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Adjunctive Colposcopic Technologies
John Tidy
Professor of Gynaecological OncologyPresident BSCCP
Chair, National Colposcopy Professional Group Committee,
Research Advisory Committee for Cervical ScreeningSheffield
Disclosures• Zilico Ltd
– Shareholder, Consultancy, Patent holder• Qiagen
– Speaker fee• Roche
– Speaker fee• Hologic
– Speaker fee• Sanofi-Pastuer
– Travel and conference fees
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
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
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
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
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
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%
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%
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
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+.
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+
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
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
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%
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%
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+
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
New Technologies in Cervical Screening and Colposcopy
• LuViva• DySIS• ZedScan• TruScreen
• Gynocular, MobileODT
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
TruScreen
• Measures both optical and electrical changes in the cervix
• Alternative to cervical cytology
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
LuViva
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
DySIS
Video-colposcopeattached to speculum
New versions more ergonomically friendly
Displays a false colourto highlight areas to biopsy
Red, yellow and white areas indicate intense/long lasting aceto-whitening
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
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
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%
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
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?
Structure of cervical epithelium
Basement membrane Stroma
Surface epithelium
Normal CIN 1 CIN 2 CIN 3 Invasion
Intermediate
Superficial
Parabasal
Basal
0.4mm
Structure of cervical epithelium
Basement membrane Stroma
Surface epithelium
Normal CIN 1 CIN 2 CIN 3 Invasion
Intermediate
Superficial
Parabasal
Basal
0.4mm
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
Finite element derived model
Normal squamous
HG-CIN
Immaturemetaplasia
Normal columnar
Walker et al 2003
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
Snout LEDs
“Push on – off” single use sensor
Real time on board data analysis
1
2
3
4
5
6
7
8
9
10
1112
ZedScan – results screens
See and Treat
Biopsy required –Single point mode
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
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
ZedScan – results screens
No biopsy required
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
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%
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
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
Utilising ZedScan in a clinical setting
Tidy et al BJOG 2013
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%
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
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?
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
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%
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%
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
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
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