Review: Anal Intraepithelial Neoplasia in HIV-Infected Men Who Have Sex with Men: Is Screening and Treatment Justified?

Abstract

Anal squamous cell carcinoma (SCC) is the fourth most prevalent cancer in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Human papillomavirus (HPV) has been detected in over 90% of anal carcinoma biopsy specimens from MSM, and is considered a necessary, but alone, insufficient factor for carcinogenesis. Anal intraepithelial neoplasia (AIN) may be precursive for SCC, and screening cytology with referral of persons with abnormality for high-resolution anoscopy-guided biopsy, and AIN treatment, has been recommended for prevention. In the absence of either randomized controlled trials or surveillance data demonstrating a reduction in anal SCC incidence, these recommendations were based on analogy with cervical cancer. HPV-mediated genetic changes associated with cervical cancer, and aneuploidy, have been documented in AIN. However, little data exist on the rate of AIN progression to SCC. The treatment of AIN is frequently prolonged and not curative, and if routinized in the care of HIV-infected MSM, would likely be recurring well into their sixth decade of life. Clinical trials demonstrating a reduction in invasive anal carcinoma incidence, as well as acceptable morbidity with repeated AIN destruction, are needed before asking our patients to commit to routine treatment.

Introduction

Non-AIDS defining cancers are now the leading cause of death, after AIDS-related diseases, in persons with human immunodeficiency virus (HIV) infection.¹ In HIV-infected men who have sex with men (MSM), squamous cell cancer of the anus is the fourth most prevalent cancer and the psychological and physical morbidity associated with treatment may be profound.^2,3 Unlike invasive cervical cancer, anal cancer is not AIDS defining, irrespective of its higher incidence in persons with immunodeficiency and linkage to coinfection with an oncogenic virus, Human papillomavirus (HPV).⁴ Anal intraepithelial neoplasia (AIN), which may be precursive for malignancy, and anal HPV coinfection (necessary for oncogenesis) are prevalent in HIV-infected MSM.^5,6 Importantly, the early detection of invasive anal carcinoma is associated with recurrence-free survival and a lower likelihood of treatment-related fecal incontinence.⁷

Screening anal cytology with referral of patients with abnormality for high-resolution anoscopy (HRA)-guided biopsy and AIN treatment have been recommended for anal cancer prevention in HIV-infected MSM.^8
–10 In the absence of either randomized controlled trials or long-term surveillance data demonstrating a reduction in anal cancer incidence, these recommendations were based on analogy with cervical cancer. Similarly, screening cervical cytology with referral for colposcopy was introduced into routine care, in the general population, in the absence of randomized trials. Subsequent reductions in cervical cancer incidence were documented by cancer registry data and retrospective investigation.^11,12

Guidelines for the management of AIN, with preventive intent, are based on the following triad: detection by cytology, lesion identification by HRA, and confirmation by HRA-guided biopsy.^8,10,13 The recommended threshold for HRA referral is any cytological abnormality.^8,10,13 While both anal and cervical carcinoma arising in stratified squamous cell epithelia are HPV linked and share risk factors, there are important tissue-level differences. These differences may limit the effectiveness of anal cancer preventive interventions and lead to intervention-related morbidity.

Evaluation of these guidelines by physicians caring for HIV-infected MSM should include the following determinations: does the incidence of anal carcinoma and its associated morbidity and mortality necessitate routine action? Is the increased relative risk in this population leading to a sizable anal carcinoma case load? Does the detection and treatment of histological abnormalities reduce the incidence of anal carcinoma, and will MSM comply with scheduled screening and treatment for AIN? And finally, will it improve outcomes for patients with anal carcinoma? Our reading of the literature suggests that, while the similarities of AIN to cervical dysplasia and oncogenic changes documented at the genetic and cellular levels are of concern, there is little data on the rate of AIN progression to anal carcinoma. In addition, the treatment of AIN may be lengthy, fraught with potential side effects, and often not curative. Thus, patient adherence may be an issue in the absence of data demonstrating reductions in anal cancer incidence. We provide an overview and discussion of these issues.

Epidemiology

While still infrequent in the general population, anal cancer incidence has been increasing 2.2% per year over the past decade.¹⁴ In the United States, the estimated 2015 incidence was 7270 cases, 80% of which were anal canal squamous cell carcinomas (SCCs).¹⁴ Male and female incidence rates were 1.5 and 2.0 cases per 100,000 persons per year, respectively.¹⁴ Most diagnoses occur in persons 45–64 years old.¹⁴ Similar to HIV infection, incidence is highest in 20–49 year old males, and black male incidence is higher compared with white and other ethnicities.¹⁴

Approximately, 80% of anal cancers in persons with HIV infection occur in MSM.¹⁵ Subsequent to the wide-spread availability of combination antiretroviral therapy (cART), anal cancer incidence increased and HIV infection was identified as an independent risk factor.^15,16 Incidence rates of 130 and 137 cases per 100,000 person-years of observation were documented in HIV-infected MSM in North American multicenter cohorts.^15,16 The rate ratio, a measure of excess incidence in HIV-infected MSM compared with HIV-uninfected men, was 78.8.¹⁵

Analysis of United States HIV/AIDS and cancer registry databases disclosed an average annual increase of 3.8% in anal cancer incidence in HIV-infected persons after the introduction of cART into clinical care.^17,18 During this period (1996–2010), the proportion of person-years of observation contributed by HIV-infected persons, 50 years old or older, increased from 13% to 27.3%.¹⁷ The lower median age at diagnosis in HIV-infected persons compared with the general population was statistically, but not clinically significant, 42 versus 45 years.¹⁹ Statistical analysis included adjustment for population age distribution differences.¹⁹

Similarly, analysis of the French Hospital HIV Database (2005–2008) disclosed increased invasive anal cancer incidence in HIV-infected MSM and a standardized incidence ratio [(observed cases/expected cases based on general population incidence) × 100], of 109.8.²⁰ In participants with CD4 ≥ 500 cells/μL for 2 or more years before cancer diagnosis, the standardized incidence ratio was markedly higher for those with nadir CD4 < 200 for >2 years, compared with those with nadir CD4 > 200 or nadir <200 for <2 years.²⁰ The Swiss HIV Cohort investigators found that CD4 < 200 in MSM 6–7 years before anal cancer diagnosis was the most predictive measure of anal carcinoma risk.²¹ Even modest deficits in immune competence effected risk in cohort participants. HIV-infected MSM with current CD4 < 500 cells/μL were at increased risk compared with those whose current CD4 was ≥500.²¹ Further elevation in risk was observed in those with current CD4 < 200 cells/μL.²¹ Similarly, the incidence of anal cancer is higher in persons without HIV infection receiving immunosuppressive therapy in association with organ allograft.²² These data sets suggest that cumulative lifetime immunodeficiency influences the natural history of anal carcinoma and early cART initiation is likely central to prevention.

Other documented risk factors for anal cancer include the following: receptive anal intercourse, lifetime number of sexual partners, anal warts, a history of syphilis or gonorrhea, hepatitis, seropositivity for Herpes simplex virus type 2, current tobacco use, and corticosteroid use for ≥6 months.^23
–25

HPV is detected in over 90% of anal carcinoma biopsy specimens from MSM and receptive anal intercourse or receptive oral-anal contact are the predominant modes of HPV acquisition.^25
–27 High-risk HPV may be detected in the anal canal of MSM in association with normal cytology, AIN, and/or SCC.^28,29 HPV 16 is the most frequently detected type (>70%) followed by HPV 18 (∼8%).²⁵ The prevalence of anal high-risk HPV carriage in urban HIV-infected MSM approaches 80–90%.^30,31 These prevalence estimates are believed to reflect persistence and an increased rate of acquisition.²⁶ Unlike cervical HPV infection, which peaks in young adulthood, anal HPV infection in MSM remains prevalent across all age groups, regardless of HIV status.^27,32

Anatomy and Histology

The anal canal is a fibroelastic tubular structure ∼3–4 cm in length extending distally from the anorectal junction at the perineal flexure to the anal verge. The interior of the anal canal is lined with stratified squamous epithelial tissue of dual embryonic derivation. The canal is divided by an encircling serrated dentate (pectinate) line formed by transverse mucosal folds, out of which longitudinal columns arise and extend proximately into the upper part of the canal.

The dentate line marks the histological transition from endoderm-derived columnar to ectoderm-derived stratified squamous epithelium. This area is referred to as the transition zone or squamocolumnar junction. Over 80% of anal carcinomas arise within the tissue of this zone.³³ Because of the larger surface area compared with the cervix and the three dimensionality of its folds, the identification and mapping of neoplasms during HRA are more challenging than during colposcopy.

Stratified squamous epithelia normally exist in a dynamic steady state where new cell production (proliferation) matches the loss of terminally differentiated cells from the surface.³⁴ Within the epithelium are three distinct compartments: (1) residing on the basement membrane are basal cells of limited replicative potential that are actively progressing through the cell cycle and relatively quiescent slow-cycling stem cells that may be induced to divide for the lifetime of the animal, (2) suprabasal differentiating cells that are being pushed toward the epithelial surface by the production of new cells beneath them, and (3) a terminally differentiated shedding compartment at the epithelial surface.³⁴

Pathogenesis

The documentation of cellular changes at the phenotypic, cytogenetic, and molecular levels in AIN, which are seen in cervical carcinogenesis, argues for its medical evaluation and intervention. These changes occur in the absence of inflammatory infiltrates, and HIV infection may create a structurally as well as immunologically permissive environment for the initiating event of anal carcinoma, which is a high-risk HPV infection.

Persistent high-risk HPV infection is considered a necessary, but alone, insufficient factor for anal carcinogenesis.^35,36 Cooperating mutations and/or epigenetic modification of host cell chromosomes are required for cellular immortalization, growth and proliferation, and progression to invasive carcinoma.^37,38 The random nature events that result in DNA modification make it difficult to predict the likelihood of developing clinically apparent carcinoma, as well as the time to onset after HPV acquisition (∼15–25 years for cervical cancer).⁴ Interestingly, once evolved, the maintenance of malignancy continues to require the expression of high-risk HPV genes.³⁹

HPVs are epitheliotropic circular double-stranded DNA viruses that have been classified into genotypes on the basis of DNA sequence and numbered in the order in which they were first isolated.⁴⁰ HPV genotypes (types) are designated as either low or high risk on the strength of their association with benign hyperproliferative lesions or neoplastic disease, respectively.

There are currently 12 World Health Organization-designated high-risk HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Persistent HPV type 16 or 18 infection, defined as detection of the same HPV type at 2 or more medical visits, has been shown to confer the highest risk for anal carcinoma.⁴¹ In addition, the International Agency for Cancer Research has designated 13 HPV types as probable or possible carcinogens: 26, 30, 34, 53, 66, 67, 68, 69, 70, 73, 82, 85, and 97. At least 1 HPV type has been detected in the anal canal of >90% of HIV-infected MSM, with 80% positive for high-risk virus.^6,30,32 Fifty-seven percent of a geographically diverse population of HIV-negative MSM at risk of HIV acquisition demonstrated anal carriage of low- or high-risk HPV and 26% for high-risk HPV.²⁷

In young sexually active females, most cervicovaginal high-risk HPV infection is of short duration and ultimately cleared.³⁰ However, in HIV-infected MSM, the mean duration of high-risk HPV infection is markedly longer with fewer clearance episodes. In a cohort of HIV-infected MSM, the mean durations of HPV16 and 18 infections were 36 and 30 months, with 12.2 and 20.4 clearance episodes per 1000 person-months, respectively.⁶ Conversely, in HIV-negative females, the mean durations of HPV 16 and 18 infections were 4.4 and 7 months, with 117.7 and 108.3 clearance episodes per 1000 person-months, respectively.⁴³

The HPV replication cycle is completely intracellular, allowing immune evasion.⁴⁰ In addition, viral progenies are released by mature cells at the epithelial surface, away from mucosal dendritic cells.⁴⁰ Nevertheless immune evasion is not a uniform finding and local immune response with clearance of HPV infection may be initiated by dendritic cell-to-CD8⁺ T cell cross-priming.^6,43,44

Infection is initiated on the epithelial basement membrane where HPV targets and persists in proliferating basal cells.^45,46 Investigative data demonstrate that HPV capsid proteins undergo conformational change and cleavage upon binding basement membrane proteoglycans.⁴⁵ This protein processing prevents viral particle loss from tissue and facilitates basal cell infection.⁴⁵ Exposure of the basement membrane by blister-type lesions from other sexually transmitted infections (e.g., Herpes simplex virus), anal canal microabrasion during receptive sexual contact, and anal fistula or fissure, may predispose MSM to HPV infection.^40,47 Similarly, the disruption of occluding junctions in the anal epithelium by HIV proteins may facilitate paracellular HPV penetration to the basement membrane.⁴⁸

The HPV genome contains eight genes under the control of an upstream regulatory region (URR).⁴⁰ The URR has cellular and viral transcription factor binding sites, two promoters, and an origin of replication.⁴⁰ Because of the prevalence of corticosteroid inhalant use for airway disease in HIV-infected MSM, steroid response elements within the URR are of particular interest.^49
–51 Their presence suggests that the increased risk for anal carcinoma in HIV/HPV coinfected MSM may, in part, be due to the upregulation of HPV gene expression.²⁵

HPV genes are numbered and designated as either early or late, based on the point in the viral replication cycle at which they are expressed. The early genes, E1 and E2, encode for proteins required for viral replication. The residual early genes, E5-E7, have evolved to modify epithelial cell behavior, that is, drive cell proliferation, resist cell death, and overcome replicative limits.⁴⁰

High-risk HPV-encoded E6 and E7 proteins have capabilities that are not present in those encoded by low-risk virus, which in turn may confer biological capabilities, characteristic of neoplastic disease, to the host cell(s).⁵² The activities of these proteins lead to behavioral changes and DNA modifications at the sequence, epigenetic, and cytogenetic levels.⁵² Indeed, the most plausible argument for identifying and treating anal neoplasia resides in the literature documenting these cellular changes and DNA modifications.

The high-risk HPV E6 and E7 proteins bind cellular p53 and pRb tumor suppressor proteins, respectively, and mark them for proteolytic degradation. Target protein degradation, which is the functional equivalent of an inactivating genetic mutation, enables HPV to overcome the stoichiometric imbalance between its proteins and their cellular targets.^40,52

Tumor suppressor p53 initiates antineoplastic responses commensurate with the degree of genomic damage sensed.^53
–55 It may block a cell's entry into the DNA synthesis phase of the cell cycle and activate DNA repair mechanisms, trigger cellular senescence, (i.e., permanent withdrawal from the cell cycle) or apoptosis (cell death).^53
–55

During anal carcinogenesis, misshapen epithelial cells demonstrate a loss of spatial regulation and stratification, and ultimately invasiveness. A highly conserved C-terminal zinc finger motif within high-risk E6 proteins enables them to recognize and mark the PDZ (for PSD95/DiscsLarge/Z0-1) domain containing cellular scaffolding proteins, for proteolytic degradation.^57,58 Loss of these scaffolding proteins at the junctional protein-to-cytoskeleton interface enables cells to evade contact-mediated polarity cues and inhibition (of proliferation).^4,56 PDZ domain containing scaffolding protein loss and localization change has been documented in the progression of cervical neoplasia to invasive carcinoma.^56,57

High-risk HPV E6 protein upregulates the human telomerase activity mediating maintenance of chromosomal telomere length, the evasion of cellular crisis, senescence, and apoptosis, which in turn may facilitate progression to invasive carcinoma.³⁶ Enzymatic upregulation is achieved, primarily, by the induction of hTERT transcription, the rate-limiting catalytic subunit of telomerase.⁵⁹

The degradation of retinoblastoma tumor suppressor proteins (pRb, Rb-like1/p107, and Rb-like 2/p130) by high-risk HPV E7 proteins sustains proliferative signals, progression through the cell cycle, and cell division.⁵² High-level E7 expression has also been documented in association with replication stress at loci prone to DNA double-strand breaks, in HPV 16-linked carcinoma.^60

–63 These loci, referred to as common fragile sites, have been associated with HPV integration into chromosomal DNA, genomic instability, and aneuploidy.^60

–63

HPV integration is a DNA recombination event, which requires DNA double-strand breaks in both the virus and a resident chromosome. The Ataxia telangiectasia-mutated DNA damage response pathway is activated by high-risk HPV to achieve high copy number amplification of its genetic material.⁶⁴ The assembly and activation of DNA damage repair machinery on viral episomes, tethered to chromosomes at common fragile sites, are thought to lead to accidental integration events during the repair of double-strand breaks.⁴⁶

The integration of HPV into chromosomal DNA and the loss of residual viral episomes have been demonstrated in majority of specimens from invasive anal and cervical carcinoma, and in a minority of those from high-grade neoplasia.^39,65,66 For HPV, integration is an abortive event; it subsequently ceases to be a replicating entity due to the loss or inactivation of large parts of its genome.⁶⁷ However, the high-risk genotypes consistently integrate with intact E6 and E7 genes and URR. The E2 gene, a negative regulator of viral transcription, is consistently disrupted or deleted.⁶⁷ The absence of trans-acting episomally encoded E2 protein allows sustained E6 and E7 gene expression and cell proliferation.^66,67

The upregulation of DNA methyltransferase (DNMT) by high-risk HPV has been associated with mitotically heritable chromatin hypermethylation and the transcriptional silencing of tumor suppressor genes.^68,69 Transcriptionally repressive methylation occurs in the promoter regions of genes with high cytosine-guanine dinucleotide content and gradually increases with older age.⁷⁰ In carcinogenesis, this process is markedly progressive, leading to little or no transcriptional activity and gene–product dose reduction or loss.⁷⁰ In addition DNMT, is expressed in all tissue strata, in contrast to normal epithelia, where it is only expressed in the basal and parabasal cell layers.⁷¹

DNMT upregulation by high-risk HPV E7 proteins occurs at the level of transcription, and post-translationally by protein–protein interaction.^68,69 Transcriptional activation is mediated by pRB degradation, leaving E2F transcription factors free to bind to DNMT gene promoter region response elements.⁶⁸ High-risk HPV E7 may also directly bind and stabilize DNMT to upregulate its enzymatic activity.⁶⁹

In the progression from normal epithelium to AIN to invasive anal cancer, differential patterns of DNA methylation and affected loci are seen in biopsy material.^72,73 In specimens from HIV-infected MSM, a mean of three methylated tumor suppressor genes was observed in high-grade AIN (HGAIN) and invasive anal carcinoma versus one in normal mucosa and low-grade AIN (LGAIN).⁷² Tumor suppressor gene methylation status correlated with tissue-level diagnosis, and specific patterns of DNA methylation were associated with HGAIN and invasive carcinoma.⁷²

In a prospective study of young females followed until histological diagnosis of high-grade cervical intraepithelial neoplasia, the clearance of high-risk HPV infection was associated with a marked reduction in tumor suppressor gene methylation.⁷¹ This association suggests that the reversal of epigenetic lesions may allow the spontaneous regression of AIN in MSM. Additional research may disclose patterns of DNA methylation that are predictive of progression to anal carcinoma, AIN persistence without progression, or regression.

The majority of anal and cervical carcinomas receiving cytogenetic evaluation are aneuploid.^53,61 Investigative data suggest that aneuploidy precedes HPV integration and is increasingly likely with increasing degree of dysplasia.⁶¹ High-risk HPV E7 protein is believed to mediate centrosome overduplication, leading to aberrant mitotic spindle formation, the asymmetric arrangement of chromosomes, or unaligned chromosomal material at the metaphase plate, which in turn results in missegregation during mitosis.^74
–76

Anal Cytology and HRA

Anal cytology

Anal dysplasia may be evaluated by cytology or histology using the Bethesda criteria and nomenclature developed for cervical lesions. Cytology may detect the presence of AIN, but it does not identify its location or the extent of disease, for example, single lesion, multifocal, or circumferential. Cytological abnormalities are generally reported as lesions and histological findings as AIN.⁷⁷ LGAIN usually represents productive HPV infection in differentiating cells destined to be shed with little risk of progression to invasive carcinoma. HGAIN is largely composed of proliferating cells, which do not support the late events of the viral replication.⁴⁰ Cells from high-grade lesions are characterized by a high nuclear-to-cytoplasmic ratio, which is pathognomonic for HPV infection. Other cellular abnormalities include koilocytotic changes (e.g., irregular nuclear membrane contour, abnormal chromatin distribution, and hyperchromatism).

Liquid-based exfoliative cytology findings may be reported as atypical squamous cells of undetermined significance; atypical squamous cells cannot exclude high-grade, low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion (HSIL). The sensitivity and specificity of anal cytology for differentiating between HSIL and non-HSIL are estimated by meta-analysis to be 30% and 93%, respectively.⁷⁸ Clinical investigators have demonstrated that abnormal anal cytology has ∼90% sensitivity and 64% specificity, for the detection of high-grade lesions in HIV-infected MSM.^79,80 Meta-analysis suggests that anal cytology is less sensitive than cervical (30% vs. 63%).⁷⁸ However, the 93% specificity, in pooled data, was higher than the previously cited clinical investigation, and comparable to cervical cytology.⁷⁸

The frequency of abnormal anal cytology in urban cohorts of HIV-infected MSM is ∼60%.^5,81 However, clinical investigators found that greater than one-third of MSM with biopsy-proven HGAIN received false-negative cytology results!^82,83

High-resolution anoscopy

The anal canal may be visualized for the identification, evaluation, and mapping of AIN by HRA with HRA-guided biopsy. Areas of the mucosa suspicious for HGAIN may be identified by the application of actetic acid and Lugol's iodine. Acetic acid will whiten neoplasms in comparison to surrounding normal squamous epithelium. Lugol's iodine will stain normal epithelium brown, leaving dysplastic or cancerous tissue unstained. Lack of iodine uptake indicated by a yellow area in an acetowhitened epithelium is suggestive for HGAIN. Other indications for HRA-guided biopsy include ulceration and abnormal vascularization, for example, punctuation or mosaic pattern.

Histological findings consistent with AIN include nuclear abnormalities, abnormal mitoses, loss of cellular differentiation, and loss of stratification. Nuclear and morphological abnormalities are limited to the lower one-third of the epithelium in AIN I, the lower two-thirds in AIN II, and in AIN III, there is full thickness involvement. HGAIN (AIN II/III) is considered precursory to invasive SCC and has been documented in 30–40% of HIV-infected MSM participating in HRA screening studies.^84
–86

HPV typing

Currently available kits for HPV detection and typing have not been approved by the US Food and Drug Administration for routine use with DNA extracted from anal specimens. Consequently, unlike cervical cytology, HPV typing is not included in current recommendations for anal cytology. This likely precludes payment for it. Of the nonapproved assays that allow type identification, linear array (Roche Molecular Diagnostics), is generally considered the reference assay. DNA level knowledge of a patient's anal HPV infection may inform decision-making with respect to screening frequency and/or AIN treatment.

Spontaneous AIN Regression

Anal SCC diagnoses in MSM remain rare in HIV-specialist physician's practices in comparison to the prevalence of high-risk anal HPV infection and HGAIN. This may be due, in part, to the spontaneous regression of HGAIN in HIV-infected MSM.⁴⁴ Investigators have documented a lesion regression rate of 70/100 person-years of follow-up in HIV-infected MSM.⁸⁷ AIN regression is thought to be mediated by local CD4⁺ T cell activation and the induction of cytolytic CD8⁺ T cell infiltration. Consistent with this hypothesis, T cell infiltration has been associated with the regression of HPV-associated warts and better therapeutic outcomes in patients with HPV16-associated oropharyngeal cancer.^43,88

HGAIN Progression to Anal Carcinoma

Investigators have documented the progression of biopsy-proven HGAIN to invasive anal carcinoma in HIV-infected MSM.⁸⁴ Patients with anal SCC may present with complaints of anal bleeding, pain, and/or mass sensation. It is important to note that anal bleeding in MSM may be misascribed to hemorrhoids and delay cancer diagnosis. However, approximately half of the patients in the aforementioned study were asymptomatic.⁸⁴ In 23 of the 27 patients with invasive carcinoma, a mass was easily palpable on digital anal rectal examination (DARE).⁸⁴ Most early invasive anal carcinoma is marked by induration or thickening, and annual DARE may be the single, most effective screening method.⁸⁹

There is little natural history literature documenting the rate of HGAIN progression to anal carcinoma. In a meta-analysis, theoretical rates of progression were calculated in HIV-infected MSM, 1 in 377 per year (0.27%) compared to 1 in 4196 per year (0.02%) in HIV-negative MSM.⁹⁰ Assuming this annual rate is constant from year to year, in the absence of HGAIN treatment, the corresponding 10-year carcinoma incidence rate in HIV-infected MSM would be 2.7% (10/377). This progression rate is markedly lower than the 20% 10-year incidence of cervical or vaginal vault carcinoma documented in females, not receiving treatment with curative intent, for high-grade cervical intraepithelial neoplasia.¹²

Treatment of HGAIN

Divergence from the analogy of anal with cervical carcinoma is also seen at the interventional level. High-grade cervical neoplasia is generally treated by excision, for example, large loop electrosurgical excision of the transformation zone.⁹¹ Surgical excision with clear margins of HGAIN, in the anal transformation zone, may result in complications such as the following: fecal incontinence or anal stenosis, abscess formation, anal spasm, and dyschezia.⁹² Similarly, excision of extensive neoplasia at the mucocutaneous junction may lead to fecal incontinence.⁹³ Therefore nonsurgical ablative techniques, infrared coagulation, electrocautery or the topically applied chemotherapeutic creams and imiquimod 5% or five-fluorouracil 5%, are first-line treatments.^94
–96 Topical 85% trichloroacetic acid may also be considered for first line therapy.⁹⁷ Close long-term follow-up is recommended for all patients receiving treatment, regardless of modality.⁹⁶

Topical creams are thought to be better for the treatment of widespread multifocal disease in highly motivated patients, considered most likely to be adherent. Duration of therapy is lengthy, up to 16 and 24 weeks for imiquimod and five-fluorouracil, respectively, and cream formulations require intra-anal application by the patient two or more days per week or in cycles of daily application.⁹⁴ Side effects are significant and typically of long duration (e.g., 5–7 weeks), and may be treatment limiting.⁹⁴ The most frequent side effects are pain, bleeding, and itching.⁹⁴ Increased urge to defecate has been reported with much greater frequency by patients receiving five-fluorouracil cream, and fatigue is somewhat more frequently reported with imiquimod cream use.⁹⁴

HRA-guided treatment with ablative devices is targeted and does not damage neighboring uninvolved tissue. Bleeding is generally of shorter duration, but greater frequency with electrocautery compared to topical therapies, however, there is greater potential for scarring and stricture formation.⁹⁴ Electrocautery is generally done every 4 weeks up to a maximum of five sessions.⁹⁴ Alternatively, infrared coagulation mediates hemostasis simultaneously with AIN destruction. The number of neoplasms destroyed during a session depends on patient tolerance and disease burden. The most frequently reported side effect is pain, which may be managed with warm baths and analgesic medication.¹⁰²

Patient education before deciding on treatment is very important. It should be understood that there is no curative treatment for HPV infection. Intervention is directed toward precancerous neoplasms to reduce morbidity and prevent their progression to malignancy, while preserving anal function. Patients should also be counseled to expect HGAIN recurrence, most frequently at a different site, and that recurrence rates are high regardless of treatment modality.^94

–98 For some patients, expectant management or watchful waiting, and DARE may be reasonable, as early anal carcinoma can be identified and cured.^86,96,99

Clinical investigators recently documented overall and cancer-specific survival rates of 71% and 82%, respectively, in HIV-infected MSM diagnosed with anal cancer, while participating in a longitudinal study of screening HRA with intervention.⁸⁶ At diagnosis, carcinomas were <5 cm in diameter (T1 or T2) with no nodal (N) involvement or metastatic (M) disease.⁸⁶ Of note, the investigators found no difference in tumor nodes metastasis (TNM) staging at cancer diagnosis between study participants and patients previously diagnosed with anal cancer at their medical center going back to 1989.⁸⁶ Importantly, there were no significant differences between the study participants and historical patients in overall or cancer-specific survival rates.⁹¹

Adjuvant qHPV Vaccination for Reduction of HGAIN Recurrence

High-risk HPV seroprevalence in MSM is associated with the detection of viral DNA in the anal canal, but not in the external genitalia, alone.¹⁰⁰ Serum IgG is actively transported across mucosal surfaces achieving high concentration in lower gastrointestinal tract secretions.¹⁰¹ Consequently, investigators sought to lower HGAIN recurrence rates in MSM by adjuvant qHPV vaccination.¹⁰²

HIV-negative MSM treated for HGAIN who received adjuvant qHPV vaccination demonstrated a 50% reduction in biopsy-proven recurrence for 2 years, with a trend toward protection in year 3.⁹⁸ Unfortunately, HIV-infected MSM receiving adjuvant qHPV vaccination in a recent AIDS Clinical Trials Group study did not demonstrate a similar reduction in HGAIN recurrence.¹⁰³

Conclusions

The literature strongly supports annual DARE in the routine care of HIV-infected MSM for the early detection of anal carcinoma. Also supported, is the early treatment of HIV infection to prevent patients' experiencing immunodeficiency or even mild CD4⁺ T cell deficits (<500 cells/μL), which is permissive for anal carcinogenesis. Additional investigative work is needed to better define the natural history of AIN, the rate of HGAIN progression to invasive anal carcinoma, and risk factors specific to HIV-infected MSM, a population with high background rates of HPV coinfection. This work should include discrete evaluation of progression in MSM who initiated cART at higher CD4 (>500 cells μ/L) and have never experienced immunodeficiency. High-risk HPV genotypes differ in their potency as carcinogens and the role of genotyping in the evaluation and management of AIN should be investigated. In consultation with their physician, patients may reasonably elect treatment for HGAIN because of the profound genetic changes with which it is associated, its histological similarity to cervical intraepithelial neoplasia, and the potentially catastrophic consequences of advanced SCC. However, the treatment of HGAIN is lengthy and if routinized in HIV patient care, would likely be recurring in MSM well into their sixth decade of life. Randomized trials demonstrating a reduction in invasive anal carcinoma incidence, as well as acceptable morbidity with repeated AIN destruction, are needed before asking our patients to commit to routine treatment.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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