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16. 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;134:1147–55.

17. Cajas-Monson LC, Ramamoorthy SL, Cosman BC. Expectant Management of High-Grade Anal Dysplasia in people with HIV: long-term data. Dis Colon Rectum. 2018;61:1357–63.

18. Tomassi MJ, Abbas MA, Klaristenfeld DD.Expectant management surveillance for patients at risk for invasive squamous cell carcinoma of the anus: a large US healthcare system experience. Int J Color Dis. 2019;34:47–54.

19. Brogden DRL, Walsh U, Pellino G, etal. Evaluating the efcacy of treatment options for anal intraepithelial neoplasia: a systematic review. Int J Color Dis. 2021;36:213–26.

20. Corral J, Parés D, García-Cuyás F, et al. Incidence of recurrent high-grade anal dysplasia in HIV-1-infected men and women following infrared coagulation ablation: a retrospective cohort study. Pathogens. 2021;10:208.

21. Goldstone RN, Hasan SR, Drury S, etal. A trial of radiofrequency ablation for anal intraepithelial neoplasia. Int J Color Dis. 2017;32:357–65.

22. Vergara-Fernandez O, Solórzano-Vicuña D, Coss-Adame E, Trejo-Avila M.Outcomes of radiofrequency ablation for anal high-grade squamous intraepithelial lesions. Tech Coloproctol. 2021;25:701–7.

23. Kerdsirichairat T, Voltaggio L, Rifkin S, Canto MI.Multifocal nitrous oxide Cryoballoon ablation for high-grade anal intraepithelial neoplasia. Am J Gastroenterol. 2019;114:1194–4.

24. Palefsky JM, Lee JY, Jay N, et al. Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer. N Engl J Med. 2022;386:2273–82.

25. Gudur A, Shanmuganandamurthy D, Szep Z, Poggio JL.An update on the current role of high resolution Anoscopy in patients with anal dysplasia. Anticancer Res. 2019;39:17–23.

26. McCutcheon T, Hawkins AT, Muldoon RL, etal. Progression of anal intraepithelial neoplasia in HIV-positive individuals: predisposing factors. Tech Coloproctol. 2019;23:325–32.

27. Gardner IH, Watson KM, Nguyen D, et al. Progression of anal intraepithelial neoplasia to cancer is low with Anoscopy surveillance and treatment. J Gastrointest Surg. 2022;26:929–31.

28. Fazendin EA, Crean AJ, Fazendin JM, etal. Condyloma Acuminatum, anal intraepithelial neoplasia, and anal cancer in the setting of HIV: do we really understand the risk? Dis Colon Rectum. 2017;60:1078–82.

29. Cleary RK, Schaldenbrand JD, Fowler JJ, et al. Treatment options for perianal Bowen’s disease: survery of American Society of Colon and Rectal Surgeons members. Am Surg. 2000;66:686–8.

30. Scholeeld JH, Ogunbiyi OA, Smith JHF, etal. Treatment of anal intraepithelial neoplasia. Br J Surg. 2005;81:1238–40.

31. Brown SR, Skinner P, Tidy J, et al. Outcome after surgical resection for high-grade anal intraepithelial neoplasia (Bowen’s disease). Br J Surg. 1996;86:1063–6.

32. Palefsky JM, Giuliano AR, Goldstone S, etal. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011;365:1576–85.

33. Wilkin TJ, Chen H, Cespedes MS, et al. A randomized, placebo-controlled trial of the Quadrivalent human papillomavirus vaccine in human immunodeciency virus-infected adults aged 27 years or older: AIDS Clinical Trials Group protocol A5298. Clin Infect Dis. 2018;67:1339–46.

34. Gosens KCM, van der Zee RP, van Heukelom MLS, etal. HPV vaccination to prevent recurrence of anal intraepithelial neoplasia in HIV+ MSM.AIDS. 2021;35:1753–64.

35. Gaisa MM, Liu Y, Deshmukh AA, et al. Electrocautery ablation of anal high-grade squamous intraepithelial lesions: effectiveness and key factors associated with outcomes. Cancer. 2020;126:1470–9.

36. Albuquerque A, Stirrup O, Nathan M, Clifford GM.Burden of anal squamous cell carcinoma, squamous intraepithelial lesions and HPV16 infection in solid organ transplant recipients: a systematic review and meta-analysis. Am J Transplant. 2020;20:3520–8.

K. S. Olortegui

Observation Versus Chemoradiotherapy

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forManagement ofSuperficial Anal

Cancer

MartinUwah, CoryNonnemacher, ErinKing-Mullins, andValentineN.Nfonsam

Background

The evolution in management of anal squamous cell carcinoma (ASCC) away from abdominoperineal resection in the mid-1900s was prompted by an unacceptable 5-year mortality rate, as well as the morbidity secondary to the operation [1]. This changed in 1974 when Nigro etal published their preliminary report on the use of combined chemotherapy and radiation for management of anal cancer which showed promising results [2]. Nigro updated his recommendations in 1984 after having managed 104 patients with radio sensitizing chemotherapy and radiation, which suggested this treatment to be at least as effective as radical surgery [3]. These recommendations from Nigro and his colleagues paved the way for chemotherapy and radiation to be the treatment of choice for ASCC, and a randomized trial in 1996 by the United Kingdom Coordinating Committee of Cancer Research (UKCCCR) conrmed these results. Their conclusion lead to a new standard of care, The Nigro Protocol, comprised of radiotherapy in combination with 5-Fluorouracil and Mitomycin [4]. Further studies have gone on to investigate

M. Uwah University of Chicago, Department of Colon and Rectal Surgery, Chicago, IL, USA

C. Nonnemacher Atrium Health Navicent, Department of General Surgery, Macon, GA, USA

E. King-Mullins Colorectal Wellness Center, Fayetteville, GA, USA

V. N. Nfonsam (*) LSU Health Department of Surgery, Louisiana State University, New Orleans, LA, USA e-mail: vnfons@lsuhsc.edu

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 K. Umanskiy, N. Hyman (eds.), Difcult Decisions in Colorectal Surgery, Difcult Decisions in Surgery: An Evidence-Based Approach,

https://doi.org/10.1007/978-3-031-42303-1_30

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alternative regimens with other agents or with induction chemotherapy prior to radiation without improvement in disease free survival [5].

Defining theProblem

While combined chemotherapy and radiation remains the gold standard for invasive anal ca, there are variations in practice patterns which are worth exploring. Surgery as the upfront treatment of low-grade tumors with certain characteristics has entered the algorithm of management and has become progressively more prevalent.

Supercially invasive squamous cell carcinoma is a minimally invasive tumor dened as having an invasive depth of <3mm from the basement membrane, a horizontal spread of <7mm and on pathology has histologically negative margins [6]. The guidelines on managing patients with primary ndings of supercially invasive squamous cell carcinoma (SISCCA) of the anus or perianal area are not very robust. One of the most challenging scenarios, that is unfortunately very common, is incidental ndings of supercially invasive squamous cell carcinoma in patients who underwent a hemorrhoidectomy or anorectal procedure. In most cases most of the tumor has been excised with very minimal residual tumor or there is a positive resection margin. The challenge, with no signicant clear guidelines, is how to manage these patients. Some have argued that re-resection is adequate, and others have advocated for a more aggressive treatment approach of chemoradiation.

PICO table

Patients Patients with

supercially invasive squamous cell carcinoma of the anus

Intervention Comparator

Surgical excision

Chemoradiotherapy with or without surgical excision

Outcome Overall survival,

disease-free survival, loco-regional recurrence

Treatment Decisions

When deciding the most appropriate management of SISCCA, we can infer from our knowledge of how we manage other low-grade tumors and use that as a treatment roadmap. Surgical resection of T1N0M0 tumors has been accepted as treatment without neoadjuvant or adjuvant chemoradiation. A retrospective cohort study using National Cancer Database and a joint program between the American College of Surgeons commission on cancer and the American Cancer Society evaluated T1N0M0 patients undergoing surgery versus chemoradiation [7]. The authors noted on their assessment after signicant literature review that most landmark trials supporting chemoradiation dealt with tumors that were T2 and above, with many trials excluding T1 tumors. Nigro’s reports and the previously mentioned UKCCCR trials did not include T1 tumors and yet are often cited as justication for treatment with chemoradiation for all ASCC.Multiple conclusions were drawn from this joint study.

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1. Those who underwent excision had smaller tumor sizes with 41.6% of tumors

<1 cm while 21.5% of those undergoing chemoradiation had sub centimeter tumors.

2. Tumors undergoing excision were more often well-differentiated, with 36.2%

being well differentiated compared to 11.8%

3. Trends from 2004 to 2012 showed a higher tendency to perform local excision.

4. 5-year survival was the same in both cohorts (85.3% versus 86.8%)

In this study, the authors did not draw the specic conclusion that surgery should be the standard treatment for T1 tumors but do outline that surgical intervention on these tumors is noninferior and is becoming a more popular treatment option. Data from this study was cited in the National Comprehensive Cancer Network (NCCN) guidelines. Current NCCN recommendations support excision of well and moderately differentiated T1N0, stage I, perianal (anal margin) tumors with a 1cm margin if the sphincter can be preserved [8]. These recommendations are specic to tumors of the perianal skin and exclude those of the anal canal.

Translating this data to the management of SISSCA, it is important to understand how SISSCA can differ from what is currently understood to be acceptable. The aforementioned research and NCCN guidelines do not give specic recommendations on the incidentally excised SISSCA which is the target in question for this chapter. SISSCA lesions do classify as T1 lesions given their size, but incidentally resected lesions may not result in achieving the recommended oncologic margins. The other critical difference is in the anatomic location of these lesions. The literature surrounding the resection of T1N0 lesions centers around the lesions being of the anal margin and excluding the anal canal. Depending on the location of incidental cancer within the specimen, a hemorrhoid for example, the tumor may instead involve the anal canal which has no good data. Lack of orientation of the specimen in non-hemorrhoidectomy specimens can lead to a diagnostic dilemma regarding margins. Extrapolating from the accepted T1N0 data to the management of SISSCA may requires accepting that tumors arising from the anal canal may be treated as anal margin tumors but this is not completely clear in the literature.

As previously mentioned, the combination 5-FU chemotherapy, mitomycin C and radiotherapy (CRT) is well established as the primary treatment regimen for anal squamous cell carcinoma with complete tumor regression in 80–90% of patients. We have also established that there are, however, subsets of these patients in whom the standard application of CRT can be challenged--early-stage anal cancer. This understudied population includes those with SISCCA as well as T1N0 perianal tumors (PAT) which replaces the previously used term anal margin, pigmented skin immediately surrounding the anal orice, extending to a radius of 5cm. The distinction between these tumors and anal canal tumors (ACT), tumors arising proximal to the anal margin and located within the canal, may prove critical in assessing prognosis and management.

Previous studies including NIGRO’s and the UKCCCR had advocated for chemoradiation treatment for all stages of PAT and ACT even without strong evidence of their utility. However, this blanket treatment of these cancers has been

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M. Uwah et al.

challenged by recent studies advocating for surgical resection in early cancers [7,

9]. The rationale for the consideration of local excision in early-stage anal cancer is

informed by several factors. While CRT offers both good local tumor control and sphincter preservation, it is also associated with multiple severe early and late adverse effects such as toxic gastrointestinal tract and hematologic effects, infections, proctitis, impotence, dyspareunia, skin dermatitis, anal and vaginal stenosis, incontinence, fecal urgency. Additionally, most of the data regarding CRT is from data of intermediate to more locally advanced diseases. The question remains if denitive CRT is necessary for all patients with early-stage disease. Several studies have looked at the safety, survival, and oncologic outcomes of CRT in early-stage disease. Chai et al. performed a retrospective cohort study that analyzed 2243 patients in the National Cancer Database (2004–2012) between the ages of 18 and 80years who were diagnosed with T1N0M0 Squamous Cell Cancer of the Anal Canal (SCCAC) [7]. They noted a statistically signicant increase in the use of local excision during the study period (17.3% in 2004 to 30.8% in 2012; P<.001). This increased use was observed among patients with primary tumors less than or equal to 2cm (P<.001). No statistically signicant difference in 5-year overall survival for the two different management strategies (85.3% for local excision; 86.8% for CRT; P=.93). These ndings remained robust when stratifying patients by tumor size and when patients who underwent abdominoperineal resection after CRT were excluded. The study concluded that with no clear difference in overall survival, local excision should be considered as a viable approach in the appropriate patient population.

Maccabe et. al assessed both survival outcomes and determine factors associated with R1 excision examining 367 consecutive patients identied with anal cancer between 2007 to 2019 [10]. Thirty-nine of these patients (10.6%) with complete follow-up data underwent local resection. These patients were further subdivided into two groups: 24 patients with perianal tumors (PAT) and 15 patients with anal canal tumors (ACT). R1 resections were observed in 27 patients (69.2%) with more frequency in ACTs than PATs (93.3% vs. 54.2%, P=0.006). This study concluded similarly that local excision (LE) alone is a viable treatment strategy for early SCCAC with the caveat that it is considered in perianal tumors and not of the anal canal. Long-term outcomes were observed to be acceptable even in the setting of an R1 resection with the use of adjuvant chemoradiotherapy.

An integrated protocol clinical trial with 3 separate arms has been designed as a non-randomized phase II multi-center trial of patients with T1N0 anal margin cancers [11]. It aims to recruit subjects having undergone LE with a goal of demonstrating a 3-year locoregional failure rate of <10% following frequent clinical assessments and pelvic magnetic resonance imaging. The strategy of low dose CRT for margins less than or equal to 1 millimeter will discourage ad hoc use of post-excision CRT and repeat excisions. The study hopes to address the concerns regarding the signicant morbidity of conventional CRT by employing lower doses of radiotherapy, based on the ndings of several published studies [12]. Interestingly, the inclusion criteria was widened to include the piecemeal excisions that often occur in clinical practice. For example, patients who incidentally present with malignancy following

30 Observation Versus Chemoradiotherapy for Management of Supercial Anal…

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349

hemorrhoidectomy will be included. Additionally, patients with supercially invasive squamous cell carcinoma of the anus (SISCCA) as dened by the Lower Anogenital Squamous Terminology (LAST) consensus also be included [6]. Given the current heterogeneity in management of this understudied group, continued prospective studies will be crucial in establishing a more dened treatment algorithm.

Conclusion andPersonal View oftheLiterature

The determination of treatment options for patients with SISCCA or early anal and perianal CA is truly a difcult decision. This difculty is accentuated when these pathologic ndings are incidental after a hemorrhoidectomy or anorectal surgery. The debate for local excision versus CRT persists but a preponderance of available retrospective cohort studies points to the consideration for local excision alone as a better alternative to chemoradiation for patients with early-stage anal cancer. The authors, therefore, propose the following recommendations:

• T1N0 perianal tumors can be locally excised while ensuring adequate margins of

1cm if possible [6].

• T1N0 anal canal tumors should be treated with primary CRT and local excision

should not be considered given the high likelihood of inadequate margins.

Interestingly, the rate of local recurrence in ACTs, even with R1/Rx resection has

been shown to be 9%, suggesting that the effectiveness of adjuvant therapy was

not signicantly undermined. Maccabe etal showed that those ACTs that got

re-resected, even to an R0, recurred locally suggesting that resection may not be

a viable option for any squamous cell tumors located in the anal canal [10].

• In the setting of an R1 resection of either variety of tumor, an acceptably low rate

of local regional recurrence can still be achieved by employing adjuvant CRT.

• Any consideration of wide local excision alone should include multidisciplinary

evaluation and discussion along with appropriate surveillance.

Hopefully, current ongoing clinical trials will provide answers and make treatment decisions for early anal and perianal cancers less difcult.

References

1. Pessia B, Romano L, Giuliani A, Lazzarin G, Carlei F, Schietroma M. Squamous cell anal cancer: Management and therapeutic options. Ann Med Surg (Lond). 2020;55:36–46.

2. Nigro ND.An evaluation of combined therapy for squamous cell cancer of the anal canal. Dis Colon Rectum. 1984;27(12):763–6.

3. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17(3):354–6.

4. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-uorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348(9034):1049–54.

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5. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C.Fluorouracil, mitomycin, and radiotherapy vs uorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299(16):1914–21.

6. Darragh TM, Colgan TJ, Cox JT, 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. J Low Genit Tract Dis. 2012;16:205–42.

7. Chai CY, Tran Cao HS, Awad S, Massarweh NN. Management of Stage I Squamous Cell Carcinoma of the Anal Canal. JAMA Surg. 2018;153(3):209–15.

9. Chakrabarti S, Jin Z, Huffman BM, Yadav S, Graham RP, Lam-Himlin DM, Lightner AL, Hallemeier CL, Mahipal A.Local excision for patients with stage I anal canal squamous cell carcinoma can be curative. J Gastrointest Oncol. 2019;10(2):171–8.

10. Maccabe TA, Parwaiz I, Longman RJ, Thomas MG, Messenger DE. Outcomes following local excision of early anal squamous cell carcinomas of the anal canal and perianal margin. Colorectal Dis. 2021;23:689–97.

11. PLATO_trial. PersonaLising Anal cancer radioTherapy dOse– Incorporating ACT3, ACT4 and ACT5.

12. Hateld P, Cooper R, Sebag-Monteore D. Involved-eld, low-dose chemoradiotherapy for early-stage anal carcinoma. Int J Radiat Oncol Biol Phys. 2008;70:419–24.

M. Uwah et al.

Is High Resolution Anoscopy Superior

https://t.me/medicina_free

toDirect Evaluation ofAnal Dysplasia?

MariaAbouKhalil andSenderLiberman

Introduction

While overall rare, anal squamous cell carcinoma is a potentially debilitating condition commonly encountered in a colorectal surgery practice. The incidence of this malignancy has been increasing, with age-adjusted rates for new anal cancer diagnosis rising on average 2.2% each year in the past decade [1]. It shares many epidemiologic, virologic and pathologic similarities with its gynecological counterpart: cervical squamous cell cancer. This is particularly true of the pathophysiology, thought to be related in the overwhelming majority of cases to infection with human papillomavirus (HPV) and the natural history of the disease evolving from precursor lesions [2, 3]. However, while guidelines and screening programs for cervical squamous cell cancer prevention and high-grade lesions exist and are well established, this public health parallel has not transpired for the management of precursor lesions in the anorectal area. This is likely multifactorial, owing amongst other reasons to the lower progression from anal dysplastic lesions to squamous cell carcinoma in the anus compared with the cervix, the lack of good quality public health data demonstrating the benet of screening program, and the inability to dene what type of screening tools to use for diagnosis and management of pre-malignant anal lesions [4].

High resolution anoscopy is a procedure very similar to colposcopy employed in

screening, diagnosis and treatment of precursor and malignant lesions. The primary

M. AbouKhalil McGill University Health Center, Montreal, QC, Canada e-mail: maria.aboukhalil@mcgill.ca

S. Liberman (*) McGill University Health Centre, Colon & Rectal Surgery, Montreal, QC, Canada e-mail: sender.liberman@mcgill.ca

https://doi.org/10.1007/978-3-031-42303-1_31

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M. AbouKhalil and S. Liberman

aim of this chapter is to review the role of high resolution anoscopy as compared to standard care with physical examination and direct anoscopy in patients with dysplastic anal lesions with regards to recurrence of these lesions or progression to cancer.

PICO Table

Patients Patients with

dysplastic anal lesions

Intervention Comparator

High resolution anoscopy

Conventional direct anoscopy

Outcome Recurrence of dysplasia,

progression to cancer

Methodology

An electronic PubMed database using the search terms “anal cancer”, “anal squamous carcinoma”, “high resolution anoscopy”, “anal dysplasia” was performed limiting the search to the years 2010–2022. Papers assessing the role of high resolution anoscopy in the identication and treatment of precursor lesions were reviewed.

Anal Dysplasia andHigh-Risk Groups

The Lower Anogenital Squamous Terminology (LAST) standardization consensus project was a multi-societal effort to unify the terminology for HPV-associated squamous lesions of the lower anogenital tract [5]. The goal was to improve communications across pathologists and clinicians across various specialties caring for patients with lesions. With regards to dysplastic lesions, they were separated into low or high-grade squamous intraepithelial lesions, respectively LSIL or HSIL. Anal intraepithelial neoplasia (AIN) was the terminology used previously for dysplastic lesions of the anal canal. In the newest terminology, LSIL corresponds to AIN I or anal condylomas, and HSIL corresponds to the higher dysplastic lesions AIN-2 and

3. Cytologic classication of lesions in the anal canal include atypical squamous

cells of undetermined signicance (ASCUS), atypical squamous cells, cannot rule out HSIL, LSIL, and HSIL.

Whether or not all anal dysplastic lesions develop into malignant ones and the rate at which they do is a matter of debate. Establishing this is important to identify screening and treatment guidelines. This contrasts with the dysplastic lesion for cervical cancer which have known rates of progression to cervical cancer from precursor lesions. In the anal region, LSIL is thought to be a marker of the risk for future HSIL diagnosis rather than a direct precursor for anal malignancy. The risk of progression to HSIL has been associated with some patient and viral factors. For example, infection with certain high-risk HPV-subtypes (particularly types 16 and 18) has been associated with increased risk of HSIL [6]. It has also been reported close to 50% of LSIL will spontaneously regress, a nding that is well described for cervical lesions [7].

31 Is High Resolution Anoscopy Superior toDirect Evaluation ofAnal Dysplasia?

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Contrary to LSIL, HSIL is considered a true precursor to anal SCC.Berry etal. showed the malignant potential of HSIL and demonstrated evidence for progression to anal SCC in men who have sex with men (MSM) [8]. While regression of HSIL does occur, it seems to be less likely than LSIL, again especially when linked to certain HPV genotypes like HPV-16 [9].

In one of the largest cohort studies available, Arens etal. evaluated the risk of progression from anal dysplasia to invasive anal cancer using the SEER database over an 11-year period [10]. They reported an incidence of anal cancer of 1.2% and

5.7% at 1 and 5-years following AIN 3 diagnosis, respectively. In their analysis, this risk did not differ by treatment status for AIN (surgical or non-surgical) or surveillance denoting anal cytology done 30days later. This study was limited by the signicant heterogeneity in the terminology (the use of AIN 3in the SEER database preceded the LAST project), population, and follow-up times. Rates of progression reported in the literature have varied from 0–1.2% at 1year and 1.7–13% at 5-years following the diagnosis of precursor lesions [9, 11–13].

As alluded to earlier, there are important risk factors for both the development of anal dysplasia and progression to anal cancer. The imbalance with which certain at-risk groups are affected results in difculty to study these issues on a large scale and create screening and management guidelines. The development of anal dysplasia being so closely related to infection with HPV infection, it goes without saying that they share many risk factors. In addition, factors that cause HPV virus persistence and non-clearance also increase the risk of anal dysplasia, and are likely closely linked to the development of anal cancer. Common risk factors for HPV infection and persistence include immunosuppression, infection with multiple HPV subtypes (particularly oncogenic subtypes 16/18), increasing age, number of sexual partners and younger age at sexual activity [14–16]. An important at risk-group for anal dysplasia are patients who have had history previous HPV-associated lesions especially gynecological or perineal disease [17–19].

Rates of anal dysplasia are particularly high in Human Immunodeciency Virus (HIV) positive patients [20]. While this increased risk in HIV positive individuals is true regardless of sexual behaviors, men who have sex with men (MSM) are a particularly high-risk group [21, 22]. The incidence of anal cancer in the HIV positive population is estimated to be 28 times that of the general population, with an incidence of 35 per 100,000 cases [23–26]. This risk increases up to 40-fold for MSM compared to the general population [27]. Owing to advances in HIV care, it has become a chronic disease with concerns shifting from acute opportunistic illnesses to chronic illnesses, in particular HPV-related anal dysplasia/cancer.

Given the above, the overwhelming majority of studies evaluating the natural history of anal dysplasia especially concerning the benet of interventions in preventing or halting progression to neoplasia have targeted these groups of high-risk individuals. The rest of this chapter will focus on these patient populations, limiting conclusions that can be generalized to the low-risk population.

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