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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_538_Библиотеки_им_академика_М_И_Перельмана.pdf
344
W. B. Gaertner and M. K. Krane
Schematic Representation of Squamous Intraepithelial Lesions (SIL)
Low-grade squamous intraepithelial lesion
Condyloma
Normal
Fig. 19.1 Schematic representation of squamous intraepithelial lesions
(SIL). With increasing severity of SIL of the anus, the proportion of the
epithelium replaced by immature cells with large nuclear-cytoplasmic
Very mild to mild dysplasia
(LSIL)
CIN/AIN 1 grade 1 CIN/AIN grade 2 CIN/AIN grade 3
Infection Precancer
High-grade squamous intraepithelial lesion
(HSIL)
Moderate dysplasia Severe dysplasia
ratios increases. Invasive cancer likely arises from one or more foci of
high-grade SIL (HSIL). (With permission from Brickman and Palefsky
[2]. Copyright © 2015 Springer Nature)
rate of conversion was much lower, with progression rates of
1in 600 per year for HIV+ MSM and 1in 4000 per year for
HIV– MSM [13]. This discrepancy may be attributed to the
mix of AIN-2 and AIN-3 patients within the meta-analysis.
Epidemiology
Anal intraepithelial neoplasia develops from HPV contact
generally through direct exposure. The Centers for Disease
Control and Prevention indicate that “nearly all sexually
active men and women will acquire at least one type of HPV
at some point in their lives.” In fact, 79 million persons are
currently infected with HPV with equal prevalence in both
the developed and developing world [14, 15]. Approximately
90% of all immunocompetent patients remain asymptomatic, and those that are infected will resolve without treatment within 2years [16]. Disease progression and presence
of condyloma or neoplasia are likely related to immune
status.
HPV infection is mainly subclinical but can present as
grossly apparent (i.e., condyloma), microscopically appar-
ent, and latent (i.e., an infection that becomes clinically
apparent months or years after exposure) and has the potential to migrate from the genitalia to the anus. Risk factors for
HPV infection include uncircumcised men, number of sex
partners (directly proportional), sex with a partner who has
had many sex partners, sex with uncircumcised men, and
rst sexual contact at an early age. There are >150 HPV serotypes. Those that are considered high risk include 16, 18, 31,
33, 35, and 45 and produce E6 and E7 proteins, which in turn
inhibit two important tumor suppressor proteins, p53 and Rb
[15, 17, 18]. HPV subtypes 6 and 11 cause 90% of genital
warts [19], while 79% of patients diagnosed with anal squamous cell carcinoma are attributable to type 16 or 18 [15].
With the introduction of the HPV vaccine in 2006, the
prevalence of HPV types 6, 11, 16, and 18 identied by
cytology specimens decreased by over 50% among teens and
young women [20]. Additionally, genital wart cases appear
to have decreased since 2011 [21], presumably because of
increased vaccination (Fig.19.2). In 2017, Oliver and colleagues [22] demonstrated a decrease in prevalence of 71%
among 14- to 19-year-olds and 61% among 20- to
24-year-olds.
Prevalence
Prevalence
6
4
2
0
Females
a
25–29
20–24
30–34
35–39
15–19
6
4
2
0
Year
25–29
30–34
30–24
35–39
15–19
19 Anal Intraepithelial Neoplasia
Fig. 19.2 Anogenital
warts– Prevalence per 1000
person-years among enrollees
in private health plans, age
15–39 by gender ((a) females,
(b) males), age group, and
year (2006–2014). (2018 STD
Surveillance [21])
345
2006 2008 2010
b
2006 2008 2010
2012 2014
Year
Males
2012 2014
Screening andSurveillance
The majority of patients at risk for anal neoplasia undergo
screening with digital rectal examination, anal cytology, and
anoscopy. Anal cytology is an easily performed procedure in
which an unlubricated, moistened Dacron swab is inserted
into the anus about 3–4cm, then removed slowly in a circular motion, and nally preserved most often in liquid medium
used for cervical cytology. Although slide preparation with a
xative is also acceptable, liquid-based is the preferred
method as it avoids obscuring factors including fecal mate-
rial, bacteria, and air-drying artifact; plus, residual tissue
may be used for ancillary studies. Bowel preparation before
the examination and swabbing is unnecessary, and cytology
must be performed before any instrumentation of the anus
and before lubrication is used. Following completion, a digital rectal examination and anoscopy can be performed.
in gynecologic samples. This may return as insufcient,
Anal cytology is graded with the same classication used
normal, atypical squamous cells of undetermined signicance (ASCUS), low-grade squamous intraepithelial lesion,
high- grade squamous intraepithelial lesion, or anal cancer.
346
W. B. Gaertner and M. K. Krane
Based on these results, physical examination, and medical
history, recommendations may include continued surveillance or more detailed evaluation with high-resolution anoscopy (HRA). Cytology results of ASCUS or higher are
typically referred for HRA.Although anal cytology results
continue to be difcult to interpret given its sensitivity (69–
93%) and specicity (32–59%), this may lead to a considerably large population requiring further evaluation with HRA
[23–25]. Also, false-negative rates may differ according to
specic risk factors such as MSM (23% in HIV– versus
45% in HIV+) [26]. Recent data from Morency and colleagues [27] including a total of 1185 patients undergoing
anal cytology, of which 376 (26.5%) had follow-up biopsy,
showed that unsatisfactory cases with squamous intraepithelial lesion (SIL) on biopsy showed LSIL in 19%, ASCUS
had an 84% rate of biopsy-proven disease, and sensitivity
was higher (92%) for high-grade anal intraepithelial neoplasia or worse (AIN2+). Another retrospective study including
a total of 327 anal cytology results demonstrated dysplasia
(75% low grade and 25% high grade) in 182 patients.
Seventy-ve percent of dysplastic anal cytology were fol-
Anal Cytology
lowed by clinical examination within 1year, and 50% were
biopsied [28]. The probability of dysplasia on histology
after dysplasia on cytology was 72%, and 28% of low-grade
cytology results were upgraded to advanced disease (highgrade or invasive cancer) on histology. Although results are
not yet available, the Anal Cancer HSIL Outcomes Research
(ANCHOR) trial aims to determine whether treating precancerous anal high- grade squamous intraepithelial lesions
(HSIL), versus active surveillance, is effective in reducing
anal cancer incidence in HIV-infected individuals. At this
time, any abnormal cytology indicates the possibility of a
high-grade lesion. Likewise, cytology may not correlate
with histology. Patients with high-grade cytology, but negative anoscopy and/or pathology, should be followed closely
(Fig.19.3).
The risk of anal neoplasia is highest in immunosuppressed
individuals as they appear to have difculty clearing HPV
from their body. Rates of anal dysplasia in all HIV+ patients
are substantial regardless of sexual practices, indicating a
value for anal cancer screening, although the highest risk has
been reported in HIV+ MSM [29–31]. This group should
Normal
HIV+ repeat in
6–12 months
HIV– repeat in
12–24 months
Fig. 19.3 Anal cytology algorithm. Management should be individualized based on many factors, which may increase or decrease the interval
of evaluation. ASCUS atypical squamous cells of undetermined signicance (cannot rule out high-grade squamous intraepithelial lesion);
HGAIN high-grade anal intraepithelial neoplasia; HIV human immuno-
Insufficient ASCUS LSIL HSIL SCC
Repeat in 6 months
Normal/atypia
Repeat in 3–6
months
Medical and
radiation
oncology
referrals
High resolution anoscopy
LGAIN HGAIN SCC
Follow or treat
if symptomatic
deciency virus; HRA high-resolution anoscopy; HSIL high-grade
squamous intraepithelial lesion; LGAIN low-grade anal intraepithelial
neoplasia; LSIL low-grade squamous intraepithelial lesion; SCC squamous cell cancer/carcinoma
Treat
19 Anal Intraepithelial Neoplasia
347
also include organ transplant patients; women with a past
history of cervical, vulvar, or perineal dysplasia; and patients
with medically induced immunosuppressive conditions [32–
35]. Individuals with a past history of sexually transmitted
infections may also represent an important screening population. Although a past history of condyloma is generally a
sign of prior contact with HPV, it is unclear whether those
individuals have a tendency to develop benign warts rather
than cancer. In addition, it is difcult to prove any synergy
between HPV and other sexually transmitted infections such
as syphilis, gonococci, and herpes simplex that may speed up
transformation to AIN [36].
The value of anal cancer screening is difcult to quantify.
Screening HIV+ homosexual and bisexual men for anal dysplasia with anal cytology offers quality-adjusted life expectancy benets at a cost comparable with other accepted
clinical preventive interventions [37]. For patients with a history of high-grade dysplasia and immunosuppression, there
seems to be a benet for surveillance given the high rate of
recurrence in this population [38]. HRA may be more costeffective than other strategies; the cost per HSIL found has
been estimated to be $809.39. A prospective screening study
of 284 high-risk MSM evaluated all 3 modalities of HPV
testing, cytology, and HRA [39]. Only 15% of the cohort
tested negative for HPV, representing a methodologic weakness in this study. Cytology missed nearly one third of highrisk lesions, suggesting that HRA would have the most
clinical use for screening. The effectiveness of HRA to prevent the progression of dysplasia or development of cancer
has only been evaluated in retrospective cohort studies. In a
retrospective review of 246 patients treated with HRAtargeted destruction of HSIL/LSIL over a 10-year period
[40], recurrent HSIL was seen in 57% of patients at an average of 19months. Despite treatment, only 1.2% progressed
to invasive cancer.
III and ultimately dedifferentiate into squamous cell cancer.
It is unclear whether the development of anal neoplasia must
traverse all these steps or if a squamous cell cancer can skip
one or more phases. Ultimately, the oncogenetic pathway is
similar to the pathway described in cervical cancer.
Once the presence of AIN has been established, dysplasia
of the anus rarely regresses [46]; however, data proving persistence of AIN are incomplete as many patients do not follow up for surveillance. It is also unclear why anal dysplasia
is thought to be more persistent than equivalent degrees of
cervical dysplasia given the common pathogenic pathway of
these two conditions. In fact, it is estimated that approximately 60% of low-grade cervical lesions will spontaneously
regress [47, 48]. Small reports with limited follow-up on the
natural history of AIN have shown higher rates of progression to anal cancer, especially in immunosuppressed patients
[11, 12]. The rate of progression from AIN to invasive cancer
is still unclear at this time due to few studies and limited
follow-up periods. Many retrospective studies have associated high-grade squamous intraepithelial lesions as a common precursor in men who have developed anal cancer [44,
49]. Scholeeld etal. [11] followed 35 patients (74% women)
with AIN III for a median duration of 63months. All subjects
were HIV negative; however, six were on long-term systemic
immunosuppressants. Three patients (8.5%) progressed to
invasive anal SCC (all of whom were on long-term systemic
immunosuppressants). Watson et al. [12] followed 72
patients (72% women) with AIN I–III for a median of
60months. The majority of patients (94%) had prior genital
malignancy, 7% were HIV+, and 23% were on chronic
immunosuppression. Fifteen percent of subjects had histologic progression of their disease (AIN II to AIN III, or AIN
III to anal SCC), and 11% developed anal SCC.
Diagnosis
Progression
Much of what is known regarding the transformation of AIN
to squamous cell cancer has been extracted from the cervical
cancer literature. A number of genetic changes are proposed
to occur after viral integration leading to phenotypic changes
of the squamous epithelium. Abnormalities to chromosomes
1, 3, 7, 8, 11, 15, and 20 have all been reported with varying
frequency [41, 42]. One of the most frequently reported
changes in chromosomal structure is a gain in the long arm
of chromosome 3q [38], which is also reported to occur in
the transition from low-grade to severe cervical dysplasia
and cervical cancer [41]. Following incorporation of the viral
genome into host DNA, cellular changes and atypia of squamous epithelium occur [43–45]. Ultimately these changes
correspond to AIN I which then can progress to AIN II and
AIN is typically asymptomatic but may cause symptoms
such as pruritus, bleeding, discharge, irritation, tenesmus,
and pain. Direct examination of the anus and a detailed digital rectal exam are important components in the diagnosis of
AIN.It is imperative that patients with AIN also have a thorough history and physical examination, with emphasis on
other HPV-related diseases such as oral cancer, gynecologic
dysplasia [50], and other genital lesions. Physical examination should include a head-to-toe evaluation for squamous
cell lesions, considering all lymph node basins. Appropriate
referrals to gynecology and urology should be considered on
an individual basis.
The diagnosis of AIN is made from cytology or biopsy.
The sensitivity of digital rectal exam and anoscopy is fairly
low, although anoscopy may identify macroscopic areas of
AIN, which often appear to be benign condylomata but may
348
W. B. Gaertner and M. K. Krane
Fig. 19.4 AIN 3. (Courtesy of Richard Billingham, MD) Fig. 19.5 AIN on high-resolution anoscopy. The arrow indicates an
return with AIN on biopsy (Fig.19.4). If screening is positive for HSIL or LSIL, then patients should be referred to a
surgeon who has experience with these lesions, for a formal
biopsy. The sensitivity and specicity of anal cytology for
the detection of any-grade AIN vary signicantly and have
been reported to range from 47 to 90% [35, 40] and 32 to
60% [36, 37], respectively. Formal biopsy can be performed
via conventional anoscopy or HRA and will typically provide sufcient tissue for microscopic evaluation to determine
the presence of LSIL or HSIL.Tissue biopsy allows for a
more denitive diagnosis compared to cytology alone.
HRA is an ofce-based tool, similar to colposcopy of
gynecologic neoplasia, which can be utilized to diagnose and
treat AIN [51]. HRA is typically performed in the left or
right lateral positions, no bowel preparation is necessary, and
area of high-grade dysplasia. (Courtesy of Rocco Ricciardi, MD)
The impact of HRA was recently evaluated in a cohort of
727 MSM who underwent ablation of all HRA-identied
lesions and followed for a median of 2.2years. With regular
follow-up, the rate of recurrence at 1year was 53% in HIV+
patients and 49% in HIV– patients. Over the follow-up
period, ve patients developed cancer, with the probability
of cancer 1.9% at 3years [53]. There are few comparisons of
HRA with other treatment strategies. A retrospective review
of 424 patients compared HRA with expectant management
in 2 cohorts, 1 treated by 3 clinicians who followed patients
with expectant management and the other treated by 2 clinicians who followed patients with HRA [54]. Anal cancer
occurred in one of the HRA patients and two of the expectant
management patients. The 5-year progression rate was similar in the two cohorts.
is most commonly performed without analgesia. After the
application of 3–5% acetic acid for 2–5minutes, a magnifying anoscope is used to examine the anus and lower rectum.
Treatment
Acetic acid causes dysplastic cells to be more visible compared with surrounding tissue. Iodine-based Lugol’s solution
may also be added to further detect dysplastic tissue. The
mechanism for Lugol’s utility is that only healthy epithelium
absorbs this compound which causes normal tissue to appear
wood-like, and dysplastic tissue does not absorb the solution
giving these tissues a yellowish hue. Our protocol is to avoid
Lugol’s solution as it interferes with proper dysplasia differentiation (i.e., AIN I versus AIN II or III), and we believe that
acetowhitening from acetic acid is sufcient to identify dysplastic tissues. The entire anal canal and anal verge should be
examined, emphasizing detailed visualization of the transition zone. Dysplastic epithelium will absorb acetic acid and
appear as scaly white with greater disarray of vascular patterns and tissue friability as the grade of dysplasia increases
(Fig.19.5). The microscopic appearance of variable grades
of anal squamous intraepithelial lesions has also been
described as similar to those described for the cervix [52].
Progression of AIN to squamous cell cancer is relatively
rare; however, diagnosis and differentiation of AIN and
determination of which patients benet from treatment and
with what modality require expertise. It is therefore recommended that patients found to have positive anal cytology or
biopsy-proven AIN should be referred to expert centers.
Even among those specializing in the identication and treatment of AIN, there is a signicant variability in guidelines
for management and surveillance paradigms which can lead
to confusion and controversy. Currently, the spectrum of
management includes observation, topical therapies, local
ablations, and surgical excision (Table19.1). However, recommendations are mostly based on literature from single
institution case controls series rather than large randomized
trials. The goal of treating dysplastic lesions is to reduce the
rate of progression to anal cancer while decreasing morbidity
and preserving function.
19 Anal Intraepithelial Neoplasia
Table 19.1 Common treatment options for AIN
Treatment Advantages Disadvantages Cure Recurrence
Observation Low cost
No side effects
Imiquimod Minimal pain
Easy to use
5-FU Easy to use Burning
Infrared coagulation Clinic-based Special equipment Good Moderate in immunosuppressed
Ablation Single use Painful
Wide local excision Removes all tissue Painful
Low cure rate
Time-consuming
Burning
Moderate cost
Moderate cost
Costly
Operating room
Cosmetic and functional issues
Poor High
Poor High after stopping
Poor High after stopping
Good Moderate in immunosuppressed
Good Low
349
Expectant Management
Observation or an expectant management approach is a conservative strategy that is advocated by some for select
patients with AIN [55]. In general, patients with low-grade
dysplasia undergo observation alone with close clinical follow- up every 4–6months. A more intense program including
cytology, HRA, and targeted biopsies has demonstrated a
clearance rate of 78% with a 1.2% rate of progression to
invasive squamous cell cancer over a 10-year period [40]. A
recent large retrospective review comparing HRA versus
expectant management for AIN demonstrated no difference
in progression to squamous cell cancer as long as patients
were compliant with frequent follow-up [54]. The expectant
management strategy is based on the relatively low rate of
disease progression and malignant potential of AIN and the
increased rates of adverse effects and morbidity of topical
and ablative or surgical treatments [56].
Topical Therapies
Trichloroacetic Acid (TCA)
TCA is generally well tolerated by patients with no reported
systemic side effects and can be efcacious after only a few
applications with further treatment possible if necessary. It
is typically applied by a provider and thus has the advantage over other topical agents of not requiring patient
adherence. Two small retrospective studies with biopsyconrmed AIN have examined the use of TCA.Cranston
etal. [57] reviewed the course of 72 patients with HSIL
3–6months after TCA treatment and noted resolution or
downgrading to LSIL in 79% of lesions. Single TCA treatment improved or resolved 49% of lesions with 28% requiring two treatments. However, the recurrence rate was 21%.
Singh and colleagues reported that 72% of lesions were
either resolved or downgraded to LSIL in 54 men with
HSIL [58]. Men who had fewer than three lesions had
greater clearance. TCA offers a clinic- based treatment for
HSIL with relatively few side effects but may not be appropriate for bulky or more extensive disease.
5-Flurorouracil (5FU)
Two retrospective studies evaluating the use of topical uorouracil reported response rates of 55–57% [59, 60]. One
study of 46 HIV-positive patients with LSIL or HSIL reported
a complete response in 12 of the 34 (39%). However, recurrence rates of 50% were observed in the complete responders
at 6 months [59]. Seventy-three to 85% of patients report
experiencing adverse effects including anal pain, irritation,
and hypopigmentation, but only one to two patients in each
study discontinued treatment [59, 60].
Cidofovir
One prospective pilot study and one retrospective cohort
study have assessed the effectiveness of 1% cidofovir applied
three times per week for 4weeks [61]. Sixteen HIV-positive
patients with HSIL were included in the pilot study which
demonstrated a complete response rate in 63% at 12weeks.
However, at 24weeks, 20% of these patients had recurred. A
single-arm clinical trial enrolled 33 HIV-positive patients
with perianal HSIL to self-apply 1% cidofovir gel to lesions
daily for a 2-week cycle consisting of 5 consecutive days on
and 9 days without treatment [62]. This was repeated for
sixcycles with a 79% completion rate. Of the 24 patients that
completed treatment, 51% had a response (15% complete
and 36% partial). Two patients had progression of their disease over the course of the study. Cidofovir can only be prepared by compounding pharmacies and may not be covered
by standard insurance limiting its potential use.
Imiquimod
Imiquimod is the most tested topical agent used in treating
SIL and has been examined in two randomized trials and one
prospective cohort study. A double-blinded randomized
placebo- controlled trial of 64 HIV-positive MSM compared
self-application of 5% imiquimod cream versus placebo in
the anal canal three times per week for 4months. Response
350
W. B. Gaertner and M. K. Krane
rates assessed by cytology, HRA, and biopsy in the 53
patients that completed the study demonstrated superior
response with imiquimod (43% vs. 4%), and 61% of imiquimod responders exhibited sustained response at 36months
[63]. A prospective study by van der Snoek etal. [64] aimed
to establish the effectiveness of imiquimod found that of 44
patients with histologically proven perianal or intra-anal
HSIL treated with 5 consecutive days per week of selfadministered 5% imiquimod, complete or partial response
was noted in 45% of patients after 16weeks of treatment.
Patients who did not demonstrate a response underwent an
additional 16weeks of treatment resulting in a total response
rate of 66%.
Topical therapies are relatively efcacious for patients
with LSIL and HSIL and have few severe side effects. The
most common is a localized skin reaction at the application
site, with erythema, itching, and burning being reported most
often. Generally, imiquimod is well accepted, with few
patients choosing to discontinue therapy or withdrawal from
clinical trials due to intolerable side effects. Patients who
nd the side effects bothersome typically respond well to
topical analgesics, warm baths, and/or dose modication. A
substantial number of patients who respond have recurrence
once treatment is discontinued, and consideration should be
given to using them in patients that cannot undergo ablative
therapy or in conjunction with ablative therapy.
Local Ablative Therapies
Local ablative therapy consists of targeted destruction of
dysplastic lesions using fulguration with electrocautery,
excision, or infrared coagulation (IRC) in conjunction with
HRA or anoscopy and is effective in achieving high rates of
complete response particularly in immunocompetent
patients. Procedures are often performed in the operating
room but are increasingly becoming clinic-based using local
anesthesia. Ablation is typically targeted to areas with evidence of dysplasia with no need for margins, and as the disease is limited to the epidermis, destruction of deeper dermal
tissues is unnecessary.
Rates of response with electrocautery may initially be as
high as 75–80%, but recurrence is common. An observational study by Burgos and colleagues of 83 HIV-positive
MSM with HSIL demonstrated a 33% complete response
and 34% partial response after treatment with electrocautery
with increased success seen in patients who underwent multiple sessions. However, consistent with other studies, recurrence was observed in 25% of patients after a median
follow-up of 30months [65].
Short-term efcacy of infrared coagulation was demonstrated in a retrospective clinical study of 74 HIV-positive
MSM with HSIL in which 64% of patients were found to
have a complete or partial response. Long-term results were
assessed in a recent retrospective analysis of 96 MSM with
HSIL treated with IRC which demonstrated resolution in
82% of HIV-positive and 90% of HIV-negative [66].
However, after 1 year from rst treatment, recurrence
(mainly metachronous) was observed in 38% and 61% of
HIV-negative and HIV-positive MSM, respectively. An
advantage of IRC is that is it associated with less pain and
can often be performed in a clinic setting.
In general, local ablative therapies are associated with
minimal morbidity and are reasonably well tolerated. Often,
multiple sessions are required and recurrence remains common. Care should be taken to avoid large eld defects, scarring, or stricture formation, with the goal of preserving
healthy tissues as patients will often need further surveillance and intervention.
Wide Local Excision
Historically, mapping biopsies with wide local excision was
the mainstay of treatment for AIN.This often resulted in the
removal of large amounts of healthy and uninvolved tissue
along with the dysplastic lesions. In addition, 9–63% of
patients would develop recurrences, with repeated procedures resulting in long-term complications including anal
stenosis and fecal incontinence particularly in patient with
circumferential lesions or those with signicant disease burden [67, 68]. With alternative techniques now available,
mapping with wide local excision is not recommended even
for cases of diffuse disease.
Treatment Summary
Few studies have compared different treatment modalities.
In one study, 148 HIV-positive MSM with SIL (57% with
HSIL) were randomized to 4months of treatment with 2%
5FU, 5% imiquimod, or monthly electrocautery [69].
Complete response as assessed by post-treatment biopsies
was 17%, 24%, and 39%, and partial/complete response in
the HSIL group was 43%, 46%, and 68%, respectively. Side
effects were reported in 27%, 43%, and 18%, and at 72weeks
post-treatment, recurrence rates were 58%, 71%, and 68%,
respectively.
Due to the lack of high-quality randomized control trials
comparing various treatment strategies, it is difcult to
develop guidelines for the care of AIN.We recommend basing treatment decisions on patient goals, history of immunosuppression and dysplasia, comorbidities, and underlying
bowel function (Fig.19.6). For patients with LSIL who will
be compliant with surveillance, expectant management with
or without the addition of HRA may be the best management
19 Anal Intraepithelial Neoplasia
351
Disease Status
AIN I AIN II/III
High risk, PMHx of CIN/AIN,
immunosuppressed
HRA every 6–12 months
plus annual cytology
Fig. 19.6 Algorithm for the treatment of AIN based on immune status and biopsy results
Immunocompetent
Annual cytology and
anoscopy OR
annual HRA
Immunocompetent Immunosuppressed
If HRA normal for 2
consecutive years,
annual anal cytology
HRA every 3–6 months
with annual cytology
If becomes normal or AIN I
Ablation
HRA every 3–4 months
with annual cytology
If recurrent or too
extensive for ablation
consider topical therapy
plus HRA every 3 months
strategy. For immunocompetent patients with HSIL, targeted
surgical ablation guided by HRA is the most effective at
eradicating dysplasia and generally well tolerated. Dening
which treatment modality to employ in immunocompromised patients with SIL is more difcult. This population
presumably has a higher likelihood of progressing from
LSIL to HSIL and squamous cell cancer which would favor
more aggressive interventions. However, they also have
increased rates of recurrence which would necessitate
repeated treatments, potentially resulting in increased scarring and stenosis. In this patient population, the best approach
is likely a combination of close observation and topical therapy versus ablative treatments depending on the extent and
severity of disease.
Surveillance/Prevention
The recurrence rate of AIN is high after all treatment modalities, and thus surveillance is necessary. However, there are
no denitive data or guidelines on what is the appropriate
surveillance strategy. In a large retrospective review, patients
with biopsy-proven AIN were enrolled in a surveillance program after ablative or topical therapy. All patients were fol-
lowed with annual digital rectal exams and anal cytology. Of
the 424 enrolled patients, 220 underwent regular HRA examinations, while the remaining 204 underwent HRA if DRE or
cytology was positive. No signicant differences were seen
between the groups in the 5-year anal cancer rate. In both
groups, those that progressed to squamous cell anal cancer
were less compliant with surveillance. Therefore, the authors
concluded that the key to reducing progression and recurrence of disease was patient compliance rather than a particular surveillance program [54]. Further studies need to be
conducted to help determine best practices for the treatment
and follow-up of patients with AIN.
In recent years, there has been increased data suggesting
that HPV vaccines may be associated with a decrease in the
incidence of AIN.In a large randomized, placebo-controlled,
double-blinded clinical trial of over 4000 boys and men,
Giuliano etal. demonstrated the efcacy of the HPV quadrivalent vaccine in preventing external genital lesions in
patients who had no prior evidence of HPV infection [70]. In
a subset analysis of 602 MSM, the efcacy of preventing
AIN, including grades 2 and 3, associated with HPV 6, 11,
16, or 18 was 50.3% in the intention-to-treat population and
77.5% in the per-protocol efcacy population [71]. The efcacy in preventing AIN associated with HPV of any type was
352
W. B. Gaertner and M. K. Krane
25.7% and 54.9% in the intention-to-treat and per-protocol
efcacy populations, respectively. A trial aimed at determining the efcacy of the quadrivalent HPV vaccine in prevention of AIN in HIV+ MSM, Vaccine Therapy in Preventing
Human Papillomavirus Infection in Young HIV-Positive
Male Patients Who Have Sex with Males, is completed, but
the results are pending [72]. It is postulated that administration of the HPV vaccine to girls and boys prior to the onset
of sexual activity may reduce the incidence of AIN, prevent
the recurrence of AIN 2 and 3, and halt progression to squamous cell carcinoma of the anus, but more robust data is
needed.
Conclusion
Anal intraepithelial neoplasia is a precursor to squamous cell
cancer of the anus. The actual rate of progression from AIN
to SCC of the anus is unknown, but detection and treatment
of dysplastic lesions likely decrease the risk of progression.
Risk factors in the development and progression of AIN
include infection with HPV (particularly high-risk strains),
HIV positivity, men who have sex with men, and transplant
patients. Treatment modalities include expectant management, application of topical agents, local ablation, and surgical excision and need to be individualized based on a number
of patient and disease factors. Regardless of treatment
approach, recurrence is common, and therefore ongoing surveillance is recommended for all patients with a history of
AIN, and patient compliance is critical. In the future we hope
to improve prevention and detection of early lesions and
develop consensus guidelines regarding nomenclature, treatment, and surveillance.
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