. 5. Cyanophilic Small Atypical parakeratototic cells
Cohesive groups of hyperchromatic cyanophilic small atypical parakeratotic (SAPK) cells with ill-defined cell
Cohesive groups of atypical cells with mostly ill-defined cell borders. The nuclei vary in size with coarse borders, which are straight with angulations better seen at periphery. N/C ratio is higher. Chromatin is smudgy.
chromatin; however, the nuclear details in most are relatively smudgy (arrows). (a & b- Cervical smear Some cells may show koilocytic space around nuclei. (a & b- Cervical smear [Papanicolaou stained SurePath™
[Papanicolaou stained Sure-Path™ Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]). Preparation], c- Cervical biopsy [Hematoxylin-eosin stained section]).
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
6A. HSIL pattern)- Syncytial pattern. Problem based learning 6B. HSIL pattern- Problem based learning
Singly scattered (so called 'litigation') cells.
Hyperchromatic crowded groups of cells without distinct cell borders. The hyperchromatic nuclei vary in size and
Scattered, isolated, atypical cells show high N/C ratio. The nuclei have coarse chromatin without nucleoli (arrows).
show coarsely granular chromatin (arrows). (a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation],
(a & b- Cervical smear [Papanicolaou stained SurePath™ Preparation], c- Cervical biopsy [Hematoxylin-eosin
c- Cervical biopsy [Hematoxylin-eosin stained section]).
stained section]).
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14 Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
Cytomorphological Patterns of ASC-H.
Reactive In summary,
1. MGH-like our study identified
2. Repair like
p y
3A. Atrophy like- with single cells
g y p g p
a cytomorphologic spectrum
3B. Atrophy like- with HCG of parabasal cell groups related with
Indeterminate
4. ASC-H: NOS ASC-H interpretations,
LSIL which demonstrated
5. Cyanophilic small atypical parakeratotic cells
HSIL an association pattern
6A. HSIL- syncytial with the results of biopsy and HPV test.
6B. HSIL- Single-cell
6
9. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
Other Twilight Zone-
Some unequivocal cases of LSIL
may also be associated some atypical
y yp
cells suspicious for HSIL.
How to evaluate them and
how to report them?
A dilema!!!!!
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
LSIL-H (with CIN2 & HPV in biopsy)
Shidham VB, Kumar N, Narayan R, Brotzman GL.
Should LSIL with ASC-H (LSIL-H) in cervical smears be an independent category? A study on SurePathTM
Cervical smear with unequivocal LSIL in other fields. This field shows rare LSIL (a & c) with some groups of cells
specimens with review of literature.
consistent with ASC-H. The cells have a high N/C ratio with rounder curving cell borders (better seen in 'b'). At 20X
CytoJournal 2007,4:7
(a), the ASC-H cell is difficult to focus because of three dimensional component in liquid based cytology. (a through
Free full text is available at: http://www.cytojournal.com/content/4/1/7
c- Papanicolaou stained SurePathTM preps)
PDF at: http://www.cytojournal.com/content/pdf/1742-6413-4-7.pdf Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
LSIL-H (with only HPV in biopsy)
Biopsy results for LSIL, LSIL-H, ASC-H, and HSIL
Cervical smear (a, b) showed unequivocal LSIL cells in other fields. This field shows rare LSIL (a & b) along with
some groups of cells consistent with ASC-H. The biopsy (c) showed only human papilloma virus cytopathic effect.
Small atypical parakeratotic (SAPK) cells with distinct and sharp angulated cell borders with tinge of cytoplasmic
eosinophilia (arrowhead in b) (see also corresponding area in a) were interpreted as ASC-H component. (a & b-
Papanicolaou stained SurePathTM preps, c- HE stained cervical biopsy Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
section). Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
7
10. A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
LSIL-H as category overlap with LSIL and ASC-H, but was distinct from HSIL.
Biopsy
Keratinizing
CIN 3
Source:
Chivukula M, Shidham V.
CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations- A potpourri of ASC-H and related interpretations-
Problem based learning Problem based learning
Conclusions Suggested Management algorithm of Women with LSIL-H.
LSIL-H as interpretation category is not a unique
biologic entity.
But it correlates with increased risk of high grade
dysplasia on biopsy.
Biopsy results pattern was intermediate between
§Diagnostic excisional
LSIL and ASC-H, but distinct from HSIL. procedure- Sampling of
transformation
zone and endocervical canal
for histological evaluation with
For optimal clinical management a separate group laser conization, cold-knife
conization, loop
of LSIL-H is justified. electrosurgical excision
(LEEP), and loop
electrosurgical conization.
Application of molecular events such as p16 may Source:
Chivukula M, Shidham V.
be useful in the future. CytoJournal 2006, 3:14
A potpourri of ASC-H and related interpretations-
Problem based learning End
vshidham@mcw.edu Milwaukee Art Museum
8
11. 11/13/2008
Objectives
Study cases and application of
two-
two-color immunochemistry Present real time case studies to
demonstrate the utility of
cytomorphology in interpretation of
y p gy p
Mamatha Chivukula MD, FASCP, FCAP ASC-
ASC-H pap tests
Assistant Professor
Associate Director of
Cytohisto correlation and follow-up
follow-
Immunohistochemistry lab HPV testing
Magee-
Magee-Women’s Hospital of UPMC
Pittsburgh, PA
Cytomorphology of ASC-H
ASC-
Case 1
MGH-like
Repair like 35 year old woman w/ a
Atrophy-like- with single cells
Atrophy-like- with HCG of parabasal
p y p
routine Pap test
cell groups
ASC-H: NOS
Cyanophilic small atypical
parakeratotic cells
HSIL- syncytial
HSIL- Single cell
1
12. 11/13/2008
Groups of atypical cells
(without distinct cell borders)
-
Follow up HPV –DNA test is Positive
for high risk HPV types
Hyperchromatic nuclei
- Coarse to fine chromatin
“Syncytial cell” pattern
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
2
13. 11/13/2008
Case 2
49 year old woman w/ a
routine Pap test
- Abundantblue cytoplasm
-Open chromatin,w/w out nucleoli
Follow up HPV –DNA test is Negative
for high risk HPV types
p16 KI -67
3
14. 11/13/2008
Atrophic “ Single-cell” pattern
Case 3
30 year old woman w/ a
routine Pap test
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:
Cohesive clusters
Follow up HPV –DNA test is Negative
for high risk HPV types
-Prominent nucleoli
P i t l li
- Low N/C ratio
4
15. 11/13/2008
“School of fish” Repair – like pattern
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:14
Case 4
35 year old woman w/ a routine
Pap test
5
16. 11/13/2008
Follow up HPV –DNA test is Positive
for high risk HPV types
“Isolated cell pattern”
Case 5
55 year old woman w/ a
routine Pap test
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:
- HCG of parabasal cells
- Small dark nuclei
- Variable, usually scant
cytoplasm
6
17. 11/13/2008
Follow up HPV –DNA test is Negative
for high risk HPV types
Atrophic “ Parabasal cell groups” Application of two-color
two-
immunochemistry
P16 is over expressed and accumulates in
nucleus and cytoplasm of dysplastic cervical
cells
S di on ASC-US, ASC-H
Studies ASC-US ASC-
Advanced kits for immunostaining cervical
specimens to detect both p16 and ki-67
ki-
simulatneously
Source: Chivukula M, Shidham V. CytoJournal 2006, 3:
State of the art….work in
progress
In a normal cell w/ intact cell cycle,
Simultaneous expression of anti-proliferative
anti-
marker (p16), proliferative marker (ki-67)
(ki-
within the same cell, mutually excludes each
other
Reversely, presence of both p16, ki-67 in
ki-
the same cell, indicates disrupted cell cycle
7
19. 11/13/2008
Multiple Slide Blinded Reviews as a
ASC-H: Quality Improvement Tool
Quality Improvement, Ancillary HPV • Identify Pap tests screened as negative or
testing, and Medicolegal aspects equivocally abnormal preceding subsequent
diagnoses of CIN2/3, AIS, or cervical cancer.
• Insert Pap tests of interest into 10-20 slide
1) Highlight blinded review quality cytology challenge sets
sets.
improvement technique employed at MWH to
enhance ASC-H detection • Ask staff cytotechnologists to rescreen and
2) medicolegal ramifications of disputed interpret all cases on anonymous answer
retrospective ASC-H interpretations. sheets.
3) Unpublished data on the usefulness of • Review rescreening findings with staff along with
HPV testing in the largest series reported to histologic and cytologic follow-up.
date from MWH
Original Review Pap#1
Paps #1 and 2 • Date: 4/7/03
Two Negative Paps Preceding • Diagnosis
CIN2 Biopsy Result – Negative for intraepithelial lesion or
malignancy.
malignancy
– Inflammatory changes.
What do you think?
• Negative
• Cancer
• Suspicious for cancer
• HSIL
• AGC (Atypical glandular cells)
• ASC-H
• LSIL
• ASCUS
1
21. 11/13/2008
Blinded Cytotechnologist
What do you think?
Review Results
• Negative • Negative: 9
• Cancer • ASC-US: 4
• Suspicious for cancer
• HSIL
• AGC (Atypical glandular cells) Retro-review Diagnosis knowing outcome:
• ASC-H Atypical Squamous Cells cannot exclude
• LSIL HSIL (ASC-H)
• ASCUS
Subsequent Surgical
Pathology Result
Paps #3 and 4
• Date: 1/4/07
• Diagnosis: Two Negative Paps Preceding
– Cervical intraepithelial neoplasia 2 (CIN 2) CIN2 Biopsy Result
3
22. 11/13/2008
Original Review Pap #3
• Date: 4/21/05
• Diagnosis
– Negative for intraepithelial lesion or
malignancy
malignancy.
– Repair.
Blinded Cytotechnologist
What do you think?
Review Results
• Negative • Negative: 8
• Cancer • Atypical glandular cells: 1
• Suspicious for cancer
• ASC-H: 2
• HSIL
• ASC-US: 2
• AGC (Atypical glandular cells)
• ASC-H
Retro-review Diagnosis knowing outcome:
• LSIL
Atypical Squamous Cells cannot exclude HSIL (ASC-H)
• ASCUS
4
23. 11/13/2008
Original Review Pap #4
• Date: 6/1/06
• Diagnosis
– Negative for intraepithelial lesion or
malignancy.
malignancy
– Adequate with cocci partially obscuring 50-
75% of epithelial cells.
5
24. 11/13/2008
Blinded Cytotechnologist
What do you think?
Review Results
• Negative • Negative: 2
• Cancer • HSIL: 4
• Suspicious for cancer • ASC-H: 5
• HSIL • ASC-US: 2
• AGC (Atypical glandular cells)
• ASC-H
Retro-review Diagnosis knowing outcome:
• LSIL
• ASCUS High-grade squamous intraepithelial lesion
(HSIL)
Subsequent Surgical Multiple Slide Blinded Review
Pathology Result (MSBR) Conclusions
• Difficult to diagnose ASC-H cases may be
• Date: 1/4/07 best recognized only with the hindsight bias
• Diagnosis: of later known histologic outcome.
– Cervical intraepithelial neoplasia 2 (CIN 2) • Standard of practice- what a reasonable peer
who do under similar circumstances
circumstances-
is different from hindsight bias-influenced
retrospective review.
• ASC Pap Litigation Guidelines state that a
violation of the standard of practice can
ONLY be confirmed with MSBR.
6
25. 11/13/2008
ASC-H and HPV Testing
Atypical squamous cells, cannot exclude HSIL
MWH Experience
p (ASC-H) subcategory was introduced in the 2001
Bethesda System.
-“Atypical (immature) Metaplasia” : small cells
with high N/C ratios.
-“Crowded Sheet Pattern”
Background Background
• Mimics:
• Atrophy • Incidence of ASC-H: 0.22% - 1.09%
• Reactive/reparative change
• Naked nuclei • Reported rate of CIN 2/3 on histologic follow-
•P k t i
Parakeratosis up: 12 2% - 68 2%
12.2% 68.2%
• Immature metaplastic cells
• Reported rates of high-risk HPV + in ASC-H:
33.3% - 85.6%
Background Background on ALTS
• All patients had previous ASC-US or LSIL
• 2006 Consensus Follow-up Guidelines pap on conventional smears based on
from the American Society for Colposcopy 1991 Bethesda terminology.
and Cervical Pathology (ASCCP)
• Participants had liquid-based Pap and
– ASC H
ASC-H go to colposcopy
HPV testing.
– Based on data from the ASCUS / LSIL Triage
Study (ALTS) • Diagnosis was made by 4 pathologists
• 110 ASC-H cases; 84% + hrHPV
• Younger than average patient population.
- Median age 24 years old.
7
26. 11/13/2008
Background GOALS
• 2001 ASCCP guidelines for ASC-US • Evaluate:
recommend “reflex” HPV DNA testing when – ASC-H paps
liquid-based cytology is used. – High-risk HPV (hrHPV) DNA test results
– ~ 85% of ASC-US paps get reflex HPV testing.
ASC US – Histologic follow up
follow-up
• Some studies suggest that HPV testing may – Presence or absence of endocervical/
help triage ASC-H patients and reduce the transformation zone (EC / TZ)
number of colposcopies. • Affect on detection of CIN
• Affect on hrHPV detection
Materials and Methods Materials and Methods
• July 1, 2005 – December 31, 2007 • Histologic follow-up
• ThinPrep Imaging System (TIS) was used – Endocervical curettage
– ASC-H called when small, rounded, squamous cells with dense
– Cervical biopsy
limited cytoplasm, enlarged and euchromatic or hyperchromatic – Cervical conization (loop or cold knife cone)
nuclei and some degree of nuclear membrane irregularities were
identified
• Two surgical pathologists confirmed CIN
– EC/TZ status based on Bethesda 2001. diagnoses.
• High-risk HPV DNA testing via Hybrid – CIN1
Capture II (HC2) – CIN 2 or higher (CIN2/3)
– Ordered by clinicians as reflex for ASC pap, women > 30 y.o., or • Stratified according to age and EC/TZ
HPV regardless. status.
Results
• ASC-H interpretations
– 1646 (1619 ThinPrep, 27 conventional)
– 0.59% of all paps
• 0.60% in TP, 0.38% in conv.
– 1187 (of TP) 73.3% had hrHPV testing done
• Presence or absence of EC/TZ made no
difference with regard to hrHPV DNA
detection or detection of CIN 2/3
8
27. 11/13/2008
Results Results
926 with ASC-H &
hrHPV testing
421 No histology 505 w/ at least 1
cervical bx*
bx
257 (50.9%) hrHPV + 248 (49.1%) hrHPV -
The difference in hrHPV + was significant
between women <40 y.o. and women >40 y.o.
*101 women had two or more biopsies
Results Results
257 (50.9%) HPV + 248 (49.1%) HPV -
160 (62.3%) CIN 35 (14.1%) CIN
• Cumulative CIN detection rate was 38.6% (195/505)
• CIN 2/3 in 87 (17.2%) of 505 ASC-H & hrHPV tested
patients
Results Results (Table 4)
• Statistical difference (P < .001) between hrHPV+
w/ CIN 2/3 and hrHPV – w/ CIN 2/3.
• Women 30 -39 y.o. w/ + hrHPV had the greatest
• 35.8% of HPV+ women < 40 y.o. had CIN 2/3;
risk.
• 20.8% of HPV+ women > 40 y.o. had CIN 2/3
• 4 women had AIS; all were hrHPV +
9
28. 11/13/2008
Results ASC-H w/ reflex hrHPV Testing
• ASC-H PPV of CIN2/3 = 17.2% < 40 y.o. <40 y.o.
Sensitivity 96.1% 100%
• ASC-H and + hrHPV PPV of CIN2/3 = 32.7% Specificity 54% 68.4%
PPV 35 8%
35.8% 20.8%
20 8%
• ASC-H and – hrHPV NPV of no CIN2/3 = NPV 98.1% 100%
98.8%
Comment Comment
• Some abstracts report increased ASC-H
reporting with the use of the ThinPrep
Imaging System (TIS)
– Decreased detection of hr HPV
– Decreased detection of CIN 2/3
CAP interlaboratory comparison program
Comment Why so much variability in hrHPV
detection rates?
• Differences in cytologic interpretation
threshold for ASC-H
ALTS
• Undercalling of HSIL
• Overcalling of ASC-H as HSIL
ASC H
• Overcalling metaplastic cells as ASC-H
• Different patient populations
– Rate of hrHPV + varies from 2.9% (current study) -
32.7% (ALTS)
– ALTS median age 24 y.o.; this study median age 30
y.o.
10
29. 11/13/2008
Summary of this study Conclusions
• Significant difference in detection of CIN in
+ hrHPV than negative. • Using both Pap test and high-risk HPV
DNA testing allows for effective risk
stratification of patients:
• The negative predictive value of – hrHPV
in ASC-H
i ASC H was 100% i women > 40 y.o.
in – HPV + to colposcopy
– HPV – to follow-up with regular Pap and
hrHPV testing.
• Highest CIN 2/3 detection rate was in
women 30-39 y.o. with ASC-H and +
hrHPV
11