Updated July 2007 — Currently Under Revision
Invasive squamous cell cancers of the anal canal are associated with certain types of human papillomavirus (HPV) infection, most notably, HPV 16 and HPV 18. Although the overall incidence of anal cancer in the general population of the United States is low (approximately 0.8/100,000),1 its incidence varies considerably depending on the presence of risk factors such as smoking, multiple sexual partners, HPV infection, and receptive anal intercourse. HIV infection confers an additional risk for development of anal cancer.2,3
Analogous to cervical tissue, the anal epithelium at the dentate line has a transformation zone between squamous and columnar epithelia; this transition zone is subject to infection with and neoplastic transformation by HPV. Precancerous lesions of the anal squamous epithelium can develop and are classified as low- or high-grade according to identical Bethesda criteria and nomenclature developed for grading cervical lesions (see Table 1).
II. RISK OF ANAL CANCER
HIV infection is an independent risk factor for anal neoplasia.4,5 Individuals with a history of long cumulative periods of immunosuppression (CD4 count 3) and/or high viral replication may be at higher risk for developing anal cancer.6 Behaviors that have been associated with anal neoplasia include multiple sexual partners, smoking, and unprotected vaginal or anal intercourse.
A. HIV-Infected Women
The risk of anal cancer in women regardless of HIV status is highest among those who have had 10 or more sexual partners, those with a history of anal or genital warts, gonorrhea, or cervical neoplasia, and those whose sexual partners have a history of a sexually transmitted infection.7 A history of receptive anal intercourse before 30 years of age or with multiple partners increases the risk of anal cancer.7
Women with HIV infection are significantly more likely to have abnormal anal cytology/histology (31%) compared with non-HIV-infected women (9%).8 Data from the United States AIDS-Cancer Registry Match calculate an increased relative risk of 134 for anal cancer among HIV-infected women younger than 30 years of age, and a relative risk of 12 for women aged 30 to 39 years compared with aged-matched non-HIV-infected women.9 From 1973 to 1989, the incidence of anal carcinoma increased by 35% and has been increasing at a rate of 2% per year. In one report, 26% of HIV-infected women had abnormal cervical cytology, and, of those women, 44% also had abnormal anal cytology.10 In the ongoing Study to Understand the Natural History of HIV/AIDS (SUN), the prevalence of HPV in the cervix and anus was 86% and 93%, respectively, and for HPV types that carry a high risk for malignancy, the prevalence rates were 68% and 85%, respectively.11 A history of anal sex was not predictive of an abnormal anal cytology.11 These results, although not completely independent of a history of anal intercourse, are explained by the anatomical proximity of the anus and the genital tract. HPV exposure of either anatomical site can result in tracking and infection of the other site.
B. HIV-Infected Men
Prior to the onset of the AIDS epidemic, the risk of anal cancer was estimated to be as high as 35/100,000 among men with a history of receptive anal intercourse.12 The risk in HIV-infected men who have sex with men (MSM) is between 70/100,000 and 144/100,000,13,14 and this risk does not appear to decrease with effective immune reconstitution as a result of HAART.15-19
Among men who do not engage in receptive anal intercourse, the risk of anal cancer is associated with 10 or more sexual partners and a history of anal warts, syphilis, or hepatitis.7 In MSM, receptive anal intercourse is the most common risk factor and compounds the risks noted above.
III. SCREENING AND DIAGNOSIS
At baseline and as part of the annual physical examination for all HIV-infected adults, regardless of age, clinicians should:
- Inquire about anal symptoms, such as itching, bleeding, diarrhea, or pain
- Perform a visual inspection of the perianal region
- Perform a digital rectal examination (III)
Clinicians should refer women with cervical HSIL and any patient with abnormal anal physical findings, such as warts, hypopigmented or hyperpigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology, for high-resolution anoscopy and/or examination with biopsy of abnormal tissue.
Clinicians should obtain anal cytology at baseline and annually in the following HIV-infected populations9,10,20-32:
- Men who have sex with men
- Any patient with a history of anogenital condylomas
- Women with abnormal cervical and/or vulvar histology
Delayed diagnosis of anal cancer is common. MSM, the group with the highest risk of anal cancer, often have benign conditions such as fissures or infections that may mask the diagnosis. Rectal bleeding, which is the most common presenting symptom of anal cancer, is often attributed to hemorrhoids. Only 30% of patients have pain or the sensation of an anal mass. As with cervical carcinoma, the precancerous stages of anal intraepithelial neoplasia are generally asymptomatic until there is invasion beyond the epithelial basement membrane, concurrent with tumor enlargement. Patients may complain of thickening and irritation of perianal skin, itching, bleeding, tenesmus, pain with defecation, constipation, change in stool caliber, or receptive anal dyspareunia. Upon visual inspection, clinicians should examine for abnormal anal physical findings, such as warts, hypopigmented or hyperpigmented plaques/lesions, or lesions that bleed.
A. Digital Rectal Examination
The standard screening test for all anal cancers is an annual digital rectal examination, which permits the clinician to feel for masses that may be missed by cytology or even by direct visualization during standard or high-resolution anoscopy (HRA). All HIV-infected adults should have an annual digital rectal examination.
If the digital rectal examination is performed in conjunction with anal cytology and/or HRA, the cytology must be obtained first, before lubrication is introduced into the anal canal.
B. Anal Cytologic Screening
The risk of anal cancer in the MSM population (between 70/100,000 and 144/100,000) is double the rate that prompted the recommendations for universal cervical screening of women.13,14 Universal cervical Pap screening for adult females was recommended in the United States in the 1960s before either the pathophysiology or oncogenesis of HPV was elucidated. There has never been a randomized control trial for standard cervical Pap screening, nor would it be ethical to conduct such a study today. The efficacy of Pap screening in preventing cervical malignancies rests exclusively on decades of epidemiological data for validation. Given that 1) it is unlikely that a 10-year clinical trial demonstrating the efficacy of obtaining anal cytology in any HIV-infected population will ever be performed and 2) HPV-initiated carcinomas are clearly preventable malignancies, this committee recommends obtaining routine anal cytology in populations that are clearly at risk.
Anal Pap testing using a Dacron swab is a well-validated technique with comparable sensitivity and specificity to cervical cytology.33 Pap test screening of the cervix has led not only to a markedly decreased incidence of invasive cervical cancer but also to an understanding of how precursor lesions of the cervical epithelium can progress to invasive disease.34 As with cervical cancer screening, cytologic screening of the anal canal is expected to reduce the incidence of invasive anal cancer and allow the detection of precancerous dysplastic lesions or treatable early invasive disease. Pap tests of the anal canal are simple to perform, clinically effective, and cost-effective to reduce the incidence of invasive disease in high-risk individuals.35,36
There is no preparation necessary before obtaining anal cytology. If the digital rectal examination is performed in conjunction with anal cytology and/or HRA, the cytology must be obtained first, before lubrication is introduced into the anal canal. Patients should not have received an enema or engaged in receptive anal sex within 24 hours before sampling because these activities can adversely affect specimen quality.
The standard technique used in obtaining anal cytology is as follows: a Dacron swab (a cotton swab will not yield accurate results) is moistened with sterile or non-sterile water. The anus is spread with the index and thumb of the non-dominant hand so that the anoderm pouts out. The swab is then gently inserted into the anal canal as far as it will go, until it hits the wall of the rectum. If the swab does not go in easily, the angle of insertion should be adjusted. The presence of external hemorrhoids may cause resistance; in this case, different insertion points should be tried until the anal canal is easily accessed. The swab must be inserted above the squamocolumnar transition zone, which is approximately 2 cm (1 inch) from the anal verge.
The swab is then slowly moved in and out without completely withdrawing it, while rotating it in a spiral motion and applying mild pressure to the anal wall. After several rotations, the swab should be withdrawn and immediately immersed in methanol-based preservative-transport solution. Feces or traces of blood on the swab will not affect the result. The swab should be agitated in the solution for 60 seconds to transfer cells from the swab to the medium.
Slides made by the thin-layer liquid-based cytology process display a thin, uniform layer of cells at a controlled density. Red blood cells and mucus are removed while the background pattern and the cell clusters are preserved. The use of this process results in increased detection of abnormal cytology. The absence of columnar cells in the sample does not affect the validity. The sensitivity, specificity, and predictive value do not hinge on the presence or absence of these columnar cells; cytological specimens should not be rejected solely on this basis.37,38 If only anucleated squamous cells are present on the sample, the swab was not inserted far enough into the anal canal, and the specimen is inaccurate or non-diagnostic.
An instructional video on performing anal Pap smears is available on CD-ROM and can be purchased by calling the Johns Hopkins Local Performance site at 888-333-2855, or at: http://aidsetc.org/resource/anal-pap-smear-simple-fast-and-easy-procedure
Clinicians should refer patients with abnormal anal cytology for high-resolution anoscopy and/or examination with biopsy of abnormal tissue.
Anal cytology has a high sensitivity (95%) for detection of dysplasia (ASIL) but a low specificity (50%) for predicting the severity of the abnormality in subsequent biopsy. Even patients with cytologic diagnoses of ASC-US and LSIL have a significant risk (46% to 56%) of being diagnosed with HSIL (AIN 2, 3) at biopsy.39,40 Although the appropriate follow-up for abnormal anal cytology remains an active area of investigation, Figure 1 provides a straightforward evaluative approach.
C. High-Resolution Anoscopy (HRA)
HRA applies the techniques of standard cervical colposcopy to the examination of the anal mucosa and is the preferred method for visualization of the anal canal in otherwise asymptomatic individuals.41,42 HRA has been found to be cost-effective in screening for anal dysplasia among HIV-infected men, and may be considered as an initial screening modality if the resources are available.43
A swab, wrapped and soaked in 3% acetic acid (as opposed to 5% in colposcopy) is passed through the anoscope; the anoscope is then removed, leaving the acetic acid-soaked gauze to oppose the epithelial tissue for at least 2 minutes. The gauze is removed, the anoscope is then reinserted, and a standard colposcope is used to visualize the perianal skin, anal canal, and distal rectal tissue.44 The dilute acetic acid highlights the mucosal abnormalities; the colposcopic magnification allows visualization and discernment of the abnormal aceto-white mucosal lesions. The squamocolumnar junction, including inflamed and dysplastic tissue, will appear dull and white. Vascular punctuation and mosaicism are indicative of dysplasia, and biopsy should be obtained. Some clinicians find that the addition of the iodine-based Lugol’s further delineates healthy from dysplastic tissue. Lugol’s is absorbed only by healthy epithelial tissue, and it appears a deep mahogany color; the dysplastic tissue does not concentrate the solution and appears a weak, mustard-yellow color. Squamous metaplasia, a normal finding, can also fail to absorb the Lugol’s solution. The combination of acetic acid and Lugol’s solution with the HRA magnification permits the identification of the subtle mucosal abnormalities that are virtually undetectable with conventional anoscopy alone.
Because obtaining routine anal cytology is a new standard of care, clinicians may face challenges identifying providers to whom they can refer patients for follow-up HRA. Currently, few primary care clinicians have expertise in HRA, although the techniques and tools have become a standard part of many obstetrical, gynecological, colorectal, surgical, and gastrointestinal clinics, practices, and training programs. The American Society for Colposcopy and Cervical Pathology offers an annual High Resolution Anoscopy Workshop in conjunction with a colposcopy postgraduate course (http://www.asccp.org/events-detail/high-resolution-anoscopy-hra). Alternatively, gynecologists or other providers, such as nurse practitioners and physician assistants, who often perform cervical colposcopy, can easily learn the techniques necessary to perform the procedure in the anus. Clinicians experienced in HRA can also train other interested clinicians outside of a formal course.
In communities where there are no clinicians available to perform HRA, patients with abnormal anal cytology should be referred to a surgeon for evaluation.
IV. TREATMENT OF ANAL HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESIONS
Patients should receive post-treatment serial monitoring with annual HRA.
In the cervix, HSIL is often treated by excision of the transformation zone (LEEP, conization), but this cannot be done in the anal canal.45 Therefore, traditional treatment of anal HSIL (AIN II, III) disease is surgical excision by a qualified colorectal surgeon. Infrared coagulation, originally developed to treat hemorrhoidal tissue, has been effectively used.44,46 Local ablative techniques are well tolerated, have minimal morbidity, and can be performed in an office setting by non-surgeons.44 In situ lesions also can be treated with local ablative therapy. Regardless of the modality used, local recurrences are to be expected. Successive treatments can lead to decreased recurrence rates. Post-treatment serial monitoring with annual HRA is recommended. Preventing the development of cancer is underscored by the substantial morbidity that even successful treatment can cause, primarily due to the radiation.
D. TREATMENT OF ANAL CANCER
Primary care clinicians should refer HIV-infected patients with anal cancer to an oncologist for treatment.
For patients with untreated invasive anal cancer without evidence of distant metastases and CD4 counts >200 cells/mm3, combined modality therapy with concurrent radiation and combination chemotherapy should generally be administered. In situ carcinoma is not treated with radiotherapy or chemotherapy.
Combined modality therapy (CMT) should also be considered in patients with untreated invasive anal cancer who are more severely immunosuppressed; however, abdominal perineal resection is an alternative treatment in such patients.
A. Tumors of the Anal Canal
Patients found to have invasive squamous lesions of the anal canal require staging prior to treatment. Examination under anesthesia generally provides a good assessment of the size of the primary tumor. Mobile lesions of ≤2 cm (T1) can be cured in approximately 80% of cases, whereas tumors ≥5 cm (T3) are cured in <50% of cases.47-49 Detection of minimally invasive lesions is rare but may become more common with cytologic screening and HRA. Pelvic computed tomography, positron emission tomography, or magnetic resonance imaging is used to assess local extension and nodal involvement. Tumors of the anal canal drain to inguinal and femoral lymph nodes. When inguinal lymph nodes are enlarged on physical examination, the cure rate decreases to 20%; however, these patients are generally still treated with curative intent. Newly diagnosed patients should also be evaluated for lung and liver metastases. Patients with distant metastases are not considered curable. Overexpression of p53 in anal cancer has been associated with poorer local control, disease-free survival, and overall survival.
2. Minimally Invasive Anal Cancer
The best treatment for minimally invasive anal cancer is not defined, and it is not known whether local excision or systemic therapy results in the best outcome. Solitary lesions on the perianal skin are often treated with wide excision; combined modality therapy is often recommended for multifocal disease. In the vast majority of patients with anal cancer, however, macroscopic disease is present, and CMT with chemotherapy (5-fluorouracil in combination with either mitomycin-C or cisplatin) and radiation is preferred. CMT cures approximately 70% of patients; however, a number of acute and chronic complications are associated with this approach and may be more severe in some subsets of HIV-infected patients.
C. Invasive Anal Cancer
The best therapy for invasive anal cancer in HIV-infected patients is not defined. Published studies are retrospective and reflect experience prior to HAART. The local toxicity of CMT has been poorly tolerated in patients with CD4 counts ≤200 cells/mm3 who were treated with standard doses. The tolerance of CMT in patients with higher CD4 counts seems to be acceptable and should be the approach in patients with well-controlled HIV infection. There is current interest in studying radioprotective agents to ameliorate local mucosal toxicity, particularly in patients with low CD4 counts. Abdominal perineal resection may be appropriate in some patients with advanced HIV infection who are unlikely to tolerate intensive chemoradiation therapy.
D. Residual or Recurrent Anal Cancer
The options for patients with residual or recurrent anal cancer are limited. In two large trials of CMT in non-HIV-infected patients, distant metastases developed in 10% and 17% of patients.50,51 The liver is the most common site of distant metastases, and no curative therapy is available. Locally recurrent or persistent anal disease after CMT, without distant metastasis, can be managed with abdominal perineal resection; this results in long-term control in approximately 50% of patients.52,53 Alternatively, patients who have not received cisplatin as part of their initial chemotherapy regimen may be treated with this drug. An additional radiation boost may be possible in patients who have received relatively low doses of radiation as part of initial therapy. The applicability of these salvage treatments to HIV-infected patients is unknown.
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