Draft Guidelines for management of Anal
Intraepithelial Neoplasia. For CSCG Consultation.
Executive Summary
Anal Intraepithelial Neoplasia (AIN) is a precursor of invasive anal squamous cell
carcinoma and involves the perianal skin and anal canal to 3mm above the dentate
line. The degree of dysplasia is graded AIN1 to AIN3. Human papilloma virus (HPV)
is implicated in the aetiology of AIN and anal squamous cancer as in cervical and
vulval intraepithelial neoplasia (CIN/VIN). Others at increased risk of AIN include
HIV positive patients, women with genital intraepithelial neoplasia,
immunosuppressed transplant patients and those with anal condylomata (warts).
The prevalence of both AIN and anal cancer is rising, particularly among HIV
patients. Around 50% of HIV positive males are found to have AIN. Low grade AIN
progresses to high grade AIN in two thirds of HIV positive patients compared with
one third progression in HIV negative patients over 2 years. 5-13% of AIN3
progresses to invasive cancer over a five year period. Incidental foci of invasive
carcinoma are found in 8.8-26% of those having AIN3 excision.
AIN may present as a symptomatic anal lesion although may rarely be asymptomatic
and an incidental histological finding. Targeted biopsies taken during anoscopy allow
histological diagnosis and grading. Histological grading is subject to inter-observer
variation.
Management of AIN is less well defined than for the other cervical intraepithelial
neoplasia. Treatment is beset by high recurrence rates and prolonged morbidity after
radical excision. Options include active observation with the aim of detection of early
invasive disease, ablation with electrocautery or cryotherapy, immunotherapy or
excision. Surgical strategies range from simple local excision to radical wide local
excision with skin graft coverage. Treatment must be individualised according to
extent of disease and presence of immunocompromise.
Follow up is essential. Twelve monthly anoscopy is appropriate for low grade AIN
whilst six monthly anoscopy is necessary for AIN3 or HIV patients. There is no
current role of screening for AIN among high risk groups. Further research, to include
the establishment of a national AIN database, is needed to better understand the
1
natural history of AIN. As the prevalence of AIN is small it may be appropriate to
centralise experience within each cancer network.
2
Contents
Background
4
Natural History
4
Aetiology
7
Risk factors
9
Presentation
11
Screening
11
Diagnosis
12
Management
13
Follow up
18
Recommendations
19
Future research
19
Appendix 1. Grading of Evidence
20
Appendix 2. Operative mapping template
21
Appendix 3. Referral pathway
22
Appendix 4. Suggested protocol for management of AIN in Wales
23
Appendix 5. Published protocols for use in AIN treatment and follow up
24
Appendix 6. Summary of appendix 5 (published algorithms)
28
Further issues for discussion
29
Bibliography
31
Glossary
AIN-anal intraepithelial neoplasia; CIN-cervical intraepithelial neoplasia; HAARThighly active anti-retroviral therapy; HIV-human immunodeficiency virus; HPVhuman papilloma virus; MDT-multidiscilpinary team; MSM- men who have sex with
men; SIL-squamous intraepithelial lesion; VIN-vulval intraepithelial neoplasia; VaINvaginal intraepithelial neoplasia
Guidelines written by DA Harris, AG Radcliffe, ATristram and A Fiander
Depts. of Colorectal Surgery and Gynaecological Oncology
Llandough Hospital
Penlan Road
Cardiff
Wales
March 2008
3
Background
Anal intraepithelial neoplasia (AIN) is the precursor to invasive squamous anal
carcinoma. The disease process involves both the perianal skin and the anal canal to 3
millimetres above the dentate line (Fenger 1986a III). It is a multifocal disease
strongly associated with human papilloma virus (HPV) bearing similarities with
cervical and vulval intraepithelial neoplasia (CIN/VIN). Less is known about the
natural history of AIN than CIN and national treatment guidelines are not currently
formulated.
Natural History
The natural history of AIN (referred to as squamous intraepithelial lesion (SIL) in the
US) is uncertain. It was first described in 1985 as 2 cases of rectal dysplasia by
McCance (1985, III) and grades were defined the following year by Fenger (1986 III).
It is characterised by cellular and nuclear epithelial abnormalities limited by the
basement membrane. Histological features include increased mitotic rate, mitotic
activity above the basal layer, nuclear pleomorphism, hyperchromatism and failure of
normal maturation (Jass 2003 IV). AIN1 and AIN2 refers to nuclear abnormalities
confined to lower one-third and middle third of the epithelium, respectively, and is
considered to be low grade dysplasia (Scholefield 1999 III). AIN3 is full thickness
involvement of the epithelium and represents high grade dysplasia or carcinoma in
situ. The Bethesda system refers to AIN as anal squamous intraepithelial lesion (SIL)
with low grade lesions (LSIL) equivalent to AIN1, and high grade (HSIL) equivalent
to AIN2 and 3 (Northfelt 1996 IV).
The exact prevalence of AIN in the general population is unknown, but is thought to
be less than 1 per cent (Ogunbiyi 1994 IIa), although the incidence is rising. A
number of groups at high risk for AIN have been defined and include HIV patients,
immunocompromised, women with a history of genital intraepithelial neoplasia and
those with anal condylomata.
Much current work on AIN relates to HIV patients. Prevalence in this group ranges
from 26% to 89% as shown in table 1. The more recent series report increasing
prevalence with 52% of HIV positive men having AIN2 or 3 versus 20% in HIV
negative men (McCloskey 2007 III). This is paralleled by a steeply rising annual
incidence of anal cancer in AIDS patients of 224 per 100,000 (Diamond 2005 III).
4
HIV positive
HIV negative
Author
n
All AIN
AIN3
All AIN
AIN3
McCloskey 2007
153
77.8%
52%
32%
20%
Chin-Hong 2005
1262
-
-
32%
6%
Piketty 2004
45
71%
22%
-
-
Goldstone 2001
200
89%
57%
68%
46%
Holly 2001
319
26%
6%
8%
2%
Palefsky 1998
498
52%
5%
17%
15%
Critchlow 1995
305
-
15%
-
5%
Kiviet 1993
489
26%
4.2%
8%
0.5%
Palefsky 1990
97
15%
-
-
-
Table 1. Prevalence of AIN in HIV positive and negative populations.
5
Progression from low to high-grade AIN is seen in 62 per cent of HIV positive and 36
per cent of HIV negative men within 2 years (Palefsky 1998a IIa). AIN3 rarely
regresses histologically (Palefsky 2001 III), but AIN 1 and 2 may regress (Scholefield
1994 IIb).
The risk of progression of AIN to invasive anal cancer approximates 10% at five
years. It was initially thought that 5% of AIN3 progresses to invasive cancer in a
median of 104 (16-273) months (Marfing 1987 III; Marchesa 1997 III). Higher
progression rates are more recently reported; Scholefield (2005 III) reported 9%
progression of AIN3 (follow up 63 (14-120) months) whilst 13% progression of AIN3
to invasive disease in 60 (80-112) months was found by Watson (2006 III). Invasive
carcinoma is found in 8.8-26% of those having AIN3 excision (Brown 1999 III,
Sarmiento 1997 III). Similarly AIN3 is found in 80% of cases of anal carcinoma
(Fenger 1986 III). Those most at risk of invasive cancer are those with multifocal
disease or immunosuppression (Scholefield 2005 III). In this series 50% of
systemically immunocompromised (transplant, SLE and asthma) patients with AIN3
developed invasive cancer within 5 years of diagnosis compared with no
immunocompetent patients developing invasive disease (Scholefield 2005 III).
6
Aetiology
Given the causal relationship between human papilloma virus (HPV) and cervical
cancer it is hypothesised that the virus plays a causal role in AIN development and
anal cancer. Palmer (1987 IIa) was the first to report an association between anal
squamous cell carcinoma and human papillomavirus type 16 (HPV 16) and there is
now strong evidence using polymerase chain reaction assays that high-risk HPV has a
causal role in AIN3 and anal cancer (Zaki 1992 IIa). HPV has been shown to be
present in 84-100% anal cancer specimens (Siegel 1992 III; Frisch 1997 IIa) with
87% of anal squamous carcinomas contain HPV 16 DNA, 7% containing HPV 18 and
6% HPV 33 (Frisch 1999 IIa). AIN3 contains high risk HPV type 16 DNA more
frequently than AIN 1 and 2 which contain low risk HPV 6 or 11, which may explain
the more benign course of these lesions.
Compared with the general population incidence of anal HPV-16 of just 13.8%
(Ogunbiyi 1994a III) anal HPV infection is seen more commonly in MSM. The
EXPLORE study found the prevalence to be 57% amongst HIV negative MSM (Chin
Hong 2004 IIa). There is thought to be repeated clearance and reinfection through
anal receptive intercourse. Similarly anal HPV infection in HIV patients is epidemic,
with 91.6% prevalence in HIV positive MSM (Crichtlow 1998 IIa). High levels of
HPV infection (46%) are also seen in HIV positive patients with no history of anal
receptive intercourse, such as intravenous drug users (Piketty 2003 IIa). Thus the
immunocompromise associated with HIV may be just as important in HPV
acquisition as an opportunistic infection.
The relationship between low CD4+ counts and AIN is complex. Low CD4+ counts
correlate with increased prevalence of oncogenic HPV such as type 16 (Palefsky
1998b III). Low nadir CD4+ count is an independent risk factor for AIN (Palefsky
1998a III; Critchlow 1995 III; Palefsky 1998b III; Palefsky 1998c III) but only in the
presence of high risk HPV (Wilkin 2004). Progression to AIN2/3 is clearly associated
with lower CD4+ counts (Palefsky 1998b III; Crichtlow 1995 III). The use of
antiretroviral therapy, which increases CD4+ count, does not seem to affect the
prevalence of established AIN (Palefsky 2005 IIa). Others (Wilkin 2004 III) have
reported decreased prevalence of AIN with HAART but due to the cross sectional
design a temporal relationship cannot be proven. Of concern is the significant increase
in incidence of anal squamous cancer in the HAART era compared with the pre-
7
treatment era (Chiao 2005 IIb) suggesting a lack of efficacy of antiretroviral
treatment.
8
Risk factors
CIN/VIN
Simultaneous or previous female genital tract intraepithelial neoplasia is a strong risk
factor for development of both AIN (Beckmann 1991 III, Scholefield 1992 IIa,
Ogunbiyi 1994 IIa) and anal cancer (Edgren 2007 IIa). Multifocal anal and female
genital tract lesions were first described by McCance (1985 III). Both disease sites
(particularly CIN and AIN) share the same viral cause (HPV), the same cloacogenic
origin and both possess a squamo-columnar junction allowing viral entry to the basal
cellular layer allowing HPV to produce a field defect leading to multicentric disease.
High concomitant levels of cervical (54%) and anal (71%) HPV infection have been
observed in conjunction with high levels of CIN/ AIN (Melbye 1996 IIb), with a three
times relative risk of abnormal anal cytology with CIN. Similarly it has been shown
that 35.7% women with anal HPV had CIN (Scholefield 1989 IIa) and 19%-47% of
women with high-grade CIN or VIN have concomitant AIN (Scholefield 1992 IIa,
Ogunbiyi 1994 IIa).
Immunocompromised patients
HIV+
The high prevalence of anal cancer in HIV positivity and MSM is well known.
Similarly HIV positivity is an independent risk factor for AIN (Carter 1995 III).
HIV+ males have a 7.5 times relative risk of AIN (Critchlow 1995 III). This is not
solely due to anal receptive sex however; 18% of HIV+ men with no history of
receptive anal intercourse had AIN based on cytology compared with 65% for those
who did practice receptive anal intercourse (Wilkin 2004 III). There is an overlap of
risk factors in action as anal HPV infection is present in 92% of HIV+ MSM
(Critchlow 1998 IIa). The risk of both prevalent and incident high grade AIN
increases as CD4+ count falls (Kiviat 1993 IIb, Palefsky 1998c III). Only one study
has shown that highly active antiretroviral therapy (HAART) reduces the incidence of
AIN (Wilkin 2004 III).
Organ transplant/ iatrogenic immunosuppression
Immunosuppression for allografts carries a greater propensity for AIN and anal
cancer, likely due to opportunistic HPV infection. Ogunbiyi (1994 IIa) found an AIN
prevalence of 24% among 133 renal allograft patients, with 12.5% having AIN3.
9
Accordingly the relative risk for anal cancer in renal transplant patients is 10 (Adami
2003 IIa).
Anal condylomata
Condylomata acuminata are associated with an increased risk of anogenital neoplasias
(Friis 1997 III) including a relative risk of 8.5 for anal cancer. AIN3 has been found
within 52% of anal condylomata associated with HIV positivity and 20% if HIV
negative (McCloskey 2007 III). A further study of 103 MSM with anal condylomata
28% had dysplasia and 3% invasive cancer (Metcalf 1995 III). The authors suggest
that the incidence of dysplasia in perianal condyloma is significant enough to warrant
consideration of biopsy in all patients.
10
Presentation
The usual modes of presentation are within symptomatic lesions, as an incidental
finding, or screening of at-risk patients.
The prevalence of incidental AIN in routine haemorrhoidectomy specimens is just
0.05% (Lemarchand 2004 III). Clinical features of AIN are non specific. Symptoms
include perianal bleeding, pain, tenesmus, pruritis or anal discharge; whilst suspicious
lesions may be raised, scaly, white plaques, erythematous, pigmented, fissured or
ecezematoid (Zbar 2002 IIb). AIN is present in 28-35% of excised anal condylomata
(Metcalf 1995 III, Carter 1995 III, Zbar 2002 IV). Any HIV positive patient with anal
symptoms should be considered to have AIN in light of its high incidence in this
group (B). Similarly women with other HPV-associated diseases (CIN, VIN, VaIN)
should be screened for AIN (B).
Consequently patients with AIN are referred from a wide range of disciplines
including genitourinary medicine, infectious diseases, gynaecology, dermatology,
transplant and general surgical specialities (see appendix 3).
Screening
Despite the similarities between anal and cervical intraepithelial neoplasia and cancer
and the success of the cervical screening programme, the role of screening for AIN is
less clear. Screening of high risk groups by anal cytology has been advocated,
however the cytological grading of anal Papanicolaou smears correlates poorly with
the histological grading of confirmed lesions. Screening of 251 HIV-negative men
showed that abnormal anal cytology had sensitivity, specificity, PPV and NPV of
47%, 92%, 35% and 95% respectively for the detection of biopsy-proven ASIL
(Palefsky 1997 IIa). AIN is unlikely to fulfil the criteria for population screening
because of the rarity of the disease in general. Although there are advocates for annual
anal cytology screening of HIV positive patients and MSM for AIN (Goldie 1999,
2000 III) there is no evidence that screening improves survival (see Chiao 2006 for
review Ib). Similarly there is no consensus method of treatment of AIN3, particularly
in the HIV population who are prone to recurrence
Accordingly both the UK (Joint BHIVA-BASHH-FFP UK SRH guidelines for
PLHA) and Canada (Medical Advisory Secretariat. Anal dysplasia screening:
evidence based analysis. Toronto, Ontario: Ministry of Health and Long Term Care;
June 2007) have deemed that AIN is not suitable for screening at the present time.
11
Diagnosis
The diagnosis of AIN is purely histological. All anal cytological abnormalities must
have high-resolution anoscopy (HRA) and biopsy to confirm the diagnosis of AIN
(Palefsky 1997 IIa, Marchesa 1997 III). HRA is performed by inserting a clear plastic
anoscope into the anal canal with visualisation through either a gynaecologic
colposcope or an operating microscope. 3% acetic acid solution is applied to the anal
canal surface to locate the transformation zone (Scholefield 1994 IIb; Jay 1997 III). In
areas of dysplasia, an opaque white ("acetowhite") plaque may be seen. If high-grade
dysplasia exists within the plaque, hallmark surface vessel changes consistent with
neovascularization may be visible under high-power (×20) magnification. Application
of Lugol’s iodine also aids clinical detection of lesions. Dysplastic cells do not absorb
Lugol’s solution and appear bright yellow, whereas normal epithelium readily take up
the iodine solution and appear dark brown.
Histological interpretation is subject to interobserver variation (Carter 1994 IIb;
Colquhoun 2003 IIb), and of concern is that invasive foci may be present in 8.8-26%
of specimens excised for AIN3 alone (Brown 1999 III, Sarmiento 1997 III). In view
of this, we recommend that histology should be reviewed by two independent
histopathologists, one of which could be as part of an anal cancer MDT in the case of
AIN3 (B).
Precise definition of extent is advised prior to definitive treatment. This is achieved
through four-quadrant punch biopsies of the anal transitional zone, anal canal and
perianal skin (12-16 biopsies) to allow mapping of disease extent. An operative
mapping sheet should be used to record biopsy sites and extent of disease (see
appendix 3) and/or photography where resources permit. Examination of the vulval
skin, vagina and cervix should be performed as there is a 21.4-31.6% increased
incidence of anogenital tract squamous cell carcinoma (Marfing 1987 III, Marchesa
1997 III).
Grade and extent of disease determines management. Localised or focal AIN is
defined as <30% circumference involved whereas extensive AIN involves >30%
circumference (Scholefield 2005 III).
Multifocal disease is more than one area of non-confluent AIN3 at one anatomical
site, and is more likely if the patient is immunocompromised (Scholefield 2005 III).
Multicentric disease refers to more than one anatomical site, for example anal canal
and cervix.
12
Management
The aims of treatment are to treat symptoms and prevent the development of anal
cancer. The optimal management of AIN is difficult to determine as large series
comparing treatments are lacking. The largest single institute experience is 47 patients
over 21 years (Marchesa 1997 III). The various treatment options that have been
subject to analysis are detailed below.
Observation alone
Expectant management extends from the fact that high recurrence rates are seen after
aggressive attempts to eradicate dysplasia. This is particularly seen in HIV positive
cases and is likely due to persistent HPV infection. This conservative approach is
based on the perceived low rate of progression of high grade AIN to invasive cancer
and aims to detect invasive disease at an early and curative stage (Devaraj 2005 III).
Low grade dysplasia (AIN 1/2) is mostly managed in an expectant way with regular
follow up (Scholefield 1994 IIB, Cleary 2000 IV).
Immunomodulation
Imiquimod 5% cream
This nucleoside analogue of the imidazoquinoline family has pro-inflammatory, antitumour and anti-viral activity through a number of subcellular mechanisms (reviewed
by Schön 2007). Use of this topical treatment caused resolution of AIN3, regression
by at least 2 histological grades and undetectable HPV-16 (Gutzmer 2002 III, Kreuter
2004 III).
In a separate uncontrolled study of 27 patients, half of whom had AIN3: 77% of
lesions resolved following 16 weeks of treatment (Wieland 2005 IIb). Total lesion
clearance has been seen in 46% of HIV positive men at 20 weeks (Sanclemente 2007
III). This agent is emerging as a safe effective topical treatment, even in HIV positive
patients with their high propensity for recurrence.
Cidofovir 1% gel
Cidofovir is an acyclic nucleoside phosphonate with broad spectrum anti-viral
activity. It has activity against vulval, vaginal and perianal IN (Tristram 2005 IIb).
When used for up to 6 weeks has been shown to be more effective than electrosurgery
in the treatment of anogenital warts in HIV-positive patients (Orlando 2002 IIb).
13
Cidofovir alone cleared all low risk HPV and 57% of high-risk HPV, which translated
into 35% relapse rate compared with 74% relapse in the surgery-alone group at six
months follow up (p=0.018), although a combined electrocautery and cidofovir gave
the best results (100% complete response).
HPV immunotherapy
Increased understanding of the molecular biology of HPV infection has led to phase
II/III trials of therapeutic vaccination. A fusion vaccine of HPV-16 E7 protein and M.
bovis heat shock protein 65 led to a partial or complete response in five of fifteen
participants with associated clearance of HPV at 48 weeks (Palefsky 2006 IIa). A
prime-boost strategy in 29 women with anogenital IN found complete histological
regression in just one patient (Fiander 2006 IIa). Research efforts continue in this
field.
Photodynamic therapy (PDT)
A pilot study of 12 HIV positive patients with high grade dysplasia used the
photosensitizer -aminolevulinic acid followed by PDT (Webber 2004 IIb).
Consistent downgrading of dysplasia was seen and the treatment was well tolerated,
although response was based on cytology and a complete response was seen in just 2
cases.
Ablation
Ablative therapies used in AIN include CO2 laser ablation (Marchesa 1997 III;
Bandieramonte 1993 III), cryotherapy (Holt 1988 III, Morton 1996 Ib) and
electrocautery fulgaration (Chang 2002 IIb). Many of these studies suffer from high
recurrence rates and significant morbidity. For example in a study of electrocautery in
HIV-positive men the recurrence rate was found to be 79% in 12 months, with an
estimated recurrence risk approaching 100% by 50 months (Chang 2002 IIb). Patients
also suffered uncontrolled post-operative pain lasting for a mean of 3 weeks, although
multifocal extensive abnormalities were being treated. Recurrences may be high
because of persistence of HPV infection and because of deep involvement of the
perianal skin and appendages by AIN (Skinner 1997 III; Cleary 1999 III), which
14
cannot be cleared by ablation. Invasive disease cannot be identified with these
destructive techniques.
Chemo-radiotherapy
This is the standard first line treatment for invasive anal cancer, but there is no
published evidence to date for AIN in the absence of invasion. Intracavity
brachytherapy has been used for VaIN however.
Surgery
Local excision
Local excision may be suitable for localised symptomatic lesions of either 1 cm or
<30% anal circumference (Scholefield 2005 III). Defects can be closed primarily or
left to heal by secondary intention.
Most studies describe preoperative mapping before excision but this does not preclude
recurrence (Margenthaler 2004 III). Brown (1999 III) described 34 patients having
local excision. 56% had margin positivity despite preoperative mapping. 63%
recurred within 1 year. Similarly Rasmussen reported 4/11 recurrences and Marchesa
(1997 III) 53.3% local recurrence after local excision (0.5-1cm macroscopic margin)
at 38 months. Others describe multiple recurrences after conservative surgery
including invasive recurrences (Marchesa 1997 III).
The validated method of high resolution anoscopy with staining to direct biopsies (Jay
1997 III) is more exact than blind ‘clockface’ mapping biopsies and allows better
preservation of normal tissue.
Wide local excision
This is described when a macroscopic lesion exceeds 30% of the anal circumference
or when there is multifocal anal disease. Anal symptoms and inability to exclude
invasive disease are the primary indications. Extensive disease such as circumferential
anal canal AIN or multicentric disease will require a multidisciplinary approach
involving gynaecology oncologists and plastic surgeons. Resultant defects are left to
heal by secondary intention or split thickness skin grafting. Others have used
advancement flaps similar to that described for anoplasty treatment of anal stenosis.
The V-Y island flap anoplasty (Core 1994 III) or the house advancement flap
(Sentovich 1996 III) are suitable for defects of up to 50% of the anal circumference
15
and can be bilateral. If greater than 50% coverage is required a full-thickness rotation
flap such as the double S-plasty technique is described with good results (Oh 1992
III).
All reported studies advocate preoperative mapping biopsies and some use
intraoperative frozen section. Recurrence rates remain high despite radical surgery;
Sarmiento (1997 III) had 16% 1-year and 33% 5-year recurrence rates (see Table 2).
Other disadvantages of wide local excision are the high morbidity rates and no direct
evidence that excision prevents invasive cancer. As the treatment of invasive disease
is primarily non-surgical there is a trend away from wide excision in favour of active
surveillance (Scholefield 2005 III).
Treatment algorithm (appendix 4)
AIN 1/2 and AIN3 have differing natural histories so are treated differently in the
algorithm. AIN 1/2 should be managed in secondary referral centres whereas AIN3
and multicentric intraepithelial neoplasia patients should be managed in tertiary
centres with a multidisciplinary approach.
Similarly patients with HIV are considered separately in view of the higher
progression rates and poorer results and higher recurrence rates after surgery
compared with immunocompetent patients. Excision of extensive high grade AIN that
was too large for topical therapy found that 23 of 29 HIV positive patients having
surgery had persistent or recurrent high grade AIN at median follow up 29 months,
compared to no recurrences in the eight HIV negative group (Chang 2002). Surgical
treatment of CIN in HIV-positive women is similarly beset with significantly higher
recurrence rates than that for HIV-negative women (73% vs. 27%, p=0.019) (Tate
2002). Surgery is likely to be less effective in the face of persistent HPV infection and
ongoing immunocompromise. Promising results of treatment with imiquimod,
particularly in HIV positive patients, reflect its inclusion as a treatment alternative to
‘watchful waiting’. Those patients with symptomatic lesions should be offered
surgery if the benefits are thought to justify the morbidity.
16
Author
n
Follow up
Margenthaler 2004
23
Brown 1999
10
41mo
Marchesa 1997
26
104mo
Sarmiento 1997
18
8.4y
Scholefield 1994
10
20mo
Strauss 1979
10
3yrs
FS
Y
Y
Mapping
RR
Coverage
83%
13% @2 yrs
Y
37% @41mo SSG
Y
23% @41mo SSG/AF
31% @5yrs
V-Y flap
Y
0
SSG
Y
10% @3yrs
SSG
Table 2. Results of wide local excision surgery (WLE) for AIN3/ Bowen’s disease.
FS=intraoperative frozen section; RR=recurrence rate; SSG=split skin graft;
AF=advancement flap.
17
Follow up/ surveillance
The aims of follow up are to detect progressive or recurrent disease after treatment or
to detect invasive changes in known AIN. Follow up of AIN patients is essential as
the natural history is still uncertain. Although there is no standardised follow up
protocol for AIN a number of aspects are agreed. AIN1 and 2 has an indolent course
in the immunocompetent and 12 monthly anoscopy is recommended (Zbar 2002 IV;
Abbasakoor 2005 IV). Women should undergo 12 monthly cervical screening if there
is a history of AIN3 (Zbar 2002 IV). HIV positive patients are considered at higher
risk of recurrence and progression so 6 monthly anoscopy is recommended
(Abbasakoor 2005 IV; Devaraj 2006 III). Extended follow up is advised as
recurrences at 9 years after surgery are described (Marchesa 1997 III).
18
Recommendations
Histological assessment of suspicious/ recurrent anal/ perianal lesions is
recommended in all patients and biopsy of all anal/ perianal lesions in high risk
groups C
Histological diagnosis of AIN3 to be confirmed by two pathologists to reduce
misdiagnosis of invasive disease C. This could be achieved through discussion of
AIN3 cases at anal cancer MDTs.
Women with AIN should have VIN excluded and have had a cervical smear within 3
years to exclude CIN B.
All cases of AIN3 with VIN/CIN to be managed in conjunction with a gynaecology
oncologist C
All confirmed cases of AIN should have high resolution anoscopy with application of
acetic acid and biopsy of suspicious areas B.
Clinicians should have appropriate training in the techniques of anal colposcopy C.
As the incidence of AIN is low it may be appropriate for AIN3 to be managed in a
centre with an interest in AIN as part of a cancer network C.
Follow up should be intensified in the presence of high risk factors such as HIV
positivity to maximum six monthly anoscopy C.
Consider testing AIN3 cases for HIV particularly if recurrent or multifocal C
Future research
HPV typing of AIN and anal cancers may be of benefit in guiding treatment and
follow up strategies and should be evaluated.
A prospective national database of AIN cases would improve our knowledge of the
natural history of AIN.
The role of screening for AIN in high risk groups such as HIV positive and transplant
patients should have ongoing appraisal. This should be combined with education of
clinicians managing patients at high risk of AIN in recognition and appropriate
referral of suspected cases.
Use of novel agents with anti-viral activity such as imiquimod and therapeutic
vaccination should be encouraged as part of clinical trials.
19
Appendix 1
a) Grading of Evidence
Ia: Evidence obtained from meta-analysis of randomised controlled trials
Ib: Evidence obtained from at least one randomised controlled trial
IIa: Evidence obtained from at least one well-designed controlled study without
randomisation
IIb: Evidence obtained from at least one other type of well-designed quasiexperimental study
III: Evidence obtained from well-designed non-experimental descriptive studies such
as comparative studies, correlation studies and case studies
IV: Evidence obtained from expert committee reports or opinions and/or clinical
experiences of respected authorities
Note: Every reference quoted in the text of the detailed version of the guidelines is
graded according to this system.
b) Grading of Recommendations
A: Requires at least one randomised controlled trial as part of the body of literature of
overall good quality and consistency addressing the specific recommendation (levels
Ia, Ib).
B: Requires the availability of well-conducted clinical studies but no randomised
clinical trials on the topic of recommendation (levels IIa, IIb, III)
C: Requires evidence from expert committee reports or opinions and/or clinical
experience of respected authorities. Indicates absence of directly applicable clinical
studies of good quality (level IV)
20
Appendix 2. Operative mapping template for extent of IN and biopsy sites.
21
Appendix 3. Referral pathway
MSM/HIV+
immunosuppressed
transplant pt’s
+anal symptoms
Anal signs/symptoms
of AINdermatology/DGH
gynae/ general surgery
Condylomatalocalised and
recurrent;
extensive
Incidental
pathology
finding of
AIN
Colorectal referral-DGH
Physical exam/proctoscopy/anoscopy
Lesion
suspicious
for AIN
No lesion
Other
anorectal
pathology
Treat appropriately
EUA/anoscopy
No lesion
Lesion
Gynae oncology
network-VIN/CIN/
VaIN
Excision/biopsy
No AIN
AIN1/2
Observe in DGH
AIN3
Anal cancer MDT
22
Appendix 4. Suggested protocol for management of AIN in Wales.
Biopsy proven AIN
AIN1/2
AIN3
Anal cancer MDT
Pathology review
Offer HIV test
HIV- or
unknown
HIV+
HRA
12mo
DGH
HRA
6mo
DGH
AIN3
confirmed
HIV test
HRA network lead
HIV-
Localised
<30%
Local excision
DGH
Invasive
disease
HIV+
Multifocal/
>30% circ
Asymptomatic
-6mo HRA
Symptomatic
-consider WLE
Localised
Symptomatic
Consider excision
then 6mo HRA
Multifocal/
>30% circ
Observe
6mo HRA
Consider
imiquimod
23
Appendix 5. Published protocols in use for AIN treatment and follow up.
From Zbar (2002)
24
From Abbasakoor/ Boulos (2005)
25
From Devaraj (2006)
26
From Chin-Hong (2002)
27
Appendix 6. Summary of appendix 5 (published algorithms)
Low risk
AIN 1/2
HIV neg
Intermediate risk
HIV+ (CD4 normal)
Transplant patients
High risk
HIV+ low CD4
MSM
CIN/VIN
AIN3
High resolution
anoscopy 6 monthly
+/- cervical colposcopy
High resolution
anoscopy
12 monthly
No macroscopic
lesion
Macroscopic
lesion
Biopsy/ excision
AIN1/2
Anoscopy
12 months
AIN3
Anoscopy
6 months
Invasive
disease
Low/ intermed
risk
High
risk
Anoscopy
12 months
Anoscopy
6 months
Excision*
/CRT
From Zbar (2002); Abbasakoor (2005); Devaraj (2006).
*local excision if T1 and <2cm from anal margin only.
28
Further issues for discussion
1. Incidence
The incidence of AIN in Wales is currently unknown. Data should be obtained
from Welsh Office statistics or from written survey of all Wales pathology
departments. Knowledge of prevalence would help predict the workload from new
cases and follow up of detected AIN cases.
2. Responsibility for cases
It will need to be decided who has responsibility for management of AIN.
Currently each colorectal/ general surgeon/ gynaecologist in the region will see a
small number each year. It is not clear how AIN cases are currently being managed or
followed up in Wales, and is likely to be subject to some variation.
A lead clinician for AIN in each of the three Welsh Cancer Networks should be
appointed, which should be someone who has reasonable experience with the
condition and expresses an interest in AIN.
It is not clear whether surgeons currently managing AIN patients would want to
continue their care unchanged, or refer all such cases to the network lead clinician, or
continue management after advice from the MDT. It may be appropriate for the
patient’s original consultant to continue follow up of the low risk AIN cases
(AIN1/2). These points should be discussed with the current stakeholders.
3. High resolution anoscopy
This is the most sensitive technique to detect AIN. Additional resources required
would include either an operating microscope or a cervical colposcope with facility
for image capture and storage. Additional theatre space would be required to perform
these examinations under anaesthesia.
It will be required that clinicians managing AIN should have training/ certification in
high resolution anoscopy, similar to those performing cervical colposcopy. This
would require a course to be set up as none currently exists.
Precise indications for high resolution anoscopy will need defining. All patients
having excision of AIN should have excision margins defined by HRA. Ideally all
AIN follow up patients should have HRA with staining to detect recurrence. Whether
this expertise should be centralised is for discussion.
29
It is not clear from the literature whether the use of HRA is associated with lower
recurrence rates, and this technique has not been formally compared with standard 4
quadrant mapping.
4. Workload from HIV population
The potential workload from the HIV population, present and future, is enormous.
It is not clear how GUM and HIV clinicians are managing HIV patients with anal
symptoms, and who is being referred on to colorectal clinics. This will be addressed.
5. Pathology review
In light of the large inter and intraobserver variation in AIN histology reporting, all
cases of AIN3 should be reviewed by a second pathologist. This could be done
informally or as part of an MDT. The designated pathologist for this is to be
determined.
30
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