john tidy - adjunctive colposcopic technologies

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Page 1: John Tidy - Adjunctive colposcopic technologies
Page 2: John Tidy - Adjunctive colposcopic technologies

Adjunctive Colposcopic Technologies

John Tidy

Professor of Gynaecological OncologyPresident BSCCP

Chair, National Colposcopy Professional Group Committee,

Research Advisory Committee for Cervical ScreeningSheffield

Page 3: John Tidy - Adjunctive colposcopic technologies

Disclosures• Zilico Ltd

– Shareholder, Consultancy, Patent holder• Qiagen

– Speaker fee• Roche

– Speaker fee• Hologic

– Speaker fee• Sanofi-Pastuer

– Travel and conference fees

Page 4: John Tidy - Adjunctive colposcopic technologies

Why do we need adjuvant technologies?

• New referral groups– HPV Triage, ToC, Primary HPV testing

• Post vaccination population• Minimise overtreatment to avoid adverse

outcomes• Improve re-assurance when discharging

women to routine screening• Triage by molecular tests may not be

effective– CINTEC Plus

Page 5: John Tidy - Adjunctive colposcopic technologies

The Performance of Colposcopy

• Colposcopy has not changed for 90 years• Understanding performance• We cannot assess sensitivity and

specificity out side of clinical trials• We use positive predictive value of a

colposcopic impression of HG-CIN to confirm HG-CIN on biopsy – as marker of performance

Page 6: John Tidy - Adjunctive colposcopic technologies

Colposcopy in different populations

• Positive predictive value (PPV) is dependent on the prevalence of disease– More HG-CIN equals better PPV

• If the proportion of women referred have no disease increases so our performance will decrease– HPV primary screening – Effect of HPV vaccination

• Non HPV16/18 disease is less prevalent

Page 7: John Tidy - Adjunctive colposcopic technologies

Colposcopy in different populations

• Service review in Sheffield 2292 women with biopsy data– Colposcopic impression HG-CIN– Referred with HG cytology PPV = 93.4%– Referred with LG cytology PPV = 54.9%– Referred HPV 16/18 pos/cyto neg PPV = 42.9%– Referred HPV O pos/cyto neg PPV = 35.0%

• But these data may reflect the performance of our cytology laboratory

Page 8: John Tidy - Adjunctive colposcopic technologies

Colposcopy in different populations

• Multiple biopsy study of 690 women– Colposcopic impression HG-CIN

• HSIL cytology PPV = 60.0%• LSIL cytology PPV = 32.2%

Wentzensen et al 2015

Page 9: John Tidy - Adjunctive colposcopic technologies

Relationship between disease prevalence and predictive value in a test with 95% sensitivity and 85% specificity.

Relationship between disease prevalence and predictive value

  Tidy et al BJOG

2013;120:400-11

Louwers et al BJOG

2011;118:309-18

van der Marel et al BJOG

2014;121:1117-26

Sensitivity 74% (63-83%) 52% (42-61%) 62 (55-67%)

Specificity 84% (75-90%) 82% (75-88%) 82% (78-86%)

PPV 78% (68-86%) 70% (60-80%) 73% (67-78%)

NPV 80% (71-87%) 67% (60-75%) 73% (69-78%)

Accuracy 78% 70% 74%

LR+ 4.46 2.13 3.4

HG cyto 43.7% 33.0% 55.4%

HG-CIN 44.4% 46.0% 60.0%

Page 10: John Tidy - Adjunctive colposcopic technologies

Primary HPV Screening• All women aged 25 - 65• Commenced April 2013 • 314,244 women underwent primary HPV

testing to Dec 2015• 651,307 women underwent primary

cytology testing to Dec 2015• hr-HPV positive rates

– Average 12.7%, range 10.5 – 15.0%– HPV 16/18 4.0%– Age 24-29 – 27.6%– Age 50-64 – 5.5%

Page 11: John Tidy - Adjunctive colposcopic technologies

hr-HPV status at Sheffield

HPV 16

HPV 18

HPV O

Negative

N=88,92415.0% of the screened population are hr-HPV positive68.4% of hr-HPV positive women are positive for only HPV O

Page 12: John Tidy - Adjunctive colposcopic technologies

HPV genotypes and CIN2+ - Sheffield

• 1597 cases of CIN2+ were detected. • 1008 (63.1%) were associated with

HPV16/18 and multiple infection. • 589 (36.9%) were HPV O only positive• 68.4% of the women who are hr-HPV

positive have only HPV O and they contribute 36.9% of all CIN2+.

Page 13: John Tidy - Adjunctive colposcopic technologies

Number of CIN2+ cases following referral with abnormal cytology -

Sheffield

HPV16+/-18+/-O HPV18+/-O HPVO0

100

200

300

400

500

600

700

800

900

1000

CIN2+

Page 14: John Tidy - Adjunctive colposcopic technologies

Primary HPV Screening

• 12 month recall– hr-HPV primary test– If negative – routine recall– If positive – reflex cytology– If cytology positive (any grade) referral to

colposcopy– If cytology negative but still positive for HPV 16

and or HPV 18 referral to colposcopy – If cytology negative but still positive for HPV O

repeat hr-HPV test at 12 months

Page 15: John Tidy - Adjunctive colposcopic technologies

Primary HPV Screening

• 24 month recall– hr-HPV primary test– If negative – routine recall– If positive – reflex cytology– If cytology positive (any grade) referral to

colposcopy– If cytology negative but still positive for HPV O

referral to colposcopy

Page 16: John Tidy - Adjunctive colposcopic technologies

Primary HPV Screening• 1076 women seen with persistent hr-HPV

positive / cytology negative• hr-HPV genotype

– HPV 16 +/- 18+/- O 46%– HPV 18 +/-O 13%– HPV O 41%

• Colposcopy– Normal 72%– Low grade 11%– High grade 11%

Page 17: John Tidy - Adjunctive colposcopic technologies

Primary HPV Screening• 1076 women seen with persistent hr-HPV

positive / cytology negative• Histology

– Biopsy rate 31%– CIN2+ 6.5%

• PPV for colposcopic impression of HG-CIN– 47.4%

• Risk of CIN2+ by hr-HPV genotype– HPV 16 +/- 18+/- O 1 in 9– HPV 18 +/-O 1 in 30– HPV O 1 in 32

• Discharge back to screening– 87.5%

Page 18: John Tidy - Adjunctive colposcopic technologies

Summary• The prevalence of disease has the greatest impact

on the performance of colposcopy• PPV outcome can be ‘gamed’ by colposcopists

– Under calling of HG lesions• Poor sensitivity of HG Colp impression to detect

HG-CIN– Biopsy of any grade of lesion because of under calling

of HG Colp Impression– Failure to discharge patients with no disease

• Changes to screening such as HPV vaccination and primary HPV screening will increase number of women referred to colposcopy at low risk of CIN2+

Page 19: John Tidy - Adjunctive colposcopic technologies

How could new technologies help?

• Increase detection of HG-CIN– Increased sensitivity

• Improve PPV for S&T and increase number of cases– Increased specificity

• Reduce number of biopsies– Improved accuracy

• Confirmation of a normal colposcopic examination– Improved negative predictive value

Page 20: John Tidy - Adjunctive colposcopic technologies

New Technologies in Cervical Screening and Colposcopy

• LuViva• DySIS• ZedScan• TruScreen

• Gynocular, MobileODT

Page 21: John Tidy - Adjunctive colposcopic technologies

New Technologies in Cervical Screening and Colposcopy

LuViva Fluorescence + ReflectanceDySIS Photo-optics to quantify

aceto-whitenessZedScan Electrical Impedance

SpectroscopyTruScreen Visible light + Infra Red +

voltage decay

Page 22: John Tidy - Adjunctive colposcopic technologies

TruScreen

• Measures both optical and electrical changes in the cervix

• Alternative to cervical cytology

Page 23: John Tidy - Adjunctive colposcopic technologies

TruScreen

• Increased sensitivity to detect CIN2+ when combined with cytology– 93% for cytology + TruScreen– 70% for TruScreen alone and 69% for

cytology alone

Singer et al 2003

Page 24: John Tidy - Adjunctive colposcopic technologies

LuViva

Page 25: John Tidy - Adjunctive colposcopic technologies

LuViva

• Placed between cytology and colposcopy• Triage of low grade cytology to colposcopy

– Increased and earlier detection of CIN2+• Sensitivity to detect CIN2+ 91.3%• Specificity 38.9%

Twiggs et al 2013

Page 26: John Tidy - Adjunctive colposcopic technologies

DySIS

Video-colposcopeattached to speculum

New versions more ergonomically friendly

Displays a false colourto highlight areas to biopsy

Page 27: John Tidy - Adjunctive colposcopic technologies

Red, yellow and white areas indicate intense/long lasting aceto-whitening

Page 28: John Tidy - Adjunctive colposcopic technologies

DySIS performance ITTn = 236

Video -Colposcopy

Dysis + Video-Colposcopy

Sensitivity (TP) 52% 80% p=0.039

Specificity (TN) 82% 63% p=0.011

PPV 76% 72%NPV 68% 68%Accuracy 70% 68%Positive likelihood ratio

2.13 2.83

Prevalence of CIN2+ 45.2% Louwers et al BJOG 2011

Page 29: John Tidy - Adjunctive colposcopic technologies

DySIS• Zaal et al (2012)

– Same study – subgroup analyses– DySIS increases detection of HPV16 related

CIN– Abnormal cytology (HG cytology 33%)– CIN2+ 46%

• Colp - HPV 16 53.0%1 vs non HPV16 61.0%2

• DySIS - HPV 16 97.0%1 vs non HPV16 74.0%2

1Colp vs DySIS p 0.009, 2Colp vs DySIS p=NS

Page 30: John Tidy - Adjunctive colposcopic technologies

DySIS• Louwers et al (2015)

– Same study – subgroup analyses– DySIS may increase detection of high grade CIN

post introduction of HPV testing or triage • Coronado et al (2016)

– Single colposcopist– 443 women (9.3% CIN2+)– Sensitivity for CIN2+

• Colp alone 73.2% vs Colp+DySIS 87.8%– Specificity for CIN2+

• Colp alone 92.3% vs Colp+DySIS 85.6%

Page 31: John Tidy - Adjunctive colposcopic technologies

DySIS• Roensbo et al (2016)

– Multiple colposcopists– Up to 5 biopsies including random bx– 239 women (28.4% CIN2+)– Sensitivity for CIN2+

• DySIS 32.4%– Specificity for CIN2+

• DySIS 83%– DySIS missed 67.6% CIN2+ cases

• Result may reflect, in part, methodology of study

Page 32: John Tidy - Adjunctive colposcopic technologies

Biological and circuit model for tissue impedance (EIS)

Extra-cellular space

Intra-cellular space

Current input

Measured voltage output

Cell membrane

Current input

Measured voltage output

R

C

S

Can we image the cervical epithelium with electricity?

Page 33: John Tidy - Adjunctive colposcopic technologies

Structure of cervical epithelium

Basement membrane Stroma

Surface epithelium

Normal CIN 1 CIN 2 CIN 3 Invasion

Intermediate

Superficial

Parabasal

Basal

0.4mm

Page 34: John Tidy - Adjunctive colposcopic technologies

Structure of cervical epithelium

Basement membrane Stroma

Surface epithelium

Normal CIN 1 CIN 2 CIN 3 Invasion

Intermediate

Superficial

Parabasal

Basal

0.4mm

Page 35: John Tidy - Adjunctive colposcopic technologies

Hierarchical Modelling

Tetrapolarelectrode array

MACROSCOPIC TISSUE MODEL

Stroma

+I -I

V

V1 V2

I

Z(f)

MUCUS

SUPERFICIAL

INTERMEDIATE

PARABASAL

BASAL

Epithelial layers

CELLULAR MODEL MODELS

Page 36: John Tidy - Adjunctive colposcopic technologies

Finite element derived model

Normal squamous

HG-CIN

Immaturemetaplasia

Normal columnar

Walker et al 2003

Page 37: John Tidy - Adjunctive colposcopic technologies

EIS in the detection of CIN

Squamous ― Low grade ― High grade CIN ― Immature metaplasia ― Columnar ―

Modelled Measured

+

Compare modelled data with measured data to derive a probability that HG-CIN is present or absent

Page 38: John Tidy - Adjunctive colposcopic technologies

Snout LEDs

“Push on – off” single use sensor

Real time on board data analysis

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1

2

3

4

5

6

7

8

9

10

1112

Page 42: John Tidy - Adjunctive colposcopic technologies

ZedScan – results screens

See and Treat

Biopsy required –Single point mode

Page 43: John Tidy - Adjunctive colposcopic technologies

43 March 2010 Commercial in Confidence

43September 2009 Commercial in Confidence 43July 2009 Commercial in ConfidenceOctober 2008 Commercial in Confidence 43

May 2, 2023 Commercial in confidence 43

                                              

     

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44 March 2010 Commercial in Confidence

44September 2009 Commercial in Confidence 44July 2009 Commercial in ConfidenceOctober 2008 Commercial in Confidence 44

May 2, 2023 Commercial in confidence 44

                                              

      12

3

4

5

67

89

10

11

12

Page 45: John Tidy - Adjunctive colposcopic technologies

ZedScan – results screens

No biopsy required

Page 46: John Tidy - Adjunctive colposcopic technologies

ZedScan – clinical performance

• Service review – 1570 new referrals– 401 (25.5%) HG cytology– 836 (53.2%)LG cytology– 333 (21.0%) hrHPV pos/cyto negative, clinical

referrals• 504 cases of HG-CIN

– 426 (84.5%) Colp + ZedScan– 59 (15.5%) ZedScan only

Page 47: John Tidy - Adjunctive colposcopic technologies

ZedScan – clinical performance

• Failure to detect HG-CIN– Colp 14.1% vs ZedScan 3.8%, p<0.0001

• 50% increase in detection of HG-CIN in women referred with low grade cytology

• Treatment at first visit including ZedScan– 68% of all HG referrals– PPV for CIN2+ 95.2%

Page 48: John Tidy - Adjunctive colposcopic technologies

ZedScan – clinical performance• Biopsy rate

– 688 underwent bx– 1.08 bx per patient– 29 extra cases HG-CIN detected by ZedScan

only directed biopsy• Glandular neoplasia

– 18 cases, 14 only had HG-CGIN and no HG-CIN– 7 had abnormalities on colp + ZedScan– 2 had abnormalities on colp only– 5 had abnormalities on ZedScan only

Page 49: John Tidy - Adjunctive colposcopic technologies
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ZedScan – international performance

• 561 women at 8 centres• Increased sensitivity of ZedScan + colp

– 92.4% vs 84.5%, p<0.01• Increased detection of CIN2+

– 36 (18.4%) extra cases• Performance is independent of colposcopy

clinic and cytology practice

Page 51: John Tidy - Adjunctive colposcopic technologies

Utilising ZedScan in a clinical setting

Tidy et al BJOG 2013

Page 52: John Tidy - Adjunctive colposcopic technologies

Can hr-HPV genotype influence colposcopic performance?

• Jeronimo 2015 (J Low Gen Tract Dis)– Screening CIN2+ 1.8%

• HPV 16 76.4% vs non HPV16 43.1%

• Jeronimo 2007 (AJOG)– Low grade referrals CIN2+ 26.7%

• HPV 16 83.0% vs non HPV16 64.7%

Page 53: John Tidy - Adjunctive colposcopic technologies

Can hr-HPV genotype influence colposcopic performance?

• Marel et al 2014 (BJOG)– Abnormal cytology (HG cytology 56.7%)– CIN2+ 42.6%

• HPV 16 88.0% vs non HPV16 87.0%

• Zaal et al 2012 (BJOG)– Abnormal cytology (HG cytology 33%)– CIN2+ 46%

• Colp - HPV 16 53.0%1 vs non HPV16 61.0%2

• DySIS - HPV 16 97.0%1 vs non HPV16 74.0%2

1Colp vs DySIS p 0.009, 2Colp vs DySIS p=NS

Page 54: John Tidy - Adjunctive colposcopic technologies

Does ZedScan increase detection of HG-CIN irrespective of hr-HPV genotype?

• ZedScan uses electrical impedance spectroscopy to detect CIN

• Independent aceto-white change• Does detection of HG-CIN by ZedScan

affected by hr-HPV genotype?

Page 55: John Tidy - Adjunctive colposcopic technologies

Detection of HG-CIN• 839 women referred to colposcopy with known

hr-HPV genotype– 202 HG cytology, 411 LG cytology, 48 F/U CIN1/2, 4

clinical, 187 hr-HPV pos/cyto neg– All had an adequate colposcopic examination (TZ1+2)

• hr-HPV genotype:– HPV16 – 303 (36.1%)

• 159 single infections; 144 with other types– HPV18 – 111 (13.2%)

• 54 single infections; 57 with other types– HPV O – 613 (73.1%)

• 443 without HPV16/18; 170 with HPV16 or 18

Page 56: John Tidy - Adjunctive colposcopic technologies

Colposcopic detection of HG-CIN by hr-HPV genotype

HPV16 Non HPV160

10

20

30

40

50

60

70

80

90

100

CIN2+p=0.0191 (86.9% vs 79.7%)N= 611

HG cytology 33.0%CIN2+ 38.9%

Page 57: John Tidy - Adjunctive colposcopic technologies

ZedScan increases detection of HG-CIN irrespective of hr-HPV genotype

HPV16 Non HPV160

20

40

60

80

100

120

Colp Impression ZedScan

p<0.0001p=0.0171

n=611HG cytology 33.0%CIN2+ 38.9%

Page 58: John Tidy - Adjunctive colposcopic technologies

ZedScan increases detection of HG-CIN irrespective of hr-HPV genotype in cytology negative referrals

HPV genotype No CIN2+ Total (%) CIN2+ only detected by ZedScan (%)

HPV 16 82 12 (14.6%) 2 (20%)

HPV 18 34 3 (8.8%) 2 (200%)

HPV O 71 3 (4.2%) 1 (50%)

Total 187 18 (9.6%) 5 (38.5%)1p=0.045

1Fisher’s extact test, two tailed

Page 59: John Tidy - Adjunctive colposcopic technologies

Summary• Colposcopic performance declines as the

prevalence of HG-CIN falls • Triage by biomarkers may help to enrich the

population referred to colposcopy and reduce referral rates but as of now are unproven or of variable performance

• HPV O infections are more frequent than HPV 16 or 18 only infections 67% vs 18.2%

• 33% of CIN2+ are associated with only HPV O infections

Page 60: John Tidy - Adjunctive colposcopic technologies

Summary• Adjunctive technologies increase detection of HG-

CIN especially in groups with low prevalence of HG-CIN

• hr-HPV genotype impacts on colposcopic performance– Some technologies, i.e. non aceto-white based, increase

detection of HG-CIN irrespective of hr-HPV genotype• More appropriate clinical management

– Increased detection of HG-CIN– Use of treatment at first visit– Appropriate discharge at first visit to screening

Page 61: John Tidy - Adjunctive colposcopic technologies