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Thames Valley Cytology Society 17 June 2009

Thames Valley Cytology Society 17 June 2009. HPV Testing at Princess Alexandra Hospital Janet Leake Pathologist. Itinerary. Background Sentinel sites Forming the business case Early results from PAH. HPV and Cancer. HPV and Cancer.

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Thames Valley Cytology Society 17 June 2009

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  1. Thames Valley Cytology Society17 June 2009 HPV Testing at Princess Alexandra Hospital Janet Leake Pathologist

  2. Itinerary • Background • Sentinel sites • Forming the business case • Early results from PAH

  3. HPV and Cancer

  4. HPV and Cancer • Persistentinfection with high risk HPV subtype is necessary but not sufficient for carcinogenesis • Sensitivity of HR-HPV is high (?too high) • Specificity is low (especially in the young)

  5. Natural History • Elimination (median 8 -14 months) • Most prevalent after sexual debut • Co-existence of more than one subtype (especially < 30s)

  6. HPV Subtypes • 66% of CIN 2 + associated with HPV16 or HPV18 • Frequency of most prevalent: 16, 52, 18 & 31 =, 51, 39 • Infection with more than one type in <30 year olds • Bivalent vaccination ineffective in approx one third

  7. Distribution of HR HPV subtypes in cervical cancer

  8. HPV Testing • Qiagen (formerly digene) hc 2 • Cervista • Greiner

  9. Qiagen (Digene) hc2

  10. Qiagen hc2 • HR-HPV types; 16/18/31/33/35/39/45/51/52/56/58/59/68 • Detection at 1pg/ml, approx 5,000 DNA copies/ml, standard for clinical relevance

  11. hc 2 • Longest track record, FDA approval and data in literature • Relatively simple • Highly consistent and reproducible

  12. hc 2 • No information on individual subtypes • Risk of false negative on acellular sample • Needs bulk runs to be cost effective; 1 kit provides 88 tests (with 8 controls)

  13. Cervista (Hologic) • Cervista HR – 14 type specific probes. PCR • Cervista 16/18 • FDA approval March 2009 for ASC-US (B/L) in women 30+ • Smaller batch size (28)

  14. PapilloCheck(Greiner) • PCR based, type specific primers • Simple kit • Identifies 18 HR subtypes & 6 LR subtypes • Consistent reproducible results published

  15. NHSCSP LBC/HPV pilot • 5,654 women 20-64 • Triage of low grade abnormalities • 45.6% borderline HR-HPV positive • 82.6% mild dysk HR-HPV positive

  16. HR-HPV status by age for low grade

  17. Impact on Colposcopy and Lab • Referrals more than doubled • Protocol modified; under 35s had repeat cytology and HPV at 6 months • Repeat cytology fell by 74%

  18. Impact on patients • Opportunity for early referral, treatment of smaller lesion • Fewer HPV + women default from colposcopy than from cytological follow up of LG abnormality • Increased detection of CIN2+

  19. ARTISTIC • A Randomized Trial in Screening to Improve Cytology • NHSCSP 24 510 women enrolled • Brit J Cancer 2006 95 56-61 • Brit J Cancer 2008 98 1704-1709

  20. hc2 +%by age (screening population)

  21. hc2+ % by cytology

  22. HPV status – clinical implications • HR – HPV + is highly sensitive (>99%) for CIN 2 or worse; false negative rate negligibly low • BUT specificity is relatively low, especially in the young; false positive rate for significant pathology relatively high • 10 year Cumulative incidence of CIN 3 or worse is 15-20% for persistent HR-HPV

  23. Protective effect of negative HC2versus negative cytology for CIN 2+

  24. NHSCSP early implementersSentinel Site Laboratories April 2008N • 6 labs – 2 clusters of 3 • Northern: Sheffield, Manchester, Liverpool • Southern: Bristol, Northwick Park, Norfolk and Norwich • Testing carried out in Manchester and Bristol • Triage of low grade abnormalities • Test of cure post treatment

  25. Low Grade Triage – Sentinel Sites

  26. Follow up arm/Test of Cure 6/12 follow up Cytology normal Cytology abnormal HPV test HPV negative HPV positive Refer to colposcopy Return to normal recall

  27. Challenges at PAH • Not a sentinel site! Strict adherence to NHSCSP guidelines on referral and surveillance • Could it be cost effective? • Informed consent of women involved

  28. Low Grade Referrals to PAH • Approx. 300 per annum • Of these, about 2/3 are over age of 30 • Many clinically inflammatory • Of those biopsied approx 25% will have significant pathology (CIN 2+) – Which ones?

  29. Costing • Staff components • BMS band 4 • BMS band 5 • AP/Pathologist (in putting and validation) • Consumables • Qiagen kits • pipettes and sundries

  30. Unit cost v run batch size Cost £ Number of tests/run

  31. Potential Savings • Reduced re-referrals to colposcopy for persistent low grade abnormalities. (Colposcopy tariff is approx. £250) • Freeing of slots for new referrals. • ?Reduced negative biopsy rate • (Quality improvement due to increased detection of CIN 2+)

  32. PAH Criteria 1 • Low grade referrals aged 30 and over • 6 month follow up after LLETZ high grade histology, any age – test of cure • ‘Borderline cannot exclude high grade’ any age

  33. PAH Criteria 2 • 12 month follow up of clinically normal/untreated HR-HPV positive low grade referrals • Clinically indicated egg. Cytology/histology non-correlation, ?HIV, miscellaneous management problems

  34. Low Grade Algorithm 1 HPV negative Negative colposcopy No biopsy, or biopsy with no CIN CIN 1 NHSCSP Cytology follow up Conservative management

  35. Low Grade Algorithm 2 HPV positive Biopsy or treat Negative colposcopy No biopsy, or biopsy with no CIN Colposcopy or biopsy positive NHSCSP Cytology follow up with repeat HPV at 12 months Manage clinically as appropriate

  36. Implementing • Patient information and opt out phone line • Communication with all smear takers • Communication with QA, contractor services • Training and education colposcopists, gynaecologists, GUM • Request generation at time of reporting pap • Failsafe of requesting

  37. Early Results • 52 analysed; 2 inappropriate - excluded • 31 Low grade referral, of which 24 were hc 2 + • 18 Post treatment, of which 2 were hc 2 + • 1 Other (had CIN 2 in 2004, neg cytol & polyp)

  38. Unexpected volumes and costs • Cost £35 based on 10/run, 2 weekly run i.e. approx 250/annum • Number performed 1st Jan – 31st May = 300 • Spoilt runs (not in costing) • Larger runs: consumable efficiency not paralleled by manpower • ? Net effect on biopsy rate

  39. hc 2 status for Low Grade and Follow up

  40. Hc 2 status for Low Grade by age

  41. Follow up group correlations • All had negative concurrent cytology • Both of hc 2 positive had a history of CIN 3, completely excised. • The only uncertainly excised CIN had negative hc 2 and negative cytology.

  42. Low Grade hc 2 status by age

  43. Low Grade triage • High hc 2 positive rate in <40s is 92.8% • In 40 – 65s, 66.6 – 62.5% • Borderline and mild not separated.

  44. Low Grade Corellations • 12 of 24 LG referrals were biopsied: • 7 CIN 1 • 2 HPV changes no CIN • 2 -negative • 1 – CIN 3, age 22, 8XS • None of 7 hc 2 negative patients were biopsied

  45. Initial Impressions • Very high hc 2 + rates among low grades < 40 • Less than 10% reduction of LG referrals < 40 • In over 40s could triage out a least one third of low grade referrals • Big saving in 10 year follow up of treated HG

  46. The Future • Definite role for follow up • Possible role for LG triage, but ?age 40+ • Possible increased specificity in selection of candidates for biopsy, increased sensitivity using triple approach i.e. Cytology, HPV test and colposcopy

  47. The End

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