Over-diagnoses in Cytopathology: Is histology the gold standard?

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1 Over-diagnoses in Cytopathology: Is histology the gold standard? Teresa M. Darragh, MD UCSF Departments of Pathology and Obstetrics, Gynecology & Reproductive Sciences

2 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

3 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.

4 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

5 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

6 Underlying Principle: Risk stratification Different Management Bethesda 3

7 Underlying Principle Similar Management for Similar Risk Treatment Colposcopy Increased surveillance Repeat screen Bethesda 3

8 Management options Repeat screen at regular intervals Increased surveillance Shorter screening interval Colposcopy Treatment

9 LSIL: Virion production & transient lesions LSIL (CIN1) LSIL Productive infection

10 HSIL: HPV E6/E7 expression & risk of cancer HSIL (CIN3) HSIL Transforming infection

11 Limitations of Cervical Screening Morphologic interpretation is subjective, leading to significant intraobserver and interobserver variability Technique % Agreement Kappa Thin-layer Colpo Bx LEEP ALTS: Interobserver Reproducibility Of Pathologic Interpretations

12 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

13 Sampling and the Gold Standard Benign LSIL HSIL AIS

14 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 Apr;139(4):422-7.

15 Harmonizing Management According To Risk Treatment Colposcopy Increased Surveillance Screening Lower risk = interval Castle et al., JLGTD, 2008

16 Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by Lesser Abnormalities * Follow-up without Treatment Cotesting at 12 months > ASC or HPV (+) HPV (-) and Cytology Negative Colposcopy * Lesser abnormalities include ASC-US or LSIL Cytology, HPV 16+ or 18+, and persistent HPV Management options may vary if the woman is pregnant or ages Cytology if age <30 years, cotesting if age 30 years Either ablative or excisional methods. Excision preferred if colposcopy inadequate, positive ECC, or previously treated. Age appropriate* retesting 3 years later No CIN CIN2,3 CIN1 Cytology negative +/- HPV (-) Manage per ASCCP Guideline If persists for at least 2 years Follow-up or Treatment Routine screening 1 of 19 different algorithms Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.

17 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(-) and Cytology Negative at both visits HPV(+) or Any cytology abnormality except HSIL HSIL at either visit Manage per ASCCP Guideline for revised diagnosis Age-specific Retesting in 3 years + 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.

18 Cervical Cancer Screening & Management Cytology + HPV Histology Colposcopy

19 Underlying principles: Cervical Cancer Screening & Management Benefits Harms Similar management for similar risk

20 Over-diagnoses in Cytopathology: Is histology the gold standard? that depends