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28 Intensive vs Conservative Management of Patients with Low Grade Squamous…
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333
Results
Over the past two decades, there have been very few studies reported on LSIL and
its progression to HSIL. However, within these studies, there is no mention of treatment to prevent further progression of disease from LSIL to HSIL.There have been
three studies which specically looked at LSIL progression to HSIL in MSM
LWHIV.All three studies employed anal cytology and HPV testing. Results of the
anal cytology were classied as normal, atypical squamous cells of undetermined
signicance (ASCUS), LSIL, HSIL, or squamous-cell carcinoma, in accordance
with the Bethesda classication. High resolution anoscopy (HRA) with biopsy was
performed after the anal pap smear. In HIV-infected MSM, Burgos etal reported a
progression rate of LSIL to HSIL to be 10.5 cases/100 person-years [4]. A similar
rate was found in de Pokomandy with 10.7 cases/100 person-years and Tong
reported rate of 13.1 cases/100 person-years [5, 6]. Together these three studies suggest that while LSIL has the potential to progress to HSIL, the overall rate of progression is relatively low.
The endpoint for all three studies was HSIL diagnosed histologically via a
biopsy. This was compared to all participants initial pap smear/biopsy to show progression of disease [4–6].
Cumulative
Study
Burgos [4] 556 HIV-
de
Pokomandy
[5]
Tong [6] 152 HIV-
Patients (N)
infected
MSM
157 HIVinfected
MSM
infected
MSM
Progression to
HSIL
10.5 cases/100
person-years
10.7 cases/100
person-years
13.1 cases/100
person-years
Incidence of
HSIL
16.2% at
24months and
24.5% at
36months
23.1% at
24months and
36.6% at
36months
16.2% at
24months and
24.5% at
36months
Median
Follow-Up
26.4months High
38months Moderate
13.2months Moderate
Quality of
Evidence
Looking at the risk of LSIL progression to HSIL, practitioners can better identify
the need to treat LSIL or simply to surveil it. The Anal Cancer HSIL Outcomes
Research (ANCHOR) trial is the only randomized controlled trial studying the
treatment of HSIL and has demonstrated that treating HSIL signicantly reduced
the incidence of anal squamous cell carcinoma in PLWHIV compared with active
monitoring via regular exams (including anal cytology combined with HRA and
biopsy of any concerning lesions) [7, 8].
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R. Ramirez et al.
Recommendations
Certain individuals are at signicantly increased risk of anal cancer and should
undergo anal dysplasia screening. ANCHOR has shown that treating HSIL prevents
SCC.All HSIL should be treated (Evidence high; recommendations high). However,
LSIL, while a risk factor for HSIL, is caused by low-risk HPV infection and is not
a direct SCC precursor. Patients with LSIL should undergo close surveillance, but
we do not recommend routinely treating LSIL (Evidence: low; Recommendation:
moderate).
Patients with LSIL should undergo close surveillance with digital anorectal
examination, anal cytology, high-risk HPV testing and HRA at regular intervals
(Evidence: low; Recommendation: moderate).
All patients with HSIL should be treated with topical therapy and/or local ablative
therapy (Evidence high; recommendations high).
Personal View
LSIL is not the direct SCC precursor and does not require treatment. If patients have
symptomatic LSIL (itching, palpable lesions, etc.) treatment is justied. Patients
with LSIL must be screened for HSIL with digital anorectal examination, anal
cytology, high-risk HPV testing and HRA at regular intervals. For higher risk
patients (increasing age, people with high-risk sexual behaviors (MSM, receptive
anal intercourse, or a history of multiple sex partners), persons living with HIV
(PLHIV), other immunocompromised individuals such as solid organ transplant
recipients (SOTRs) or autoimmune diseases, and women diagnosed with HPVrelated gynecological (pre)cancers)) with LSIL, screening intervals may be shortened. All HSIL should be treated.
References
1. Roberts JR, Siekas LL, Kaz AM.Anal intraepithelial neoplasia: a review of diagnosis and management. World J Gastrointest Oncol. 2017;9(2):50. https://doi.org/10.4251/wjgo.v9.i2.50.
2. Stanley MA, Winder DM, Sterling JC, Goon PKC.HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues. BMC Cancer. 2012;12(1) https://doi.org/10.118
6/1471- 2407- 12- 398.
3. Clifford GM, Georges D, Shiels MS, etal. A meta-analysis of anal cancer incidence by risk
group: toward a unied anal cancer risk scale. Int J Cancer. 2021;148:38–47. https://doi.
org/10.1002/ijc.33185.
28 Intensive vs Conservative Management of Patients with Low Grade Squamous…
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4. Burgos J, Curran A, Tallada N, Guelar A, Navarro J, Landol S, Villar J, Crespo M, Ribera
E, Falcó V.Risk of progression to high-grade anal intraepithelial neoplasia in HIV-infected
MSM.AIDS. 2015;29(6):695–702.
5. de Pokomandy A, Rouleau D, Ghattas G, Trottier H, Vézina S, Coté P, et al. HAART and
progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are
infected with HIV.Clin Infect Dis. 2011;52:1174–81.
6. Tong WW, Jin F, McHugh LC, Maher T, Sinclair B, Grulich AE, et al. Progression to and
spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected
and un-infected men. AIDS. 2013;27:2233–43.
7. Palefsky JM, Lee JY, Jay N, Goldstone SE, Darragh TM, et al. ANCHOR investigators
group. Treatment of anal highgrade squamous intraepithelial lesions to prevent anal cancer
N. Engl. J. Med. 2022;386(24):2273–82. https://doi.org/10.1056/NEJMoa2201048. https://
anchorstudy.org/.
8. Jones MP, Carroll S, Martin J, Hillman R, Grulich A, O’Connell D, Young C, Poynten
IM.Management of early anal cancer: need for guidelines and standardisation. Int J Color Dis.
2017;32(12):1719–24. https://doi.org/10.1007/s00384- 017- 2913- 6.
335
How Aggressive Should
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WeBeinManagement ofPatients
29
withHigh Grade Squamous
Intraepithelial Lesion?
KingaS.Olortegui
Introduction
Anal squamous intraepithelial neoplasia is a rare lesion, but increasingly encountered by the colorectal surgeon [1]. Expert consensus supports expectant management for patients with low grade squamous intraepithelial lesions. High grade
squamous intraepithelial lesions (HSIL or HGSIL, or anal intraepithelial neoplasia
grade II or III) present a signicant clinical challenge. HSIL may be found during
recommended screening in a high-risk population [2, 3]. Frequently, lesions are
identied incidentally during excision of condyloma or upon pathology review after
hemorrhoidectomy. [4] Occasionally, HSIL may be visually identied at colonoscopy, particularly during retroexion [5]. Once found, there is little guidance on
how aggressively these lesions should be treated, and this has been a major area of
debate among colorectal surgeons [6]. Historically, the rate of progression from
HSIL to anal squamous cell cancer (SCC) was thought to be quite low, but a review
of 2074 patients with AIN III in the Surveillance, Epidemiology, and End Research
(SEER) database between 1973 and 2014 found the rate to be 1.9% per year, for an
overall rate of 9.5% at 5years [7]. Of patients who developed anal cancer in this
study, nearly one third had stage T2 or higher tumors at time of diagnosis. A limitation of the study was that HIV status was unknown, and this subgroup is known to
be at higher risk of anal SCC [8–10]. In fact, HSIL or anal SCC has been shown to
correlate with the CD4/CD8 cell ratio, suggesting that treatment and control of HIV
is an important contributor to decreasing risk of cancer in this population [11].
While this study showed an alarmingly high rate of anal SCC, another recent study
K. S. Olortegui (*)
Section of Colon & Rectal Surgery, Department of Surgery, UChicago Medicine,
Chicago, IL, USA
e-mail: kskowron@bsd.uchicago.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
K. Umanskiy, N. Hyman (eds.), Difcult Decisions in Colorectal Surgery,
Difcult Decisions in Surgery: An Evidence-Based Approach,
https://doi.org/10.1007/978-3-031-42303-1_29
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K. S. Olortegui
specically of HIV-positive patients, also using the SEER database but using a more
narrow and recent timeframe (2000–2011), showed an incidence of anal SCC of
1.2% at 1year and 5.7% at 5years [12].
Of course, no one wants to miss an opportunity to prevent progression to an anal
cancer. Yet, aggressive treatments can be highly morbid. Aggressive surveillance
programs come at a personal cost to the patient, time off work for procedures and
emotional distress at the prospect of developing cancer [13]. This leads us to the
question, are aggressive treatments strategies for HSIL justied?
PICO table
Patients
Patients with high grade anal
intraepithelial neoplasia
Intervention Comparator
Ablation Expectant
management
Outcome
Recurrence of dysplasia or
progression to anal cancer
Search Strategy
A literature search was conducted using PubMed and Google Scholar to identify all
English language publications regarding anal intraepithelial neoplasia treatment
from 2017–2022. A strict time interval was chosen, as older studies were extensively reviewed in a prior edition of this book on a similar topic [14]. The search was
conducted using following terms: “anal intraepithelial neoplasia,” “anal high grade
squamous intraepithelial lesion,” “anal Bowen’s disease” and “perianal Bowen’s
disease,” “anal HSIL,” and “AIN.” Studies were excluded if they did not describe
treatment patterns and algorithms. References of studies identied were reviewed to
identify any historic studies of interest.
Results
As mentioned in the introduction, high risk populations should be aggressively
screened for anal cancer and anal dysplasia. The options for treatment for anal dysplasia once it is diagnosed vary considerably, and will be reviewed here, beginning
with the least invasive, through the most invasive.
The 2018 Clinical Practice Guidelines of the American Society of Colon and
Rectal Surgeons (ASCRS) recommend that patients who are diagnosed with anal
dysplasia (HSIL or AIN III) be followed clinically at regular intervals, with history
and physical exam [6]. These recommendations are based upon the fact that the rate
of progression from HSIL to anal SCC is poorly understood. In fact, in a study of
574 patients with HIV who underwent anal cancer screening, authors describe an
incidence of 12.5% of HSIL [15]. In this study, only 6 cancers were detected, of
which 2 had a prior history of HSIL.Importantly, 24% of patients with HSIL demonstrated spontaneous regression (to normal exam or LSIL). Many observational
studies support the use of expectant management after diagnosis of HSIL.The exact
interval for surveillance visits is not specied, as various studies have reported
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339
different follow up strategies. In a report of the University of California, San
Francisco Anal Neoplasia Study and Anal Neoplasia Clinic, approximately 2,000
men with HIV were followed over time [16]. Initial lesions were treated with 85%
trichloroacetic acid if they were small, and excision / ablation if they were larger.
Those who declined therapy, had extensive lesions, or developed recurrent HSIL
were followed with digital exam and high resolution anoscopy every 3–4months.
The vast majority of patients who developed anal SCC had tumors detectable on
digital exam alone. In another report of 341 patients with HSIL and HIV followed
by a single surgeon for over 20years, anal cancer was detected at a rate of 1.3% per
patient-year [17]. The follow up strategy included a history and exam (visual and
digital) every 6months. In a large retrospective review of nearly 6 million patients
treated in the Kaiser Permanente Southern California healthcare system, patients
were followed with exam and referred for excision or fulguration of grossly abnormal or symptomatic lesions only. [18]. 90.7% of anal cancers were diagnosed in
patients without HIV or prior high-risk lesions. The cumulative incidence of anal
cancer among patients with prior anal dysplasia was 0.69% (6 out of 872 patients).
Therefore, a minimum follow up strategy of anal exam (including digital exam)
with ofce anoscopy (high resolution or basic) at an interval of 3–6months is reasonable and supported by data.
Numerous studies have described the use of topical therapies for chemical abla-
tion of HSIL. Topical therapies are an attractive option, as they reduce the need for
invasive procedures, and can typically be applied in the privacy of one’s home. They
certainly are not without side effects, and can cause pain and bleeding which may
limit compliance with this treatment option. The agents described include 5%
imiquimod, 1% cidofovir, 5-uorouracil (5-FU), and 80% trichloracetic acid (TCA),
based upon small, but randomized clinical trials or case series in the late 2000s and
early 2010s. A recent systematic review evaluated these studies together [19].
Unfortunately, the vast majority of such studies suffered from a signicant degree
of bias. Compliance rates were quite good, at least 79%, though many studies
reported 100% compliance. The ranges for the rate of complete response were
14–74% for imiquimod, 15–59% for cidofovir, 9–86% for 5-FU, and 28–72% for
TCA.Rates of recurrence ranged from 16–71% for imiquimod, unknown-12% for
cidofovir, 0–58% for 5-FU, and 15–28% for TCA.Obviously, such wide ranges
should raise suspicion about the true result. Furthermore, many of these therapies
are not FDA-approved for treatment of anal HSIL, and depending on the patient’s
insurance status, may be prohibitively expensive. Therefore, topical ablation can be
used safely and is generally well-tolerated, but the effectiveness is really unknown.
The next category of treatment options for HSIL is that of physical ablation.
Methods typically used for this include electrocautery, infrared coagulation and
laser. As with chemical ablation, reports of physical ablation began to appear in
large numbers in the late 2000s and frequently in the 2010s. These were largely
retrospective reviews of single institution experiences. This is also true of the majority of the more recent literature on this topic. Electrocautery is by far the most common technique used, and newer literature explores other options. For example, a
retrospective review of 81 patients treated with infrared coagulation via high
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K. S. Olortegui
resolution anoscopy demonstrated a recurrence rate of 25% at a median of 6months
of follow up. [20] Two recent reports have described the use of radiofrequency ablation (RFA) as another option for treatment of HSIL.A small single-institution study
of 21 patients treated with RFA showed a relatively high rate of recurrence of 29%
at 1year [21]. A retrospective review of 12 patients demonstrated a 58% response
rate; the remaining patients were retreated with electrocautery and achieved disease
eradication at 1year from treatment [22]. Case reports have also described the use
nitrous oxide cryoablation as another method for ablation [23]. Such novel therapies
thus far lack high quality evidence to support their use, and therefore electrocautery
remains the favored method for mechanical destruction of HSIL.Finally, the results
of the much-awaited Anal Cancer-HSIL Outcomes Research (ANCHOR) trial have
been published this year [24]. This was a large, phase 3 randomized, controlled trial
comparing ablation of HSIL with active monitoring. Patients with HIV were invited
to participate in a screening protocol, in which they underwent a physical exam,
anal swab for cytology, and high resolution anoscopy (HRA). Any suspicious
lesions at HRA were biopsied. If HSIL was conrmed, patients were invited to participate in the study. 10,723 patients were screened, of which 4,459 patients were
randomized at 25U.S. sites between September 2014 and August 2021, 2,237in the
treatment group and 2,222in the monitoring group. Patients in the treatment arm
underwent immediate treatment with a goal of eradication of HSIL.The treatments
included were ablation using with infrared coagulation, electrocautery and laser,
excision or ablation under anesthesia, or topical treatments. Patients in the active
monitoring arm underwent HRA every 6months; any visible lesions were biopsied
annually to conrm HSIL and exclude anal cancer. Patients in either arm with concerning lesions were followed more closely (every 3months), and any lesions suspicious for cancer were biopsied. Patients found to have cancer were removed from
the trial and referred for treatment. 4,446 patients were ultimately analyzed, 2227in
the treatment group and 2219 in the monitoring group, with a median 25.3 and
27.2months of follow up, respectively. The vast majority of patients in the treat-
ment arm underwent ofce-based electrocautery ablation (83.6%). 86.3% of patients
received only one type of ablative treatment, and 10.5% received two methods.
There were 9 patients with SCC in the treatment group, and 21in the monitoring
group. This translated to a cumulative incidence of anal cancer at 48months of
0.9% in the treatment group and 1.8% in the monitoring group, or a difference in
incidence between groups of about 0.2% per year. While this study showed a
statistically- signicant reduction in progression from HSIL to anal cancer with
aggressive treatment of HSIL over monitoring, the incidence of anal cancer in both
groups was quite low. The number needed to treat to prevent one patient developing
anal cancer is 111 ablations. With considerable cost, commitment from patients and
pain, it remains a question whether this approach is justied.
One point of variability between the various techniques used for screening and
treatment is the use of HRA, as seen in the ANCHOR study above. HRA is performed in the ofce or operating room using a magnication anoscope and a topical
agent, usually acetic acid or Lugol’s solution, to aid in the visualization of
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HSIL. Numerous studies have discussed using HRA as a screening tool to identify
HSIL, and have shown it to be superior to cytology for detection of HSIL.However,
once HSIL is diagnosed, it is not clear that HRA is superior to standard anoscopy
for treatment of HSIL lesions, as no high quality comparative studies in this context
exist; several recent studies conrm a low rate of progression to cancer in cohorts
followed with standard anoscopy [25–28]. The ASCRS clinical practice guidelines
leave this as an optional method of surveillance. [6] What is clear, is that patients
should be followed with some type of anoscopy, and any visible or palpable lesions
should be treated.
For completeness of discussion, we will review the historical option of wide
excision of HSIL. This was a common practice described in the 1990s. In survey of
642 ASCRS members in 2000, 96% used wide local excision for small lesions of
HSIL and 87% used it for large lesions [29]. Full thickness excision of lesion and
surrounding skin was carried out, often requiring skin ap coverage. Scholeeld,
etal. described 27 patients with AIN III treated with excision; they report a recurrence rate of 30% and progression to cancer in 9% [30]. Brown, etal. described
surgical excision in 34 patients, with a recurrence rate of 18% with a median
41months of follow up. [31] Importantly, only 14% of patients in this study achieved
negative margins (free of high grade AIN). This study reported no progression to
cancer, but a nearly 10% risk of anal stenosis or fecal incontinence. Due to the high
risk of morbidity for little to no benet over less invasive options, wide surgical
excision is no longer recommended.
Another exciting option which came and went was the HPV vaccine used as an
adjuvant treatment for HSIL. Vaccination against the human papillomavirus (HPV)
has dramatically decreased the rate of HPV-associated squamous cell cancers, such
as cervical, head and neck, and anal cancer. Vaccination of patients not infected with
the HPV virus has shown to decrease the rate of HSIL as well in an industrysponsored trial [32]. However, two double-blinded, randomized, controlled trials of
patients with HIV have now shown that patients treated for HSIL prior to vaccination were not less likely to have HSIL recurrence (63% recurrence in the vaccinated
group versus 57% in the placebo group in one study, and 68.8% versus 61.3% in the
other) [33, 34]. Therefore, vaccination as an adjuvant treatment for HSIL is not
recommended.
341
Recommendations
Based upon the above discussion, treatment or follow up for HSIL is important in
the prevention of progression to anal SCC, based upon moderate-quality evidence.
The challenge with this disease for the clinician is the lack of standardized follow
up intervals for HSIL, or for surveillance after ablation of HSIL, as those which
exist for cancer, guided by the National Comprehensive Cancer Network. There is
also a paucity of data for treatment of HSIL in patients without HIV, compared with
the HIV-positive population.
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K. S. Olortegui
Personal View
In my practice, I do not typically perform primary screening for anal dysplasia, but
work closely with specialists who do. Patients are referred to our clinic from a
screening program with a lesion noted on digital exam or anoscopy, or a positive
anal Pap smear. Other patients present with bothersome anal lesions. Rarely, distal
rectal or anal lesions are biopsied at colonoscopy, resulting in a diagnosis of HSIL. In
all of these cases, I recommend a careful anal exam under anesthesia in the operating room. I use high magnication loupes, and stain the anal canal with acetic acid
to assist with identication of HSIL.Lesions are biopsied to conrm the diagnosis,
and ablated with electrocautery. Patients are then entered into a follow up program,
which I will detail below. Occasionally, patients are found to have HSIL incidentally on pathologic evaluation after hemorrhoidectomy or excision of condylomas.
These patients are similarly entered into the below follow up program.
The intensity of follow up after the initial encounter for HSIL depends upon each
patient’s risk factors and personal risk tolerance. Patients without obvious immunosuppression are tested for HIV, as this clearly affects their risk of future anal cancer;
any patient diagnosed with HIV is referred for treatment. Patients who are smoking
are referred for smoking cessation [9, 35]. Patients who are immunosuppressed due
to transplantation have been shown to be at higher risk for HSIL [36]. When they are
diagnosed with HSIL, I discuss the diagnosis with their transplant medicine team,
and discuss whether there is room to reduce the degree of immunosuppression without compromise to the transplant.
For patients who are not immunosuppressed, I typically recommend ofce anos-
copy and digital exam at 6months, and a surveillance biopsy / ablation at 12months.
If there is no recurrent or residual HSIL, then I recommend annual ofce exam and
anoscopy. If there is recurrent HSIL, then we repeat the follow up and surveillance
pattern.
For patients who are immunosuppressed (HIV positive, transplant, inammatory
bowel disease on immunosuppression, etc.), I recommend an ofce exam in
3months, and surveillance biopsy / ablation at 6months. If there is no HSIL at that
point, I recommend ofce exam and anoscopy every 6months. If there is recurrent
HSIL, we repeat the follow up and surveillance pattern, but in that case, I prescribe
a course of imiquimod prior to the next visit. I nd that this is generally welltolerated, and based upon the above data, it may be helpful, particularly in a highrisk population. I have a frank conversation with patients about the limited utility of
this method of ablation compared with electrocautery, and discuss with them that if
the cost is prohibitive or if they experience any side effects, we would not use this
modality.
If at any point there is a visible or palpable lesion at the ofce visit, I recommend
repeat biopsy and ablation. If HSIL is conrmed, the follow up plan restarts. Of
course, any patient found to have anal cancer is referred for appropriate treatment.
Particularly for patients without immunosuppression, we discuss the overall low
risk of SCC, paucity of data and variability in treatment and surveillance options. If
patients are less risk averse, and more concerned with missing work for procedures
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or having pain from biopsies, we may forgo the surveillance biopsy visit and follow
with ofce exam and standard anoscopy instead. What is clear from the data is that
some type of treatment and follow up is necessary, and I do my best to tailor this for
each individual patient.
References
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1977–2011: distinct patterns by histology and behavior. Cancer Epidemiol Biomark Prev.
2015;24:1548–56.
2. Milanés Guisado Y, Sotomayor C, Fontillón M, etal. Incidence rate and risk factors for anal
squamous cell carcinoma in a cohort of people living with HIV from 2004 to 2017: implementation of a screening program. Dis Colon Rectum. 2022;65:28–39.
3. Revollo B, Videla S, Llibre JM, etal. Routine screening of anal cytology in persons with
human immunodeciency virus and the impact on invasive anal cancer: a prospective cohort
study. Clin Infect Dis. 2020;71:390–9.
4. Peixoto A, Silva M, Castro R, etal. Anal condylomas: predictors of recurrence and progression
to high-grade dysplasia/carcinoma in situ. J Gastrointest Oncol. 2017;8:1114–5.
5. Voss JK, Kurdi AT, Neto MB, etal. Detection of anal intraepithelial neoplasia and anal squamous cell carcinoma on colonoscopy. ACG Case Rep J. 2022;9:e00792.
6. Stewart DB, Gaertner WB, Glasgow SC, etal. The American Society of Colon and Rectal
Surgeons clinical practice guidelines for anal squamous cell cancers (revised 2018). Dis Colon
Rectum. 2018;61:755–74.
7. Lee GC, Kunitake H, Milch H, etal. What is the risk of anal carcinoma in patients with anal
intraepithelial neoplasia III? Dis Colon Rectum. 2018;61:1350–6.
8. Frisch M, Biggar RJ, Goedert JJ.Human papillomavirus-associated cancers in patients with
human immunodeciency virus infection and acquired immunodeciency syndrome. J Natl
Cancer Inst. 2000;92:1500–10.
9. Gaisa M, Ita-Nagy F, Sigel K, etal. High rates of anal high-grade squamous intraepithelial lesions in HIV-infected women who do not meet screening guidelines. Clin Infect Dis.
2017;64:289–94.
10. Faber MT, Frederiksen K, Palefsky JM, Kjaer SK. Risk of anal cancer following benign
anal disease and anal cancer precursor lesions: a Danish Nationwide cohort study. Cancer
Epidemiol Biomark Prev. 2020;29:185–92.
11. Sanger CB, Xu Y, Carchman E, etal. Prevalence of high-grade anal dysplasia and anal cancer
in veterans living with HIV and CD4/CD8 ratio as a marker for increased risk: a regional retrospective cohort study. Dis Colon Rectum. 2021;64:805–11.
12. Arens Y, Gaisa M, Goldstone SE, etal. Risk of invasive anal cancer in HIV-infected patients
with high-grade anal dysplasia: a population-based cohort study. Dis Colon Rectum.
2019;62:934–40.
13. Chesson HW, Laprise J-F, Brisson M, et al. The estimated lifetime medical cost of diseases attributable to human papillomavirus infections acquired in 2018. Sexual Trans Dis.
2021;48:278–84.
14. Lightner AL, Welton ML. Anal dysplasia/cancer: Management of Patients with AIN 3. In:
Hyman N, Umanskiy K, editors. Difcult decisions in colorectal surgery. Difcult decisions
in surgery: an evidence-based approach. Cham: Springer International Publishing; 2017.
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15. Tong WWY, Jin F, McHugh LC, et al. Progression to and spontaneous regression of
high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men.
AIDS. 2013;27:2233–43.
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