03 Asc H Medicolegal Austin

ASC-H: Quality Improvement, Ancillary HPV testing, and Medicolegal aspects 1) Highlight blinded review quality improvement technique employed at MWH to enhance ASC-H detection 2) medicolegal ramifications of disputed retrospective ASC-H interpretations. 3) Unpublished data on the usefulness of HPV testing in the largest series reported to date from MWH

Multiple Slide Blinded Reviews as a Quality Improvement Tool
Identify Pap tests screened as negative or equivocally abnormal preceding subsequent diagnoses of CIN2/3, AIS, or cervical cancer.
Insert Pap tests of interest into 10-20 slide cytology challenge sets.
Ask staff cytotechnologists to rescreen and interpret all cases on anonymous answer sheets.
Review rescreening findings with staff along with histologic and cytologic follow-up.

Paps #1 and 2 Two Negative Paps Preceding CIN2 Biopsy Result

Original Review Pap#1
Date: 4/7/03
Diagnosis
Negative for intraepithelial lesion or malignancy.
Inflammatory changes.

What do you think?
Negative
Cancer
Suspicious for cancer
HSIL
AGC (Atypical glandular cells)
ASC-H
LSIL
ASCUS

Blinded Cytotechnologist Review Results
Negative: 9
LSIL: 1
ASC-US: 4
Retro-review Diagnosis knowing outcome: Atypical Squamous Cells cannot exclude HSIL (ASC-H)

Original Review Pap #2
Date: 3/26/04
Diagnosis
Inflammatory changes.

What do you think?
Negative
Cancer
HSIL
ASC-H
LSIL
ASCUS

Negative: 9
ASC-US: 4

Subsequent Surgical Pathology Result
Date: 1/4/07
Diagnosis:
Cervical intraepithelial neoplasia 2 (CIN 2)

Paps #3 and 4 Two Negative Paps Preceding CIN2 Biopsy Result

Date: 4/21/05
Diagnosis
Repair.

What do you think?
Negative
Cancer
HSIL
ASC-H
LSIL
ASCUS

Negative: 8
Atypical glandular cells: 1
ASC-H: 2
ASC-US: 2

Date: 6/1/06
Diagnosis
Adequate with cocci partially obscuring 50-75% of epithelial cells.

What do you think?
Negative
Cancer
HSIL
ASC-H
LSIL
ASCUS

Negative: 2
HSIL: 4
ASC-H: 5
ASC-US: 2
Retro-review Diagnosis knowing outcome: High-grade squamous intraepithelial lesion (HSIL)

Subsequent Surgical Pathology Result
Date: 1/4/07
Diagnosis:
Cervical intraepithelial neoplasia 2 (CIN 2)

Multiple Slide Blinded Review (MSBR) Conclusions
Difficult to diagnose ASC-H cases may be best recognized only with the hindsight bias of later known histologic outcome.
Standard of practice- what a reasonable peer who do under similar 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.

ASC-H and HPV Testing MWH Experience

Atypical squamous cells, cannot exclude HSIL ( ASC-H ) subcategory was introduced in the 2001 Bethesda System.
“ Atypical (immature) Metaplasia” : small cells with high N/C ratios.
“ Crowded Sheet Pattern”

Background
Mimics :
Atrophy
Reactive/reparative change
Naked nuclei
Parakeratosis
Immature metaplastic cells

Background
Incidence of ASC-H: 0.22% - 1.09%
Reported rate of CIN 2/3 on histologic follow-up: 12.2% - 68.2%
Reported rates of high-risk HPV + in ASC-H: 33.3% - 85.6%

Background
2006 Consensus Follow-up Guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP)
ASC-H go to colposcopy
Based on data from the ASCUS / LSIL Triage Study (ALTS)

Background on ALTS
All patients had previous ASC-US or LSIL pap on conventional smears based on 1991 Bethesda terminology.
Participants had liquid-based Pap and HPV testing.
Diagnosis was made by 4 pathologists
110 ASC-H cases; 84% + hrHPV
Younger than average patient population. - Median age 24 years old.

Background
2001 ASCCP guidelines for ASC-US recommend “reflex” HPV DNA testing when liquid-based cytology is used.
~ 85% of ASC-US paps get reflex HPV testing .
Some studies suggest that HPV testing may help triage ASC-H patients and reduce the number of colposcopies.

GOALS
Evaluate:
ASC-H paps
High-risk HPV (hrHPV) DNA test results
Histologic follow-up
Presence or absence of endocervical/ transformation zone (EC / TZ)
Affect on detection of CIN
Affect on hrHPV detection

Materials and Methods
July 1, 2005 – December 31, 2007
ThinPrep Imaging System (TIS) was used
ASC-H called when small, rounded, squamous cells with dense limited cytoplasm, enlarged and euchromatic or hyperchromatic nuclei and some degree of nuclear membrane irregularities were identified
EC/TZ status based on Bethesda 2001.
High-risk HPV DNA testing via Hybrid Capture II (HC2)
Ordered by clinicians as reflex for ASC pap, women > 30 y.o., or HPV regardless.

Materials and Methods
Histologic follow-up
Endocervical curettage
Cervical biopsy
Cervical conization (loop or cold knife cone)
Two surgical pathologists confirmed CIN diagnoses.
CIN1
CIN 2 or higher (CIN2/3)
Stratified according to age and EC/TZ 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

Results The difference in hrHPV + was significant between women <40 y.o. and women > 40 y.o.

Results 926 with ASC-H & hrHPV testing 421 No histology 505 w/ at least 1 cervical bx * 257 (50.9%) hrHPV + 248 (49.1%) hrHPV - * 101 women had two or more biopsies

Results 257 (50.9%) HPV + 248 (49.1%) HPV - 160 (62.3%) CIN 35 (14.1%) CIN

Results
Cumulative CIN detection rate was 38.6% (195/505)
CIN 2/3 in 87 (17.2%) of 505 ASC-H & hrHPV tested patients

Results
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 risk.
4 women had AIS; all were hrHPV +

Results (Table 4)
35.8% of HPV+ women < 40 y.o. had CIN 2/3;
20.8% of HPV+ women > 40 y.o. had CIN 2/3

Results
ASC-H PPV of CIN2/3 = 17.2%
ASC-H and + hrHPV PPV of CIN2/3 = 32.7%
ASC-H and – hrHPV NPV of no CIN2/3 = 98.8%

ASC-H w/ reflex hrHPV Testing
< 40 y.o.
Sensitivity 96.1%
Specificity 54%
PPV 35.8%
NPV 98.1%
< 40 y.o .
100%
68.4%
20.8%
100%

Comment CAP interlaboratory comparison program

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

Comment ALTS

Why so much variability in hrHPV detection rates?
Differences in cytologic interpretation threshold for ASC-H
Undercalling of HSIL
Overcalling of ASC-H as HSIL
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.

Summary of this study
Significant difference in detection of CIN in + hrHPV than negative.
The negative predictive value of – hrHPV in ASC-H was 100% in women > 40 y.o.
Highest CIN 2/3 detection rate was in women 30-39 y.o. with ASC-H and + hrHPV

Conclusions
Using both Pap test and high-risk HPV DNA testing allows for effective risk stratification of patients:
HPV + to colposcopy
HPV – to follow-up with regular Pap and hrHPV testing.

03 Asc H Medicolegal Austin

by vshidham

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