Over-diagnoses in Cytopathology:
Is histology the gold standard?
Teresa M. Darragh, MD
UCSF
Departments of Pathology and
Obstetrics, Gynecology & Reproductive Sciences
Faculty Disclosures:
Teresa M. Darragh, MD
• Hologic: Research supplies for anal cytology
• OncoHealth: Advisory Board (Ended August 2014)
• Roche: Advisory Board (October 2013)
– Honorarium paid to UCSF
• Roche-Ventana: Speaker’s Bureau (August 2014)
– Honorarium paid to UCSF
• TheVax: Advisory Board (August 2014)
– Honorarium paid to UCSF
Pap test = Screening test
• Dorland’s Medical Dictionary
• Screening test: any test used to eliminate
those who are definitely not affected by the
disease in question, the remainder (those with
positive reactions) being subjected to more
refined diagnostic tests.
Cervical Cancer Screening: Options
• Pap test
– ASC-US triage: Reflex HPV
testing
• Cotesting = Pap test +
HPV testing
• Primary HPV testing (one
HPV test FDA-approved for this indication)
– HPV 16/18  colposcopy
– Non-HPV 16/18 triage:
• Pap test
NB: HPV testing = high-risk HPV testing with FDA-approved method
Diagnostic Test
• In medicine, a diagnostic test is any kind of
medical test performed to aid in the diagnosis or
detection of disease.…such a test may be used to
confirm that a person is free from disease, or to
fully diagnose a disease, including to sub-classify
it regarding severity and susceptibility to
treatment.
• Diagnostic test - Wikipedia, the free encyclopedia
• en.wikipedia.org/wiki/Diagnostic_testWikipedia
Underlying Principle:
Risk stratification
Different
Management
Bethesda 3
Underlying Principle
Similar Management for Similar Risk
Treatment
Colposcopy
Increased
surveillance
Repeat screen
Bethesda 3
Management options
• Repeat screen at regular
intervals
• Increased surveillance
– Shorter screening interval
• Colposcopy
• Treatment
LSIL:
Virion production & transient lesions
LSIL (CIN1)
LSIL
Productive infection
HSIL:
HPV E6/E7 expression & risk of cancer
HSIL (CIN3)
HSIL
Transforming infection
Limitations of Cervical Screening
• Morphologic interpretation is subjective,
leading to significant intraobserver and
interobserver variability
Technique
% Agreement
Kappa
Thin-layer
62.0
0.46
Colpo Bx
62.0
0.46
LEEP
69.9
0.49
ALTS: Interobserver Reproducibility
Of Pathologic Interpretations
What is the Gold Standard?
• Cytology:
• Not a gold standard – significant variation in sensitivity and
specificity based on sampling, locator skills and training
• Colposcopy:
• Not a gold standard – significant variability in accuracy and
sensitivity based on lesion size, location and characteristics
and the skill and experience of the colposcopist
• Biopsy:
• Not a gold standard – significant variation in diagnosis based
on terminology used and training
• Sampling: A sample from one area does not
necessarily represent the most significant disease
Sampling and
the “Gold Standard”
Benign
LSIL
HSIL
AIS
The “Gold Standard” and Diagnostic Error
17% of all cones = “Negative”
Carrigg A et al. Examination of sources of diagnostic error leading to cervical cone biopsies with no
evidence of dysplasia. Am J Clin Pathol. 2013 Apr;139(4):422-7.
Harmonizing Management According To Risk
Treatment
Colposcopy
Increased
Surveillance
Screening
Lower risk = 
interval
Castle et al., JLGTD, 2008
Management of Women with No Lesion or Biopsy-confirmed Cervical
Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by “Lesser Abnormalities”*∞
*“Lesser abnormalities” include ASC-US
or LSIL Cytology, HPV 16+ or 18+, and
persistent HPV
Follow-up without Treatment
∞ Management
options may vary if the
woman is pregnant or ages 21-24
+Cytology
Cotesting at 12 months
if age <30 years, cotesting if
age ≥30 years
> ASC or HPV (+)
†
HPV (-)
Colposcopy
Either ablative or excisional methods.
Excision preferred if colposcopy
inadequate, positive ECC, or previously
treated.
and
Cytology Negative
Age appropriate* retesting
No CIN
CIN2,3
CIN1
3 years later
If persists for
at least 2 years
Cytology negative
+/-
HPV (-)
Routine
screening
Follow-up or
Treatment †
Manage per
ASCCP Guideline
1 of 19 different algorithms
© Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial
Neoplasia - Grade 1 (CIN1) Preceded by ASC-H or HSIL Cytology
Cotesting at 12 and 24 months*
Or
Diagnostic
Excision
Procedure ^
Or
Review of cytological,
histological, and
colposcopic findings
HPV(-)
HPV(+) or Any HSIL
cytology at either visit
Cytology Negative abnormality
at both visits
except HSIL
and
Age-specific
Retesting
in 3 years+
Manage per
ASCCP Guideline
for revised diagnosis
Colposcopy
*Only if colposcopy was adequate and endocervical sampling negative
^
Except in special populations (may include pregnant women and those ages 21-24)
+
Cytology if age <30; cotesting if age ≥30 years
© Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
Cervical Cancer Screening &
Management
Cytology + HPV
Histology
Colposcopy
Underlying principles:
Cervical Cancer Screening &
Management
Benefits
Harms
Similar management for similar risk
“Over-diagnoses” in Cytopathology:
Is histology the gold standard?
…that depends…