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59
Posterior Sagittal
Anorectovaginourethroplasty
(PSARVUP)
The posterior sagittal approach is also used to
repair cloacal malformations. These anomalies
form part of a wide spectrum of structural disor-
ders with a common channel of variable length.
As the anatomy is very variable and inconsistent,
the procedure is often performed by a paediatric
surgeon in conjunction with a paediatric urolo-
gist. The operative technique of total urogenital
mobilisation is most commonly employed. The
urethra, vagina and bowel are mobilised en bloc
before separating the different structures. This
technique has greatly improved outcome and in
particular the avoidance of urethrovaginal fi stu-
lae and vaginal stenosis. In infants where the
common channel is very long (>3 cm), recon-
struction may be very diffi cult. It may be close to
impossible to reconstruct an adequate urethra and
vagina. In some, vaginal hypoplasia or absence
may mandate some form of vaginal substitution.
This may necessitate staged reconstruction per-
formed at an older age.
Post-operatively infants with a low malforma-
tion who have undergone limited PSARP may be
discharged once they are passing stool regularly
and all diagnostic imaging has been performed.
Following repair of a higher anomaly, a urethral
catheter should remain in situ for a minimum of a
week. Catheter removal is done in hospital and
discharge home occurs when adequate voiding is
established.
Wound infection and dehiscence remain a real
concern; intravenous antibiotics are continued
for 5–7 days and the infants are nursed prone to
keep pressure off the wound. Some surgeons rec-
ommend routine examination under anaesthetic
and anal calibration 2 weeks following the proce-
dure. The use of regular anal dilatation by the
parents for several months is popular and widely
recommended. In our experience this is distress-
ing for parents and child and is unnecessary. We
prefer to perform an examination under anaesthe-
sia several months following anoplasty prior to
stoma closure. If the anus is of satisfactory cali-
bre, the stoma can be closed.
Outcome
Outcome is related to a number of different fac-
tors including the anatomy of the original malfor-
mation and degree of associated anomalies, in
particular spinal or sacral problems. As a general
principle, higher anomalies are associated with a
worse long-term functional outcome as are those
with an associated sacral or spinal abnormality. It
should be remembered that the aim of anorectal
reconstructive surgery is to achieve a normal
functional outcome. This includes being able to
pass stool voluntarily without soiling or signifi -
cant constipation. Overall, in large series of
patients comprising the full spectrum of anorec-
tal anomalies, voluntary bowel motions are
reported by 70 % of patients, but only about half
reports total continence. The remainder reports
regular soiling and/or signifi cant constipation.
Whilst ‘normal’ bowel function can be achieved
in up to 80–90 % of patients with a rectoperineal
fi stula, only 10–15 % of patients with a recto-
bladder neck fi stula experience such a good
outcome.
An important consideration is that what is
generally considered to be normal stooling func-
tion is in fact not achieved by 100 % of healthy
individuals. A recent study of healthy Finnish
patients reported normal stooling frequency in
only 92 % of adults and that 10 % of adults
reported some degree of social compromise as a
result of disordered bowel function. Just over
one-quarter of adults reported faecal soiling with
a frequency of less than once per week and 3.5 %
reported faecal accidents with an identical fre-
quency. These fi ndings have implications for the
assessment of outcome of children born with
anorectal anomalies. In attempting to achieve
‘normality’, it is important to consider what nor-
mal bowel function actually is.
For children and their families, the conse-
quences of an abnormal stooling pattern and in
particular frequent faecal soiling are signifi cant.
These children are best treated with a bowel
management programme in order to achieve
‘social continence’ to enable the child to come
out of nappies and attend school without disrup-
tion. A programme of daily or alternate day
5 Congenital Abnormalities of the Anus
60
enemas is commenced to completely evacuate
the colon and avoid faecal incontinence during
the following 24–48 h. By manipulating this
regime of enemas and combining it with an oral
laxative preparation, incontinence and soiling
can be ‘managed’ in many children such that the
impact on daily life can be minimised and child
and family quality of life improved. Some chil-
dren and their families do not tolerate rectal
enemas well and may benefi t from surgical cre-
ation of an antegrade continence enema (ACE)
channel. This involves surgical creation of an
appendicostomy to allow antegrade instillation
of an enema solution. Such a procedure is usu-
ally not tolerated below the age of 7 years due to
lack of motivation and cooperation from the
child.
Long-term outcomes into adolescence and
beyond are only recently being reported for chil-
dren born with anorectal malformations.
Encouragingly the majority of children experi-
ence some improvement around the time of
puberty. The outcome in regard to sexual func-
tion and fertility is not clear at the present time.
Our experience, which predates use of the
PSARVUP technique, suggests that pregnancy
was unusual in girls with high anomalies.
Further Reading
Bischoff A, Levitt MA, Peña A. Laparoscopy and its use
in the repair of anorectal malformations. J Pediatr
Surg. 2011;46(8):1609–17.
Georgeson K. Laparoscopic-assisted anorectal pull-
through. Semin Pediatr Surg. 2007;16(4):266–9.
Herman RS, Teitelbaum DH. Anorectal malformations.
Clin Perinatol. 2012;39(2):403–22.
Kluth D, Hillen M, Lambrecht W. The principles of nor-
mal and abnormal hindgut development. J Pediatr
Surg. 1995;30(8):1143–7.
Kyrklund K, Koivusalo A, Rintala RJ, Pakarinen MP.
Evaluation of bowel function and fecal continence in
594 Finnish individuals aged 4 to 26 years. Dis Colon
Rectum. 2012;55(6):671–6.
Levitt MA, Bischoff A, Peña A. Pitfalls and challenges of
cloaca repair: how to reduce the need for reoperations.
J Pediatr Surg. 2011;46(6):1250–5.
Rintala RJ, Pakarinen MP. Imperforate anus: long- and
short-term outcome. Semin Pediatr Surg. 2008;
17(2):79–89.
Sen G, Sebire NJ, Olsen O, Kiely E, Levitt GA. Familial
Currarino syndrome presenting with peripheral primi-
tive neuroectodermal tumour arising with a sacral ter-
atoma. Pediatr Blood Cancer. 2008;50(1):1–4.
Van der Putte SC, Neeteson FA. The pathogenesis of
hereditary congenital malformations of the anorectum
in the pig. Acta Morphol Neerl Scand. 1984;22(1):
17–40.
Warne SA, Hiorns MP, Curry J, Mushtaq I. Understanding
cloacal anomalies. Arch Dis Child. 2011;96(11):
1072–6.
N.J. Hall and E.M. Kiely
61
R. Cohen, A. Windsor (eds.), Anus,
DOI 10.1007/978-1-84882-091-3_6, © Springer-Verlag London 2014
Introduction
The diagnosis of premalignant conditions of the
anus remains a challenge, in particular differenti-
ating between lesions which have a malignant
potential and those which are of no concern. The
use of anal cytology and high-resolution anos-
copy (HRA) has helped to diagnose clinically
suspicious lesions. In addition, HRA allows
biopsy and treatment of clinically suspicious
lesions. These investigations can be used to
screen high-risk patients, such as HIV-positive
men who have sex with men. The human papil-
lomavirus is implicated in the aetiology of many
premalignant lesions, and vaccination against it
in at-risk populations may reduce the prevalence
of these lesions.
The premalignant conditions of the anus
which will be discussed in this chapter are:
1. Anal intraepithelial neoplasia (AIN)
2. Paget’s disease of the anus
3. Bowen’s disease of the anus
Clinical Assessment
It is important to ascertain if the patient has any
risk factors for developing premalignant condi-
tions of the anus such as HIV status, sexual his-
tory, history of immunotherapy and history of
prior anal, perianal or gynaecological lesions.
Examination of patients involves thorough
inspection of the perianal skin and anal mar-
gin, a digital rectal examination and proctos-
copy. At-risk patients should have anal cytology.
Patients with abnormal cytology or lesions iden-
tifi ed on initial examination should be referred
for high-resolution anoscopy allowing biopsy
and/or treatment of suspicious lesions.
Symptoms
Patients are often asymptomatic; however, com-
mon symptoms are pruritus ani and bleeding. The
patient may notice an anal lesion, though often
worrying lesions are fl at.
Signs
On anal inspection, a premalignant lesion
may present as a plaque. AIN may be found in
anal warts. AIN lesions may be eczematoid, pap-
illomatous, papular or plaque-like. Induration
and ulceration are more sinister signs of invasion.
J. Crosbie , MD, FRCSI (*) • J. McCullough , FRCS
P. Boulos , MS, FRCS
Department of Surgery , University College
London Hospital , London , UK
e-mail: james.crosbie@uclh.nhs.uk
6
Premalignant Conditions
of the Anus
James Crosbie , Jonathan McCullough ,
and Paul Boulos
62
Anal Cytology
Anal cytology involves rotating a water-
moistened Dacron swab inside the anal canal.
Dacron is used instead of cotton because cells
cling to cotton and this may decrease the cellular
yield. To increase the cellular exfoliative yield,
patients are instructed to refrain from anal sex
and avoid douching or having enemas before test-
ing. The cytological fi ndings are classifi ed as:
1. Normal
2. Atypical squamous cells of undetermined sig-
nifi cance (ASCUS)
3. Low-grade squamous intraepithelial lesion
(LSIL)
4. High-grade squamous intraepithelial lesions
(HSIL)
The sensitivity of anal cytology is 90 % but its
specifi city is 50 %. It is suggested that all patients
with abnormal cytology are referred for HRA and
biopsy of visible lesions. While HSIL has a high
predictive value for detection of biopsy-proven
AIN 2 or 3, especially in HIV-positive patients,
ASCUS or LSIL are not reliable for the determi-
nation of the true grade of the lesion [
1 ].
High-Resolution Anoscopy
High-resolution anoscopy is similar to cervical col-
poscopy and uses identical equipment (a powerful
light source and a binocular lens). Lesions identi-
fi ed on HRA are characterised by colour, contour,
surface confi guration and vascular patterns.
Colour
Acetic acid is applied to the mucosa, and ‘ace-
towhitening’ of the abnormal tissue compared
with surrounding normal tissue is observed,
which can be improved by the administration of
Lugol iodine solution, in which the abnormal
cells remain unstained or appear yellow, in
contrast to the mahogany colour of the surround-
ing stained normal tissue.
Contour
This is described as regular or irregular.
Surface Confi guration
Lesions are described based on the presence or
absence of papillae, raised or fl at, smooth or
granular and papillary or non-papillary.
Vascular Patterns
The vascular pattern may be normal or warty. In
addition vascular punctuation, which is seen as a
series of dots on acetowhite epithelium and
represents the end on view of dilated and promi-
nent intraepithelial capillaries, can be coarse or
fi ne.
Mosaicism is caused by normal interconnec-
tion of capillaries causing a tile-like pattern and it
can be coarse or fi ne.
Anal Intraepithelial Neoplasia
Anal intraepithelial neoplasia (AIN) was fi rst
described in 1986 by Fenger and Neilsen [ 2 ].
AIN is a multifocal premalignant disease process
that affects the perianal skin and the anal canal
including the anal transition zone. It has three
grades (Fig. 6.1 ):
AIN 1: nuclear abnormalities affect the lower
one-third of the epithelium.
AIN 2: nuclear abnormalities affect the lower
two-thirds of the epithelium.
AIN 3: nuclear abnormalities involving the full
thickness of the epithelium.
The term anal squamous intraepithelial
lesions is also used to describe AIN and is clas-
sifi ed into low-grade anal squamous intraepithe-
lial lesions (LSIL) which is equivalent to AIN
grade 1 and high-grade anal squamous intraepi-
thelial lesions (HSIL) which is equivalent to
AIN grade 2 or 3.
J. Crosbie et al.
63
AIN is more common in the immune-
suppressed patient and in particular in HIV-
positive patients. The prevalence of AIN in
HIV-positive men who have sex with men
(MSM) is estimated to be around 26–36 %. The
prevalence of high-grade AIN in this subgroup is
around 5 % [
3 , 4 ].
AIN is associated with the human papilloma-
virus (HPV), which is usually transmitted by
genital contact during sexual intercourse [ 5 ]. The
risk of persistence and progression of the HPV
infection to precancerous lesions varies by the
HPV type [
6 ]. There are over 100 HPV types
identifi ed and about 40 of these can cause ano-
genital disease in humans [ 7 ]. They are graded
according to their association with cervical can-
cer into low-, intermediate- and high-risk
subgroups:
Low-risk HPV
Types
6 , 11 , 40, 42 , 43 , 44 , 54, 61, 70, 72
Medium-risk
HPV Types
26, 53, 66
High-risk HPV
Types
16 , 18 , 31 , 33, 35, 39, 45 , 51, 52, 56,
58, 59, 68, 73, 82
HPV types 16 and 18 are most commonly
isolated in cervical, anal, vulvar and penile can-
cer. Among men who have sex with men (MSM)
and women (commercial sex workers and intra-
venous drug users) who are HIV positive, the
incidence of HPV infection, multiplicity of
HPV types and abnormal anal or cervical cytol-
ogy and the prevalence of AIN are higher than
in HIV- negative men and women [ 8 ]. The pro-
gression from low- to high-grade AIN is related
to HIV status and occurs in more than 50 % of
Ain 1
Ain 3Ain 2
Normal
Fig. 6.1 AIN lesions
6 Premalignant Conditions of the Anus
64
HIV- positive patients within 2 years [ 9 ]. The
rate of progression to squamous cell carcinoma
is probably <1 % per annum [ 9 ]. It is thought
that HPV infections occur in areas of trauma
and result in cellular hyperplasia of the basal
layer of the squamous, transitional and cuboi-
dal epithelial cells. Viral genomes have been
cloned from infected tissue. HPV E6 and
E7gene products inactivate p53 and Rb protein
products of tumour suppressor genes. This is
postulated to result in inactivation of their
tumour suppressor function under appropriate
circumstances, such as defi cient immune state,
thereby allowing malignant transformation and
tumorigenesis [ 10 , 11 ].
Diagnosis of AIN
HPV-associated premalignant conditions are
often asymptomatic. The diagnosis of AIN
should always be considered in high-risk patients
who include all men who have sex with men
(MSM) regardless of HIV infection; women with
cervical intraepithelial neoplasia (CIN), high-
grade vulva disease or cancer; all HIV-positive
men and women regardless of sexual orientation;
individuals with perianal condylomata; and
transplant recipients. Kreuter et al. have classi-
fi ed commonly seen lesions into bowenoid,
erythroplakia and verrucous [ 12 ]. Examination
of the external genitalia should be performed in
both sexes and women should be offered colpos-
copy. As AIN is often multifocal, patients should
have mapping biopsies performed. Mapping
involves performing four quadrant biopsies of
the anal canal, anal margin and perianal skin and
also biopsying any suspicious lesions. Scholefi eld
et al. fi rst described the use of high-resolution
anoscopy with acetowhitening of the anal
mucosa in diagnosing AIN [ 13 ]. Subsequently
Palefsky described in detail the colposcopic
appearances of anal squamous intraepithelial
lesions [ 14 ]. High-grade AIN is usually smooth
and fl at with vascular punctuation. It is uncom-
mon for high-grade AIN to have papillae, warty
vessels or mosaicism. However, it is advised that
any abnormal lesion is biopsied to confi rm its
histology.
Screening for AIN
A protocol for AIN screening was proposed
by Palefsky et al. [ 1 ]. The fi rst step involved is
taking anal cytology followed by confi rmation of
the disease stage by high-resolution anoscopy
and biopsy. HRA testing has a high predictive
value for normal mucosa and for AIN 3 but not
for AIN 1 or 2 [ 14 ]. Patients with normal cytol-
ogy or normal HRA are rescreened in 1 year if
they are HIV positive or 2–3 years if HIV nega-
tive. Patients with AIN 1 are screened every
6 months. AIN 2 and 3 will require treatment.
Treatment of AIN
The rationale for treating AIN is to prevent the
progression into high-grade and invasive cancer.
Sceptics argue that involvement of AIN 2 or 3 of
deeper areas of the perianal skin and its append-
ages in up to 50 % of cases and sweat glands in
25 % of biopsy specimens may not be accessible
to anal colposcopy, and ablative techniques such
as cryotherapy, laser vaporisation and electro-
cautery are inadequate forms of treatment [ 15 ].
HPV is epitheliotropic, the entire genital area is
likely to be involved, and eliminating the virus
may not be possible. AIN 1 and 2 could be
treated expectantly since their natural course is
unclear and occasionally regress spontaneously;
furthermore, they are frequently associated with
HPV 6 and 11 which is less oncogenic than
HPV 16 [ 16 ].
Small perianal lesions are treated by topical
agents that include podophyllotoxin, Imiquimod,
Cidofovir, 80 % trichloroacetic acid and liquid
nitrogen. Small intra-anal lesions can be treated
with 80 % trichloroacetic acid. Medium and
larger lesions are treated by surgical excision,
electrocautery, laser ablation, photodynamic
therapy or infrared coagulation. The advantage of
surgical excision is that the tissue can be sent for
histological analysis. Regardless of the mode of
treatment, local recurrence is common. Chang
et al. reported local recurrence in two-thirds of
patients treated with HRA-directed surgical exci-
sion of intra-anal lesions [ 17 ]. Goldstone et al.
reported a similar recurrence rate for treating
J. Crosbie et al.
65
AIN using infrared coagulation under local
anaesthesia [ 18 ]. Ablative techniques must ensure
a depth of penetration 2.2 mm below the base-
ment membrane to adequately treat the disease.
Imiquimod Cream
Imiquimod cream as a treatment option has the
advantage of being applied by the patient and
also it can be used for extensive disease. It is an
immune stimulant with minimal side effects.
Systemic absorption can cause transient fl ulike
symptoms the day after application. Imiquimod
cream has been shown to be effective in treating
vulva intraepithelial neoplasia. Van Seters et al.
demonstrated a 35 % clearance rate of VIN 2/3
after a 12-month treatment period and an 81 %
improvement in symptoms [ 19 ]. Imiquimod
cream is not licensed for use in or around the
anus; however, initial studies have shown consid-
erable promise. In an uncontrolled study by
Wieland et al., 77 % of lesions resolved after
16 weeks of treatment and were associated with a
reduction of HPV viral load. However, approxi-
mately half of the patients in the study had low-
grade AIN [ 20 ]. More recently Fox et al., in a
double-blind randomised placebo-controlled
trial, demonstrated that Imiquimod cream has a
role in treating high-grade AIN. It can be used as
an adjuvant to or alternating with other treatment
for high-grade multifocal AIN. High-grade AIN
resolved in 4 out of 28 patients and was down-
graded in another 8 patients [ 21 ].
Cidofovir Cream
A 1 % gel used topically for 5 days a week for up
to 6 weeks has been shown to be more effective
than electrosurgery in the treatment of anogenital
warts in HIV-positive patients [ 22 ]
Electrocautery
Treating lesions in the anal canal with electrocau-
tery has been disappointing with a high recurrence
rate (79 % in 1 year and 100 % in 50 months) [ 17 ].
Infrared Coagulation
This procedure is better tolerated than electro-
cautery. Goldstone pioneered this technique and
showed an initial response rate of 72 % per treat-
ment cycle [ 18 ]. Infrared coagulation can be
performed in the outpatient setting with adminis-
tration of local anaesthetic. It provides good hae-
mostasis and no smoke plume. It uses an infrared
beam of light pulsed at 0.5–3.0 s intervals and
prevents damage to the deeper tissues. The depth
of penetration in millimetres is approximately
equal to the length of pulse applied in seconds.
For example, a 1 s pulse penetrates approxi-
mately 1 mm of tissue. Typically a lesion is
treated by touching it with IRC and fi ring for
1.5 s and repeating as necessary to remove the
lesion. Patients can expect 1–2 weeks of pain and
bleeding with bowel movements.
Photodiagnosis and Photodynamic
Therapy for AIN
There are a few studies showing the feasibility
of photodynamic therapy in treating AIN.
5-Aminolevulinc acid (ALA), when added to
many tissues, results in the accumulation of
suffi cient quantities, especially in tumour and
dysplastic cells, of the endogenous photosensi-
tizer protoporphyrin IX, which exhibits red fl u-
orescence with blue light and produces a
photodynamic effect when exposed to activat-
ing light by generating cytotoxic singlet oxy-
gen. Topical application of ALA followed by
exposure to activating light has been used as a
treatment for AIN.
Human Papillomavirus Vaccination
HPV vaccination is safe and well tolerated. There
are two vaccines available:
1. Gardasil—a quadrivalent vaccine which pro-
tects against HPV 6, 11, 16 and 18
2. Cervarix—a bivalent vaccine which protects
against HPV types 16 and 18
Both vaccines result in a decrease in anogenital
abnormalities [ 23 , 24 ].
6 Premalignant Conditions of the Anus
66
However, these vaccines do not exert thera-
peutic effects on existing lesions and are unlikely
to have an immediate impact on the prevalence of
anogenital cancer and its precursor lesions. It is
suggested that therapeutic HPV vaccines could
result in the elimination of pre-existing lesions
and infections by generating cellular immunity
against HPV-infected cells. These vaccines could
play a major role in controlling HPV-associated
premalignant lesions in the future [ 25 ].
Bowen’s Disease of the Anus
Bowen’s disease was fi rst described by John T.
Bowen in 1912 [ 26 ]. It is an intraepithelial squa-
mous cell carcinoma of the skin. While it is more
common on the trunk, it can also occur in the
perianal region and perineum where it is associ-
ated with the human papillomavirus types 16 and
18 [ 27 – 30 ]. Bowen’s disease is more likely to
present in female patients than males and it com-
monly presents in the fi fth decade [ 30 , 31 ]. In
comparison with extramammary Paget’s disease,
the incidence of internal malignancy in Bowen’s
disease is low (5 vs. 52–73 %), and the incidence
of invasive carcinoma at the site of the lesion is
also low (2–6 vs. 50 %). Bowen’s disease is
often asymptomatic and found coincidentally in
haemorrhoidectomy specimens (25–40 %).
Often there is a delay in diagnosis of months to
years due to its slow-growing nature and the
paucity of symptoms [ 31 , 32 ]. Patients who do
develop symptoms tend to complain of pruritus,
perianal bleeding and anal discharge. On clinical
examination, there may be a dry scaly raised
lesion with an irregular margin and brownish-
red eczematoid appearance [ 27 , 30 , 33 ].
Microscopically Bowen’s disease is character-
ised by hyperchromatic enlarged nuclei with
easily identifi able mitotic fi gures, parakeratosis
and hyperkeratosis in the superfi cial surface lay-
ers, loss of cellular polarity, marked epidermal
hyperplasia with elongation and thickening of
the rete ridges and randomly distributed dysker-
atotic cells with densely prematurely enlarged
eosinophilic cytoplasm [ 15 ]. Large haloed
hyperchromatic nuclei are present and stain neg-
ative with periodic acid- Schiff stain for glycogen
[ 27 , 31 ]. This is in contrast to Paget’s disease
which stains for carcinoembryonic antigen and
usually mucin [ 30 , 33 ]. It is thought that the nat-
ural history of Bowen’s disease is relatively
benign with an estimated 2–6 % conversion to
invasive squamous cell carcinoma [ 28 , 31 , 34 ].
The treatment options available for Bowen’s dis-
ease are similar to those for AIN and include
wide local excision with primary closure [ 35 ,
36 ], wide local excision with split-thickness skin
graft [ 37 , 38 ], wide local excision with advance-
ment cutaneous anoplasty [ 30 , 39 , 40 ], local
excision of macroscopic lesions alone [ 35 , 36 ],
cautery fulguration [ 10 ], CO
2
laser ablation [ 31 ,
41 ], cryotherapy [ 10 , 42 , 43 ], topical 5-fl uoro-
uracil cream [ 41 ], photodynamic therapy [ 44 ],
argon beam laser therapy [ 41 , 45 ] and observa-
tion alone [ 15 ].
Paget’s Disease of the Anus
In 1874 Sir James Paget described 15 patients in
whom the nipple and the surrounding skin of the
breast was diseased, and within 2 years all
patients developed an ipsilateral breast carci-
noma. Extramammary Paget’s disease (EMPD)
was fi rst described by Crocker in 1889 [ 46 ], and
in 1893 Darier and Coulillaud described EMPD
of the anogenital area.
Extramammary Paget’s disease (EMPD) can
be classifi ed as primary or secondary. Primary
EMPD is an in situ adenocarcinoma of apocrine
gland ducts or pluripotent keratinocyte stem cells
[ 47 ]. Secondary EMPD is an intraepithelial
spread due to an underlying carcinoma of the
skin or other organ systems. EMPD affects areas
of the skin containing apocrine sweat glands with
approximately 65 % affecting the vulva, 15 % the
perianal area, and 14 % the penis, scrotum and
inguinal regions. EMPD is a rare neoplasm with
only a few hundred cases reported in the litera-
ture. EMPD occurs in older patients and is more
common in women than men. The lesion spreads
epidermotropically for years and even decades
prior to becoming invasive. The risk of an associ-
ated cancer is high and all patients should be
J. Crosbie et al.
67
thoroughly investigated. It is thought that there is
a 25–35 % risk of an associated cancer in peri-
anal extramammary Paget’s disease [ 48 ].
The commonest symptom in perianal EMPD
is intense pruritus, while pain and bleeding may
occur later. Most patients present with a non-
resolving eczematous lesion of the perineum. In
the early stages, the clinical signs are often sub-
tle, and they include some erythema, skin exco-
riation and lichenifi cation. In an established
EMPD lesion, there will be a sharply defi ned ery-
thematous plaque of abnormal tissue which may
have superfi cial erosions. The differential diag-
nosis includes Bowen’s disease, basal cell carci-
noma, dermatitis, cutaneous candidiasis and
intertrigo.
The diagnosis of EMPD is usually made by
histological analysis which shows Paget cells.
These are large, faintly basophilic or vacuolated
cells situated at the dermoepidermal junction.
The nuclei are vesicular and either central or
compressed at the periphery. Paget cells contain a
lot of mucin and carcinoembryonic antigen [ 49 ].
There is little mitotic activity. They also express
gross cystic disease fl uid protein, which can be
regarded as a specifi c marker for that cell [ 50 ].
Gross cystic disease fl uid protein (GCDFP-15) is
a marker of apocrine glands and is strongly
expressed in perianal EMPD. It is thought that
expression of the c-ErbB-2 oncoprotein may play
a role in promoting intraepithelial spread of
adenocarcinoma cells [ 51 ]. There is also a vari-
able degree of hyperkeratosis and acanthosis.
The superfi cial dermis shows a chronic infl am-
matory infi ltrate with vascular dilatation and
engorgement.
Following confi rmation of the diagnosis, all
patients should have a full skin examination,
palpable of all lymph nodes, rectal examination,
sigmoidoscopy and cystoscopy. In addition
female patients should have a full gynaecological
assessment to include breast examination and
colposcopy.
Treatment of EMPD is predominantly surgi-
cal; however, there have been some case reports
detailing the use of chemotherapeutic agents
5-fl uorouracil [ 52 ], Imiquimod [ 52 ] and a combi-
nation of paclitaxel and trastuzumab [ 53 ]. Topical
agents may have a role when surgery is contrain-
dicated in high-risk patients, and its future will
need to be confi rmed by more studies [ 54 ].
The treatment of primary EMPD is wide local
excision of the affected area with a margin of his-
tologically normal skin [ 49 ]. However, tradi-
tional surgical excision is associated with high
recurrence rates (30–60 %). Mohs micrographic
surgery is associated with a lower rate of recur-
rence (8–26 %) and a smaller margin of normal
skin excised with the specimen [ 55 , 56 ]. The
average time to recurrence is 2.5 years. Mohs
micrographic surgery involves removing the sur-
gical specimen, analysing the tissue and its mar-
gins and re-excising any involved margin until
such time as all margins are clear. It was fi rst
described by Dr. Frederic Mohs in 1938 while he
was still a medical student. Follow-up of patients
after surgery should be every 3 months for 2 years
and annually after that if there are no signs of
recurrence. Treatment of secondary EMPD
involves mainly treating the underlying cancer.
Summary
Premalignant lesions of the anus remain a chal-
lenge, in relation to both diagnosis and subse-
quent treatment. Traditional surgical treatment of
wide local excision has been associated with a
high recurrence rate and signifi cant morbidity.
Screening of high-risk patients with anal cytol-
ogy and subsequent high-resolution anoscopy-
directed treatment of early lesions has soon
considerable promise. Prevention of premalig-
nant lesions of the anus may be achieved by vac-
cination of patients in their teens against the
human papillomavirus.
References
1. Palefsky JM, Holly E, Hogeboom CJ. Anal cytology
as a screening tool for anal squamous intraepithelial
lesions. J Acquir Immune Defi c Syndr Hum Retrovirol.
1997;14:415–22.
2. Fenger C, Neilsen VT. Intraepithelial neoplasia in the
anal canal. Acta Pathol Microbiol Immunol Scand A.
1986;94:343–9.
6 Premalignant Conditions of the Anus
68
3. Palefsky JM, Holly EA, Ralston ML. Anal squamous
intraepithelial lesions in HIV positive and HIV nega-
tive homosexual and bisexual men. J Acquir Immune
Defi c Syndr Hum Retrovirol. 1998;17:320–6.
4. Kiviat NB, Critchlow CW, Holmes KK. Association
of anal dysplasia and HPV with immunosuppression
and HIV infection among homosexual men. AIDS.
1993;7:43–9.
5. Winer RL, Lee SK, Hughes JP. Genital human papil-
lomavirus infection: incidence and risk factors in a
cohort of female university students. Am J Epidemiol.
2003;157:218–26.
6. Wheeler CM, Hunt WC, Schiffman M. Human papil-
lomavirus genotypes and the cumulative 2-year risk
of cervical precancer. J Infect Dis. 2006;194:1291–9.
7. Palefsky J, Holly EA. Molecular virology and epidemi-
ology of human papilloma virus and cervical cancer.
Cancer Epidemiol Biomarkers Prev. 1995;4:451–8.
8. Chin-Hong PV, Palefsky JM. Natural history and clin-
ical management of anal human papillomavirus dis-
ease in men and women infected with human
immunodefi ciency virus. Clin Infect Dis.
2002;35(9):1127–34.
9. Klencke BJ, Palefsky JM. Anal cancer: an HIV asso-
ciated cancer. Hematol Oncol Clin North Am. 2003;
17:850–72.
10. Northfelt DW, Swift PS, Palefsky JM. Anal neoplasia.
Pathogenesis, diagnosis, and management. Hematol
Oncol Clin North Am. 1996;10:1177–87.
11. Surawicz CM, Kiviat NB. A rational approach to anal
intraepithelial neoplasia. Semin Colon Rectal Surg.
1998;9:99–106.
12. Kreuter A, Brockmeyer NH, Hochdorfer B,
Weissenborn SJ, Stucker M, Swoboda J, et al. Clinical
spectrum and virologic characteristics of anal intraep-
ithelial neoplasia in HIV infection. J Am Acad
Dermatol. 2005;52(4):603–8.
13. Scholefi eld JH, Sonnex C, Talbot IC, Palmer JG,
Whatrup C, Mindel A, et al. Anal and cervical intraep-
ithelial neoplasia: possible parallel. Lancet. 1989;
2(8666):765–9.
14. Jay N, Berry JM, Hogeboom CJ. Colposcopic appear-
ance of anal squamous intraepithelial lesions: rela-
tionship to histopathology. Dis Colon Rectum.
1987;40:919–28.
15. Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler
JM, Lampman RM. Perianal Bowen’s disease and
anal intraepithelial neoplasia: review of the literature.
Dis Colon Rectum. 1999;42(7):945–51.
16. Zbar AP, Fenger C, Efron J, Beer-Gabel M, Wexner
SD. The pathology and molecular biology of anal
intraepithelial neoplasia: comparisons with cervical
and vulvar intraepithelial carcinoma. Int J Colorectal
Dis. 2002;17(4):203–15.
17. Chang GC, Berry JM, Jay N. Surgical treatment of
high-grade anal squamous intraepithelial lesions: a pro-
spective study. Dis Colon Rectum. 2002;45:453–8.
18. Goldstone SE, Zawalek MD, Huyett JW. Infrared coag-
ulation: a useful tool for treating anal squamous intraep-
ithelial lesions. Dis Colon Rectum. 2005;48:1042–54.
19. van Seters M, van Beurden M, Kate JW, Eijkemans
M, Kagie M. Treatment of vulvar intraepithelial neo-
plasia with topical imiquimod. N Engl J Med.
2008;358:1465–73.
20. Wieland U, Brockmeyer NH, Weissenborn SJ,
Hochdorfer B, Stucker M, Swoboda J, et al.
Imiquimod treatment of anal intraepithelial neoplasia
in HIV-positive men. Arch Dermatol. 2006;142(11):
1438–44.
21. Fox PA, Nathan M, Francis N, Singh N, Weir J, Dixon
G, et al. A double-blind, randomized controlled trial
of the use of imiquimod cream for the treatment of
anal canal high-grade anal intraepithelial neoplasia in
HIV-positive MSM on HAART, with long-term fol-
low- up data including the use of open-label imiqui-
mod. AIDS. 2010;24(15):2331–5.
22. Orlando G, Fasolo MW, Beretta R. Combined surgery
and cidofovir is an effective treatment for genital
warts in HIV-infected patients. AIDS. 2002;16(3):
447–50.
23. Paavonen J, Lehtinen M. Introducing human papillo-
mavirus vaccines-questions remain. Ann Med.
2008;40:162–6.
24. Rogers LJ, Eva LJ, uesley DM. Vaccines against cer-
vical cancer. Curr Opin Oncol. 2008;20:570–4.
25. Ma B, Xu Y, Hung C. HPV and therapeutic vaccines:
where are we in 2010? Curr Cancer Ther Rev.
2010;6:81–103.
26. Bowen JT. Precancerous dermatoses: a study of 2
cases of chronic atypical epithelial proliferation.
J Cutan Dis. 1912;30:241–55.
27. Beck DE. Paget’s disease and Bowen’s disease of the
anus. Semin Colon Rectal Surg. 1995;6:143–9.
28. Stearns Jr MW, Grodsky L, Harrison Jr EG, Quan S,
Rob CG. Malignant anal lesions. Dis Colon Rectum.
1966;9:315–27.
29. Marfi ng TE, ABel ME, Gallagher DM. Perianal
Bowen’s disease and associated malignancies: results
of a survey. Dis Colon Rectum. 1987;30:782–5.
30. Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA,
Ilstrup DM. Perianal Bowen’s disease: associated
tumours, human papillomavirus, surgery and other
controversies. Dis Colon Rectum. 1997;40:
912–8.
31. Marchesa P, Fazio VW, Oliart S, Goldblum JR,
Lavery IC. Perianal Bowen’s disease: a clinicopatho-
logic study of 47 patients. Dis Colon Rectum.
1997;40:1286–93.
32. Beck DE, Fazio VW. Perianal Bowen’s disease. Dis
Colon Rectum. 1988;31:419–22.
33. Beck DE, Fazio VW. Premalignant lesions of the anal
margin. South Med J. 1989;82:470–4.
34. Schwartz RA, Stoll Jr HL. Epithelial precancerous
lesions. New York: McGraw-Hill; 1993. p. 804–21.
35. Ramos R, Salinas H, Tucker L. Conservative approach
to the treatment of Bowen’s disease of the anus. Dis
Colon Rectum. 1983;26:712–5.
36. Rasmussen OO, Christiansen J. Conservative man-
agement of Bowen’s disease of the anus. Int J
Colorectal Dis. 1989;4:164–6.
J. Crosbie et al.