Don’t ASCUS, Don’t Tell:Nuances of Cervical Cancer Screening         Kathleen McIntyre-Seltman          Magee Womens Hospi...
Disclosures• In the last 2 years I have no conflicts of interest to  disclose• Prior to this time, I gave lectures for whi...
Learning ObjectivesAs a result of this presentation, the learner will be able to:• Discuss the epidemiology of HPV, cervic...
U.S. Prevalence of HPV Disorders                    CA                   8000             Cancer Precursor                ...
The 2001 Bethesda System (Abridged)INTERPRETATION/RESULTNegative for Intraepithelial Lesion or MalignancyEpithelial Cell A...
The 2001 Bethesda System (Abridged)Epithelial Cell AbnormalitiesSquamous cell- Atypical squamous cells (ASC)        - of u...
A Brief History of Cervical ScreeningBefore 1950’s:• No screening in USA• Colposcopy for screening in Europe and elsewhere...
A Brief History of Cervical Screening1980 – 90’s• Early understanding of role of HPV• The Bethesda System → ASCUS• Underst...
A Brief History of Cervical Screening21st century• More sophisticated understanding of HPV  epidemiology and natural histo...
What the heck is ASCUS?Squamous epithelial  cells that look  slightly abnormal but  do not fulfill TBS  criteria for LSIL
Risk of High Grade Disease     when Pap is minimally abnormal         PAP            Any CIN            CIN 3 or          ...
Triage of ASC - US       what we learned from ALTS• Approximately half ASC-US is HPV +• HPV triage of ASC-US is cost effec...
What the heck is ASC-H?Atypical squamous cells  not meeting criteria for  LSIL, but with one or a  very few small cells  s...
Triage ASC-H                               % HPV +   % CIN 2+ALTS data                       84%        50%Sherman Cancer ...
Triage HPVMagee Womens Hospital dataJLGT 14 2010AGE       %HPV+   o <40, approx half HPV+20-29      58      o >40 approx o...
What is HPV?          DNA virus          circular genome          7 genes               –   Early regulatory              ...
How is HPV Transmitted?• Almost certainly requires  sexual contact• Does NOT require  penetrative intercourse• Skin/mucosa...
Who gets HPV?• half of women within 3 yrs of starting sex   – 31% get HPV 16   – 20% get HPV 18• 80% women by age 25• ~100...
It’s easier to get HPV   than to get pregnant!        - Dame Margaret Stanley
Prevalence of HPV Infection                       in US womenAULT: ClinObstetGynecol, Volume 51(3).September 2008.527-532
Prevalence of HPV Schiffman, M. et al. J Natl Cancer Inst 2003;2003:14-19Copyright restrictions may apply.
Prevalence of HR HPV by Age  Population Based – 4 cohorts
Acquisition Of HPV                                             Declines With Age                      5.0%                ...
Prevalence of HPV
Natural History of HPV        0–1 Year             0–5 Years             1–20 Years                   Continuing          ...
Natural History of HPV Infection• Clearance of virus (“sustained remission”) 80 –  90%• Persistent expression of virus: 10...
HPV Type and Cancer RiskHPV TYPE % cancers % controls   ORHPV 16            53   3.0      434HPV 18            11   1.0   ...
Carcinogenesis• Integration of viral genome• E6 and E7 alter control of cell growth  – Decrease tumor suppressors  – Incre...
Success of ScreeningPap testing has decreased the rate of cervical  cancer by 75% (less in less resourced countries)BUT:• ...
Natural History of HPV Infection• Clearance of virus (“sustained remission”):  80 – 90%• Persistent expression of virus: 1...
Cumulative Incidence CIN 3/CA        women with normal pap, single HPV test at entryKhan et al JNC 2005; 97:1072      Pap ...
Development of CIN 3+ in 7 CountriesDillner, J. et al. BMJ 2008;337:a1754
Primary HPV ScreeningRijkaart Lancet Oncol 2012:7815 year follow up cohort Swedish women, age 30-60, screened q 5 yrsHPV d...
Primary HPV ScreeningARTISTIC trial – primary screening in England: f/u after 3 roundsKitchener Eu J Cancer 47:2011:864   ...
Follow up HPV - women                outcome                    HPV -      HPV- /Pap - Pap -Kaiser No       Cancer/100,000...
Co Test ScreeningARTISTIC trial – primary screening in England: f/u after 3 roundsKitchener Eu J Cancer 47:2011:864       ...
Risk of Developing CIN             Cytol - / HPV + women2020 women CYTOL - HPV + followed: ages 16-81, mean 28Castle et al...
Risk of Developing CIN            Cytol - / HPV + women1138 women followed, mean 54 months, age mean 41Zhao et al,GynOnc 1...
HPV Types and Cancer Risk            ALTS trial: Number (%) women developing > CIN 3          2 yr f/u,women > 30, by cyto...
Self Collection of HPVZhou et al JNCI 201213,000 underscreened women in rural China+ HPV 14.7 vs 15.6 clinician collected ...
Self Collection of HPVZhou et al JNCI 201213,000 underscreened women in rural China+ HPV 14.7 vs 15.6 clinician collected ...
HPV Screening: Summary• More sensitive than cytology• HPV q 3 yrs more sensitive than cytology q yr• HPV testing detects C...
Current Screening Recommendations          starting and stopping• Begin screening no earlier than age 21• Continue until 6...
Current Screening Recommendations              Frequency• Q 2 years 21-30• Q 2 years > 30 unless cotesting  – After 3 neg ...
ARHQ review 2011         When should screening start?Initiation of screening no earlier than 21• High prevalence but low p...
ARHQ Review 2011:      Should LBC be recommended?LBC compared with conventional cytology• LBC less unsatisfactory Paps• Po...
ARHQ review 2011: Should HPV screening be recommended?HPV primary screening +/- cytology triage• HPV more sensitive for CI...
ARHQ 2011:Should HPV/Pap Cotesting be recommended? •   Cumulative CIN 3+ equal •   CIN 3+ detected earlier •   50-60% more...
ARHQ review 2011:     Should HPV be used to triage minor              abnormalities?Triage of minor abnormalities• Increas...
ARHQ review 2011: What are the harms of HPV testing?Harms of HPV testing• Increased anxiety, fear, distress immediately  b...
ARHQ review 2011:                     Conclusions• 21 reasonable age to start screening• LBC equal sensitivity to CC but m...
Cervical Cancer Screening            Future Directions• Decreased frequency of screening using  cytology only (reflex HPV ...
How can we prevent cervical cancer?   Secondary prevention   • Screen for cancer precursors   • Diagnose and treat cancer ...
Who Needs Referral for Colposcopy?• Non adolescents with > ASC US HPV +• Women > 30 with HPV Pap screening  – ASCUS: IF HP...
How can we prevent cervical cancer?   Secondary prevention   • Screen for cancer precursors   • Diagnose and treat cancer ...
HPV Vaccines• Gardasil®  – Quadrivalent against 6/11/16/18  – FDA approved 2006 for women ages 9 – 26  – FDA approved 2009...
Efficacy of Vaccine                                                  % decrease Women neg for all vaccine viral types     ...
Summary• HPV is necessary but not sufficient for cancer• Everybody gets HPV, but most people clear the infection• Current ...
Pm 4.45 mcintyre-seltman
Pm 4.45 mcintyre-seltman
Pm 4.45 mcintyre-seltman
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Pm 4.45 mcintyre-seltman

  1. 1. Don’t ASCUS, Don’t Tell:Nuances of Cervical Cancer Screening Kathleen McIntyre-Seltman Magee Womens Hospital University of PittsburghWomen’s Health 2012: The 20th Annual Congress
  2. 2. Disclosures• In the last 2 years I have no conflicts of interest to disclose• Prior to this time, I gave lectures for which I was compensated – HPV vaccine – HPV test• I stopped giving those lectures when policy required using company slides rather than my own slides
  3. 3. Learning ObjectivesAs a result of this presentation, the learner will be able to:• Discuss the epidemiology of HPV, cervical cancer and pre-cancer• Compare different strategies for cervical cancer screening• Counsel patients regarding new screening guidelines
  4. 4. U.S. Prevalence of HPV Disorders CA 8000 Cancer Precursor HSIL 300,000 Trivially Abnormal Pap ASCUS / LSIL 3 million HPV INFECTION 9-10 million
  5. 5. The 2001 Bethesda System (Abridged)INTERPRETATION/RESULTNegative for Intraepithelial Lesion or MalignancyEpithelial Cell Abnormalities Squamous cell Atypical squamous cells (ASC) of undetermined significance (ASC-US) cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (LSIL) encompassing: human papillomavirus/mild dysplasia/cervical intraepithelialneoplasia (CIN) 1 High-grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, carcinoma in situ; CIN 2 andCIN 3 Squamous cell carcinoma Glandular cell Atypical glandular cells (AGC) (specify endocervical, endometrial, or NOSAtypical glandular cells, favor neoplastic (specify endocervical or NOS Endocervical adenocarcinoma in situ (AIS) AdenocarcinomaOtherAUTOMATED REVIEW AND ANCILLARY TESTING (Include as appropriate)EDUCATIONAL NOTES AND SUGGESTIONS (Optional)
  6. 6. The 2001 Bethesda System (Abridged)Epithelial Cell AbnormalitiesSquamous cell- Atypical squamous cells (ASC) - of undetermined significance (ASC-US) - cannot exclude HSIL (ASC-H)- Low-grade squamous intraepithelial lesion (LSIL)encompassing: human papillomavirus mild dysplasia cervical intraepithelial neoplasia (CIN) 1
  7. 7. A Brief History of Cervical ScreeningBefore 1950’s:• No screening in USA• Colposcopy for screening in Europe and elsewhere• Cone for severe dysplasia, hyst for CIS1950’s – 70’s• Pap screening• Women and clinicians socicalized to annual exams• Colposcopy appears in US• Office treatment (cryo) of dysplasia• CIN terminology• Cause of cervical cancer unknown but known to be related to sex
  8. 8. A Brief History of Cervical Screening1980 – 90’s• Early understanding of role of HPV• The Bethesda System → ASCUS• Understanding that Paps have lower sensitivity• Aggressive “search and destroy” of low grade changes• LASER (80’s) and LEEP (90’s)
  9. 9. A Brief History of Cervical Screening21st century• More sophisticated understanding of HPV epidemiology and natural history• Distinction between HPV infection and neoplasia• HPV vaccination• Novel approaches to screening
  10. 10. What the heck is ASCUS?Squamous epithelial cells that look slightly abnormal but do not fulfill TBS criteria for LSIL
  11. 11. Risk of High Grade Disease when Pap is minimally abnormal PAP Any CIN CIN 3 or Cancer ASCUS 20-30% 3-8% LSIL 50-70% 15-40%Importance of minimally abnormal pap:• Detecting high grade disease• Identifying women at risk to develop high risk disease
  12. 12. Triage of ASC - US what we learned from ALTS• Approximately half ASC-US is HPV +• HPV triage of ASC-US is cost effective• 85% LSIL HPV + therefore HPV triage is not useful• ALMOST ALL CIN 3+ in HPV + group
  13. 13. What the heck is ASC-H?Atypical squamous cells not meeting criteria for LSIL, but with one or a very few small cells suspicious but not diagnostic of HSIL
  14. 14. Triage ASC-H % HPV + % CIN 2+ALTS data 84% 50%Sherman Cancer 2006 108:298Multi site –CAP review 50% 34%Davey et al JLGT 14:206 2010Ince et al 43%GynOnc 2011 121:152Univ Pittsburgh 2010 55% 35%
  15. 15. Triage HPVMagee Womens Hospital dataJLGT 14 2010AGE %HPV+ o <40, approx half HPV+20-29 58 o >40 approx one third30-39 42 HPV+ o Approx 1/3 have CIN 2+40-49 35 o NPV over age 40 100%50-59 4060-69 43
  16. 16. What is HPV? DNA virus circular genome 7 genes – Early regulatory – Late capsid assembly 2 capsid proteins coded by L1 and L2 More than 100 types identified L1 unique to each type Vaccine = L1 antigen
  17. 17. How is HPV Transmitted?• Almost certainly requires sexual contact• Does NOT require penetrative intercourse• Skin/mucosa to skin/mucosa contact
  18. 18. Who gets HPV?• half of women within 3 yrs of starting sex – 31% get HPV 16 – 20% get HPV 18• 80% women by age 25• ~100% of women with > 3 lifetime partnersWhat about men?
  19. 19. It’s easier to get HPV than to get pregnant! - Dame Margaret Stanley
  20. 20. Prevalence of HPV Infection in US womenAULT: ClinObstetGynecol, Volume 51(3).September 2008.527-532
  21. 21. Prevalence of HPV Schiffman, M. et al. J Natl Cancer Inst 2003;2003:14-19Copyright restrictions may apply.
  22. 22. Prevalence of HR HPV by Age Population Based – 4 cohorts
  23. 23. Acquisition Of HPV Declines With Age 5.0% 4.0%%Acquisition HPV 16 3.0% 2.0% 1.0% 0.0% <25 25 - 34 35 - -44 45--- 54 55- - 64  65 Age Castle et al., J Inf Dis 2005;
  24. 24. Prevalence of HPV
  25. 25. Natural History of HPV 0–1 Year 0–5 Years 1–20 Years Continuing CIN 2/3 Invasive Infection AIS Cervical Cancer Initial HPVInfection CIN 1 Cleared HPV Infection
  26. 26. Natural History of HPV Infection• Clearance of virus (“sustained remission”) 80 – 90%• Persistent expression of virus: 10 – 20%These are the women at risk for cancerRisk factors for persistence: – Viral type and variant – Younger age at acquisition – Smoking – Immune suppression – Nutritional? Genetic? Other factors?
  27. 27. HPV Type and Cancer RiskHPV TYPE % cancers % controls ORHPV 16 53 3.0 434HPV 18 11 1.0 248HPV 45 4 0.5 197HPV 31 3 0.6 123HPV 52 2 0.2 200HPV 33 2 0.2 373Muñoz NEJM 2003
  28. 28. Carcinogenesis• Integration of viral genome• E6 and E7 alter control of cell growth – Decrease tumor suppressors – Increase tumor promoters – Inhibits apoptosis – Alter immune response, especially interferon – Synergism results in cell immortalization
  29. 29. Success of ScreeningPap testing has decreased the rate of cervical cancer by 75% (less in less resourced countries)BUT:• Relies on repeated testing (false negative rate of 1 pap between 30 and 50%)• Requires highly trained cytologists• Relies on visual pattern recognition• Expensive
  30. 30. Natural History of HPV Infection• Clearance of virus (“sustained remission”): 80 – 90%• Persistent expression of virus: 10 – 20%These are the women at risk for cancer
  31. 31. Cumulative Incidence CIN 3/CA women with normal pap, single HPV test at entryKhan et al JNC 2005; 97:1072 Pap NL/ASC/LSILKaiser study of 20514 women
  32. 32. Development of CIN 3+ in 7 CountriesDillner, J. et al. BMJ 2008;337:a1754
  33. 33. Primary HPV ScreeningRijkaart Lancet Oncol 2012:7815 year follow up cohort Swedish women, age 30-60, screened q 5 yrsHPV detected more abnormalities in first screen HPV CytolBASELINE CIN 2+ 1.34 1.07 CIN 3+ 0.86 0.75 Cancer 0.06 0.03SUBSEQUENT ROUNDS 0.93 CIN 2+ 0.82 0.93 CIN 3+ 0.45 0.62 Cancer 0.02 0.07
  34. 34. Primary HPV ScreeningARTISTIC trial – primary screening in England: f/u after 3 roundsKitchener Eu J Cancer 47:2011:864 DETECTION CIN 2+ % of population HPV CYTOLRound 1 2.46 2.19Round 2 0.74 0.89Round 3 0.77 0.69 HPV - HPV + CYTOL - (nl) CYTOL abn (+)Round 1 0.17 14.5 0.15 17.7Round 2 0.27 4.2 0.58 2.26Round 3 0.42 2.57 0.68 1.21
  35. 35. Follow up HPV - women outcome HPV - HPV- /Pap - Pap -Kaiser No Cancer/100,000 3.8 3.2 7.5Cal in 5 yKaiser CIN 3+ <1%PortlandARTISTIC CIN 3+ 0.48 0.42Turkey cancer 1/2175 or 0.5% Kaiser No Calif Katri et al Lancet Onc 2011:12:663 Kaiser Portland Khan et al JNCI 2005 ARTISTIC Kitchener Eu J Ca 2011:864 Sweden Bulkmanset et al 2009
  36. 36. Co Test ScreeningARTISTIC trial – primary screening in England: f/u after 3 roundsKitchener Eu J Cancer 47:2011:864 DETECTION CIN 2+ % of population HPV - / cytol - HPV + / cytol + HPV + / cytol - HPV+ /cytol +Round 1 0 2.23 1.48 32.6Round 2 0.25 0.44 3.67 5.03Round 3 0.42 0.48 2.77 2.2
  37. 37. Risk of Developing CIN Cytol - / HPV + women2020 women CYTOL - HPV + followed: ages 16-81, mean 28Castle et al Cancer 95:2145 2002Cytology detection of Pap showing: Cum risk > ASCUS 16.8% > LSIL 6.4% > HSIL 2.2%RISK FACTORS• HPV 16/18• young age• high viral load
  38. 38. Risk of Developing CIN Cytol - / HPV + women1138 women followed, mean 54 months, age mean 41Zhao et al,GynOnc 122:291 2011 HISTOL CIN 1+ HIGH GRADE CIN 2+ Total 24% 2.4% < 30 27.6% 2.4% > 30 21% 2.4%
  39. 39. HPV Types and Cancer Risk ALTS trial: Number (%) women developing > CIN 3 2 yr f/u,women > 30, by cytology and HPV status at entry into trialHPV status ASCUS LSILHC and/or PCRHPV - 2% 5%Oncogenic HPV + 15% 17%Oncogenic HPV + / 16 - 8% 11%HPV 16 + 32.5% 39%Schiffman et al JNCI 2005
  40. 40. Self Collection of HPVZhou et al JNCI 201213,000 underscreened women in rural China+ HPV 14.7 vs 15.6 clinician collected Sensitivity to Detect Disease SELF CLINICIAN Cytology VIA HPV HPV CIN 2+ 83% 95% 72% 48% CIN 3+ 86% 98% 89% 65%
  41. 41. Self Collection of HPVZhou et al JNCI 201213,000 underscreened women in rural China+ HPV 14.7 vs 15.6 clinician collected Comparing Screening Techniques Detection CIN 2+ SELF CLINICIAN Cytology VIA HPV HPV SENS 86 97 81 50 SPEC 81 83 94 87
  42. 42. HPV Screening: Summary• More sensitive than cytology• HPV q 3 yrs more sensitive than cytology q yr• HPV testing detects CIN 2+ earlier than cytology; detection “catches up” with repeated cytology screening• Negative predictive value of HPV very high, meaning that women who are HPV – are “protected” from dx CIN 3+ for several years
  43. 43. Current Screening Recommendations starting and stopping• Begin screening no earlier than age 21• Continue until 65 or 70, then d/c: – Unless hx CIN 3 or cancer in last 20 yrs – Unless fewer than 3 paps in lst 10 yrs• Stop screening after hyst when cervix removed – Unless hx CIN 3 or cancer – Continue age appropriate screening if cervix present
  44. 44. Current Screening Recommendations Frequency• Q 2 years 21-30• Q 2 years > 30 unless cotesting – After 3 neg tests, can increase interval to 3 yrs• Q 3 years at earliest if pap and HPV both neg
  45. 45. ARHQ review 2011 When should screening start?Initiation of screening no earlier than 21• High prevalence but low persistence in younger women• < 25 high proportion false + paps• Screening < 25 does NOT decrease cervical CAVesco KK et al Screening for Cervical Cancer: a systematic evidence review forUSPHSTFNo 86, AHRQ pub no. 11-05156-EF-1
  46. 46. ARHQ Review 2011: Should LBC be recommended?LBC compared with conventional cytology• LBC less unsatisfactory Paps• Possible increase in minor abnormalities• NO DIFFERENCE in detection CIN 2+• Unclear whether cost-effective Vesco KK et al Screening for Cervical Cancer: a systematic evidence review for USPHSTF No 86, AHRQ pub no. 11-05156-EF-1
  47. 47. ARHQ review 2011: Should HPV screening be recommended?HPV primary screening +/- cytology triage• HPV more sensitive for CIN 2+ (30-50%)• HPV less specific (3-5%)• Similar rate of colpo referral with cytol triage• Less invasive cancer in HPV screened cohortsVesco KK et al Screening for Cervical Cancer: a systematic evidence review forUSPHSTFNo 86, AHRQ pub no. 11-05156-EF-1
  48. 48. ARHQ 2011:Should HPV/Pap Cotesting be recommended? • Cumulative CIN 3+ equal • CIN 3+ detected earlier • 50-60% more sensitive than cytol alone • 5% less specific in women >30 • No impact in women <30 • Minimal benefit compared with HPV screening Vesco KK et al Screening for Cervical Cancer: a systematic evidence review for USPHSTF No 86, AHRQ pub no. 11-05156-EF-1
  49. 49. ARHQ review 2011: Should HPV be used to triage minor abnormalities?Triage of minor abnormalities• Increased detection of CIN 2+ (12%)• Possible detection of CIN 3+ earlier in women <30• Increased referral to colposcopyVesco KK et al Screening for Cervical Cancer: a systematic evidence review forUSPHSTFNo 86, AHRQ pub no. 11-05156-EF-1
  50. 50. ARHQ review 2011: What are the harms of HPV testing?Harms of HPV testing• Increased anxiety, fear, distress immediately but resolved at 6 mo f/u Vesco KK et al Screening for Cervical Cancer: a systematic evidence review for USPHSTF No 86, AHRQ pub no. 11-05156-EF-1
  51. 51. ARHQ review 2011: Conclusions• 21 reasonable age to start screening• LBC equal sensitivity to CC but may decrease unsatisfactory slides - ? Cost effectiveness• HPV primary screening “appears promising” when paired with cytology triage• Co testing HPV/Pap similar to HPV only with cytol triage; does not add to sensitivityVesco KK et al Screening for Cervical Cancer: a systematic evidence reviewfor USPHSTFNo 86, AHRQ pub no. 11-05156-EF-1
  52. 52. Cervical Cancer Screening Future Directions• Decreased frequency of screening using cytology only (reflex HPV testing for ASC-US) ages 21-30: Q 3 years• Primary HPV screening >30 – Reflex cytology – Q 3-5 years
  53. 53. How can we prevent cervical cancer? Secondary prevention • Screen for cancer precursors • Diagnose and treat cancer precursors Primary prevention • Education • Vaccine
  54. 54. Who Needs Referral for Colposcopy?• Non adolescents with > ASC US HPV +• Women > 30 with HPV Pap screening – ASCUS: IF HPV 16/18 + – ASCUS: IF either Pap or HPV abnormal after 1 yr• Menopausal women: can repeat LSIL if desired – or HPV test – or colpo• ANY AGC
  55. 55. How can we prevent cervical cancer? Secondary prevention • Screen for cancer precursors • Diagnose and treat cancer precursors Primary prevention • Education – GET WOMEN TO BE SCREENED • Vaccine
  56. 56. HPV Vaccines• Gardasil® – Quadrivalent against 6/11/16/18 – FDA approved 2006 for women ages 9 – 26 – FDA approved 2009 for men• Cervarix® – Bivalent against 16/18 – FDA approved 2009• Both synthetic VLPs• Both given time 0, 2 mo, 6 mo
  57. 57. Efficacy of Vaccine % decrease Women neg for all vaccine viral types >99% Women pos for at least 1 viral type OR 40 – 60% off protocol (missed or late doses) Similar for bivalent and quadrivalent vaccines• Cross protection in phylogenetically related HPV families• Bivalent or quadrivalent vaccine 59%  in CIN 2/3 due toHPV 31/45
  58. 58. Summary• HPV is necessary but not sufficient for cancer• Everybody gets HPV, but most people clear the infection• Current screening with cytology has limitations• Primary HPV screening is the future, likely with cytology triage• Vaccination is a safe and effective way to prevent HPV related disease• Rapid HPV test self collected specimen combined with VIA /treat in underresourced environments is cost effective CERVICAL CANCER CAN BE NEARLY ELIMINATED!

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