High-Resolution Anoscopy

Number: 0808

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses high-resolution anoscopy.

1. Medical Necessity

   Aetna considers high-resolution anoscopy (HRA) medically necessary for the following:

   1. Diagnosis of a suspicious anal lesion in persons with abnormal anal physical findings (e.g., anogenital warts, hypo-pigmented or hyper-pigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology);
   2. HRA guidance for biopsy and ablation of high-grade anal intraepithelial neoplasia.

2. Experimental and Investigational

   Aetna considers HRA experimental and investigational because the effectiveness of this approach has not been established (not an all-inclusive list):

   1. Estimation of the risk of treatment failure of anal canal carcinoma after chemoradiotherapy;
   2. Screening of asymptomatic persons for anal dysplasia and anal cancer;
   3. Surveillance after treatment for anal squamous cell carcinoma.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered for indications listed in the CPB:
46601	Anoscopy; diagnostic, with high-resolution magnification (HRA) (eg, colposcope, operating microscope) and chemical agent enhancement, including collection of specimen(s) by brushing or washing, when performed
46607	Anoscopy; with high-resolution magnification (HRA) (eg, colposcope, operating microscope) and chemical agent enhancement, with biopsy, single or multiple
ICD-10 codes covered if selection criteria are met:
A63.0	Anogenital (venereal) warts
C21.0 - C21.1	Malignant neoplasm of anal canal and anus, unspecified
C44.520	Squamous cell carcinoma of anal skin
C78.5	Secondary malignant neoplasm of large intestine and rectum
D01.3	Carcinoma in situ of anus and anal canal
D12.7 - D12.9	Benign neoplasm of rectum and anal canal
K62.0 - K62.1	Anal and rectal polyp
K62.5 - K62.89	Other diseases of anus and rectum
R85.610 - R85.619	Abnormal cytological findings in specimens from anus
R85.81	Anal high risk human papillomavirus (HPV) DNA test positive
R85.82	Anal low risk human papillomavirus (HPV) DNA test positive
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
Z12.10 - Z12.13	Encounter for screening for malignant neoplasm of intestinal tract
Z12.89	Encounter for screening for malignant neoplasm of other sites
Z12.9	Encounter for screening for malignant neoplasm, site unspecified
Z85.048	Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus [estimation of the risk of treatment failure of anal canal carcinoma after chemoradiotherapy]

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Background

Anal squamous dysplasia refers to a spectrum of diseases that ranges from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive anal squamous cell carcinoma (SCC).  Recent reports have shown a significant increase in both the incidence and prevalence of both HSIL and anal SCC, especially in immunocompromised individuals and men who have sex with men (MSM).  These lesions are associated with chronic infection with the human papillomavirus (HPV).  There are controversies as to the optimal management of patients with HSIL.  There is an ongoing controversy over whether screening of high-risk patients with anal cytology is useful in identifying those who require further evaluation.

Examination of the anorectal region is enhanced with the use of high-resolution anoscopy (HRA), which is analogous to cervical colposcopy.  Moreover, HRA can also be used to direct therapy.  During HRA, a lubricated anoscope is inserted about 2 inches into the anal canal.  A cotton swab wrapped in gauze and soaked in 3 % acetic acid is then inserted through the anoscope, and the anoscope is removed, leaving the gauze in place.  The acetic acid reacts with the skin, giving dysplastic epithelium a white appearance.  After 2 minutes, the gauze is removed and the anoscope re-inserted.  A high-resolution colposcope (magnification of 10x to 40x) is used to view the walls of the anus (Pineda and Welton, 2008; Wilkin, 2010).

Human papillomavirus infections belong to the most common sexually transmitted infections worldwide.  In human immunodeficiency virus (HIV)-infected MSM, anal HPV prevalence is more than 90 % and infections with multiple HPV types are common.  Consequently, HPV-associated anogenital malignancies occur with high frequency in patients with HIV infection.  Anal intraepithelial neoplasia (AIN) is a potential precursor lesion of anal SCC.  Similar to cervical intraepithelial neoplasia (CIN), AIN is causally linked to persistent infections with high-risk HPV types such as HPV16 or HPV18.  As AIN and CIN share distinct biological similarities, some investigators have suggested AIN screenings analogous to Papanicolaou (Pap) smear programs for CIN in high-risk populations to reduce the incidence of anal carcer.  These screenings include cytological analysis followed by HRA in case of anal dysplasia.  Treatment guidelines for AIN are not yet available.  Treatments can be divided into topical (e.g., imiquimod, photodynamic therapy [PDT], podophyllotoxin, and trichloroacetic acid) and ablative (e.g., electrocautery, infrared coagulation, laser ablation, and surgical excision) measures.  However, controlled studies on AIN treatment have not been performed.  The impact of HPV vaccination on AIN development will also need to be assessed.  Long-term follow-up of these patients is essential to gain more insight into the natural history of anogenital HPV infection in HIV-positive MSM (Kreuter et al, 2008). 

Anderson and colleagues (2004) stated that some investigators have proposed screening homosexual men for anal cancer and its probable precursor, high-grade AIN.  Using widely accepted criteria for the introduction of screening programs, these investigators reviewed the evidence for screening for this condition in this high-risk population and highlighted areas where additional research is needed.  While it is accepted that the incidence of anal cancer is at least 20 times higher in homosexual men than the general population, the natural history of anal cancer and its precise relationship with AIN is not clearly understood.  Anal intraepithelial neoplasia is a very highly prevalent disease among homosexual men, but little is known about what predicts progression to invasive disease.  The screening tests, exfoliate cytology and HRA, have a sensitivity of between 45 % and 70 %.  Treatment options for AIN are limited by morbidity and high recurrence rates and there are no randomized controlled trials studying the effectiveness of therapeutic agents or surgery for high-grade AIN, although immunotherapies show very early promise.  Theoretically, early detection may lead to better treatment outcomes.  Studies of the potential negative consequences of screening programs on the homosexual population are needed.  The authors concluded that available data do not support the implementation of a screening program for AIN and anal cancer in homosexual men.

No leading medical professional organizations setting the standard for healthcare maintenance of HIV-infected persons have adopted published recommendations for routine screening of anal dysplasia and anal cancer.

The Centers for Disease Control and Prevention's treatment guidelines on Special populations: Sexually transmitted diseases (STD) (2006) stated that "[r]outine laboratory screening for common STDs is indicated for all sexually active MSM".  Anoscopy, HRA in particular, for anal dysplasia and anal cancer was not mentioned.  The Ontario Health Technology Advisory Committee (OHTAC, 2007) reviewed the role of anal dysplasia screening in those at high-risk.  It did not recommend screening of high-risk individuals based on the low specificity for cytological screening, inadequate evidence of effectiveness for current treatment of pre-cancerous lesions, high recurrence rates, and no evidence that cytological screening reduces the risk of developing anal cancer.  High-resolution anosopy was not discussed in the OHTAC report.  The Standards Practice Task Force of the American Society of Colon and Rectal Surgeons (Fleshner et al, 2008) noted that based on numerous similarities between AIN and CIN, anal Pap smear cytology has been proposed for both screening of high-risk individuals and surveillance after treatment of AIN.  High-resolution anosopy was not mentioned as a tool for screening of anal squamous neoplasms.  Furthermore, the National Comprehensive Cancer Network's clinical practice guidelines in oncology on anal carcinoma (2010) does not mention anal cancer screeing.

Berry et al (2009) compared detection of high-grade anal neoplasia by HRA-guided biopsy to that by anal cytology, HPV testing, or the combination.  A total of 125 MSM were enrolled in this study: HIV-negative = 85, HIV-positive = 35, and unknown status = 5.  A specimen was taken for anal cytology and HPV testing, followed by HRA-guided biopsy of any lesions.  A total of 91 % of HIV-positive and 57 % of HIV-negative MSM had anal HPV infection.  In HIV-positive men, the sensitivity of abnormal cytology to detect high-grade anal neoplasia was 87 %, and in HIV-negative MSM it was 55 %.  Among HIV-negative men, 9 of 20 cases of high-grade anal neoplasia would have been missed because cytology was negative, but the addition of HPV positivity increased sensitivity for the combination to 90 %.  The authors concluded that sensitivity and specificity of anal cytology and HPV testing are different in HIV-positive and HIV-negative MSM for detecting high-grade anal neoplasia when patients have HRA-guided biopsy of lesions.  The optimum use of HPV testing has yet to be defined.  They stated that HRA is an effective tool for diagnosing high-grade anal neoplasia.

Fox (2009) examined whether current evidence and expert opinion support the routine use of anal cytology and HRA in MSM.  Most recently published guidelines do not recommend routine anal cytology, but anal cancer is undoubtedly a serious and growing problem for HIV-positive patients.  Two recent cohort studies have provided data that suggested that the precursor lesion, HSIL, might not be more prevalent in patients on highly active anti-retroviral therapy than in historical pre-highly active anti-retroviral therapy cohorts or in HIV-negative MSM.  If substantiated by further studies, this would make it easier to focus intervention with HRA on a smaller group of patients.  This would be helpful because HRA remains a resource that is both costly and difficult to access in most countries.  The sensitivity and specificity of anal cytology is poor and adjuncts to cytology such as p16(ink4a) staining and HPV viral loads might be utilized to further reduce the number of patients requiring HRA.  Despite the burden of HSIL in HIV-negative MSM, anal cancer remains uncommon in this group.  The author concluded that although routine anal cytology is not advisable for MSM at present, be they HIV-positive or HIV-negative, clinicians should be regularly performing digital rectal examination in those at high-risk of anal cancer.

Kreuter et al (2010) stated that anal dysplasia is common in HIV patients, especially in HIV-positive MSM.  High-grade anal dysplasia can progress to invasive anal cancer.  As in cervical carcinoma, there is a cause-and-effect relationship between anal cancer and HPV infection, especially with high-risk types such as HPV16.  Several experts have recommended screening programs for anal cancer, including anal cytology along the lines of the Pap smear in women.  Such screenings should only be performed if pathological findings result in further diagnostic steps and, if necessary, appropriate treatment.  Clinical inspection, lesion biopsy, and treatment of anal dysplasia are performed under HRA.

Park and Palefsky (2010) stated that the incidence of HPV-associated anal cancer in MSM is striking and has not been mitigated by the use of highly active anti-retroviral therapy.  Detection and treatment of high-grade AIN may reduce the incidence of anal cancer.  Anal cytology is a useful tool to detect high-grade AIN; annual screening of HIV-positive MSM and biennial screening of HIV-negative MSM appears to be cost-effective.  Men who have sex with men and who exhibit abnormal cytology should be referred for HRA and biopsy.  Individuals with high-grade AIN should receive treatment; treatment modalities for high-grade AIN show moderate effectiveness and are usually well-tolerated, but greater study is needed to ascertain which treatment is optimal.  The authors also noted that large prospective studies are needed to document the effectiveness of screening and treatment of high-grade AIN on the incidence of anal cancer.

Santoso and colleagues (2010) estimated the prevalence of AIN in heterosexual women with genital intraepithelial neoplasia, and compared anal cytology with colposcopy for their effectiveness in AIN screening.  Women with confirmed intraepithelial neoplasia on the cervix, vagina, or vulva were referred for gynecological oncology care.  Subjects underwent anal cytology and HRA.  Any lesion detected on HRA was biopsied.  Wilson score method was used to estimate 95 % confidence interval for prevalence.  McNemar's test compared the 2 screening methods.  Women with average age of 39.6 years (range of 14 to 83 years) underwent anal cytology and anoscopy (n = 205).  Of the 205 patients with genital intraepithelial neoplasia, 25 patients (12.2 %) had biopsy-proven AIN.  Twelve patients (5.9 %) had abnormal anal cytology (9 with atypical squamous cells of undetermined significance [ASC-US], 3 with LSIL).  None of the 9 patients with anal ASC-US had biopsy-proven AIN.  Of the 3 patients with anal LSIL, 2 had AIN II and 1 had condyloma on biopsy.  However, 78 patients (38 %) had abnormal anoscopic findings that resulted in 25 biopsy-proven AIN (8 AIN I, 5 AIN II, 12 AIN III), condylomas (n = 11), and hyper-keratosis (n = 8).  Anoscopy identified 32 % (n = 25) with AIN out of 78 abnormal anoscopic examinations.  In diagnosing AIN, anoscopy has 100 % sensitivity and 71 % specificity; anal cytology has 8 % sensitivity and 94 % specificity.  The authors concluded that patients with cervical, vulvar, and vaginal intraepithelial neoplasia have 12.2 % prevalence of AIN and should be screened with HRA.  In AIN screening, anoscopy is more sensitive, but less specific than anal cytology.

The authors noted that this study has several drawbacks.  One of them was that the study population and screening procedures were carried out by 1 gynecological oncologist, which may limit the application of the results to other populations and practices.  Another limitation was that the high rate of AIN in this study may not be a good representation of the general population of patients because the authors' facility is a referral center for genital intraepithelial neoplasia.  Also, the total number of 26 patients with the diagnosis of AIN is still inadequate to assess the role of HIV, sexual practice, number of sexual partners, smoking, and other factors that may contribute to the development of AIN and anal cancer.  These investigators stated that further studies are needed to clarify factors that may contribute to the development of AIN and confirm a better screening method for AIN.

In an editorial that accompanied the afore-mentioned paper, Eckert (2010) stated that "[t]he 8.3 % prevalence of anal intraepithelial neoplasm 2-3 found in this study is higher and raises concern.  However, before recommending routine anal screening in women with HPV disease, we need better understanding of both disease burden and the natural history of this disease.  Currently, neither the U.S. Preventive Task Force, nor the American College of Obstetricians and Gynecologists has screening recommendations for anal intraepithelial neoplasia.  In my opinion, we are not ready for a recommendation that all women with genital intraepithelial neoplasm undergo anal screening.  Nor are we ready to state definitively how to screen and whom to treat.  In HIV-seronegative women, a provider should use clinical judgment with the understanding that HPV disease is multifocal and that a woman with high-grade cervical, vulvar, or vaginal intraepithelial neoplasm is at risk for anal disease ... We can prevent the need for future evaluation of genital intraepithelial lesions in a significant portion of women by increasing HPV vaccine coverage.  Let us seize our current prevention opportunity, even as we continue to gather needed data regarding anal HPV disease".

Guidelines on Human papillomavirus (2007) and Preventive medicine: Gynecologic care (2009) from the New York State Department of Health recommended that clinicians should refer women with cervical HSIL and individuals with abnormal anal physical findings (e.g., anogenital warts, hypo-pigmented or hyper-pigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology) for HRA and/or examination with biopsy of abnormal tissue.

The Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America's guidelines on Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents (Kaplan et al, 2009) noted that no national recommendations exist for routine screening for anal cancer.  Until such time, certain specialists recommend an annual digital rectal examination as an important procedure to detect masses on palpation that might be anal cancer (BIII).  In addition, certain specialists recommend anal cytologic screening for HIV-sero-positive men and women (CIII).  If anal cytology is performed and indicates atypical squamous cell of undetermined significance or atypical squamous cells suggestive of high-grade, LSIL, or HSIL (BIII), then it should be followed by HRA.  Visible lesions should be biopsied to determine the level of histological changes and to rule out invasive cancer (BIII). 

• Strength of the recommendation "B" refers to moderate evidence for efficacy -- or strong evidence for efficacy but only limited clinical benefit -- supports recommendation for use.  Should generally be offered.
• Strength of the recommendation "C" refers to evidence for efficacy is insufficient to support a recommendation for or against use.  Or evidence for efficacy might not outweigh adverse consequences (e.g., drug toxicity, drug interactions) or cost of the treatment or alternative approaches. Optional.
• Quality of evidence supporting the recommendation "III" denotes evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

Treatments for anal squamous dysplasia vary in terms of morbidity and success rates.  Wide local excision is associated with significant morbidity.  Newer therapies such as topical immuno-modulation, PDT, and therapeutic vaccines have been proposed, but long-term follow-up is unavailable.  Compared with the use of wide local excision, the use of a comprehensive approach of cytology and office-based and/or operating room procedures directed with HRA has been reported to result in less morbidity, clearance of HSIL in up to 80 % of patients, and malignant progression in 1 % (Pineda and Welton, 2008).

Pineda et al (2007) reviewed 42 patients who underwent HRA-targeted surgical therapy of anal dysplasia in the past 10 years.  Patients were followed-up with physical examination, cytology, HRA, and biopsy if indicated.  Patients with disease amenable to local therapy were treated with office-based HRA-directed therapies.  A total of 30 men (mean age of 39 years, range of 21 to 63 years) and 12 women (mean age of 50 years, range of 31 to 71 years) were included in the study.  High-grade squamous intraepithelial lesions were present in 33 patients, with 4 undergoing planned staged treatment due to circumferential disease.  These lesions recurred in 45 %, and most were re-treated successfully in-office.  Progression to HSIL was seen in 1 patient with LSIL and to squamous SCC in 1 patient with HSIL despite therapy.  No patients with LSIL had dysplasia at last follow-up.  Minor complications occurred in 3 patients.  Surgical therapy under HRA guidance coupled with surveillance and re-treatment with office-based therapies offered an effective method in controlling anal dysplasia in immuno-competent patients.  Morbidity is minimal, and the progression to cancer rate is low (2.4 %).

Anal intraepithelial neoplasia III (AIN III) is a risk factor for anal cancer with poor curative results and high morbidity.  High-resolution anoscopy is a minimally invasive means of identifying and treating AIN III early.  Chung and Rosenfeld (2007) retrospectively reviewed HRA in the treatment of AIN III in a community setting.  From January 2002 through November 2005, a total of 76 patients with AIN III diagnosed by anal Pap smear, colposcopy, or biopsy underwent HRA for diagnosis and treatment; 21 patients with AIN III on initial HRA underwent follow-up HRA for re-assessment and treatment at 6 months.  Recurrence/persistence of disease was recorded and compared with patient characteristics.  Of the 21 patients with repeat HRA, 4 were HIV-negative and 17 were HIV-positive; 12 of 21 (57 %) had intra-anal recurrence/persistence; 9 of 21 (43 %) had no AIN III.  Eleven (92 %) with recurrence were HIV-positive; 1 (8 %) was HIV-negative.  Three (75 %) HIV-negative patients had no recurrence/persistence; 1 of 4 (25 %) had recurrence; and 11 of 17 (65 %) HIV-positive patients had persistence of disease.  The authors concluded that HRA is an alternative tool to treat AIN III and can be performed in a community setting yielding results comparable to the university setting.

Pineda et al (2008) examined if HRA-directed surgical destruction of anal HSIL is effective in controlling these lesions while preserving normal tissues.  A retrospective review of 246 patients with HSIL treated with HRA-targeted surgical destruction from 1996 to 2006 was performed, with at least 1 follow-up at a minimum 2 months with physical examination, HRA, cytology, and biopsy when indicated.  Lesions were extensive in 197 patients (81 %); 207 (84 %) were men, and 194 (79 %) were immuno-compromised (HIV or other).  Persistent disease occurred in 46 patients (18.7 %), requiring planned staged therapy; 10 required surgery.  Recurrent HSIL occurred in 114 patients (57 %) at an average 19 (range of 3 to 92) months; 26 of these required surgery.  All other patients were re-treated in-office with HRA-directed therapies.  Complications were seen in 9 patients (4 %).  Despite treatment, 3 patients progressed to invasive cancer (1.2 %).  At their last visit, 192 patients (78 %) had no evidence of HSIL.  The authors concluded that HRA-targeted destruction combined with office-based surveillance and therapy is effective in controlling HSIL and is superior to expectant management or traditional mapping procedures.

The Standards Practice Task Force of the American Society of Colon and Rectal Surgeons (Fleshner et al, 2008) stated that targeted destruction guided by HRA is effective to identify, biopsy, and destroy high-grade AIN without the morbidity associated with wide local excision; however there is a high risk for persistent or recurrent disease among HIV-positive patients.

Goon et al (2015) noted that anal cancer is uncommon, with an incidence rate of 0.5 to 1.0 per 100 000 of the population but incidence rates have been steadily increasing over the last 3 decades.  Biological and epidemiological evidence have been mounting and demonstrated that anal cancer has many similarities to cervical cancer, especially in regard to its etiology.  High-resolution anoscopy of the anal region, analogous to colposcopy of the cervix, is a technique that is not well-known in the medical and surgical fraternity.  Evidence to support the use of HRA for detection and treatment in the surveillance of AIN exists and strongly suggests that it is beneficial, resulting in reduced rates of cancer progression.  Pilot data from these researchers’ study showed a local disease failure rate of 1.73 per 1,000 patient-months compared with a published rate of 9.89 per 1,000 patient-months.  This demonstrated a 5.72-fold reduction in local disease failure rates of patients with T1-T3 tumors; these data therefore suggested that use of HRA for detection and treatment in surveillance of anal cancer patients will help prevent local regional relapse at the anal site.  The authors concluded that there is an urgent need for a large, randomized controlled clinical trial (RCT) to definitively test this hypothesis.

Dalla Pria and colleagues (2014) stated that the ability to detect and treat pre-malignant anal lesions suggests screening may prevent anal cancer.  The incidence of anal cancer in men who have sex with men (MSM) living with HIV exceeds that of cervical cancer before screening was introduced.  These researchers reported the longitudinal results from a pilot study of HRA screening of HIV-positive MSM.  High-resolution anoscopy with intervention for HSILs was offered to asymptomatic HIV-positive MSM.  Patients with HSILs were treated and follow-up HRA performed after 6 months, while patients with LSILs had a repeat HRA after 12 months.  A total of 368 asymptomatic MSM had a total of 1,497 HRAs during a median follow-up of 4.2 years (maximum of 13 years).  At first HRA, 36 % had normal appearances, 16 % had no dysplasia, 15 % AIN-1, 19 % AIN-2 and 13 % AIN-3.  During follow-up, 5 patients (1.4 %) developed invasive anal cancer (incidence 2.7 per 1,000 person-years).  The 5-year cancer rate for the 368 patients was 0.3 % (95 % confidence interval [CI]: 0 to 0.6 %).  Progression to cancer was associated with higher age (p = 0.049) and AIN-3 (p = 0.024); 90 patients had AIN-3 present at least at one HRA.  The cumulative risk of cancer from first AIN-3 diagnosis was 3.2 % (95 % CI: 0 to 7.8 %) at 5 years; 171 patients had HSILs (AIN-2 or 3) present at least once.  The cumulative risk of cancer from first HSIL diagnosis was 0.6 % (95 % CI: 0 to 1.8 %) at 5 years.  The authors concluded that AIN-3 is a significant risk factor for subsequent anal cancer, although the tumors detected in screened patients were small localized, and generally the outcomes were favorable.

In a prospective cohort study, Schofield and colleagues (2016) examined the feasibility and acceptability of anal screening among men MSM. Participants of this study were known HIV-positive and negative MSM who have anal intercourse, and they underwent anal screening with HPV testing, liquid-based cytology and HRA with biopsy of anoscopic abnormalities.  Participants completed questionnaires at baseline and at 6 months.  Anal HPV was highly prevalent in MSM (HIV-positive, 88 % and HIV-negative, 78 %).  Despite the high prevalence of cytological abnormality in both HIV-positive (46.2 %) and negative (35.0 %) MSM, almost 50 % of AIN of all grades were associated with negative cytology.  Anoscopically directed biopsies detected AIN3 or worse (AIN3+) in 14/203 (6.9 %) of HIV-positive MSM and 3/81 (3.7 %) HIV-negative MSM.  The corresponding prevalence of AIN2+ was 26.6 and 20.9 %, respectively; 1 case of AIN3 was detected at the second visit.  Screening was considered to be highly acceptable by participants.  The authors concluded that the high prevalence of high-risk-HPV and frequency of false negative cytology in this study suggested that HRA would have most clinical utility, as a primary screening tool for anal cancer in a high-risk group.  The prevalence of AIN3+ in HIV-positive MSM lent support for a policy of screening this group, but the high prevalence of lower grade lesions that do not warrant immediate treatment and the limitations of treating high-grade lesions requires careful consideration in terms of a screening policy.

An UpToDate review on "Anal intraepithelial neoplasia: Diagnosis, screening, prevention, and treatment" (Palefsky and Cranston, 2016) states that "There are no randomized clinical trials that document the value of screening for anal SIL in an at-risk population. 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 … 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".

Sambursky and colleagues (2018) stated that more than 90 % of anal cancers are caused by HPV, and HPVstrains 16 and 18 are the most oncogenic.  Anal HSIL are cancer precursors; treating these HSIL likely reduces the risk of cancer, but cytology is an imperfect screening test.  In a retrospective, single-center study, these researchers examined if HPV 16 and/or 18 testing better predicts the presence of HSIL.  A total of 894 consecutive patients underwent anal dysplasia screening with digital anorectal examination, anal cytology, high-risk HPV testing, and HRA with biopsy.  They calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each test and for a novel screening protocol.  The absolute and relative risk of HSIL for all of the cytology/HPV combinations were also calculated; 92 % of participants were men who have sex with men; 42 % were HIV-positive individuals who were well controlled on anti-retroviral therapy.  The median age was 50 years.  The presence of HSIL as a function of HPV and the cytology results were measured.  High-risk HPV testing alone demonstrated better sensitivity (96 % versus 89 %; p = 0.03) and NPV (99 % versus 96 %; p = 0.008) over cytology; HPV 16/18 testing increased specificity (48 % to 71 %; p < 0.0001) and PPV (24 % to 37 %; p = 0.003) over testing for all of the high-risk strains.  For each cytology category, HSIL were more prevalent when HPV 16/18 was detected.  Benign cytology with 16/18 had a 31-fold increased risk of HSIL.  The authors concluded that testing of high-risk HPV strains 16/18 improved specificity and PPV over cytology for anal dysplasia screening.  Patients testing positive for strains 16/18 were at a high risk for HSIL and should undergo HRA regardless of the cytology result.  The main limitation of this study was that it was conducted in a single private practice specializing in anal dysplasia screening with a mostly male population, and results might not be generalizable.

Surveillance After Anal Squamous Cell Carcinoma

Cappello and colleagues (2020) stated that local recurrence is a significant risk after anal SCC.  In a retrospective, observational study, these researchers examined the occurrence of high-grade squamous intraepithelial lesions (HSILs) and local recurrence after anal cancer at surveillance with HRA.  There were 76 anal/peri-anal cancers from 1998 to 2018; 63 patients were eligible and 3 were excluded, for a total of 60 patients; 35 of 60 (58 %) patients were men.  Interventions were HRA after chemoradiation (CRT) or excision only (EO) for anal SCC.  The primary outcomes measured were local recurrence and HSIL detection rates.  A total of 60 patients, 27 % HIV-positive, underwent surveillance over a median 42 (range of 7 to 240) months of follow-up; 7 had had a prior local recurrence at study entry so were analyzed separately; 30 of 53 underwent CRT (57 %) and 23 of 53 underwent EO (43 %); 33 had peri-anal cancer and 20 had anal cancer; 10 of 30 of the CRT group had had stage 1 (33 %) disease in comparison with 22 of 23 of the excision only group (96 %, p < 0.001).  HSILs were detected in 4 of 30 (13 %) patients after CRT and in 17 of 23 (74 %) patients after EO (p < 0.001); 20 of 21 (95 %) high-grade lesions were treated with ablation; 6 of 7 (86 %) patients with prior local recurrence had HSILs over a median of 21 months follow-up.  One local recurrence (T1N0M0) occurred during surveillance after primary CRT (0.56/1,000 person-months), none occurred after EO, and 2 of 7 with prior local recurrence developed further local recurrence (6.86/1,000 person-months).  All 3 local recurrences occurred after treatment of HSILs.  There were no metastases, abdominoperineal excisions, or deaths from anal SCC.  The authors concluded that HSILs after anal SCC were more common after EO than after CRT.  Local recurrence was low in this HRA surveillance group in which high-grade squamous intraepithelial disease was ablated.  Excision of small peri-anal cancers appeared safe; however, a subset of patients was at excessive risk.  Moreover, these researchers stated that, to their best knowledge, this was the largest study of patients after anal SCC followed-up with HRA.  They stated that further prospective studies of HRA in this population are needed to understand the optimal follow-up after CRT and EO, and to examine the impact of treatment of HSILs on local recurrence, and ultimately survival.

The authors stated that this study had several drawbacks.  This was a retrospective analysis of a prospectively collected data set.  The retrospective nature of the data meant a power calculation a priori was not possible, and, hence, the study was likely under-powered.  Because of the tertiary referral nature of the practice, this cohort may not be representative.  Furthermore ,there were notable background differences between groups.

Furthermore, an UpToDate review on “Treatment of anal cancer” (Ryan and Willett, 2021) states that “Patients with clinical suspicion for persistent disease on the initial post-treatment physical examination can be watched for up to 6 months following completion of RT and chemotherapy as long as there is no progressive disease during this period of follow-up.  Progression of disease at any time or a clinical suspicion for persisting disease 6 months or more after completion of chemoradiotherapy should prompt a biopsy, with salvage therapy (typically APR) offered to those with biopsy-proven disease persistence/recurrence.  There are no prospective trials to guide the post-treatment surveillance strategy for patients treated for anal cancer.  In general, LRFs [locoregional failures] predominate after primary chemoradiotherapy, and early identification of those with persistent or recurrent locoregional disease who need salvage therapy (typically an abdominoperineal resection) is an important goal of the post-treatment surveillance strategy.  The majority of recurrences develop within 3 years, providing justification for more intensive surveillance during this period … Given that most patients relapse locoregionally rather than at distant sites, regular CT scans for metastatic surveillance are controversial as the evidence for benefit of metastasectomy, as carried out in colorectal cancer, is lacking.  There is insufficient evidence to recommend integrated fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT in the assessment of treatment response or follow-up of treated anal canal.  Its ability to impact earlier salvage compared with clinical evaluation remains inconclusive ”.  This UTD review does not mention high-resolution anoscopy as a surveillance tool.

Artificial Intelligence for Identification of Anal Squamous Cell Carcinoma Precursors

Saraiva et al (2022) stated that HRA is the gold standard for detecting anal squamous cell cancer (ASCC) precursors.  Although it is superior to other diagnostic methods, especially cytology, the visual identification of areas suspected of having HSIL remains difficult.  Convolutional neural networks (CNNs) have shown great potential for evaluating endoscopic images.  These researchers developed a CNN-based system for automatic detection and differentiation of HSIL versus LSIL in HRA images.  A CNN was developed based on 78 HRA examinations from a total of 71 patients who underwent HRA at a single high-volume center between January 2021 and January 2022.  A total of 5,026 images were included, 1,517 images containing HSIL and 3,509 LSIL.  A training dataset comprising 90 % of the total pool of images was defined for the development of the network.  The performance of the CNN was evaluated using an independent testing dataset comprising the remaining 10 %.  The sensitivity, specificity, accuracy, PPV, NPV, and area under the curve (AUC) were calculated.  The algorithm was optimized for the automatic detection of HSIL and its differentiation from LSIL.  The model had an overall accuracy of 90.3 %.  The CNN had sensitivity, specificity, PPV, and NPV of 91.4 %, 89.7 %, 80.9 %, and 95.6 %, respectively. The AUC was 0.97.  The authors concluded that the CNN architecture for application to HRA accurately detected precursors of squamous anal cancer.  Moreover, these researchers stated that further development and implementation of these tools in clinical practice may significantly modify the management of these patients.

High-Resolution Anoscopy for Estimation of the Risk of Treatment Failure in Anal Canal Carcinoma After Chemoradiotherapy

De Felice et al (2023) developed a predictive index model, integrating both clinical and HRA features to further personalize the decision-making process in anal canal carcinoma in the COVID-19 era.  These researchers evaluated HRA parameters following definitive chemoradiotherapy (CRT) in patients with anal canal malignant lesions.  HRA features could be important to examine the effect of CRT and a risk stratification system should be introduced in clinical practice to better allocate therapeutic interventions.  The authors concluded that, to their knowledge, this is the 1st proposal for HRA findings in anal canal cancer after definitive CRT.  These researchers believe that a risk score can be useful to estimate the risk of treatment failure (in term of persistence disease and/or recurrence) and its clinical relevance should not be under-estimated.  These investigators will carry out a reliable survival analysis in order to provide a standard approach on how COVID-19 deaths should be classified in survival analysis to obtain comparable results.  They hope to propose a predictive score that could help to guide future research in anal canal cancer field in the COVID-19 era.

High-Resolution Micro-Endoscopy

Brenes et al (2023) noted that in the U.S., the effectiveness of anal cancer screening programs has been limited by a lack of trained professionals proficient in HRA and a high patient lost-to-follow-up rate between diagnosis and treatment.  Simplifying AIN grade-2 or more severe (AIN 2+) detection could radically improve the access and efficiency of anal cancer prevention.  Novel optical imaging providing point-of-care (POC) diagnoses could markedly improve existing HRA and histology-based diagnosis.  In a pilot study, these researchers examined the potential of high-resolution micro-endoscopy (HRME) coupled with a novel machine learning (ML) algorithm for the automated, in-vivo diagnosis of anal pre-cancer.  The HRME, a fiber-optic fluorescence microscope, was employed to capture real-time images of anal squamous epithelial nuclei.  Nuclear staining was achieved using 0.01 % wt/vol proflavine, a topical contrast agent.  HRME images were analyzed by a multi-task deep learning network (MTN) that computed the probability of AIN 2+ for each HRME image.  The study accrued data from 77 individuals living with HIV.  The MTN achieved an area under the receiver operating curve (AUC) of 0.84 for detection of AIN 2+.  At the AIN 2+ probability cut-off of 0.212, the MTN achieved comparable performance to expert HRA impression with a sensitivity of 0.92 (p = 0.68) and specificity of 0.60 (p = 0.48) when using histopathology as the gold standard.  The authors concluded that this pilot study demonstrated that high-resolution microscopy combined with deep learning image interpretation could achieve a sensitivity and specificity equivalent to expert HRA impression that could reduce the need for pathology-based diagnoses by providing POC diagnostic capabilities.  These researchers stated that these findings encourage a follow-up study with higher statistical power to compare the HRME performance with the expert impression of multiple anoscopists.

The authors stated that 1 drawback of this system was that placement of the HRME probe depends on HRA guidance and thus on appropriate identification of a possible anal pre-cancerous lesion by the clinician.  It will consequently not alleviate the need for procedural acumen, and proficiency in HRA techniques will remain a prerequisite for successful HRME or tissue diagnosis.  Advancements in the development of algorithms to localize suspicious lesions in HRA images, like those in the field of colposcopy image analysis, may aid HRME probe placement.  In addition, the HRME could be used as a triaging tool that may allow for a potential “see and treat” approach, eliminating the need for additional treatment-related visits.  Furthermore, because of the HRME's small field of view and its susceptibility to motion artifacts, only a small area of the anal anatomy can be surveyed within the limited time frame of a clinical visit.  Therefore, the clinician operating the instrument must carefully decide which areas to prioritize for HRME imaging.  This decision will affect the performance of the HRME in anal pre-cancer detection.  To overcome these drawbacks, recent developments in HRME instrumentation have sought to decrease motion blur by employing a higher frame rate camera and increasing the HRME field of view by mosaicking sequentially acquired frames.  The new instrumentation coupled with rapid real-time scoring would allow clinicians to survey more extensive areas of interest at a higher speed.  These investigators also noted that this study did not evaluate the trade-off of training and validating in their model using cervical instead of anal HRME images.  Based on their previous evaluation of the number of samples needed to train the MTN for cervical pre-cancer detection, these researchers could infer that they currently do not have sufficient samples to train and validate the MTN exclusively on anal HRME data.  However, future work could examine using anal HRME data to refine the MTN and improve its diagnostic performance once more data become available.

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References