Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and treatment

Authors
Joel M Palefsky, MD
Ross D Cranston, MD
Section Editor
Bruce J Dezube, MD
Deputy Editor
Michael E Ross, MD
Disclosures: Joel M Palefsky, MD Grant/Research/Clinical Trial Support: Merck and Co [HPV infection
(Quadrivalent and nonavalent HPV vaccines)]; Hologic [HPV infection (HPV assay)]. Consultant/Advisory Boards:
Merck [HPV infection (Quadrivalent and nonavalent HPV vaccines)]; TheVax [HPV infection (therapeutic HPV
vaccine)]; Hera Therapeutics [HPV infection (HPV therapeutics)]. Ross D Cranston, MD Grant/Research/Clinical
Trial Support: Merck & Co [Inflammatory bowel disease/HPV (Gardasil)]. Bruce J Dezube, MD Nothing to
disclose. Michael E Ross, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: Apr 16, 2015.
INTRODUCTION
The anal and cervical canal share embryologic, histologic, and pathologic characteristics. Both
develop from the embryonic cloacal membrane, and are sites of fusions of endodermal and
ectodermal tissue to form a squamocolumnar epithelial junction. Both areas may display normal
metaplastic change and abnormal dysplastic change related to infection with human papillomavirus
(HPV) (figure 1). (See "Virology of human papillomavirus infections and the link to cancer".)
The pathology, risk factors, clinical manifestations, screening, prevention, and treatment of anal SIL
are discussed here. Anal cancer is discussed separately. (See"Clinical features, staging, and
treatment of anal cancer".)
NOMENCLATURE The classification of lower genital tract squamous terminology for HPV
associated lesions has recently been re-evaluated with consensus reached that there will be a
single set of diagnostic terms for the lower anogenital tract (LAT). A two tiered nomenclature is
recommended for HPV associated squamous proliferations of the LAT, with low-grade and highgrade squamous intraepithelial lesions (LSIL and HSIL respectively), that may be further classified
to intraepithelial neoplasia (IN) of the cervix, vulva, vagina, penis and anus to grade 1, 2, or 3. For
example, AIN 1 corresponds to anal LSIL, and AIN 2 and 3 to anal HSIL [1].
The biologic consequences of anal SIL, are considered analogous to those of cervical SIL. Anal
HSIL, corresponding to AIN grade 2 or 3, is considered premalignant and may progress to anal
cancer, similar to the progression of cervical HSIL to cervical cancer [2]. Anal LSIL, corresponding to
AIN 1, is not considered to be a direct precursor of anal cancer, but may progress to HSIL [3].
(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)
PATHOLOGY Anal SIL and the histopathologic manifestations of HPV infection are most
apparent at the anal transition zone (ATZ) where rectal columnar epithelium and anal squamous

epithelium meet (figure 2) [2]. Anal SIL and cervical SIL share cytopathologic features, and both
anal and cervical cytology are described using the 2001 Bethesda classification system (table 1).
Cytologic changes are reported, in increasing severity, as atypical squamous cells of undetermined
significance (ASC-US), LSIL, ASC-suggestive of HSIL (ASC-H), and HSIL [4]. A diagnosis of
atypical squamous cells cannot rule out the presence of a higher grade lesion. (See "Cervical
intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention".)
A biopsy is diagnosed as HSIL when abnormal basaloid cells, characterized by an increased
nuclear to cytoplasmic ratio, replace more than one-half of the epithelium (figure 1). LSIL is
diagnosed when 20 to 25 percent of the epithelium is replaced by abnormal cells [5]. LSIL is also
characterized by the presence of koilocytes, enlarged cells with a cytoplasmic halo surrounding the
nucleus that is indicative of active HPV replication.
Lesions showing evidence of LSIL may spontaneously regress, as is well documented in the cervix,
or progress to HSIL. In contrast, HSIL rarely regresses, regardless of HIV status [6]. Since HSIL is
considered to be the true precursor of invasive anal squamous cell carcinoma, ablative treatments
should be considered, similar to the management of cervical HSIL [7,8].
In the cervix, regression and progression rates for each grade of cervical lesion have been
characterized [9]. However, relatively little is known to date about the long-term natural history of
anal SIL, and studies are currently in progress to address this issue. (See "Cervical and vaginal
cytology: Interpretation of results".)
EPIDEMIOLOGY AND RISK FACTORS A number of risk factors have been identified in the
development of anal SIL. The most important of these include anal HPV infection [10,11], high risk
sexual behavior [12], and HIV infection, specially with lower CD4 levels [10].
HPV infection HPV infection of the anal canal and perianal region may be latent, subclinical, or
clinically apparent as condylomata:
Latent infection occurs after acquisition of HPV but before any clinical evidence of infection.
This period may last eight months or longer, and some individuals never develop clinically
apparent lesions.
Subclinical anal infections, such as the presence of HSIL, may be identified by highresolution anoscopy (HRA), a method of examining the anal canal that uses the application
of acetic acid and magnification [13].
Condylomata, when present, are usually clinically obvious and often have a frond-like or
plaque-like appearance (picture 1). (See "Condylomata acuminata (anogenital warts) in
adults".)
The prevalence of anal SIL correlates well with observed patterns of HPV infection, a causative
factor for both anal SIL and anal cancer [7,14-16]. Using polymerase chain reaction (PCR)
technology, one group has identified 29 individual HPV types and 10 HPV groups from the anal
canal of men who have sex with men (MSM), both with and without HIV infection [17]. The spectrum
of HPV types with both low-risk and high-risk phenotypes in the dysplastic anal canal is similar to
that described in the dysplastic cervix. (See "Virology of human papillomavirus infections and the
link to cancer".)

These observations about the risk factors for anal SIL are consistent with the observed relationship
between HPV infection and anal cancer. In certain populations, such as MSM and HIV-infected
individuals, there is an especially high incidence of anal cancer. (See "Classification and
epidemiology of anal cancer", section on 'Epidemiology and risk factors'.)
Some individuals, particularly those who are HIV-infected, are more frequently infected with multiple
HPV types [14,17]. This has been associated with both the presence of prevalent anal SIL and also
an increased risk of progression from LSIL to HSIL compared to infection with a single HPV type or
absence of detectable infection [17].
High-risk sexual behavior High-risk sexual behavior in men is associated with anal SIL.
In a detailed study of 1262 HIV-uninfected MSM, anal SIL, as detected by anal cytology, was
present in 20 percent of the population (5 percent with HSIL and 15 percent with LSIL) [14]. The
age-related prevalence of anal SIL was analyzed in terms of underlying behavior patterns and
infection with HPV. Using multivariate analysis, the factors significantly associated with the
presence of anal SIL included anal HPV infection, the number and type of HPVs present, and highrisk sexual behavior.
The prevalence of anal HPV infection in MSM is high at all ages between 18 and >50 years and
ranges between 50 and 60 percent [18]. It has been suggested that HPV infection is transient and
that individuals remain at risk for developing new HPV infections if high-risk behavior continues. The
observation that there was no increase in HPV prevalence with increasing age in this population is
consistent with this observation [14]. This is also consistent with the absence of immunity following
initial infection. As expected, the presence of abnormal anal cytology in MSM does not vary with
age [14]. Both high HPV detection rates and abnormal cytology likely reflect the high number of new
sexual partners in these urban MSM.
In women, there are contrasting findings as HIV-uninfected women whose initial high cervical HPV
detection rates and rates of cytological abnormality at younger age groups are not sustained over
time. In women, risk factors for anal SIL include a history of receptive anal intercourse and presence
of HPV DNA [19]. Anal HPV infection appears to be at least as common as cervical HPV infection in
HIV-infected women [20]. Furthermore, HIV-infected women with abnormal cervical cytology have
an increased risk of concurrent abnormal anal cytology [19].
HIV infection HIV infection is associated with an increased prevalence of HPV infection overall
including the most frequent oncogenic strains of HPV in MSMs.
In a meta-analysis that included data from 53 studies, the prevalence of anal canal HPV of any type
was statistically significant greater in HIV-infected individuals compared with those who were HIV
uninfected (93 versus 64 percent) and there was also an increase in the prevalence of high risk
HPV types (74 versus 37 percent) [21]. Furthermore, HIV infection was associated with a
statistically significant increased prevalence of anal SIL (57 versus 19 percent), including both LSIL
(28 versus 7 percent) and HSIL (6.7 versus 2.7 percent), as assessed by cytology.
The increased prevalence of HPV infection and anal SIL may be due to multiple factors including a
greater likelihood of high-risk sexual behavior and infection with multiple HPV types and an
impaired mucosal immune response that facilitates HPV replication [14,17]. Although lower baseline

CD4 cell counts are a risk factor for HSIL in MSM, high rates are found at all CD4 [6]. In a study of
357 HIV-infected MSM, over 80 percent had anal SIL and 95 percent had HPV infection [22].
In the general population, anal cancer incidence, although increasing, is approximately 2 per
100,000. In contrast, the rate of anal cancer was estimated to be as high as 35 per 100,000 among
MSM prior to the HIV epidemic, similar to that of cervical cancer in women prior to the introduction
of cervical Papanicolaou (Pap) smear screening. The current incidence of anal cancer among HIVinfected MSM has been estimated to be at least twice that of HIV-uninfected MSM with data from
the North American ACCORD study reporting rates of 131 per 100,000 for HIV infected MSM, and
46 per 100,000 for other HIV-infected men [23]. (See "Classification and epidemiology of anal
cancer" and "Classification and epidemiology of anal cancer", section on 'Human papillomavirus
infection'.)
The widespread use of potent antiretroviral therapy (ART) has had a profound impact on reducing
the incidence of HIV-associated malignancies such as Kaposis sarcoma. However, ART does not
appear to alter the prevalence of anal SIL, and ART may be associated with an increased incidence
progression of HSIL to anal cancer due to the increased life expectancy of HIV infected individuals
[24,25]. Multivariate analysis that included length of HIV infection and viral load showed that the use
of ART and detection of 6 HPV types were associated with the presence of anal SIL.
(See "Classification and epidemiology of anal cancer".)
HIV infection is also a risk factor for anal SIL in women. This was illustrated in a study in which 251
HIV-infected and 68 high-risk HIV-uninfected women underwent clinical examination including anal
cytology, anal HPV testing, and high resolution anoscopy [19]. Compared with HIV-uninfected
women, HIV-infected women had an increased risk of abnormal anal cytology (26 versus 8 percent)
and high-grade AIN (6 versus 2 percent). Risk factors for anal SIL in this population included a lower
CD4 cell count, a higher level of plasma HIV RNA, a history of receptive anal intercourse, and
concurrent abnormal cervical cytology [26].
Other risk factors Others risk factors that have been associated with the development of anal
SIL in men include a history of rectal discharge [10], history of genital warts [10], injection drug use
[27], and current cigarette smoking [27]. Additional risk factors in women include a history of cervical
cancer [28], vulvar cancer [29], high-grade cervical intraepithelial neoplasia or vulvar intraepithelial
neoplasia [30], and iatrogenic immunosuppression, such as following solid organ transplantation
[29,31].
NATURAL HISTORY
Progression from LSIL to HSIL Risk factors for progression of anal LSIL to HSIL include HIVrelated immunosuppression with a lower CD4 cell count, anal HPV infection, and the presence of
multiple HPV types including the high risk types [7,8,17,28,32,33].
In a study that included 346 HIV-infected and 262 HIV-uninfected MSM, the incidence of HSIL within
two years of enrollment was 20 percent in HIV-infected men and 8 percent in HIV-uninfected men
with normal baseline examinations [6]. In total, 62 percent of HIV-infected and 36 percent of HIVuninfected men with LSIL at baseline progressed to HSIL.

Regression of HSIL It has been a broadly held opinion that intra-anal HSIL only infrequently
regresses to lower grades of dysplasia or normal epithelium. Thus, when HSIL is identified, the
lesion should be treated to prevent progression to cancer.
However, a more recent retrospective analysis of clinical practice from Australia found that almost
one quarter of HSIL diagnosed by anal cytology or biopsy spontaneously regressed, mostly to AIN 1
[34]. This finding needs to be more fully assessed in prospective studies; until that observation is
confirmed, the current management standard remains that any HSIL is treated to prevent
progression.
Progression to anal cancer There are only very limited prospective data on the progression of
either internal or external HSIL to cancer. However, retrospective studies have clearly demonstrated
that HSIL can progress to invasive anal cancer.
A retrospective series of 138 HIV-infected men who developed anal carcinoma over a 15 year
period included 72 who developed anal cancer while under observation [3]. In 27 of these cases,
the anal cancer developed at a site that had previously been biopsied for HSIL. The average
interval between the diagnosis of HSIL and the development of anal cancer was approximately five
years. Two smaller series have also documented the progression from HSIL to anal cancer [35,36].
Two observational treatment studies have demonstrated progression of biopsy proven HSIL to
cancer. The first was a study of 35 HIV-uninfected patients with biopsy proven HSIL in which three
of six immunosuppressed patients with multifocal HSIL developed squamous cell cancer at a
median of 5 years following initial HSIL diagnosis [35]. The second study of 446 HIV-infected MSM
who were followed for 5 years and 10 months during which time 5 men with HSIL who refused
treatment developed cancer at a median time of 8.6 months from HSIL diagnosis [36]. In both of
these studies no information was presented on the evolution of HSIL, so it is not known if the anal
cancers developed from incident HSIL or if the HSIL was prevalent at baseline. If prevalent, the
length of time to progress from HSIL to cancer will likely be longer than stated. Prospective,
carefully controlled studies are needed to define the risk of progression of anal HSIL to invasive
cancer.
CLINICAL MANIFESTATIONS AND DIAGNOSIS Anal SIL is typically asymptomatic although it
may be associated with local symptoms such as pruritus, bleeding, discharge, irritation, and
tenesmus.
The diagnosis of anal SIL ultimately requires histopathological examination of the anal cytology and
biopsy specimens. The evaluation of asymptomatic individuals at increased risk of anal SIL should
begin with a comprehensive medical history and physical examination. Key areas in the medical
history include:
History of clinical HPV infection and other sexually transmitted infections
Sexual history including specific inquiry about receptive anal intercourse
HIV serostatus and markers of infection (CD4 cell count and viral load)
Previous anal/gastrointestinal conditions
Local symptoms (pain, itch, bleeding, discharge, irritation, tenesmus)
Smoking history
The physical examination should include:

Visual inspection of the perianal skin (picture 2).

Digital and high-resolution anoscopy examination of the anal canal. If anal cytology is
planned, it should be performed before the digital or anoscopic examination and in the
absence of lubricant.
Examination of the inguinal lymph nodes.
SCREENING FOR ANAL SIL
Rationale There are no randomized clinical trials that document the value of screening for anal
SIL in an at-risk population [37]. Instead, the rationale for screening relies upon the similarities
between the anus and cervix, and the established success of cervical cytology screening in
reducing the incidence of cervical cancer.
There is indirect evidence supporting the use of screening for anal SIL in high-risk populations that
is derived from several sources [37]. This includes the following:
The high incidence of anal cancer in the populations for which screening is proposed.
(See "Classification and epidemiology of anal cancer", section on 'Epidemiology and risk
factors'.)
The availability of screening modalities that can effectively diagnose the precursor lesion
HSIL. (See 'Methodology' below.)
The availability of effective treatments that can ablate HSIL. (See 'Approach to
treatment' below.)
The significant morbidity and mortality associated with anal cancer if it is not prevented by
effective screening and treatment. (See "Clinical features, staging, and treatment of anal
cancer".)
The cost-effectiveness of screening. (See 'Cost-effectiveness' below.)
For at-risk populations, it is appropriate to discuss the risk of anal cancer and the symptoms that
should lead to a consultation with a clinician and digital anorectal examination. It is inappropriate to
screen this population with anal cytology without local expertise in result interpretation and
availability of a referral structure for high-resolution anoscopy with biopsy that also includes access
to ablative treatments and follow-up. (See "Cervical cancer screening tests: Techniques for cervical
cytology and human papillomavirus testing".)
Who should be screened for anal SIL? We screen for anal SIL among patient populations that
are at increased risk of anal cancer (table 2) when there is local expertise in cytologic result
interpretation and availability of a referral structure for high-resolution anoscopy with biopsy, as well
as ablative treatments and follow-up. Given the low incidence of anal cancer among
immunosuppressed individuals under the age of 30 years and immunocompetent individuals under
the age of 40 years, we generally defer screening HIV-infected individuals and those with other
forms of immune suppression until after 30 years of age, and defer screening at-risk
immunocompetent individuals until after 40 years of age.
Numerous studies have documented the high prevalence of anal high-grade SIL in men who have
sex with men (MSM), particularly in the setting of HIV infection. The risk of progression from HSIL to
anal cancer among HIV-infected MSM has been estimated to be 1/377 per year [38].

The data for screening in other populations are more limited. However, there is a scientific rationale
for anal cytology screening based on the reported high prevalence of anal HPV and SIL in HIVinfected men who have sex with women without a history of anal intercourse [39,40], HIV-infected
women [19,40], women with high-gradevulval/vaginal or cervical SIL [41], individuals with perianal
HPV lesions, and solid organ transplant recipients [41,42]. (See "Development of malignancy
following solid organ transplantation", section on 'Anogenital cancers'.)
Formal guidelines recommending anal screening for precancerous lesions have not been adopted
by the United States Public Health Service. For HIV-infected patients, the HIV Medical Association
of the Infectious Diseases Society of America makes a weak recommendation based on moderate
quality evidence for screening with anal cytology in MSM, women with a history of receptive anal
intercourse or abnormal cervical Pap test results, and those with genital warts.
Methodology The anal screening program relies upon cytology as the initial screening test in
high-risk populations. The goal of screening is to identify individuals with abnormal cytology (ASCUS, ASC-H, LSIL, HSIL) who should then ideally undergo high-resolution anoscopy to assess the
anal canal and map areas with visual markers consistent with HSIL by biopsy and histopathologic
evaluation. (See 'Pathology' above.)
Anal cytology Anal exfoliative cytology should be performed using a water-moistened polyester
fiber (not cotton) swab to collect cells prior to anoscopy or anal examination. Patients should be
instructed to avoid anal sex, douching, and the use of enemas prior to this procedure, since these
practices may decrease the cellular yield.
The patient is positioned in the left lateral position, and the swab gently inserted until the swab
cannot be advanced any further because it has reached the wall of the rectum, thus positioning the
swab proximal to the anorectal transformation zone (squamocolumnar junction). The swab is then
withdrawn with lateral pressure using a spiral motion to sample the entire circumference of the anal
canal. Since the procedure is performed blindly, cells from the lower rectum, squamocolumnar
transformation zone, and anal canal are sampled.
After removal, the sample may be fixed either conventionally with ethanol or processed using a
liquid cytology technique before staining with the Papanicolaou method. The latter method is
preferable, when available, since it may yield better results among clinicians with limited experience
in performing anal cytology [10]. Although other liquid cytology media are available, none have been
specifically tested with anal specimens.
The sensitivity of anal cytology to detect biopsy-proven anal dysplasia in HIV-infected and HIVuninfected MSM was 81 and 50 percent, respectively, when results from multiple screenings were
considered and when ASC-US results were included in the abnormal category. This is similar to
that the sensitivity of cervical cytology for the detection of cervical disease [43-45].
Self-collection of anal cytology samples appears to have similar sensitivity to that of cliniciancollected samples, and may serve to increase patient compliance and decrease the cost of
screening [46-48]. This was illustrated by a series of 125 MSM, in which self-collected and clinician
collected samples were compared with the results of high-resolution anoscopy [48]. Overall, 66
percent of the cohort was positive for HPV and 30 percent had biopsy-proven HSIL. Among those
who were HIV infected, the sensitivity of cytology to detect anal SIL was 75 and 90 percent,

respectively, for self- and clinician-collected samples. Among those who were HIV uninfected, the
sensitivities were 48 and 62 percent, respectively.
Another cross-sectional study of HIV-uninfected MSM demonstrated adequate anal cytology in 92
percent of clinician-collected samples compared to 83 percent in self-collected samples (p<0.001)
with both groups using the same liquid cytology collection method at the same clinic visit [47]. Most
cytological diagnoses were of lower grades such as ASC-US and LSIL. However there were less
frequent diagnoses of anal SIL than in the predominantly HIV-infected group 21 versus 33 to 39
percent [46,47].
Other data suggest that anal cytology is an inaccurate predictor of the presence of HSIL, regardless
of HIV status. One series included 153 MSM (100 HIV-infected) who were referred to an anal
dysplasia clinic because of abnormal screening anal cytology (n = 46), HSIL on pathologic
evaluation of surgically removed anogenital condylomata (n = 25), or a history of
internal and/or external anal condylomata (n = 54) [49]. When compared to the histologic findings,
the sensitivity of anal cytology was only 47 percent for detection of a HSIL histological finding (AIN
grade 2 or 3, or invasive squamous cell cancer). Moreover, a cytologic diagnosis of ASC-US (n =
30) showed a nearly equal distribution of histologic grade (with histology being normal, AIN 1, AIN 2,
or AIN 3 in 11, 7, 5, and 7 participants, respectively). Thus, the presence of any abnormal anal
cytologic finding indicates a potential for HGAIN on histologic examination. These results are
consistent with those reported in an earlier larger series [44].
Collectively, these data suggest that when HSIL is found on anal cytology there is a high probability
of HSIL disease on high-resolution anoscopy-guided biopsy. The finding of LSIL or ASC-US on
cytology, however, does not exclude the presence of HSIL. For this reason, referral for highresolution anoscopy should be considered for individuals with any cytologic abnormality.
Alternatively, individuals considered to be at high risk for anal SIL, such as HIV-infected MSM, may
be referred directly for high-resolution anoscopy and biopsy given the well-documented, high
prevalence of anal SIL in these individuals.
High-resolution anoscopy If abnormal anal cytology is present, the next step in the diagnostic
evaluation is high-resolution anoscopy. This procedure allows the clinician to visualize lesions that
represent the source of the abnormal cells and obtain biopsy specimens for histopathologic
assessment. As in the cervix, anal histopathology is necessary to grade the severity of the disease,
as this cannot be accurately established by visual evaluation or cytology alone. The goal of the
biopsy is to identify HSIL or anal cancer since these may be targeted for prevention and treatment
of anal cancer, respectively.
By wrapping a 4x4 gauze swab around a Q-tip, then soaking it in 3-5 percent acetic acid, the acid
may be applied evenly to the anal canal prior to visualization. The acetic acid produces a white
appearance in areas of abnormal transitional epithelium and facilitates mucosal examination for
anoscopy as it does for cervical colposcopy [50]. Anoscopic changes most often associated with
high-grade AIN are similar to those seen in cervical colposcopy [13].
Specifically, these abnormalities are the presence of acetowhite change on flat/slightly raised or
thickened epithelium with or without abnormal blood vessels (mosaicpattern/punctuation). Tissues
with these features that stain negatively with Lugols iodine should be considered highly suspicious
for HSIL and biopsied. Tissues that do not take up Lugols stain in the absence of these features

may also contain HSIL and should be considered for biopsy, particularly when the patient has HSIL
on cytology.
Cost-effectiveness Cost-effectiveness analyses suggest that periodic screening of both HIVuninfected and HIV-infected MSM may be beneficial [51,52]. In one study, a statetransition Markov
model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life
expectancy for no screening versus several screening strategies in a population of HIV-infected
MSM [52]. Strategic variables in this model included screening interval and stage of HIV infection.
Annual screening for anal SIL increased quality-adjusted life expectancy at all stages of HIV
disease.
Annual screening of HIV-infected MSM and screening every two to three years for HIV-uninfected
MSM provided benefits in both life expectancy and cost effectiveness that were comparable to
those achieved with the accepted use of trimethoprim-sulfamethoxazole for Pneumocystis jirovecii
pneumonia prophylaxis in HIV disease. (See"Overview of primary prevention of opportunistic
infections in HIV-infected patients".)
PREVENTION Vaccines directed against the HPV types associated with cervical and anal
neoplasia in women and anal lesions in males have been developed. In a randomized trial in 4065
males, a quadrivalent vaccine was effective in preventing infection with HPV types 6, 11, 16, and 18
and prevented the development of external genital lesions [53]. The overall results of that trial are
presented separately. (See "Clinical trials of human papillomavirus vaccines", section on 'Clinical
trials of HPV vaccine in males'.)
A planned substudy of that trial analyzed the impact of HPV vaccine on the development of anal SIL
in 602 MSM [54]. The study population consisted of males aged 16 to 26 years who had a history of
five or fewer lifetime sexual partners. Participants with a history or evidence of anal lesions were
excluded, as were participants who were HIV infected at enrollment on the protocol. The primary
endpoint of the trial was the development of anal SIL associated with HPV types 6, 11, 16, or 18.
Two separate analyses were performed. The intent to treat analysis included all participants
regardless of HPV positivity at baseline who received at least one dose of vaccine and had at least
one follow-up visit. The analysis included all documented events after enrollment on the protocol. In
a separate per protocol analysis, events were analyzed in patients who received all three doses of
vaccine, and were HPV seronegative and had HPV DNA negative swab and biopsy specimens for
the vaccine HPV types both at baseline and at month seven. In this analysis, only events that
occurred after the completion of the vaccination sequence were counted.
Overall, 598 patients received one or more doses of vaccine, and 551 of these were eligible for the
intent to treat analysis. Key results included the following:
The incidence of anal SIL associated with HPV 6, 11, 16, or 18 was decreased by 50 percent
in those receiving vaccine compared with placebo (6.3 versus 12.6 events per 100 person
years at risk).
There was a 50 percent decrease in the incidence of LSIL with vaccine (5.0 versus 9.9
events per 100 person years at risk).
There was a 54 percent decrease in the incidence of HSIL with vaccine (2.7 versus 6.0
events per 100 person years at risk). There were no cases of anal cancer in either group.

The incidence of persistent infection with the relevant HPV types was decreased by 59
percent (8.8 versus 21.6 events per 100 person years at risk), and the detection of HPV DNA
was decreased by 49 percent (15.9 versus 30.9 events per 100 person years at risk).
The per protocol analysis included 402 of the 598 men (67 percent) who received all three doses of
vaccine. Results included the following:
The incidence of anal SIL associated with HPV 6, 11, 16, or 18 was decreased by 78 percent
in those receiving vaccine compared with placebo (1.3 versus 5.8 events per 100 person
years at risk).
There was a 73 percent decrease in the incidence of LSIL with vaccine (1.0 versus 3.9
events per 100 person years at risk).
There was a 75 percent decrease in the incidence of HSIL with vaccine (0.8 versus 3.1
events per 100 person years at risk).
The incidence of persistent infection with the relevant HPV types was decreased by 95
percent (0.5 versus 10.2 events per 100 person years at risk), and the detection of HPV DNA
was decreased by 84 percent (2.7 versus 16.7 events per 100 person years at risk).
The results of this trial indicate that the use of the quadrivalent vaccine can decrease the incidence
of anal SIL in MSM. Recommendations for the use of HPV vaccines are discussed separately.
(See "Recommendations for the use of human papillomavirus vaccines".)
APPROACH TO TREATMENT At the University of California, San Francisco, and the University
of Pittsburgh, we routinely recommend that individuals with anal HSIL receive treatment [55].
Intra anal lesions:
For individual small lesions, or lesions that represent less than 50 percent of the
circumference of the anal TZ, local approaches are suggested. This may include application of
80 percent trichloroacetic acid, infrared coagulation or electrocautery/hyfrecation.
For lesions that represent over 50 percent of the TZ circumference, treatment may be with
infrared coagulation/hyfrecation. If there is concern for stenosis, these procedures may be
undertaken locally in a step-wise manner with no more that 50% of the TZ circumference
treated at any one visit. Alternatively use of the immune modifier imiquimod (in either 3 or 5
percent formulations) or 5 percent fluorouracil may be used intra anally. This may result in
either complete resolution of the lesions or a reduction in size when local therapies may then
be used. None of these approaches are approved by the U.S. Food and Drug Administration
and data on their efficacy to reduce or clear HSIL are very limited [56-58].
Perianal lesions: Treatments have tended initially to involve more conservative modalities
that again depend on the extent of the lesion(s). Small discrete lesions may be treated with
local ablation or surgical excision while more extensive lesions can be approached initially with
the application of imiquimod or 5 fluorouracil in addition to continued close observation, prior
to considering surgical intervention.
Treatment of LSIL, including condyloma, is optional since these lesions do not directly progress to
invasive cancer. However, patients with LSIL may elect to have therapy for a variety of reasons
including symptoms (burning, itching, and bleeding) or psychological distress. Patients with LSIL
who are not treated should be followed every six months because of the established high rate of

progression to HSIL. Prior to treatment, a thorough assessment should be performed to exclude

anal cancer.
There are few data on the efficacy of treatments for anal SIL, and those that exist are discussed
below.
TREATMENT MODALITIES
Topical therapy For small lesions (<1 cm2 at the base), local application of bichloroacetic
or trichloroacetic acid (TCA) is a reasonable option. Topical application of TCA is generally well
tolerated, but can occasionally be painful.
In a study of 72 HIV positive men with 98 HSIL, 79 percent of lesions resolved to normal epithelium
or LSIL, and only two lesions (2 percent) required more than two treatments [59]. Similar results
were obtained in a study of 54 men, 65 percent of whom were HIV positive [60]. In both studies,
TCA was more effective in younger patients.
Preliminary data suggest that a course of topical 5-fluorouracil may also be effective [61]. A 16-week
course of self-administered twice weekly treatment resulted in a complete response in 18 and a
partial response in eight (overall response rate 57 percent).
Immune modulation A course of self-applied, intraanal imiquimod, an immune modulator, can
result in pathological resolution of anal SIL in HIV-infected MSM on HAART [56,57]. This approach
may be best for patients with widespread, multifocal disease.
In one reported series, 64 men with HSIL were randomly assigned to imiquimod or placebo, applied
to the anal canal three times per week for four months. Of the 28 patients given imiquimod, four had
complete resolution and eight had the HSIL downgraded to LSIL Only one of 25 patients on
placebo had resolution of HSIL. At a median follow-up of three years, 61 percent of patients had
sustained absence of HSIL.
Infrared coagulation For lesions that are too large for TCA, office-based infrared coagulation
(IRC) can be used. This device is approved by the United States Food and Drug Administration
(FDA) for the treatment of hemorrhoids and for anal warts. (See "Treatment of
hemorrhoids" and "Condylomata acuminata (anogenital warts) in adults".)
Treatment consists of the direct application of a 1.5 second pulse of irradiation in the infrared range
to dysplastic anal epithelium, which results in tissue destruction to a depth of approximately 1.5 mm.
The coagulated tissue can then be debrided using Tischler biopsy forceps. Possible procedurerelated complications include immediate and delayed bleeding and infection [62].
IRC is not yet FDA approved for treatment of anal SIL. Multiple studies have demonstrated the
safety and efficacy of IRC, in both HIV-infected and HIV-uninfected individuals [63-67]. As an
example, in a retrospective study of 96 men, treatment with IRC was followed by recurrence in 62
percent of those who were HIV uninfected in a mean of 14 months, and 91 percent of those who
were HIV infected [67]. Although multiple retreatments were required in the majority of cases, none
of the men progressed to squamous cell carcinoma. There were no serious adverse events.
Anoscopy-directed lesion ablation For lesions that are too large for office-based local therapy,
high-resolution anoscopy can be used to visually define areas of involvement for electrocautery
ablation [65]. For patients with circumferential or very extensive lesions, this approach may require

a staged approach using multiple procedures. The use of high-resolution anoscopy, rather than
mapping biopsies, may minimize complications.
The effectiveness and safety of this approach was illustrated by a retrospective review of the
experience with 246 patients treated at the University of California San Francisco over a ten-year
period [65]. Overall, 200 patients (81 percent) were treated with a single procedure, although 57
percent of these did develop recurrent disease at an average of 19 months after the initial
procedure. In 46 patients (19 percent), multiple staged treatments were required for complete lesion
ablation. Significant complications were observed in only nine patients (including one with bleeding
requiring reoperation, two with anal stenosis, and four with anal fissures).
Similar results were observed in a series of 232 men treated with electrocautery in New York City
[68]. The probability of disease control of the initial lesion after a single treatment was approximately
80 percent. Recurrent disease occurred in both HIV-uninfected and HIV-infected men (53 and 61
percent, respectively), but only one patient (0.4 percent) progressed to anal squamous cell
carcinoma.
The high rate of local recurrence, even in patients initially thought to have been completely ablated
with a single procedure, mandates careful surveillance following treatment [65]. Nonetheless, most
such recurrences can be successfully managed with office-based therapy. (See 'Posttreatment
surveillance' below.)
Observation For some patients with extensive HSIL, none of the currently available therapeutic
options will likely result in complete clearance, even if a stepped (staged) procedure is used.
Clinical judgment may dictate less aggressive management, with a "watch and wait" approach.
If this approach is chosen, patients should be instructed to report any new anal symptoms that may
suggest progression to invasive anal cancer (eg, bleeding, continuous pain, or the development of a
mass), and they should be seen every three to four months for repeat high-resolution anoscopy.
Patients in whom eradication of HSIL is not complete require careful monitoring, since HSIL can
progress to invasive cancer relatively rapidly [36]. Routine follow-up evaluation increases the
likelihood that if a cancer develops, it will be diagnosed at a very early stage, increasing the
likelihood that curative treatment can be applied.
Choice of therapy Only limited data are available comparing different treatment modalities in
men with HSIL. In the only randomized trial, 156 men were randomly assigned to imiquimod,
topical fluorouracil, or electrocautery. All grades of anal SIL were included; HSIL was present in 57
percent of cases. Patients with perianal SIL constituted 17 percent of the study [58].
Among the 148 patients actually treated (modified intent to treat), the complete response rates
with imiquimod, fluorouracil, and electrocautery were 24, 17, and 39 percent, respectively.
Recurrences were common, and by 72 weeks after initial treatment the cumulative recurrence rates
were 71, 58, and 68 percent, respectively.
Posttreatment surveillance Due to high rates of recurrence and evolving anal SIL, surveillance
is required following initial treatment. Although the optimal schedule has not been established, our
approach is to follow up in four to six months, including a re-biopsy of the treatment site if there is
lesion persistence. Anal cytology may also be useful as an adjunctive test to confirm lesion
clearance.

PERIANAL HSIL AND CARCINOMA HPV related condylomatous perianal disease presents
much more frequently to clinicians than does internal SIL. Standard therapeutic approaches for
these lesions are discussed elsewhere. (See "Condylomata acuminata (anogenital warts) in
adults".)
On the other hand, perianal dysplasia (Bowen's disease, squamous cell skin cancer in situ) is less
well described and recognized. In 1912, Bowen first described the lesions that bear his name as
chronic, red or hyperpigmented, well-defined scaly plaques [69]. Histologic examination shows HSIL
without dermal invasion. Perianal HSIL is less often associated with HPV than those involving the
anal canal, and approximately 5 percent of these lesions progress to invasive squamous cell cancer
[70]. Other studies have confirmed the malignant potential of these lesions [71-73]. Treatment
modalities for Bowen's disease include electrodessication and curettage, and excisional surgery
[74]. Imiquimod or topical 5-fluorouracil cream may also be tried. (See "Treatment and prognosis of
cutaneous squamous cell carcinoma".)
Anal SIL of varying grades may occur in the perianal skin without classical Bowenoid appearances,
and unfortunately there is a paucity of clinical literature describing the gross or anoscopic
appearances of these lesions. There are no nationally recognized treatment guidelines for perianal
dysplasia.
SUMMARY
The rates of anal cancer are increasing in the general population and are particularly high in
HIV-infected men who have sex with men (MSM). The use of antiretroviral therapy (ART) has
not altered the prevalence of anal squamous intraepithelial lesions (SIL), and may be
associated with an increased incidence of progression to anal cancer due to the longer life
expectancy of HIV infected individuals. (See 'Epidemiology and risk factors' above.)
The biologic consequences of anal SIL are considered analogous to those of cervical
intraepithelial neoplasia. Anal high grade SIL has been demonstrated to progress to invasive
anal cancer in limited series, providing the rationale for active treatment. (See 'Natural
history' above.)
For at-risk populations, (table 2) it is appropriate to discuss the risk of anal cancer and the
symptoms that should lead to a consultation with a clinician and digital anorectal examination.
It is inappropriate to screen this population with anal cytology without local expertise in result
interpretation and availability of a referral structure for high-resolution anoscopy with biopsy
that also includes access to ablative treatments and follow-up. (See 'Screening for anal
SIL' above.)
HPV vaccines can significantly decrease the incidence of infection with the HPV types
associated with cervical and anal neoplasia. This decrease was associated with a decrease in
the development of anal SIL in MSM in a population of young men with no more than five
lifetime sexual partners. Recommendations for the use of HPV vaccines are discussed
separately. (See 'Prevention' above and "Recommendations for the use of human
papillomavirus vaccines".)
Randomized trials have not compared active treatment with observation in patients with SIL.
Although the optimal approach has not been defined, our approach is to treat those men with
HSIL. Treatment for those with low-grade SIL is optional. Although treatment with a variety of
approaches may result in complete regression, recurrences are frequent and post-treatment

surveillance is necessary. The availability of treatment modalities for HSIL varies by

geographic location and the presence of clinical expertise and familiarity with this disease.
(See 'Approach to treatment' above.)
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REFERENCES
1.

Darragh TM, Colgan TJ, Thomas Cox J, et al. The Lower Anogenital Squamous
Terminology Standardization project for HPV-associated lesions: background and consensus
recommendations from the College of American Pathologists and the American Society for
Colposcopy and Cervical Pathology. Int J Gynecol Pathol 2013; 32:76.

2.

Palefsky JM. Anal human papillomavirus infection and anal cancer in HIV-positive
individuals: an emerging problem. AIDS 1994; 8:283.

3.

Berry JM, Jay N, Cranston RD, et al. Progression of anal high-grade squamous
intraepithelial lesions to invasive anal cancer among HIV-infected men who have sex with men. Int J
Cancer 2014; 134:1147.

4.

Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for
reporting results of cervical cytology. JAMA 2002; 287:2114.

5.

Palefsky JM, Holly EA. Molecular virology and epidemiology of human papillomavirus and
cervical cancer. Cancer Epidemiol Biomarkers Prev 1995; 4:415.

6.

Palefsky JM, Holly EA, Ralston ML, et al. High incidence of anal high-grade squamous
intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS
1998; 12:495.

7.

Palefsky JM, Holly EA, Hogeboom CJ, et al. Virologic, immunologic, and clinical parameters
in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIVnegative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:314.

8.

Palefsky JM. Cutaneous and genital HPV-associated lesions in HIV-infected patients. Clin
Dermatol 1997; 15:439.

9.

Arends MJ, Buckley CH, Wells M. Aetiology, pathogenesis, and pathology of cervical
neoplasia. J Clin Pathol 1998; 51:96.

10.

Palefsky JM, Holly EA, Ralston ML, et al. Anal squamous intraepithelial lesions in HIVpositive and HIV-negative homosexual and bisexual men: prevalence and risk factors. J Acquir
Immune Defic Syndr Hum Retrovirol 1998; 17:320.

11.

Palefsky JM, Shiboski S, Moss A. Risk factors for anal human papillomavirus infection and
anal cytologic abnormalities in HIV-positive and HIV-negative homosexual men. J Acquir Immune
Defic Syndr 1994; 7:599.

12.

Moscicki AB, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young
heterosexual women. Cancer Epidemiol Biomarkers Prev 1999; 8:173.

13.

Jay N, Berry JM, Hogeboom CJ, et al. Colposcopic appearance of anal squamous
intraepithelial lesions: relationship to histopathology. Dis Colon Rectum 1997; 40:919.

14.

Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-related prevalence of anal cancer
precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst 2005; 97:896.

15.

Kiviat NB, Critchlow CW, Holmes KK, et al. Association of anal dysplasia and human
papillomavirus with immunosuppression and HIV infection among homosexual men. AIDS 1993;
7:43.

16.

Palefsky JM. Anal squamous intraepithelial lesions in human immunodeficiency viruspositive men and women. Semin Oncol 2000; 27:471.

17.

Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human
papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIVnegative homosexual men. J Infect Dis 1998; 177:361.

18.

Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-Specific prevalence of anal human
papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE
study. J Infect Dis 2004; 190:2070.

19.

Holly EA, Ralston ML, Darragh TM, et al. Prevalence and risk factors for anal squamous
intraepithelial lesions in women. J Natl Cancer Inst 2001; 93:843.

20.

Williams AB, Darragh TM, Vranizan K, et al. Anal and cervical human papillomavirus
infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virusinfected women. Obstet Gynecol 1994; 83:205.

21.

Machalek DA, Poynten M, Jin F, et al.. Anal human papillomavirus infection and assoicated
neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet
Oncol 2012.

22.

Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active
antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005; 19:1407.

23.

Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIVuninfected individuals in North America. Clin Infect Dis 2012; 54:1026.

24.

Bower M, Powles T, Newsom-Davis T, et al. HIV-associated anal cancer: has highly active
antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic
Syndr 2004; 37:1563.

25.

Crum-Cianflone NF, Hullsiek KH, Marconi VC, et al. Anal cancers among HIV-infected
persons: HAART is not slowing rising incidence. AIDS 2010; 24:535.

26.

Hessol NA, Holly EA, Efird JT, et al. Anal intraepithelial neoplasia in a multisite study of HIVinfected and high-risk HIV-uninfected women. AIDS 2009; 23:59.

27.

Palefsky JM, Holly EA, Ralston ML, et al. Anal cytological abnormalities and anal HPV
infection in men with Centers for Disease Control group IV HIV disease. Genitourin Med 1997;
73:174.

28.

Melbye M, Sprgel P. Aetiological parallel between anal cancer and cervical cancer. Lancet
1991; 338:657.

29.

Ogunbiyi OA, Scholefield JH, Raftery AT, et al. Prevalence of anal human papillomavirus
infection and intraepithelial neoplasia in renal allograft recipients. Br J Surg 1994; 81:365.

30.

Lamm J, Pattaratornkosohn T, Mercado-Abadie J, et al. Concurrent anal human

papillomavirus and abnormal anal cytology in women with known cervical dysplasia. Obstet
Gynecol 2014; 124:242.

31.

Tramujas da Costa e Silva I, de Lima Ferreira LC, Santos Gimenez F, et al. High-resolution
anoscopy in the diagnosis of anal cancer precursor lesions in renal graft recipients. Ann Surg Oncol
2008; 15:1470.

32.

Palefsky JM, Barrasso R. HPV infection and disease in men. Obstet Gynecol Clin North Am
1996; 23:895.

33.

Burgos J, Curran A, Tallada N, et al. Risk of progression to high-grade anal intraepithelial

neoplasia in HIV-infected MSM. AIDS 2015; 29:695.

34.

Tong WW, Jin F, McHugh LC, et al. Progression to and spontaneous regression of highgrade anal squamous intraepithelial lesions in HIV-infected and uninfected men. AIDS 2013;
27:2233.

35.

Scholefield JH, Castle MT, Watson NF. Malignant transformation of high-grade anal
intraepithelial neoplasia. Br J Surg 2005; 92:1133.

36.

Kreuter A, Potthoff A, Brockmeyer NH, et al. Anal carcinoma in human immunodeficiency

virus-positive men: results of a prospective study from Germany. Br J Dermatol 2010; 162:1269.

37.

Chiao EY, Giordano TP, Palefsky JM, et al. Screening HIV-infected individuals for anal
cancer precursor lesions: a systematic review. Clin Infect Dis 2006; 43:223.

38.

Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated
neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet
Oncol 2012; 13:487.

39.

Piketty C, Darragh TM, Da Costa M, et al. High prevalence of anal human papillomavirus
infection and anal cancer precursors among HIV-infected persons in the absence of anal
intercourse. Ann Intern Med 2003; 138:453.

40.

Gaisa M, Sigel K, Hand J, Goldstone S. High rates of anal dysplasia in HIV-infected men
who have sex with men, women, and heterosexual men. AIDS 2014; 28:215.

41.

Scholefield JH, Sonnex C, Talbot IC, et al. Anal and cervical intraepithelial neoplasia:
possible parallel. Lancet 1989; 2:765.

42.

Sillman FH, Sentovich S, Shaffer D. Ano-genital neoplasia in renal transplant patients. Ann
Transplant 1997; 2:59.

43.

Sonnex C, Scholefield JH, Kocjan G, et al. Anal human papillomavirus infection: a

comparative study of cytology, colposcopy and DNA hybridisation as methods of detection.
Genitourin Med 1991; 67:21.

44.

Palefsky JM, Holly EA, Hogeboom CJ, et al. Anal cytology as a screening tool for anal
squamous intraepithelial lesions. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:415.

45.

Nathan M, Singh N, Garrett N, et al. Performance of anal cytology in a clinical setting when
measured against histology and high-resolution anoscopy findings. AIDS 2010; 24:373.

46.

Cranston RD, Darragh TM, Holly EA, et al. Self-collected versus clinician-collected anal
cytology specimens to diagnose anal intraepithelial neoplasia in HIV-positive men. J Acquir Immune
Defic Syndr 2004; 36:915.

47.

Lampinen TM, Miller ML, Chan K, et al. Randomized clinical evaluation of self-screening for
anal cancer precursors in men who have sex with men. Cytojournal 2006; 3:4.

48.

Chin-Hong PV, Berry JM, Cheng SC, et al. Comparison of patient- and clinician-collected
anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia
in men who have sex with men. Ann Intern Med 2008; 149:300.

49.

Panther LA, Wagner K, Proper J, et al. High resolution anoscopy findings for men who have
sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial
neoplasia and the impact of HIV serostatus. Clin Infect Dis 2004; 38:1490.

50.

Palefsky JM, Gonzales J, Greenblatt RM, et al. Anal intraepithelial neoplasia and anal
papillomavirus infection among homosexual males with group IV HIV disease. JAMA 1990;
263:2911.

51.

Goldie SJ, Kuntz KM, Weinstein MC, et al. Cost-effectiveness of screening for anal
squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative
homosexual and bisexual men. Am J Med 2000; 108:634.

52.

Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and cost-effectiveness
of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive
men. JAMA 1999; 281:1822.

53.

Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against
HPV Infection and disease in males. N Engl J Med 2011; 364:401.

54.

Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and
anal intraepithelial neoplasia. N Engl J Med 2011; 365:1576.

55.

Chin-Hong PV, Palefsky JM. Natural history and clinical management of anal human
papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect
Dis 2002; 35:1127.

56.

Kreuter A, Potthoff A, Brockmeyer NH, et al. Imiquimod leads to a decrease of human

papillomavirus DNA and to a sustained clearance of anal intraepithelial neoplasia in HIV-infected
men. J Invest Dermatol 2008; 128:2078.

57.

Fox PA, Nathan M, Francis N, 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 HIVpositive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod.
AIDS 2010; 24:2331.

58.

Richel O, de Vries HJ, van Noesel CJ, et al. Comparison of imiquimod, topical fluorouracil,
and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have
sex with men: an open-label, randomised controlled trial. Lancet Oncol 2013; 14:346.

59.

Cranston RD, Baker JR, Liu Y, et al. Topical application of trichloroacetic acid is efficacious
for the treatment of internal anal high-grade squamous intraepithelial lesions in HIV-positive men.
Sex Transm Dis 2014; 41:420.

60.

Singh JC, Kuohung V, Palefsky JM. Efficacy of trichloroacetic acid in the treatment of anal
intraepithelial neoplasia in HIV-positive and HIV-negative men who have sex with men. J Acquir
Immune Defic Syndr 2009; 52:474.

61.

Richel O, Wieland U, de Vries HJ, et al. Topical 5-fluorouracil treatment of anal

intraepithelial neoplasia in human immunodeficiency virus-positive men. Br J Dermatol 2010;
163:1301.

62.

Halasz CL. Treatment of common warts using the infrared coagulator. J Dermatol Surg
Oncol 1994; 20:252.

63.

Goldstone S, personal communication.

64.

Cranston RD, Hirschowitz SL, Cortina G, Moe AA. A retrospective clinical study of the
treatment of high-grade anal dysplasia by infrared coagulation in a population of HIV-positive men
who have sex with men. Int J STD AIDS 2008; 19:118.

65.

Pineda CE, Berry JM, Jay N, et al. High-resolution anoscopy targeted surgical destruction
of anal high-grade squamous intraepithelial lesions: a ten-year experience. Dis Colon Rectum 2008;
51:829.

66.

Weis SE, Vecino I, Pogoda JM, Susa JS. Treatment of high-grade anal intraepithelial
neoplasia with infrared coagulation in a primary care population of HIV-infected men and women.
Dis Colon Rectum 2012; 55:1236.

67.

Goldstone RN, Goldstone AB, Russ J, Goldstone SE. Long-term follow-up of infrared
coagulator ablation of anal high-grade dysplasia in men who have sex with men. Dis Colon Rectum
2011; 54:1284.

68.

Marks DK, Goldstone SE. Electrocautery ablation of high-grade anal squamous

intraepithelial lesions in HIV-negative and HIV-positive men who have sex with men. J Acquir
Immune Defic Syndr 2012; 59:259.

69.

Bowen JT. Centennial paper. May 1912 (J Cutan Dis Syph 1912;30:241-255).
Precancerous dermatoses: a study of two cases of chronic atypical epithelial proliferation. By John
T. Bowen, M.D., Boston. Arch Dermatol 1983; 119:243.

70.

Frisch M, Fenger C, van den Brule AJ, et al. Variants of squamous cell carcinoma of the
anal canal and perianal skin and their relation to human papillomaviruses. Cancer Res 1999;
59:753.

71.

Fenger C, Nielsen VT. Precancerous changes in the anal canal epithelium in resection
specimens. Acta Pathol Microbiol Immunol Scand A 1986; 94:63.

72.

Marfing TE, Abel ME, Gallagher DM. Perianal Bowen's disease and associated
malignancies. Results of a survey. Dis Colon Rectum 1987; 30:782.

73.

Jaeger AB, Gramkow A, Hjalgrim H, et al. Bowen disease and risk of subsequent malignant
neoplasms: a population-based cohort study of 1147 patients. Arch Dermatol 1999; 135:790.

74.

Cleary RK, Schaldenbrand JD, Fowler JJ, et al. Perianal Bowen's disease and anal
intraepithelial neoplasia: review of the literature. Dis Colon Rectum 1999; 42:945.
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