Evolving Concepts in the Management of Anal Dysplasia

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AIDS CLINICAL ROUNDS

Evolving concepts in the
management of anal dysplasia
Edward Cachay, M.D., M.A.S.
Associate Professor of Clinical Medicine
UCSD Owen Clinic
8/14/2014 1Copyright © Edward Cachay MD, MAS.

Incidence of invasive anal cancer on the HAART era
8/14/2014 2
Piketty et al. J Clin Oncol 2012, 30:4360-4366
Copyright © Edward Cachay MD, MAS.

Clin Infect Dis. 2014 ;58(1):1-10.
1. Men who have sex with men
2. Anyone with a history of anogenital condylomas
3. Women with history of
A. Cervical/vulvar dysplasia
B. Anal receptive intercourse
In whom is indicated to
perform an anal PAP ?

The outline for today
8/14/2014 4
Federico (26yo) Satish (40yo) Roger (45yo)

Federico is 24yo male and is studying to become a
fashion designer. He came complaining of anal pain.
• Following diagnosis of HIV infection in
January 2014 he started Epzicom +
dolutegravir. Recent CD4: 490 and VL
was undetectable.
• You performed a rectal GC/CT PCR and
tested positive for chlamydia spp. His
concurrent intake anal pap collected:
ASCUS
• He completed proper treatment for his
proctitis but did not show for his
recommended high resolution
anoscopy (HRA) last month.
8/14/2014 5

Today, Federico tells you that he was accepted for advances
studies in Parsons The New School for Design in New York,
starting in spring 2015.
What is your recommendation for the management of his
abnormal anal cytology?
1. Discuss with him that you need to perform a baseline
digitorectal exam because the last time you did not
perform one due to his anal pain.
2. Encourage to reschedule a new HRA appointment
3. Initiate HPV vaccine series
4. Only 1 & 2
5. All of the above

8/14/2014 7
Cachay et al AIDS Rev. 2013;15:122-33

2
Mathews ,Wm C. et al JAIDS 2014, 37:1610-1615.
Yield of biopsy diagnosis of anal intraepithelial
neoplasia 3 (HSIL) by concurrent cytology category.

Patients with an abnormal anal pap will
benefit from a staging HRA evaluation.

What is the goal of the anal cancer screening
program of your institution?
Early Diagnosis of
Invasive anal cancer
Prevention of Invasive
anal cancer
Minimalist
Annual DRE ± anal cytology
to identify higher risk patients
Maximalist
Annual DRE + anal cytology
+ HRA directed biopsy to
identify microinvasive
disease
Annual DRE + anal cytology
+ HRA directly biopsy +
Treatment of HSIL
(unproven efficacy)

IAC Outcomes: the importance of early diagnosis
8/14/2014 11
Bentzen et al. Int J Radiation Oncol Biol Phys, 2012, 83: e173-e180
0 12 24 36 48 60 72
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
T1
T2
T3
T4
CumSurvival

Early detection matters:
• The most important predictor of survival of
Invasive anal cancer is tumor size at diagnosis.
• Annual DRE is an essential component of any
annual physical exam.

Federico complete a HRA evaluation 2 weeks later and
findings are noted below
03 biopsies showed LSIL
8/14/2014 13
Cachay E. Owen anal dysplasia clinic

Federico ask whether he needs the HPV vaccine,
he has a good PPO insurance. Is he a candidate for
HPV vaccination?
1. Yes
2. No

8/14/2014 15
HPV vaccination is
recommended for all:
1. Females ages 9-26years
2. Males ages 9-21years Males 22-26yo also if
not vaccine at younger age
Clin Infect Dis. 2014 ;58(1):1-10.

8/14/2014 16
Critical steps for the development of HPV vaccine
2005
1991
1986
1983
Zhou et al demonstrated that
using yeast media can
generate Virus-like particles
without infectious capacity
HPV genome
Harald zur Hausen

Papillomavirus Virion-related Structures
Schiller JT, Lowy DR. Nat Rev Microbiol. 2012 Oct;10(10):681-92 17

HPV infectivity
8/14/2014 18
Epithelium
Epithelial disruption
Basal membrane
HPV invasion

Infectivity cycle: molecular level
8/14/2014 19
HPV
virion
Heparan Sulphate proteoglycan
Conformational change
exposing N terminus of L2
Furin mediated
cleavage of L2
Exposure of cell-receptor-
binding site on L1
Basement
membrane
Dermis
Basal epithelial
keratinocyte
Several hours
Cachay E. AIDS Rev. 2014; 16:90-100
Cell receptor

8/14/2014 20
Virus-like particle (VLP) HPV vaccines
Cachay E. AIDS Rev. 2014; 16:90-100Copyright © Edward Cachay MD, MAS.

Percentage seroconverting (anti-HPV) 4 weeks after vaccination in males,
protocol per intention to treat
99.9
%ofseroconversion
20
40
60
80
100
HPV 6
9 -15 years 16 -26 years
99.4
100
98.9 99.9 99.2
100
99.4
98.4
99.6
HPV 11
99.8
100
99.2
98.8
99.3
97.9
HPV 16
99.8 97.4
99.2
100
98.2
96.3
HPV 18
Nº individuals
contributing to analysis
884 1093 885 1093 882 1136 887 1175

Per-protocol efficacy population(PPE): intraepithelial
neoplasia associated with HPV 6,11,16 ó 18.
0 6 12 18 24 30 36
0
10
20
30
40
50
60
70
80
90
100
quadrivalent
HPV vaccine
Placebo
Months after randomization
Cumulativepercentageofpatientswithanal
intraepitheliallesions
Palefsky et al, NEJM 2011, 365;17
Specific efficacy: 77.5% (95% CI, 39.6 to 93.3)
8.9 per 100 person-years
4 per 100 person-years

Intention to treat (ITT) efficacy population: intraepithelial
neoplasia associated with HPV 6,11,16 ó 18
0 6 12 18 24 30 36
quadrivalent
HPV vaccine
Placebo
Palefsky et al, NEJM 365;17, 2011
20
10
30
40
50
60
70
80
90
100
17.5 per/100 persons-years
13 per/100 person-years
Specific efficacy: 50.3% (95% IC: 25.7 to 67.2)
Cumulativepercentageofpatientswithanal
intraepitheliallesions

Be proactive about HPV vaccination in your
HIV-infected patients who are 26 years-old or
younger.

Satish is a 40yo successful biotech engineer with
CD4:580 and undetectable HIV Viral load who lives in
Dallas.
• He comes to discuss ‘more definitive
ways’ to screen him for dysplasia.
• Satish is aware of the new
recommendations for cervical cancer
screening where HPV DNA testing is
preferred over cervical cytology.
• Satish is willing to pay cash for
anorectal HPV DNA testing if he could
avoid a HRA.
• His anal cytology performed 3 months
ago showed ASCUS.

Your laboratory has COBAS HPV DNA testing for
cervical samples. Would you favor anorectal HPV
DNA testing for Satish?
8/14/2014 26
1. Yes
2. No

Bio-markers investigated for the detection of
anal precancerous lesions:
- HPV genotyping
- HPV mRNA detection
- p16 INK4a/Ki-67 immunohistochemistry

The one lesion, one virus concept
8/14/2014 28
1 clinical dysplastic lesion
Contains 1 specific HPV Type
in whole tissue analysis
The same HPV type is found using
in LCM in the dysplastic area
within whole tissue section
Most cervical cancers are caused for HPV type 16/18.
Cervical swabs correlates ≥ 94% cases with isolated
specific HPV type in dysplastic lesion.

Selection of dysplastic regions for laser-capture microdissection (LCM).
Richel O et al. J Infect Dis. 2014;210:111-120

The suspicious clinical lesion under laser-
captured microdisection
8/14/2014 30
Multiple HPV staining
dysplastic lesions

Results using anal swabs for HPV DNA showed that HIV-infected
people have multiple types at any given time
8/14/2014 31
MSM Women
Median Nº of HPV genotypes (IQR) 6 (4-8) 5 (2-7)
is it possible to link a specific HPV type to the high grade AIN
lesion in cases with multiple HPV genotypes in a swab?
Adapted from Conley et al, JID 2010; 202: 1567-1576

Flowchart with single versus multiple human papillomavirus (HPV) types in the 31 high-grade
anal intraepithelial neoplasia (HGAIN) biopsy specimens.

Whole-tissue section with a collision region.

Two nondysplastic control lesions containing human papillomavirus type 74 (HPV74).

8/14/2014 35
Multiple human papillomavirus (HPV) types in 2 regions.

HPV Analysis of Anal Swabs
• The median number of HPV types per swab was 4
(range, 1–13 genotypes).
• The predominant HPV type was HPV16 , followed by
HPV18, HPV39, HPV51, HPV52, and HPV70.
• 50% of anal swab specimens did not contain all of
the lesional HPV types found in the whole-tissue
sections or LCM-selected areas.

Larger studies illustrate the limit predictive value of
HPV anal swabs DNA
8/14/2014 37
Test & HPV status
Performance (%) of indicated test to detect
AIN-2 or AIN-3 (n =68)
Sensitivity Specificity PPV NPV
LA (linear array)
HPV 16 & 18
Any carcinogenic type
65.1
98.4
72.6
28.9
35.0
23.9
90.1
98.8
Cobas
HPV 16 & 18
Any carcinogenic type
66.2
100.0
67.8
26.0
32.6
24.1
89.5
100.00
Anal cytology
≥ASCUS 83.6 51.1 28.9 92.9
HPV genotype & anal cytology
≥ASCUS or HPV16/18 95.5 40.1 27.7 95.2
Wentzensen et al. J Clin Microbiol. 2014;52:2892-7

HPV DNA anal swabs are not useful for
detecting lesion-specific HPV types.

Roger is a 45yo nurse who has had HIV for 15 years.
Recently he transferred his care to the Owen clinic
- Recent CD4; 430 and HIV VL
undetectable
- Roger reports than in 2001 he
had surgical resection of anal
warts.
- Feb 2014: Anal cytology: HSIL
- April 2014: HRA with 2
biopsies showing HSIL

What is the best recommendation for management
of Roger’s identified HSIL lesions?
1. Observation with annual cytology and DRE
2. Ablative therapy using infrared coagulation
3. Topical 5-fluoracilo
4. Quadrivalent HPV vaccine followed by
ablation with IRC

Current management options for anal dysplasia
8/14/2014 41
Expectant monitoring InterventionVS.
Topical Ablation
Immune
modulation
- 5% Fluorouracil cream
- Imiquimod
- Trichloroacetic acid
- Photodynamic therapy
- Topical lopinavir
- Infrared coagulation
- Electrosurgey
- CO2 laser
- Quadrivalent
HPV vaccine

Challenges of ablative therapy
8/14/2014 42
Treatment is imperfect
- No categorical proof of effectiveness:
Ongoing randomized trials
- Recurrence rate is high
- Associate to personal discomfort

Comparative efficacy 4 weeks after ablative or topical
therapy in the only Randomized controlled study
8/14/2014 43
Richel et al. Lancet Oncol 2013; 14: 346–53
Ablation
(n=19)
Fluorouracil
(n=28)
Imiquimod
(n=24)
Complete response
Nº participants
% (95% CI)
10
53% (32-73%)
6
21% (10-40)
5
21% (9-41)
Partial response
Nº participants
% (95% CI)
3
16% (32-73)
6
21% (10-40)
6
25% (12-45)
No response
Nº participants
% (95% CI)
6
32% (15-54)
16
57% (39-74)
13
54% (35-72)
Difference between 3 groups on complete response p=0.010

Rate of recurrences is high independently of the
treatment modality
8/14/2014 44
Created using data from Richel et al. Lancet Oncol 2013; 14: 346–53
22%
38%
19%
46%
50%
47%
67%
58%
71%
0
10
20
30
40
50
60
70
80
Ablation Flurouracil Imiquimod
24 weeks
48 weeks
72 weeks
Ablation Flurouracil Imiquimod

What is the risk of progression to invasive anal cancer
(IAC)
8/14/2014 45
HSIL IAC
Cachay et al . HIV Medicine 2014. In press
Historical surgical cohorts 9 -15% of patientsCumulative incidence 1.65 (95% CI 0.59 – 4.52)

Why is the rate of progression to invasive
anal cancer lower than initially reported?
8/14/2014 46

Model for progression of anal dysplasia
8/14/2014 47
HSIL
Invasive
anal
cancerLSIL
Regression
Progression
Cachay et al AIDS Rev. 2013;15:122-33

The Australian SPANC study
8/14/2014 48
0 6m 1y 2y 3y
3 years
- Anal PAP
- HPVDNA
- HRA
HSIL = Cytology and/or
Histology
1a
Outcome

450 MSM by June 2014. 31% were HIV+, all were age ≥
35yo, with a median age of 49 years.
8/14/2014 49
- Most observations consistent with literature
Description of their HSIL clearance rate *
164 MSM
HSIL
HIV+
64 (38%)
HIV –
105 (62%)
20 HIV+
41 HIV -
112 MSM
HSIL
Nº analyzed
Nº patients
downgrade
Grulich AE, et al. 20th IAC. 2014. Melbourne. Abstract WEAB0102
41.7
41.8
Clearance of
HSIL per 100PY

The snapshot approach ignores anal canal is a
dynamic process with multistate lesions
Squamous columnar junction
Anal verge
Left
Midcanal wall
Dentate line
Cachay E. Clin Infect Dis. 2014 ;58:906-7

Model for progression of anal dysplasia

8/14/2014 52
The top part of figure presents Kaplan-Meier curves depicting infection clearance
patterns for 3 of the most common HPV types.
4.4 new cases
per 1000 person-months
4.0 new cases
10.8 new cases
12.2 cleared episodes
20.4 cleared episodes
26 cleared episodes
The lower part of figure shows the cumulative incidence for 3 of the most
common HPV types.
Pokomandy et al. JID; 2009; 199:965–73
Dynamic process and reinfection is a frequent
phenomena

Owen clinic contribution
8/14/2014 53
2804 patients with at least 1 anal cytology followed
between 2001-2012 for median of ~ 5 years in a
universal inception cohort.
At baseline:
- Median age:40yo, 62% white,78% MSM
- 55% CD4 ≥ 350
- Three quarters were on ART 75% and 64% had HIV
viral load undetectable

Estimated 2 Year transition probabilities for progression
and regression in 3-State Hidden Markov Model
Adjusted for Cytology Misclassification Assumptions
0.07 – 0.12
< HSIL HSIL IAC
0.013 – 0.019
0.28 – 0.62
Mathews Wm C. et al. PLoS One. 2014;9:e104116
0.37 – 0.71

Estimated 5 Year transition probabilities for progression
and regression in 3-State Hidden Markov Model
Adjusted for Cytology Misclassification Assumptions
0.13 – 0.15
< HSIL HSIL IAC
0.021 – 0.038
0.51 – 0.80
0.18 – 0.45

How does it compare to cervical cancer?
64 studies, 274 carcinomas, 15,473 CIN cases,
Follow-up <1-12 years
0.22
Invasive
cervical CA
CIN 3CIN 2
> 0.12
0.32
~ 0.55
Ostör AG. Int J Gynecol Pathol. 1993;12:186-92

Similar trends for anal dysplasia regression base
on severity of HSIL lesions:
AIN-2: 61 per 100 PY
8/14/2014 57
AIN-3: 36.9 per 100 PYVS
P = 0.037
AIN-2 has greater chances of regression than AIN-3

Are there any HIV-related factor that influence the progression
of anal dysplasia
ART: HR: 0.5 (0.4-0.8)
< HSIL HSIL IAC
HIV VL UD: HR: 0.5 (0.4-0.7)
CD4 > 350: HR: 0.3 (0.2-0.5)
Protective
effect
ART: HR: 0.9 (0.6-1.3)
HIV VL UD: HR: 1.1 (0.8-1.5)
CD4 > 350: HR: 0.8 (0.6-1.1)

Molecular biology of invasive squamous anal cell
carcinoma in HIV positive patients
HPV
infection
HPV
persistence
HPVDNA
integration
11q
Microsatellite
instability ??
Normal AIN 1-2 AIN -3 SCCA
Gervaz. Br J Surg. 2006 May;93(5):531-8

Effect of IRC
8/14/2014 60
< HSIL HSIL IAC
HR 4.2 (2.0–8.5)
HR 2.2 (0.6–7.9)
2.7 (0.6–11.7)
Eight percent (n= 218) underwent one or more IRC ablations for HSIL lesions
between 2007–2012.

Conclusion
Given the:
A. The low short term (2-year) probabilities of progression to IAC
B. Moderate to high probabilities of regression of HSIL to less
than HSIL cytology
C. Morbidity of HSIL ablative treatment
D. High recurrence rates among HIV-infected patients
61

Conclusion
• After careful initial HRA evaluation and biopsy:
“ It may be reasonable to defer routine immediate
treatment for HSIL provided that close monitoring
with HRA and DRE is available”
62

8/14/2014 63
Close up SCJ, left posterior quadrant
Coarse punctation on background of severe
acetowhitening and thickening
Perhaps, IRC should be reserved for patient with lesions with
the highest risk to progress to invasive anal cancer

Acknowledgements
• Our patients • Christopher Mathews
• Connie Languido
• Bard Cosman
• Wollelaw Agmas
• Charles Hicks
• Owen clinic colleagues
8/14/2014 64

Evolving Concepts in the Management of Anal Dysplasia

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