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Keywords:

  • anal cancer;
  • anal intraepithelial neoplasia;
  • anal cytology;
  • cancer screening;
  • high resolution anoscopy

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Cervical cancer and anal cancer share many similarities including causation by oncogenic human papillomaviruses; however, significant differences exist in their epidemiology, risk factors, biologic behavior, management, and treatment. Although rare, the incidence of anal cancer is alarmingly high and continues to increase in high-risk populations, particularly men who have sex with men regardless of their human immunodeficiency virus (HIV) status. There are no national screening guidelines for anal cancer. Using the success of cervical cancer screening as a model, anal cancer screening approaches apply anal cytology, high-resolution anoscopy, and directed biopsy to guide treatment and management strategies. Although much has been learned about the natural history and epidemiology of anal intraepithelial neoplasia (AIN), the rate of progression of high-grade anal intraepithelial neoplasia (HGAIN) to invasive squamous cell carcinomas is not known. The impact of screening and treatment of HGAIN on morbidity and mortality from anal cancer are also unknown. Because the incidence of HGAIN and anal squamous cell carcinoma continue to increase, it is imperative to find pathways for effective screening, early detection, and therapeutic intervention. This article provides an overview of anal cancer screening while highlighting its differences from cervical cancer screening and the remaining obstacles and controversies to implementation of a successful anal cancer screening program. Cancer (Cancer Cytopathol) 2011;. © 2010 American Cancer Society.

Compared with cervical cancer, anal cancer is rare. The National Cancer Institute estimates that 5260 patients will be diagnosed with anal cancer in 2010 and that 720 men and women will die of the disease.1 Compare this to cervical cancer statistics in the United States for 2010: 12,200 will be diagnosed with cervical cancer and 4210 women will die and this is with successful opportunistic Papanicolaou (Pap) testing to screen for this cancer in the United States. Yet, in patients with the highest risk of anal cancer, its incidence was more than double that of cervical cancer priorto the initiation of Pap screening and is increasing, while rates for cervical cancer continue to decrease. As the incidence of anal carcinoma increases in populations at risk, cytologic screening, combined with early detection and treatment, has been proposed as a method to reduce the morbidity and mortality from invasive anal squamous cell carcinoma (ASCC).

The success of cervical cancer screening has led to its use as a template for anal cancer screening in high-risk groups. The guide for treatment is based on a triad comprising cytologic screening, colposcopic identification, and histologic confirmation. Parallels between the models for anal cancer screening and cervical cancer screening are also based on the biologic and morphologic similarities between anal intraepithelial neoplasia (AIN) and cervical intraepithelial neoplasia (CIN). The key biologic similarity between AIN and CIN is the causal relation between the oncogenic or high-risk human papillomaviruses (hr-HPV) and the development of squamous carcinoma in both the anus and the cervix. The association with hr-HPV is also responsible for the microscopic resemblance between AIN and CIN, both cytologically and histologically.

On the clinical side, there are also many general similarities between anal and cervical HPV-related squamous mucosal disease. These manifestations range from overt gross disease in the form of genital condyloma to more subtle, flat, intraepithelial lesions. Clinical approaches to the diagnosis of AIN also borrow from the cervical cancer model and include the application of colposcopy to the evaluation of the anal canal and perianal region. This has led to the development of a new subspecialty of colposcopy referred to as high resolution anoscopy (HRA). HRA is used for the colposcopic identification of lesions and directed biopsy; the results are integrated into a variety of management and treatment strategies.

Despite the many similarities between AIN and CIN, anal cytology has had a very different evolution from the cervical Pap test, and many questions remain about the specifics of its use. Significant differences in epidemiology, natural history, and treatment response of AIN have stimulated ongoing debate, and no national screening guidelines for anal cancer have been adopted. This review focuses on the key differences between cervical cancer and anal cancer (Table 1), including the potential role of anal cytology in screening those at highest risk for anal cancer.

Table 1. Key Differences Between Cervical Cancer and Anal Cancer
Key DifferencesCervical CancerAnal Cancer
  1. ASC-US indicates atypical squamous cells of undetermined significance; CMT, combined modality therapy (radiation and chemotherapy); DARE, digital anal-rectal examination; HR, high risk; HRA, high resolution anoscopy; IRC, infrared coagulation; OR, operating room.

Population affectedWomenMen and Women
IncidenceDecreasingIncreasing
Prevalence: General population18.1/100,000 (includes unscreened)1.6/100,000
Prevalence: HIV positive25.6/100,00034.6/100,000
Median age at Cancer Diagnosis/Death148 y/57 y60 y/65 y
HPV types in cancer (cervix75, anus20)Type 16: 53.5%Type: 16: 65.6%
Type 18: 17.2%Type 18: 5.1%
HPV prevalencePeaks in 3rd decadeHigh (50-60%) prevalence over all ages in HIV-negative MSM
Histologic typeSquamous and glandularSquamous
National screening guidelinesYesNo (limited guidelines in NY state only)
Palpation useful for detection of early invasionNoYes, DARE
Cytologic screening efficaciousYesProbable, not proven
HR-HPV testing for triage of ASC-USYesNot clear, probably not
HR-HPV testing useful in primary screeningYes, in women ≥30 y, with PapNo
ManagementColposcopyHRA
Availability of trained, experienced cytopathology and clinical personnelWidespreadVery limited
Treatment: high-gradeAblative: cryotherapy, laserAblative: IRC, fulguration
 Excision: LEEP in officeExcision: Usually in OR
Treatment: cancer
 EarlyConization (microinvasion)Not defined
 LateSurgical +/− CMTStandard: CMT

Epidemiology and Pathogenesis of Anal Cancer

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The populations at highest risk for the development of anal cancer are men who have sex with men (MSM), regardless of their HIV status.2, 3 Other high-risk groups include women and heterosexual men with HIV disease4, 5 and those who are immunosuppressed for other reasons, such as organ transplantation.6 Women with multicentric lower genital tract squamous intraepithelial neoplasia are also at increased risk to develop anal intraepithelial and invasive lesions.7

Although anal cancer is rare, its incidence in HIV-positive MSM is alarmingly high and continues to increase. Before the HIV pandemic, the incidence of anal cancer in MSM8 was approximately 35 per 100,000—a rate similar to that of cervical cancer before the initiation of Pap test screening. In HIV-positive MSM, the reported incidence rates range from 42 to 137 per 100,000 per year2, 9-12 and are continuing to increase even with the use of highly active antiretroviral therapy (HAART) therapy.2, 12

In the population of MSM, both HIV-positive and negative men, prevalence rates of biopsy-proven high-grade AIN—the precursor lesion—are also remarkably high: approximately 50% in HIV-positive MSM and 25% in HIV-negative MSM have biopsy-proven high-grade AIN.13, 14 Unlike other viral diseases in HIV patients, AIN is not decreasing despite HAART.15, 16

HPV infection is even more common in MSM; it is detected in 72% to 92% of HIV-positive MSM and in 57% to 61% of HIV-negative MSM.13, 14 Interestingly, the prevalence of HPV by age is very different in MSM compared with HPV in the general population of women, which peaks in young adulthood and then rapidly declines in prevalence with age. Among HIV-negative MSM, HPV prevalence is around 50% to 60% and remains at a plateau high throughout adulthood, well into the sixth decade of life.17 Presumably, the rate in HIV-positive men during the life span is even higher.

Hr-HPV infection is etiologically associated with essentially all cervical cancers and 90% to 96% of anal cancers.18, 19 Persistent hr-HPV infection is the causal link to the vast majority of cancers of both the cervix and anal canal. HPV 16 is the most common type associated with anal cancer; it contributes to an even greater proportion of anal cancers than cervical cancers. HPV 16 is present in 65% to 75% of anal cancers, followed in prevalence by HPV 18. Types 16 and 18, alone or in association, are found in 78% of all anal cancers.19-21

Both the cervix and anal canal have transformation zones, regions of active metaplasia replacing glandular epithelium with squamous epithelium. Immature squamous metaplastic epithelium is at risk for hr-HPV infection presumably because of the ease with which the virus gains access to the basal cell layers. Once hr-HPV has entered the basal cells, it can cause either a productive infection with terminal differentiation and maturation of squamous cells or interruption of the cell cycle leading to the development of cancer precursors.22 The morphologic equivalent of a productive HPV infection includes condyloma and/or low grade intraepithelial neoplasia on histology or low-grade squamous intraepithelial lesion (LSIL) on cytology; the morphologic equivalent of a potential cancer precursor is histologic high-grade intraepithelial neoplasia (IN) or cytologic high-grade squamous intraepithelial lesion (HSIL). Persistence of hr-HPV is a known risk for the development of high-grade IN and cancer. If left untreated, high-grade IN, whether cervical or anal, has the potential for progression to invasive carcinoma.23-25 Although progression rates for high-grade CIN have been documented during decades of research, the rate of progression of high-grade AIN to invasive disease remains to be elucidated.26 Given the high prevalence of AIN in at-risk MSM and HIV-positive individuals, it is likely that only a minority of established high-grade AIN will progress to invasion. However, whether an individual high-grade precursor lesion will persist, regress, or progress to cancer cannot be predicted currently for either the cervix or anus.

Screening for anal cancer: The triad of cytology, colposcopy, and biopsy

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The obvious goal of anal cancer screening is to identify and treat both early invasive ASCC and high grade AIN. However, no randomized clinical trials have been performed to validate the efficacy of any type of screening for anal cancer. Regional considerations have differed, and in 2007, the New York State Department of Public Health AIDS Institute recommended a digital anal-rectal examination and anal cytologic screening at baseline, and annually, in HIV-infected MSM, any patient with a history of anogenital condyloma, and women with abnormal cervical and/or vulvar histology.27

One of the crucial differences between the diagnosis of anal cancer and cervical cancer is the index of clinical suspicion. Understanding the importance of cervical cancer screening is widespread and embedded in the consciousness of the medical community and the public. Recognition of the risk of anal carcinoma has been slow to be appreciated even among the medical and public groups where MSM and HIV-positive individuals have the highest visibility. An essential clinical tool in high-risk individuals is the digital anal-rectal exam (DARE). This is because most early invasive anal cancers are easily palpable by the examining finger, even in the absence of clinical symptoms, and are marked by the presence of induration or thickening. This low-cost, low-tech tool is woefully underused. Suspicion for anal cancer needs to be heightened, and DARE used, as part of routine clinical care in the MSM and HIV communities.

Following the cervical model, anal cytology is used to detect precursor lesions and is followed by HRA and directed biopsy when an abnormality is detected. Screening for anal cancer differs from cervical screening in the size and nature of the targeted population. For women older than the age of 21 years, screening for cervical cancer incorporates the entire sexually active female population as the at-risk group; its effectiveness has been proven by the declining rates of death from cervical cancer for decades. Anal cancer screening remains controversial because the targeted groups are much more limited, the effectiveness and methodology of screening have yet to be determined, and the long-term effects of screening cannot yet be assessed. Targeted screening of the highest-risk groups is an important concept in anal cancer screening. How and who to screen in this time of limited, skilled, medical resources is a subject of debate. Those at highest risk for the development of anal cancer are HIV-positive MSM. When HIV disease is well controlled by HAART, the clinical course of HIV is changed from a life-threatening to a chronic illness. Normalization of the lifespan has allowed the natural history of HPV-related cancers to play out in HIV-infected patients. HIV-negative MSM also have an increased, albeit lower, anal cancer risk compared with HIV-positive MSM. The efficacy of screening in these limited groups varies on the basis of prevalence. Direct referral to HRA in the highest-prevalence subgroups may be the most direct method for diagnosis and management, but referral is restricted by the availability of personnel experienced in HRA.14, 28, 29

In a systematic review of anal cancer screening in HIV-positive patients, Chiao and colleagues30 found the sensitivity of anal cytology for high-grade AIN, using atypical squamous cells of undetermined significance (ASC-US) as the threshold for triage to HRA, ranged from 69% to 93%, and the specificity ranged from 32% to 59%. As recently reviewed by Bean and Chhieng,31 studies published since then have shown similar findings. In the study by Salit and colleagues29 from 2010, anal cytology had a sensitivity of 84% and a specificity of 39% using ASC-US as the threshold; HSIL on anal cytology had 91% specificity for high grade AIN. In studies by the Palefsky group28, 32, 33 of both HIV-positive and HIV-negative MSM, the sensitivity of ASC-US or greater on conventional anal cytology was 87% in HIV-positive MSM and 55% in HIV-negative MSM; specificity was 42% and 81%, respectively (Table 2). The sensitivity, using LSIL or greater as the threshold, was 77% and 50% in HIV-positive and HIV-negative MSM, respectively; the specificity was 53% and 85%, respectively.33 In HIV-positive MSM, the specificity and positive predictive (PPV) value of HSIL cytology was high at 93% and 89%, respectively. The specificity of LSIL cytology plus the presence of HPV type 16 (86%) in HIV-positive MSM was similar to the specificity of HSIL cytology.33

Table 2. Sensitivity and Specificity of Anal Cytology for HG-AIN in MSM
 Sensitivity for HG–AINSpecificity for HG–AIN
Anal CytologyHIV+ MSMHIV− MSMHIV+ MSMHIV− MSM
  1. MSM indicates men who have sex with men; HIV+, human immunodeficiency virus seropositive; HIV−, human immunodeficiency virus seronegative; HG−AIN, high-grade anal intraepithelial neoplasia; ASC−US+ atypical squamous cells of undetermined significance or greater; LSIL+, low-grade squamous intraepithelial lesion or greater; HSIL+, high-grade squamous intraepithelial lesion or greater. Adapted from Park IU, Efird JT, Berry JM, et al. Performance of HPV testing and anal cytology to detect high-grade anal intraepithelial neoplasia in men who have sex with men. Abstract Poster #414. Presented at the 26th International Papillomavirus meeting, Montreal, Canada, July 2010.

ASC−US+87%55%42%81%
LSIL+77%50%53%85%
HSIL+46%Not reported93%Not reported

The higher sensitivity of anal cytology in HIV-positive MSM is most likely due to the large burden of disease seen in these patients, allowing improved sampling and enhanced cytologic detection. Serial cytology improves the predictive value of cytology in MSM. In a large prospective cohort study, the PPV of anal cytology improved from 38% to 78% with repeat testing during a 2-year period; negative predictive value (NPV) similarly improved from 46% to 79% after consecutive testing.32

Even given these limited test parameters, Goldie and colleagues estimate that defined use of anal cancer screening in the United States, annual anal cytology in HIV-positive MSM, and biannual anal cytology in HIV-negative MSM would be cost effective.34, 35 A modeling study in the United Kingdom predicted much higher costs for anal cancer screening but used different assumptions. The cost effectiveness of anal cytologic screening needs to be analyzed in specific healthcare systems and populations.36

Anal Cytology

Most cytologists have limited experience with interpreting anal samples. Anal cytology was first introduced into the College of American Pathologists (CAP) Interlaboratory Comparison program for nongynecologic cytology in 2005. Data published in the CAP 2009 Year End Summary Report37 indicate that the categorization of HSIL remains problematic; only 61% of HSIL challenges were categorized to the target reference interpretation. By comparison, on cervical cytology, more than 85% of HSIL educational challenges were correctly categorized to the reference interpretation. Increased familiarity with anal cytology should help. The recent review of anal-rectal cytology by Bean and Chhieng31 provides an excellent overview of anal cytology.

The cytomorphology of HPV-related lesions of the anus overlaps with gynecologic cytology, and similar diagnostic criteria are applied. Cytology of the anal canal is evaluated by using modified criteria and terminology as in the Bethesda system.38 The goal of anal cytology is to sample the entire anal canal thoroughly, including the transformation zone. The cell sample is collected by using a water-moistened, synthetic-fiber swab with a nonscored stick. The swab is inserted into the anal canal past the dentate line until it abuts the distal rectal wall. The cells are harvested by using a circular motion as the swab is retracted while applying firm lateral pressure to sample the epithelium in the mucosal folds of the canal. Either liquid-based preparations or conventional smears can be used. Liquid-based cytology increases cell yield while decreasing the fecal contamination and air-drying artifacts common on direct smears.39, 40

Patient-collected samples for anal cytology have a slightly lower specimen adequacy rate than provider-collected samples; however, self-collected samples have a comparable sensitivity for detection of AIN.14, 41 Self-collected anal samples have been used for the diagnosis of other sexually transmitted diseases and may be more acceptable to some patients.42

Specimen adequacy

Little is known about how cellularity influences sensitivity and specificity of anal cytology. The cellularity of anal cytology obtained by experienced clinicians matches that of cervical cytology. According to the Bethesda System recommendations, the minimal cellularity for an adequate sample is at least 2000-3000 nucleated squamous cells.38 This is equivalent to 1-2 nucleated squamous cells per high-powered field (hpf) for ThinPreps (Hologic, Bedford, Mass) and 3-6 nucleated squamous cells/hpf for SurePath preparations (BD Diagnostics, Franklin Lakes, NJ). More cellular specimens have better performance characteristics.43 The presence or absence of transformation zone components (rectal columnar cells and squamous metaplastic cells) is reported as a quality indicator. Samples that lack the minimal number of nucleated squamous cells, are composed predominately of anucleate squames, or those with only fecal matter should be designated as unsatisfactory for evaluation when no identifiable abnormal cells are present.

Interpretation of anal cytology

In a normal anal cytology sample, nucleated squamous cells of both superficial and intermediate type, anucleated squames, squamous metaplastic cells, and rectal columnar cells are seen. Anucleate squamous cells are a normal component and arise from sampling of the keratinized, distal portion of the anal canal. Reparative changes are seen less frequently than on cervical cytology. A variety of organisms can also be encountered on anal cytology, some causing local cytopathic changes similar to those seen in gynecologic cytology (eg, herpes virus and Candida). Others, such as ameba and pinworm eggs, are essentially unique to the gastrointestinal tract and extremely rare on Pap tests.44, 45

Compared with gynecologic cytology, more keratinizing lesions and degenerative changes are seen in anal cytology.44, 45 The close approximation of the keratinized and nonkeratinized portions of the anal canal may contribute to the former. These changes can be seen both in normal and abnormal samples. LSIL and HSIL show similar features to cervical cytology, particularly when they are derived from regions of immature metaplasia or nonkeratinized epithelium (see Figs. 1 and 2); however, more keratinizing abnormalities are encountered. Atypical parakeratosis is commonly identified with these lesions.46 Frequently, a mixture of LSIL and HSIL is seen in the same sample.44, 45

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Figure 1. LSIL with HPV cytopathic effect. (Anal Cytology, ThinPrep Pap, high magnification).

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Figure 2. HSIL is seen in immature squamous metaplastic cells. (Anal Cytology, ThinPrep Pap, high magnification).

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Anal cytology often under-represents the severity of lesions found on HRA-guided biopsy.31, 43, 47 Even in experienced hands, the prospective diagnosis of ASCC is infrequent and challenging on cytology. The differential diagnosis between HSIL and invasive ASCC can be difficult. When invasive carcinoma is identified, malignant squamous cells, similar to those seen on cervical cytology, are seen. This is particularly true for keratinizing squamous cell carcinoma. However, cytologic clues of invasion, such as tumor diathesis, are not as readily appreciated on samples from the anal canal as they are in gynecologic cytology. This may be due, in part, to the normal functioning of the anus as part of the gastrointestinal system. In addition, fecal matter, common on cytologic preparations from the anal canal, may be difficult to differentiate from the necrotic debris associated with a tumor diathesis.

HPV testing

In cervical cancer screening, hr-HPV testing is combined with the Pap test to screen women aged 30 years and older and to triage patients with ASC-US cytology to colposcopic examination. Hr-HPV may also be used postcolposcopy and post-treatment as stated in the American Society of Colposcopy and Cervical Pathology (ASCCP) management guidelines.48 None of the currently available HPV detection methods are FDA-approved for the use on anal samples; therefore, HPV DNA testing of anal cytologic material requires internal validation by the laboratory.

Moreover, the potential role of HPV DNA testing in screening and triage of anal cancer is not clear. Studies in MSM have shown hr-HPV testing for triage of ASC-US or greater on anal cytology to be very sensitive, ranging from 84% to 100%, and there is a high NPV, ranging from 75% to 100%. However, HPV DNA testing has very poor specificity (16%-18%) and low PPV (28%-50%).28, 29, 49 Given the high prevalence of hr-HPV in HIV-positive MSM—the highest risk population targeted for screening—it is unlikely that hr-HPV testing will play a major role in primary screening in this risk group.3, 29 The use of HPV 16 type-specific testing in HIV-negative MSM may prove to be more useful because the presence of HPV 16 is so specific (92%) for high-grade AIN,28 albeit at a lower sensitivity (35%). Anal HPV testing may also be useful in other at-risk populations with a lower prevalence of anal HPV, in post-treatment and post-HRA follow-up, because of its excellent NPV.50

High Resolution Anoscopy

HRA is the equivalent of cervical colposcopy and uses the same basic principles and procedures.45, 51 Dilute acetic acid, vinegar, is applied to the mucous membrane to highlight areas of abnormality, which turn white compared with the adjacent squamous epithelium. The colposcope provides magnification and a strong light source to facilitate identification of potential lesions and to target them for biopsy. Colposcopic features used to identify abnormalities include acetowhitening, lesion margin and surface contour, vascular changes of punctation and mosaicism, and Lugol iodine staining pattern. HRA examples of a low-grade and a high-grade lesion are seen in Figures 3 and 4. A comprehensive review of HRA can be found in Colposcopy: Principles and Practice by Apgar, Brotzman and Spitzer.45

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Figure 3. Condyloma of the anal canal. (High resolution anoscopy; 16× original magnification). Image courtesy of J. Michael Berry, MD, UCSF Anal Neoplasia Clinic.

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Figure 4. High-grade lesion of the distal anal canal with acetowhite epithelium and punctation. Biopsy showed high-grade AIN. (High resolution anoscopy; 16× original magnification). Image courtesy of J. Michael Berry, MD, UCSF Anal Neoplasia Clinic.

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Tissue biopsy remains the gold standard for the diagnosis of AIN. However, just like cervical colposcopy, the performance of HRA as a diagnostic test depends on the ability of the colposcopist to adequately observe and correctly target lesions for biopsy. On the basis of the experience of the group at the University of California, San Francisco (UCSF), headed by Joel Palefsky, MD, there is a steep learning curve to become competent in HRA.3 As a technique, HRA is more challenging than traditional cervicovaginal colposcopy. No large studies, analogous to the study by Gage52 for the ASC-US/LSIL Triage Study for cervical biopsies, have been conducted on interobserver variability and sensitivity of HRA for the detection of high-grade AIN. Many clinicians who learn HRA come from clinical specialties outside of gynecology and typically are not exposed to colposcopic training during their residency. Clinicians who care for at-risk patients are drawn from a variety of medical specialties. They include advanced practice clinicians, primary care physicians, and specialists in dermatology, infectious disease, gastroenterology, oncology, and surgery; all can perform HRA with the appropriate training.

The current shortage of skilled HRA providers is a significant obstacle to initiating anal cancer screening. Although cervical colposcopy training is often included in residency training programs and readily available as a continuing education course, training adequate numbers of HRA providers is a major challenges in the development of an anal cancer screening program. Few HRA training resources are currently available. In collaboration with the ASCCP, the Palefsky group at UCSF provides an annual course in HRA. Clinicians may also receive advanced training and experience under the guidance of experienced anoscopists, including on site at UCSF's Anal Neoplasia Clinic.

Histology of AIN and Anal Cancer

It is important to distinguish between anal canal disease and perianal or anal margin neoplasia; they have different treatment approaches and prognosis. By definition, the perianal region or anal margin is located from the anal verge (which can be observed by gentle traction on the buttocks) to within 5 cm of the anal opening. Neoplasia of the perianal region is akin to vulvar disease. The anal canal or intra-anal region extends proximally from the anal verge to the distal rectal vault; visual examination requires the use of an anoscope or similar clinical tool.

Squamous cell carcinoma is the primary histologic type of cancer seen in the anal canal. The cancers can be either keratinizing or nonkeratinizing. Historically, multiple histologic terms, such as basaloid carcinoma and cloacogenic carcinoma, have been used to characterize the nonkeratinizing variants of anal squamous cell carcinoma. However, there are no diagnostic, prognostic, or therapeutic reasons for separating these histologic subtypes. The use of related antiquated terminology engenders confusion and should be avoided.53 In the anal canal, there is no defined counterpart to microinvasive cervical carcinoma with its specific treatment and prognostic implications.

Unlike the case of endocervical adenocarcinoma, the role of HPV in rectal glandular neoplasia is not well defined. Although several investigators have found an association between HPV and colorectal carcinoma,54-56 the role of HPV in carcinogenesis of the colon remains to be elucidated.57

Morphologically, low-grade and high-grade HPV-related squamous mucosal lesions are similar whether they occur in the anus or cervix. Their morphologic similarities far outweigh their differences, both cytologically and histologically, as seen in Figures 5 and 6.

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Figure 5. Low-grade AIN in the anal transformation zone with surface keratinization. Note underlying rectal glands. (hematoxylin and eosin [H&E] stain, medium magnification).

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Figure 6. High-grade AIN in the anal transformation zone. Note rectal gland underlying metaplastic and dysplastic squamous epithelium. (hematoxylin and eosin [H&E] stain, medium magnification).

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There is moderate interobserver agreement in the interpretation of anal SIL and AIN.58 As with cervical biopsies, the diagnosis of the atypical and immature transformation zone can be challenging. On histopathology, p16INK4a (mtm Laboratories, Heidelberg, Germany) immunostaining improves interobserver agreement59, 60; and its role in anal cytopathology is under investigation.61 ProEx C reagent (BD, Franklin Lakes, NJ) and other molecular markers used to aid the diagnosis of cervical disease are also being investigated.53

Triage and Clinical Management

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The natural history of high-grade CIN and its implication for management are well accepted and documented.48 Although accumulating evidence confirms that high-grade AIN is the precursor to anal cancer,23-25 the rate of progression of high-grade AIN to cancer is not known. The effect of therapeutic intervention on the natural history and progression of AIN also needs to be defined more fully.

Given the specificity and sensitivity issues inherent to anal cytology, Palefsky and colleagues advocate the triage of all patients with ASC-US or higher to HRA; Figure 7 outlines the management algorithm recommended.3 Others suggest using HPV testing of anal cellular material with indications similar to Pap testing. As noted above, the prevalence of hr-HPV is high in MSM and may obviate the role of HPV testing in the screening and triage of these high-risk patients. HPV genotyping may be useful however. In HIV-positive MSM, the presence of HPV-16 was significantly more specific for high-grade AIN than cytology alone (71% vs 47%), but sensitivity was significantly reduced (87% vs 40%).28 Among HIV-positive MSM, the combination of LSIL cytology and HPV-16 positivity was significantly more specific than cytology alone (86% vs 57%).33 Type-specific testing for HPV 16 DNA may have significance for the development of future triage algorithms.

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Figure 7. Protocol for screening of anal intraepithelial neoplasia (AIN) is depicted. ASC-H—atypical squamous cells, cannot rule out HSIL; ASC-US—atypical squamous cells of undetermined significance; HSIL—high-grade squamous intraepithelial lesion; LSIL—low-grade squamous intraepithelial lesion. Used with permission of Ina U. Park, MD and Joel M. Palefsky, MD, UCSF Anal Neoplasia Clinic. From: Curr Infect Dis Rep. 201012:126-133. Open Access.

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Applying the principles of the management of high-grade CIN, treatment of high-grade AIN is advocated. Although AIN frequently recurs in high-risk populations, treatment has been shown to be effective for both low- and high-grade AIN.62, 63 As with cervical and vulvar disease, there are multiple treatment modalities that can be used: ablative or excisional surgical therapies and patient-applied or provider-applied topical therapies. Ablative techniques for AIN include therapies used for CIN; reported therapies include cryotherapy, laser, and infrared coagulation64-66 and fulguration. Topical therapies for AIN, commonly used for HPV-related disease of the vulva, include imiquimod,67, 68 trichloroacetic acid,69 and 5-fluorouracil.70 Park and Palefsky3 have recently reviewed the various treatment modalities for AIN. As with cervical disease, the goal of treatment is to reduce the risk of invasion by targeting high-grade AIN. Particularly in HIV-positive patients, successful treatment can be challenging; additional studies into efficient treatment and follow-up strategies are ongoing.

Prevention and early detection of cancer of the anal canal is important because of their impact on survival. Patients with cancer localized to the anus have a 5-year survival rate of 80%, whereas survival rates drop to 30% for those with metastatic disease.1 Combined modality therapy (CMT) with radiation and chemotherapy is the gold standard for the treatment of localized anal cancer, although it can have significant side effects.25, 71, 72 The role of sphincter-sparing surgical excision for the earliest invasive cancers, those potentially detected by screening and DARE, are ongoing.

With the development of vaccines that target hr-HPV, the potential for primary prevention of infection—and ultimately, cancer—is a reality. The quadrivalent HPV vaccine was approved by the FDA for boys and men, ages 9 through 26 years, in October 2009 for the prevention of genital warts due to HPV types 6 and 11. The quadrivalent vaccine is safe and immunogenic in HIV-positive men.73 Studies of its efficacy against AIN are underway. Beyond the indication for the prevention of genital warts, a potentially greater benefit of both the quadrivalent and bivalent vaccines is the primary prevention of anal cancer and other HPV-related cancers, such as head and neck cancers in both sexes. Modeling studies have yet to include these parameters when the cost effectiveness of HPV vaccines in boys is analyzed.74 The success of the HPV vaccines in preventing cervical cancer or any other related cancers depends on its wide uptake and the development of herd immunity, a goal that has not yet been achieved in the United States.

Summary

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Anal cancer screening and prevention form a nascent clinical specialty that crosses many disciplines. The prevalence of AIN and anal cancer is unacceptably high in MSM, the population at highest risk and in the greatest need for screening. Anal cancer screening uses the traditional 3-pronged approach consisting of cytology, HRA, and guided biopsy. All 3 prongs are imperfect and are limited by sensitivity, specificity, and interobserver variability; however, when used together, they are the most valuable resource currently available to evaluate those at high-risk for anal cancer.

Pathologists have limited experience in the evaluation of anal cytology. It behooves the cytopathology community to work with our clinical colleagues to improve the use of anal cytology as a screening tool, to improve specimen collection and preparation, and to improve our accuracy in evaluating anal canal specimens both cytologically and histologically.

The clinical community can readily start anal cancer screening simply by performing DARE on all at-risk patients. Given the reality of limited resources, the 3-pronged approach to anal cancer screening needs to be stratified and directed to those who would receive maximal benefit. Initially, anal cytology should be focused on screening for AIN in the highest at-risk groups, particularly MSM. Until more clinicians are trained in HRA, as an alternative to triaging all patients with ASC-US or worse to HRA, triage can at first be limited to patients with HSIL or worse on anal cytology, whereas those with LSIL or less may potentially be followed by serial examinations combining DARE and cytology. HRA training efforts and study of effective therapeutic interventions need to continue.

We now have the tools to institute systematic prevention strategies for anal cancer control. Enhanced public and medical awareness and high clinical suspicion are needed to curb a potential epidemic of anal carcinoma in at-risk groups. Screening, albeit with imperfect tools, should be instituted until newer and more effective modalities become available. Until we have adequate numbers of clinicians trained in HRA, anal cytology is a practical and useful screening methodology. Primary prevention of HPV-related neoplasia can be obtained by widespread use of HPV vaccines in men and women.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Teresa M. Darragh, MD, receives research supplies from Hologic and is on the OncoHealth Scientific Advisory Board.

REFERENCES

  1. Top of page
  2. Abstract
  3. Epidemiology and Pathogenesis of Anal Cancer
  4. Screening for anal cancer: The triad of cytology, colposcopy, and biopsy
  5. Triage and Clinical Management
  6. Summary
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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