Human Papillomavirus Triage for Young Women with Atypical Squamous Cells of Undetermined Significanc

1
Human Papillomavirus Triage for Young Women
with Atypical Squamous Cells of Undetermined
SignificanceObstetrics Gynecology 2006 107
822-9.

• Adela Tam, MD
• Family and Community Medicine
• Journal Club
• June 30, 2006

2
Outline

• Background
• Study Design
• Results
• Conclusion
• Appraisal
• Discussion Points

3
Clinical Question

• Is human papillomavirus (HPV) testing useful for
  managing adolescent and young women with atypical
  squamous cells of undetermined significance
  (ASCUS)?

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Cytologic Abnormalities Histologic Diagnoses
ASCUS Atypical squamous cells of undetermined
significance LSIL low-grade squamous
intraepithelial lesion HSIL high-grade
squamous intraepithelial lesions CIN cervical
intraepithelial neoplasia
(Kahn Hillard, 2004)
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Management of ASCUS Remains a Challenge

• Cells that appear abnormal but do not fulfill
  strict criteria for dysplasia
• 3-36 ASCUS will have underlying high-grade
  cervical lesions (CIN 2) confirmed on biopsy
  (Wright et al, 2006)
• 0.1-0.2 risk of invasive cancer (Wright et al,
  2001)
• 39 high-grade cervical lesions identified by
  evaluation of ASCUS (Wright et al, 2006)
• Most common abnormal result on cytology (3-8)
• Poor inter-rater reliability with 43 agreement
  between raters (Stoler Shiffman, 2001)

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CHN guidelines for initial management of ASCUS
follow the 2001 Consensus Guidelines by the
American Society of Colposcopy and Cervical
Pathology.
Here at SFGH
(Sawaya, G. (2003). CHN Guidelines for Initial
Management of Abnormal Cervical Cytology)
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Initial Management of ASCUS
(Sawaya, 2005)
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GOAL OF ASCUS MANAGEMENT

• To maximize identification of high-grade
  dysplastic lesions while minimizing unnecessary
  colposcopy and overtreatment of lesions that
  would otherwise resolve.

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Immediate Colposcopy Not For Everyone

• A reference standard for detecting high-grade
  lesions and cancer in studies
• Patient discomfort
• False concern for lesions that might resolve
• Expensive
• Risk of overdiagnosis and overtreatment

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Why HPV Testing for Management of ASCUS?

• High-risk strains of HPV linked with cervical
  cancer
• ASCUS-LSIL Triage Study (2003)
• Large, mutlicenter, randomized NCI trial of 3
  management strategies for ASCUS LSIL (n3488)
• Repeat cytology vs. HPV testing vs. immediate
  colposcopy
• HPV testing, as compared to immediate colpo, was
  much more sensitive for CIN 3 and led to less
  referrals for colposcopy
• HPV testing, as compared to repeat cytology, was
  slightly more sensitive and led to similar number
  of referrals for colposcopy

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Why are Adolescents Different?

• HPV prevalence with ASCUS much higher in young
  women (Sawaya, 2005)
• 71 in ages 18-22 yo
• 20 in ? 40 yo
• Average length of detectable HPV is 13 months
• HSIL prevalence 0.2-3
• CIN 1 resolves in 70 (ACOG, 2006)
• CIN 2 resolves in 50 (ACOG, 2006)

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Risk of Progression to Cancer in Adolescents
Unknown

• Progression to high-grade lesions in older women
  typically takes several years
• In ? 25 y.o., progression from CIN 2 to CIS/
  invasive CA took 54 to 60 mths
• Invasive cervical cancer exceedingly rare
• 0/100,000 in 10- to 19-yo group
• 1.7/100,000 in 20- to 24-yo group
• (NCIs Surveillance, Epidemiology and End Results
  1995-1999)

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In 2005, ACOG Adjusted Recommendations for
Adolescent Patients with ASCUS
(ACOG Committee Opinion, 2006)
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Dilemma

• Adolescents with ASCUS found to have high rate of
  HPV positivity, but low prevalence of high-grade
  lesions
• Is HPV testing in this population useful?

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Study Objectives

• To estimate, in younger vs. older subjects
• Rates of HPV positivity
• Incidence of high-grade cervical dysplasia
• Sensitivity specificity of HPV testing for
  women with ASCUS
• To examine whether age affected patterns of care
  for women with ASCUS and subsequent management

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Methods

• Retrospective review using the pathology database
  at an academic medical center
• Inclusion women with first-time ASCUS on pap
  over a two-year period
• Exclusion women with cytologic diagnosis other
  than ASCUS (including ASC-H) and prior ASCUS
• ASC-H atypical squamous cells, cannot rule out
  high-grade squamous intraepithelial lesions

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Methods

• Liquid-based cytology interpreted by staff
  cytopathologist
• Reflex HPV testing for 13 high-risk types in all
  subjects
• Follow-up pathology (cytology, biopsy,
  conizations, endocervical curetttings,
  hysterectomy) were queried in database for all
  subjects
• Follow-up specimens were processed in routine
  fashion and interpreted by staff pathologist

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Analysis

• For ? 25, 26-40, 41-50, and gt 50 age groups,
  estimated rates of HPV positivity, rates of
  high-grade dysplasia, sensitivity, and
  specificity
• Analysis conducted for data at entry, at
  follow-up, and cumulatively.
• In cumulative analysis, outcomes dichotomized
  the most severe outcome was used.
• Normal or low-grade normal, ASCUS, atypical
  glandular cells of undetermined
  significance, LSIL, CIN 1
• High-grade HSIL, CIN2, CIN3, invasive cancer
• Groups compared by ?2 and Fishers exact test

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Results

• 1290 women with ASCUS cytology identified
• Age 36 (mean), 13-91 (range)
• 34 HPV, 62 HPV-, 4 equivocal
• Overall follow-up was 66
• Follow-up occurred in 79 of HPV and 57 of HPV-
  group (p0.001)
• Among HPV, follow-up was 100 in ? 50 and 74 in
  ? 25 age groups (p0.002)
• Among HPV-, follow-up was 67 in ? 50 and 52 in
  ? 25 age groups (p0.006)

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Management of ASCUSSimilar Regardless of Age

• Cervical Biopsies at Follow-Up
• HPV ? 25 yo 68 (p0.21)
• ? 50 yo 70
• HPV- ? 25 yo 12 (p0.46)
• ? 50 yo 13

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HPV Positivity Decreased with Advancing Age (p
lt0.001)
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Cumulative Pathologic Outcome, Stratified by Age
HPV Status
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Dichotomized Outcome, Stratified by Age HPV
Status
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Performance of HPV Testing, Stratified by Age
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Sensitivity Specificity Comparison
In this study

• Wright et al, 2001.
• 2. Arbyn et al, 2004.

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Conclusions

• In young women, HPV triage for ASCUS has high
  sensitivity but low specificity for high-grade
  lesions
• High prevalence of HPV-positive ASCUS in young
  women leads to colposcopic referrals for a large
  portion despite low specificity for detection of
  high-grade disease in this population
• HPV testing may be more appropriate in older
  women

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Limitations

• 34 lost to follow-up, particularly young women
• Pathology interpreted by a single staff
  pathologist ASCUS associated with poor
  inter-rater reliability (43 agreement)
• Possible disease ascertainment bias
  pathologists not blinded to previous results
• CIN 2 and 3 lumped into High-grade some (e.g.
  ASCCP) argue that CIN 2 tends to regress and can
  be observed
• No comparison group e.g. HPV triage vs. repeat
  cytology in adolescents

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What is done here at FHC Dysplasia Clinic?

• Most common repeat cytology, colposcopy if
  ASCUS or worse
• HPV testing is never done regardless of age
• SFGH uses conventional cytology, not
  liquid-based cytology (evidence lacking)
• Management of HPV/CIN-absent not known
• Counseling for informed consent and significance
  of result is not straightforward
• Psychological sequelae of positive result with
  no available tx
• (Correspondence with G. Sawaya, June 28, 2006)

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Discussion

• HPV triage of ASCUS would lead to colposcopic
  referral of
• 18-22 yo 71
• ? 29 yo 31
• In some young populations, up to 80 test HPV ?
  sending so many to colposcopy is impractical
• Concern for identification and overtreatment of
  lesions that would naturally regress

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Repeat Cytology for ASC-US

• ADVANTAGES
• Identify women with persistent dysplasia while
  allowing CIN 2 to resolve

• DISADVANTAGES
• High sensitivity requires repeated paps
• At least 2 return visits required
• Risk of delayed diagnosis
• Up to 2/3 adolescents will have ASCUS 6mths later
  and be referred to colpo

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HPV Triage for ASC-US

• ADVANTAGES
• Slightly better specificity than repeat pap
• If LBC, no return visit needed
• If negative, reassuring and just repeat pap in 12
  months
• Preliminary data suggest more cost-effective than
  colpo rpt pap (long-term data n/a)

• DISADVANTAGES
• Conventional cytology requires return visit
• If positive no colpo, pt returns for rpt pap or
  HPV test management unchanged
• Majority of adolescents with ASCUS are HPV and
  would be referred for colposcopy
• Psychological effects
• Counseling time

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Ideal ASCUS triage would balance

• Sensitivity (cases of CIN 2 identified
  cervical cancer cases averted)
• Specificity (women referred for positive tests
  who do not have CIN 2)

• Inconvenience of return visits
• Expense of additional testing
• Psychological effects
• Impact on quality of life

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Discussion Points

• Are there cases in which you think HPV testing
  would be the best option?
• Are there other triage strategies for ASCUS that
  you could imagine?

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• Article Reviewed
• Wright JD, Rader JS, Davila R, Powell MA, Mutch
  DG, Gao F, Gibb RK. (2006). Human
  Papillomavirus Triage for Young Women with
  Atypical Squamous Cells of Undetermined
  Significance. Obstet Gynecol, 107(4), 822-9.
• References
• ACOG Committee Opinion. Evaluation and
  Management of Abnormal Cervical Cytology and
  Histology in the Adolescent. Obstet Gynecol.
  2006, 107 963-8.
• ASCUS-LSIL Triage Study (ALTS) Group. Results of
  a randomized trial on the management of cytology
  interpretations of atypical squamous cells of
  undetermined significance. Am J Obstet Gynecol.
  2003, 188 1383-92.
• Kahn, JA Hillard, PA. Human Papillomavirus and
  cervical cytology in adolescents. Adolescent Med
  Clinics. 2004, 15(2).
• Kahn, JA Hillard, PA. Cervical Cytology
  Screening and Management of Abnormal Cytology in
  Adolescent Girls. J Pediatr Adolesc Gynecol.
  2003, 16 167-71.
• Sawaya GF. A 21 year-old Woman with Atypical
  Squamous Cells of Undetermined Significance.
  JAMA. 2005, 294 2210-8.
• Sawaya, GF. CHN Guidelines for Initial
  Management of Abnormal Cervical Cytology. 2003.
• Stoler MH, Shiffman M. Interobserver
  reproducibility of cervical cytologic and
  histologic interpretation realistic estimates
  from the ASCUS-LSIL Triage Study. JAMA. 2001,
  285 1500-5.
• Wright TC, Cox JT, Massad LS, Twiggs LB,
  Wilkinson EJ. 2001 Consensus Guidelines for the
  Management of Women with Cervical Cytological
  Abnormalities. JAMA. 2002, 287 2121-9.